Review Of Treatments Of Advanced Colorectal Cancer Biology Essay

Published: 2021-06-18 23:35:05
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Contents
Abstract
(150-200 words) write this at the end to make sure everything is included
Mention about resistance that has started to occur and link the end into what furture developments are being investigated and maybe mention a timeframe with them. Also mention where people believe the future developments should go not just what is already being looked at if possible.
Introduction
Colorectal cancer (also known as rectal, bowel or colon cancer) affects the lower part of the digestive system and is the third most common type of cancer in men and the second most common in women. Colorectal cancer (CRC) is a cause of significant mortality and morbidity and the current 5 year survival rate of for patients diagnosed with advanced stage 4 colon cancer is only 6.6% (Cancer Research UK). About 25% of patients present with metastatic disease, and of this group, 50% to 75% will have disease confined to the liver (Weiss et al 1896, Manfred et al 2006). In patients who present initially with early-stage disease, up to 50% will eventually develop metastatic disease, with the liver being the most common site. Another 10% to 20% of patients will present with disease involving the lung and other less common sites of metastatic involvement, including the peritoneum, ovaries, adrenal glands, bone, and brain (Labianca et al, 2010, Sundereyer, 2010). Therefore advanced/metastatic colorectal cancer is a considerable problem both for the healthcare system and society in general.
The best approach to this disease would of course be prevention, however complete prevention has not yet been accomplished and improved treatment options, including surgery, chemotherapy and radiotherapy, are key to improved outcomes. Until the mid-1990s, the only approved agent for colorectal cancer was 5-fluorouracil (Cercek and Saltz, 2010, Davis & Goldberg, 2011). While there have been new agents discovered to help deal with CRC the overall patient survival rate have tended to be small, and some of the newer drugs can have some serious adverse effects. However, fundamental advances in understanding the biology and genetics of colorectal cancer are taking place. This knowledge is slowly making its way into the clinic and being employed to firstly to increase progress in detection (e.g imaging), better stratify individual risks of developing colorectal cancer, discover better screening methodologies and treatment strategies. New agents that became available in the past 10 years include cytotoxic agents such as irinotecan and oxaliplatin, (Sanoff, 2008) oral fluoropyrimidines (capecitabine and tegafur), and biologic agents such as bevacizumab, cetuximab, and panitumumab (Chu, 2008). These and other new agents will likely translate into improved cure rates for patients with early stage disease (stage II and III) and prolonged survival for those with stage IV disease. Further advances are likely to come from the development of new targeted agents and integration of those agents with other treatments such as surgery, radiation therapy, and liver-directed therapies. Even patients with metastatic disease can be cured with a multi-modal treatment approach of intensive chemotherapy, followed by surgery (ESMO guidelines, 2012)
Proper treatment of patients with metastatic CRC today therefore requires careful consideration of the risks and benefits to the patient, considering the merits of combination therapy compared to single-agent regimens, and development of individual strategies to optimize treatment for each patient (Cercek, A and Saltz, L, 2010). This article reviews and discusses the treatments available and their risks and benefits.
Epidemiology.
Incidence & Mortality
Colorectal cancer, cancer of the large bowel, which includes both the colon and rectum, is a cause of significant mortality and morbidity. It is the third most common cancer in the UK (after breast and lung cancer) with approximately 41,000 new cases being diagnosed each year (Cancer Research UK’s ‘CancerStats" – Key Facts Bowel Cancer, January 2013). In the United States this year, there will be an estimated 147,000 new cases diagnosed and nearly 50,000 deaths resulting from this disease (Sigel et al, 2011). Worldwide it is estimated that there were 1.24 million new cases in 2008 [Cancer Research UK’s ‘CancerStats" – Key Facts Bowel Cancer, January 2013], with nearly 500,000 deaths attributed to this disease annually.
The incidence of colon cancer has a significant geographic variation (Cappell, 2005). Industrialized nations, except Japan, have the highest incidence, whereas South American countries and China have a relatively low incidence (Cappell, 2005). The wide variation in incidence is largely attributed to national differences in diet and other environmental factors. The incidence of colon cancer rises sharply with age, beginning at age 50 years (Miller, 1988). This phenomenon is attributed to accumulation of chance mutations with age. The condition is rare in people under 40 and almost 85 per cent of cases are diagnosed in over 65-year-olds (Cancer Research UK, Fact sheet). While cancer of the colon affects men and women equally, cancer of the rectum is a little more common in men. One in 15 men and one in 19 women in the UK develops bowel cancer (Cancer Research UK).
Colon cancer is treatable if caught early (University of Maryland Medical Center, 2011). Cancers that are confined within the wall of the colon are often curable with surgery while cancer that has spread widely around the body is usually not curable and management then focuses on extending the person's life via chemotherapy and improving quality of life.Screening and surveillance colonoscopy regimen can largely avoid this morbidity by colonoscopic removal of premalignant polyps, and can significantly improve survival by early detection of colon cancer at a curable stage. However, only a small percentage of eligible patients undergo screening. However screening rates for colon cancer screening are relatively low. This failure results in tens of thousands of preventable deaths and even greater morbidity. This is due to patient reluctance to undergo colonoscopy because of the invasiveness, risks, and discomfort of the procedure.
Environmental factors
Colon cancer has numerous environmental and demographic risk factors including activity, diet, alcohol and smoking (Capell, 2005). These factors can play a major causal role in colon cancer despite the importance of genetic mutations in colon cancer pathogenesis. Environmental factors presumably modulate the risk of the genetic mutations responsible for colon cancer, although the precise molecular mechanisms are currently unknown.
What is colorectal cancer?
Pathophysiology
Colon cancer arises from mucosal colonic polyps. The two most common types, based on histology are hyperplastic and adenomatous (Capell, 2005). 90% of all colon cancers arise from adenomas (Midgley, 1999). This is demonstrated by multiple epidemiologic, clinical, and pathologic findings (Capell, 2005):
a third of operative specimens containing colon cancer contain adenomas
the risk of colon cancer markedly increases with increasing number of adenomatous polyps
adenomatous tissue is frequently found next to carcinoma
patients with familial adenomatous polyposis (FAP), who have hundreds or thousands of adenomatous colonic polyps, inevitably develop colon cancer if colectomy is not performed
patients who refuse polypectomy for adenomas develop colon cancer at a rate of about 4% after 5 years and 14% after 10 years
The majority of these begin as benign adenomas, or polyps that grow on the inner lining of the colon or rectum. These adenomatous polpys develop from the normal colonic mucosa and are present in about a third of European and US populations (Midgley, 1999). These growths spread very slowly, taking from 10 - 20 years to become cancerous. The more difficult to detect flat adenomas account for about 10% of all lesions and may have a greater propensity to malignant change (Hardy et al, 2000). Only a small proportion of polyps (1-10%) develop into invasive bowel cancer.26 Indicators for progression from adenomas to cancer include large size, villous histology and severe dysplasia (Scholrfield, 2000 and Terry et al, 2002).
Stage
Carcinoma in situ, or high-grade dysplasia, is histologically cancer but is pathologically confined to the mucosa without penetration of the muscularis mucosa. Invasive colon cancer is commonly staged from A through D according to the Dukes classification (Cappell, 2005), with stage A penetrating beyond the colonic muscularis mucosa into the submucosa. Stage B1 extends beyond the submucosa into the muscularis propria; stage B2 extends through the muscularis propria into the serosa. Stage C has regional lymph node metastases, and stage D has distant metastases. About 20% to 25% of patients initially present with Dukes D colon cancer with identifiable metastases (Boland, 2003). Staging is important because it helps to predict how the cancer is likely to progress and which treatments are most appropriate. For example, among those with Dukes' A stage bowel cancer (the earliest stage) 93% survive more than 5 years. Colon cancer can also be staged according to the tumor–node–metastases (TNM) classification by depth of the primary tumor (T), by presence of local lymph node metastases (N), and by presence of distant metastases (M)(Cappell, 2005) . In the TNM classification, invasive colon cancer is classified from stage I to IV. Stage I in the TNM classification corresponds to Dukes A or B1 lesions, stage II corresponds to a Dukes B2 lesion, stage III corresponds to a Dukes C lesion, and stage IV corresponds to a Dukes D lesion.
Molecular biology
Colon cancer is one of the best understood but highly complex, multistep cancer in terms of molecular genetics (Cappell, 2005). Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Investigations into the pathogenesis of two uncommon familial colon cancer syndromes, Familial adenomatous polyposis (FAP) and hereditary non-polyposis colon cancer (HNPCC), were responsible for breakthroughs in understanding the molecular basis of the disease (Cappell, 2005). Patients with FAP develop hundreds or even thousands of adenomatous polyps throughout the colon beginning after puberty and inevitably developed colon cancer. The sequence of molecular and genetic events leading to transformation from adenomatous polyps to overt malignancy has been characterized by Vogelstein and Fearon. FAP was shown to be caused by mutation of the adenomatous polyposis coli (APC) gene located on chromosome 5q. The protein encoded by APC is important in activation of oncogene c-myc and cyclin D1, which drives the progression to malignant phenotype. Although FAP is a rare hereditary syndrome accounting for only about 1% of cases of colon cancer, APC mutations are very frequent in sporadic colorectal cancers.
In HNPCC multiple cases of colon cancer, without gastrointestinal polyposis, occur within a family. HNPCC was shown to be caused by mutations of one of the mismatch repair genes, including hMSH2, hMSH6, hMLH1, hMLH3, hPMSI, and hPMS2 (Cappell, 2005). Germ line mutations of the hMLH1 and hMSH2 genes account for most of the cases. Mismatch repair enzymes, encoded for by mismatch repair genes, normally recognize errors in nucleotide matching of complementary chromosome strands and initiate segmental excision of the newly synthesized strand to ensure faithful strand replication (Miyaki et al, 1994). Cells with mismatch repair gene mutations cannot repair spontaneous DNA errors and progressively accumulate mutations throughout the genome with succeeding DNA replications. This progressive accumulation leads to genetic hyper mutability and chaos; mutations accumulate in oncogenes and tumour suppressor genes that can result in colon cancer (Miyaki et al, 1994). These breakthroughs provided not only the molecular basis of syndromic hereditary colon cancer but also of sporadic colon cancer. Colon cancer is believed caused by a cascade of genetic mutations leading to progressively disordered local DNA replication and accelerated colonocyte replication. The progressive accumulation of multiple genetic mutations results in the transition from normal mucosa to benign adenoma to severe dysplasia to frank carcinoma. Mutations of the mismatch repair genes are believed to account for about 15% of sporadic colon cancers (Miyaki et al, 1994). APC mutation is believed to account for about 80% of sporadic colon cancers (Miyaki et al, 1994).
Adenomas usually remain benign. Malignant transformation requires further genetic alterations, for example in DCC, p53, K-ras (Cappell,2005) . The DCC (deleted in colon cancer) gene encodes for a neural cell adhesion molecule receptor and normally promotes apoptosis and suppresses tumours. Loss of the normal DCC gene is believed to be important in the transition from an intermediate to a late adenoma. Its role in this transition is supported by its frequent allelic deletion during this transformation (Vogelstein et al, 1988). The normal p53 gene product arrests the cell cycle following DNA injury to permit either DNA repair if the damage is correctable, or apoptosis if the damage is too severe. The wild-type p53 protein product is up-regulated after cell stress from radiation exposure, DNA injury, or other noxious events to prevent new DNA synthesis and halt cell division (Baker et al, 1989). Loss of p53 function can promote genomic instability as genetic errors are replicated without check. Mutation of the p53 gene is believed to be important in the transition from late adenoma to frank carcinoma. About 50% of lesions with high-grade dysplasia and about 75% of frank cancers exhibit loss of normal p53 function, usually from a missense point mutation of one allele and deletion of the other, wild-type, allele (Baker et al, 1989).
The K-ras gene encodes for a protein involved in signal transduction from the cell membrane to the nucleus . Specific mutations of this gene result in activation of this signal pathway and increased colonocyte replication. About 50% of colon cancers have K-ras mutations (Vogelstein, et al, 1988).
Molecular Genetics of colon Cancer (Capell, 2005). Other important genes in colon carcinogenesis include chromosome 18 loss of heterozygosity (LOH) leading to inactivation of SMAD4 (DPC4), and DCC (deleted in colon cancer) tumor suppression genes. Chromosome arm 17p deletion and mutations affecting p53 tumor suppressor gene confer resistance to programmed cell death (apoptosis) and are thought to be late events in colon carcinogenesis.
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Symptoms of colorectal cancer
Symptoms are common and prominent late in colon cancer when the prognosis is poor but are less common and less obvious early in the disease. Common symptoms include abdominal pain, rectal bleeding, altered bowel habits, and involuntary weight loss (Falterman, 1974).
Typical Symptoms
Bleeding from the back passage (rectum) or blood in your stools
A change in normal bowel habits to diarrhoea or looser stools, lasting longer than 6 weeks
A lump that your doctor can feel in your back passage or abdomen (more commonly on the right side)
A feeling of needing to strain in your back passage (as if you needed to pass a bowel motion)
Losing weight
Pain in your abdomen or back passage
A lower than normal level of red blood cells (anaemia)
Because bowel tumours can bleed, cancer of the bowel often causes a shortage of red blood cells ie anaemia and may cause tiredness and sometimes breathlessness.
If cancer blocks, symptoms include
Griping pains in the abdomen
Feeling bloated
Constipation
Being sick
Insert reference:
Although colon cancer can present with either diarrhea or constipation, a recent change in bowel habits is much more likely to be from colon cancer than chronically abnormal bowel habits. Symptoms depend on cancer location, cancer size, and presence of metastases. Just as with symptoms, colon cancer tends not to produce signs until advanced. Anemia from gastrointestinal bleeding may produce pallor. Iron deficiency anemia can cause changes in nails. A palpable abdominal mass is a rare finding that suggests advanced disease. Rectal examination, including fecal blood testing is important in the evaluation of possible colon cancer, Rectal cancer may be palpable by digital rectal examination.
Prevention & Screening of Colorectal Cancer
Invasive colorectal cancer is a preventable disease. Early detection through widely applied screening programs is the most important factor in the recent decline of colorectal cancer in developed countries). Full implementation of the screening guidelines can cut mortality rate from colorectal cancer in the United States by an estimated additional 50% (emedicine, 2013); even greater reductions are estimated for countries where screening tests may not be widely available at present. New and more comprehensive screening strategies are also needed.
Screening
A range of screening procedures are available (Cappell, 2005), including Fecal blood Testing, barium Enema, Sigmoidoscopy and colonosocopy. Bowel cancer screening aims to detect bowel cancer at an early stage in people with no symptoms. Early treatment is more likely to work. Bowel cancer screening can also find polyps. Polyps are not cancers, but may develop into cancers over time. They can easily be removed, reducing the risk of bowel cancer developing.
In England, men and women aged between 60 and 69 years old are invited for bowel screening every 2 years. This is gradually being extended to include people up to the age of 75 (NHS)
Fecal occult blood testing: FOBT was the traditional mainstay of screening for colon cancer and colonic polyps (Capell, 2005) . It has advantages as a screening test of low cost, test simplicity, noninvasiveness,and safety. It has a disadvantage as a screening test because of low specificity.
FOBT is based on increased microscopic rectal bleeding in patients with colon cancer compared with patients without colonic disease.
Barium enema:. Bariumenema, however, is only moderately sensitive at detecting colon cancer. For example, in a review of 2193 consecutive colorectal cancers, barium enema was much less sensitive (82.9% sensitivity) than colonoscopy (95% sensitivity) in detecting colon cancer.
Flexible sigmoidoscopy: this test examines the inside of the rectum and lower bowel, with a flexible sigmoidoscopy or bowel scope. It is being introduced as part of the NHS bowel screening programme (CRUK, 2013). However, The role of flexible sigmoidoscopy is limited in the screening and diagnosis of colon cancer. Sigmoidoscopy is relatively insensitive at colon cancer or colon polyp detection because the proximal half of the colon is not endoscopically visualized.
Diagnostic colonoscopy: Colonoscopy is recommended for screening of patients more than 50 years old at average risk for colon cancer or colonic polyps . Colonoscopy is highly sensitive at detecting large (>1 cm) colonic polyps, At colonoscopy polyps are removed and masses biopsied for a pathologic diagnosis.Colonoscopy, however, has disadvantages as a screening test because it is resource intensive; expensive; somewhat invasive; uncomfortable; and entails a small, but significant, risk of serious complications.
Once diagnosed other procedures are routinely used to monitoir intramural penetration and extracolonic spread of colon cancer. These include MRI, CT and ultrasound (Capell, 2005)
Prevention of Colon Cancer
Dietary modifications
Dietary fibre may reduce the risk of colon cancer. In a number of older studies some scientist proposed that dietary fibre (non-starch polysaccarides) lowers the risk of developing colorectal cancer. Proposed mechanisms include decreased mucosal exposure to intraluminal carcinogens caused by stimulated intestinal transit, decreased concentration of carcinogens in stool caused by increased stool bulk, increased concentrations of anticarcinogenic short-chain fatty acids, and stabilization of insulin levels caused by delayedstarch absorption that might otherwise promote colonic carcinogenesis (Hawk et al, 2002).
The effect of dietary fiber is controversial (Cappell, 2005) with numerous studies suggesting a large protective effect and several studies suggesting no effect .
Topic
Publications
Main results
Fibre
Lancet 2003, Bingham S et al
Inverse relation of dietary fibre with colorectal cancer incidence with the greatest protective effect in the left colon, and least in the rectum. No food source of fibre is significantly more protective than others.
Fibre 2
Bingham S et al, submitted 2004
Confirmation of the above findings after adjustment for folate and with a longer follow-up.
Nuts
Cancer Epidemiol Biomarkers Prev 2004, Jenab et al
Higher nut and seed intake is not significantly associated to the risk of colorectal, colon, and rectal cancers in men but did show an inverse association with colon cancer in women.
Meat, fish, poultry
Norat T et al, provisionally accepted 2004
High consumption of processed and/or red meat is associated with an increase in colorectal cancer risk, not explained by the substitution of fish by red meat and is less apparent in high fibre consumers. Fish consumption is significantly inversely associated with risk while there is no association with poultry.
Dairy foods
Riboli E et al, Paper in preparation
Intake of milk and cheese was significantly associated with reduced colorectal cancer risk. The data suggested an inverse association for yogurt. Dietary calcium and calcium from dairy products are also significantly inversely associated.
In reports from studies that took place in the USA, Finland and Sweden found no protective effects of fibre (Fuchs, C et al, 1999)(Terry, P et al, 2001)(Pietinen, P et al, 1999). There have also been a number of investigations into whether supplements of bran, soluble fibres or vegetables could reduce reoccurrence rates of colorectal polyps, however this been shown to be untrue (Schatzkin, A et al, 2000)(Alberts, D et al, 2000)(Bonithon-Kopp, C et al, 2000). These studies have challenged the recommendations by the American Institute for cancer research and the UK department of health, who suggested that population intakes of fibre should be increased to reduce the risk of colorectal cancer (Bingham, S et al, 2003).
EPIC One of the largest studies to investigate the relationships between diet, nutritional status, lifestyle and environmental factors and the incidence of cancer and other chronic diseases. EPIC is the largest study of diet and health ever undertaken, having recruited over half a million (520,000) people in ten European countries: Denmark, France, Germany, Greece, Italy, The Netherlands, Norway, Spain, Sweden and the United Kingdom. There was little loss to follow up with little loss to follow-up during this time period, and the identification of over 26,000 incident CRC cases and nearly 16,000 deaths. Recruitment into the study, which was initiated in 1992, was principally from the general population aged 20 years or over, and took place between 1993 and 1999. Detailed information on diet and lifestyle was obtained by questionnaire, and anthropometric measurements and blood samples were taken at recruitment.
The hypothesis that a diet high in fibre reduces colorectal cancer risk has been corroborated in the EPIC study. Findings were published in parallel with the results from the PLCO cohort of the NIH-NCI. In that study, a similar protective effect of fibre on colorectal cancer polyps was observed. Together, these results indicate that fibre is protective both for the development of adenomatous polyps and for their malignant transformation. The hypotheses that consumption of red and processed meat increases colorectal cancer risk while intake of fish decreases risk is also strongly supported by the EPIC results. The combination of four dietary factors (i.e. fibre, fish, red and processed meats) plays a major role in colorectal cancer etiology in addition to alcohol intake, obesity and low physical activity. [Source: http://epic.iarc.fr/keyfindings.php]
Chemoprevention with aspirin and other nonsteroidal anti-inflammatory Drugs
Aspirin and drugs called non steroidal anti inflammatory drugs (NSAIDs, such as ibuprofen or Nurofen) may help to prevent bowel and other digestive system cancers. Nonsteroidal anti-inflammatory drugs (NSAIDs) may work by reducing cellular proliferation,slowing cell cycle progression, stimulate apoptosis (Capell, 2005) The Cancer Prevention Study II prospectively analyzed the effect of aspirin on colon cancer mortality during a 6-year period in more than 600,000 adults who provided information on theiraspirin use at their enrollment in the trial. The relative mortality from coloncancer was about 0.6 in men and 0.58 in women who used aspirin 16 or moretimes per month compared with nonusers of the same sex (Thun, 1991). NSAIDs are believed to reduce adenoma formation and inhibit colon cancer development by inhibiting the cyclooxygenase (COX) enzymes required for the synthesis of prostaglandin E2; prostaglandin E2 promotes cell proliferation and tumor growth (Marnett, 1992).
Treatment for advanced Colorectal Cancer
Treatment of recurrent colon cancer depends on the sites of recurrent disease demonstrable by physical examination and/or radiographic studies. In addition to standard radiographic procedures, radioimmunoscintography may add clinical information that may affect management. Such approaches have not led to improvements in long-term outcome measures such as survival.
Treatment Options for Stage IV and Recurrent Colon Cancer
Treatment options for stage IV include the following:
Surgery
Surgical resection of locally recurrent cancer.
Surgical resection and anastomosis or bypass of obstructing or bleeding primary lesions in selected metastatic cases.
Resection of liver metastases in selected metastatic patients
Resection of isolated pulmonary or ovarian metastases in selected patients.
Palliative Chemotherapy
Palliative Radiotherapy.
Targeted therapy.
Clinical trials evaluating new drugs and biological therapy.
Clinical trials comparing various chemotherapy regimens or biological therapy, alone or in combination.
Surgery
The main treatment option for bowel cancer is surgery and if the disease can be caught before it breaks through the bowel wall, chances of success are much higher. When CRC is discovered in the later stages, the two options are surgical resection and ostomy. Ideally if the cancer has been found early enough then a simple colonoscope can be used to remove the tumour, however this is not always the case and some more extreme surgery may need to be done. The primary objective of surgery for CRC is to completely remove all tumour tissue. The secondary objective is to avoid the formation of a permanent stoma (Braithwaite, B and Scholefield, J, 2000). Usually, the piece of bowel that contains the cancer is removed and the two open ends are joined back together. This operation, a bowel resection, may cure early cancers that haven't spread (Braithwaite, B and Scholefield, J, 2000). If the two sections can't be joined back together, often because the tumour is too low, the bowel can be brought out through the abdominal wall. This is called a stoma, which is connected to a colostomy bag. Although this procedure is more likely after removal of a tumour in the rectum, it isn't always necessary and may only be temporary. In these cases, further treatment may not be necessary (Braithwaite, B and Scholefield, J, 2000).
A high percentage of colon cancer patients will be diagnosed with hepatic metastases, either at the time of initial presentation or as a result of disease recurrence. Although only a small proportion of patients with hepatic metastases are candidates for surgical resection, advances in tumour ablation techniques and in both regional and systemic chemotherapy administration provide for a number of treatment options (Gayowski et al, 1994).
Hepatic metastasis may be considered to be resectable based on the following; (NIH website)
Limited number of lesions.
Intrahepatic locations of lesions.
Lack of major vascular involvement.
Absent or limited extrahepatic disease.
Sufficient functional hepatic reserve.
For patients with hepatic metastasis considered to be resectable, a negative margin resection resulted in 5-year survival rates of 25% to 40% in mostly nonrandomized studies, such as the (source; http://www.cancer.gov/clinicaltrials/search/view?version=healthprofessional&cdrid=63648 NCCTG-934653 trial) (Gayowski et al, 1994).
Chemotherapy
Chemotherapy and, in some cases, radiotherapy are increasingly being used to treat bowel cancer in addition to surgery, especially in more advanced tumours. Chemotherapy may be used to destroy cancer cells left behind after surgery, especially if the tumour has advanced past the earliest stage. This is called adjuvant chemotherapy. A number of different chemotherapy drugs may be used and several research studies are on-going to try to work out which ones are most effective.
Current Agents for treatment of Advanced CRC
A number of agents for advanced dieaese are aviable. However, despite there being many attempts over the years to develop a drug that works better than fluoropyrimidine 5FU, fluoropyrimidine 5FU remains the focus for most CRC treatment strategies (Cercek, A and Saltz, L, 2010).
Trials in patients with locally advanced, unresectable, or metastatic disease have sucesfully demonstrated partial responses and prolongation of the time-to-progression (TTP) of disease (Peterelli, 1987., Peterelli, 1989) as well as improved survival and quality of life for patients receiving chemotherapy, compared with the best supportive care.
Other available able drugs include
Capecitabine.
Capecitabine is a prodrug, that is enzymatically converted to 5-fluorouracil in the tumor
Irinotecan.
Irinotecan prevents DNA from unwinding by inhibition of topoisomerase 1.
Oxaliplatin.
Oxaliplatin is a platinum-based antineoplastic
Bevacizumab.
Bevacizumab is a partially humanized monoclonal antibody that binds to vascular endothelial growth factor.
Cetuximab.
Aflibercept.
Aflibercept is a novel anti-VEGF molecule and has been evaluated as a component of second-line therapy in patients with metastatic colorectal cancer
Panitumumab
Panitumumab is a fully humanized antibody against the EGFR
Cetuximab
Cetuximab is a partially humanized monoclonal antibody against the epidermal growth factor receptor (EGFR).
Reference table:
Drug combinations are also typically used, often developed by specific hospitals or local institutions. For example the NIH website lists the following:
•The Arbeitsgemeinschaft Internische Onkologie (AIO) or German AIO regimen (folic acid, 5-FU, and irinotecan): Irinotecan (100 mg/m2) administered as a 2-hour infusion on day 1; leucovorin (500 mg/m2) administered as a 2-hour infusion on day 1; followed by 5-FU (2,000 mg/m2) intravenous (IV) bolus via ambulatory pump administered for a period of 24 hours on a weekly basis four times a year (52 weeks).
•The CAPOX regimen:Capecitabine (1,000 mg/m2) twice a day on days 1 through 14 plus oxaliplatin (70 mg/m2) on days 1 and 8 every 3 weeks.
•The Douillard regimen (folic acid, 5-FU, and irinotecan):Irinotecan (180 mg/m2) administered as a 2-hour infusion on day 1; leucovorin (200 mg/m2) administered as a 2-hour infusion on day 1 and day 2; followed by a loading dose of 5-FU (400 mg/m2) IV bolus, then 5-FU (600 mg/m2) via ambulatory pump administered for a period of 22 hours on day 1 and day 2 every 2 weeks.
•The FOLFOX4 regimen (oxaliplatin, leucovorin, and 5-FU):Oxaliplatin (85 mg/m2) administered as a 2-hour infusion on day 1; leucovorin (200 mg/m2) administered as a 2-hour infusion on day 1 and day 2; followed by a loading dose of 5-FU (400 mg/m2) IV bolus, then 5-FU (600 mg/m2) administered via ambulatory pump for a period of 22 hours on day 1 and day 2 every 2 weeks.
•The FOLFOX6 regimen (oxaliplatin, leucovorin, and 5-FU):Oxaliplatin (85–100 mg/m2) administered as a 2-hour infusion on day 1; leucovorin (400 mg/m2) administered as a 2-hour infusion on day 1; followed by a loading dose of 5-FU (400 mg/m2) IV bolus on day 1, then 5-FU (2,400–3,000 mg/m2) administered via ambulatory pump for a period of 46 hours every 2 weeks.
•The FOLFIRI regimen (folic acid, 5-FU, and irinotecan):Irinotecan (180 mg/m2) administered as a 2-hour infusion on day 1; leucovorin (400 mg/m2) administered as a 2-hour infusion on day 1; followed by a loading dose of 5-FU (400 mg/m2) IV bolus administered on day 1, then 5-FU (2,400–3,000 mg/m2) administered via ambulatory pump for a period of 46 hours every 2 weeks.
•The FUFOX regimen:Oxaliplatin (50 mg/m2) plus leucovorin (500 mg/m2) plus 5-FU (2,000 mg/m2) as a 22-hour continuous infusion on days 1, 8, 22, and 29 every 36 days.
•The FUOX regimen:Continuous infusion 5-FU (2,250 mg/m2) during 48 hours on days 1, 8, 15, 22, 29 and 36 plus oxaliplatin (85 mg/m2) on days 1, 15, and 29 every 6 weeks.
•The IFL (or Saltz) regimen (irinotecan, 5-FU, and leucovorin):Irinotecan (125 mg/m2), 5-FU (500 mg/m2) IV bolus, and leucovorin (20 mg/m2) IV bolus administered weekly for 4 out of 6 weeks.
•The XELOX regimen:Oral capecitabine (1,000 mg/m2) twice a day for 14 days plus oxaliplatin (130 mg/m2) on day 1 every 3 weeks.
(NIH website)
For patients with liver metastases, multiple studies with multiagent chemotherapy have demonstrated that patients with metastatic disease isolated to the liver, which historically would be considered unresectable, can occasionally be made resectable after the administration of chemotherapy (Leonard et al, 2005).
Patients with hepatic metastases that are deemed unresectable will occasionally become candidates for resection if they have a good response to chemotherapy. These patients have 5-year survival rates similar to patients who initially had resectable disease.(Leonard et al. 2005)
The role of adjuvant chemotherapy after potentially curative resection of liver metastases is uncertain (NIH website). Further studies are required to evaluate this treatment approach and to determine if more effective systemic combination chemotherapy alone may provide similar results compared with hepatic intra-arterial therapy plus systemic treatment.
Radiation therapy
The aim of radiation therapy is to deliver as high and as homogeneous a dose as possible to the diseased tissue without causeing any unwanted and unnecessary side effects for the patient. This recognises that it is not enough to destroy tumor cells and prolong the life of the patient but that the quality of the life of the patient must be high in this extended period of time. Tis form of therapy is not often used when it comes to colon cancer but is used to kill cancerous cells that have started in the rectum (Cancer research UK). This form of therapy is often used in conjunction with other therapies, for example with the drug fluoropyrimidine 5FU, where the chemotherapy makes the cancer cells more sensitive to radiation. It is also used in conjunction with surgery, it can be used both before and after surgery. Two forms of radiation therapy can be used preop, internal and external radiation therapy. Before surgery external therapy can be used to lower the risk of the cancer coming back after surgery, as well as causing the tumour to shrink making it easier to completely remove during surgery. Internal therapy can also be used before surgery. This is a newer form of surgery called brachytherapy. Results from studies seem to show that people who have internal radiotherapy are less likely to need a colostomy than people who have external radiotherapy. But it is not clear whether internal radiotherapy helps people to live any longer (Cancer Research UK).
Problems/limitations with treatment
Resistance
How much resistance has been seen
Paper on the emergence of KRAS mutations and accuired resistance to anti-EGFR therapy
Are there any other therapies that have come up against problems for for treatment such as resistance
The main limitation of the therapies that selectively target kinase signalling pathways is the fact that secondary drug resistance has started to occur. – an example of this is to do with cetuximab
Conclusions
Colorectal cancer (CRC) is the most common tumour type in both sexes combined in Western countries. Although screening programmes including the implementation of faecal occult blood test and colonoscopy might be able to reduce mortality by removing precursor lesions and by making diagnosis at an earlier stage, the burden of disease and mortality is still high. Improvement of diagnostic and treatment options increased staging accuracy, functional outcome for early stages as well as survival. Although high quality surgery is still the mainstay of curative treatment, the management of CRC must be a multi-modal approach performed by an experienced multi-disciplinary expert team. Optimal choice of the individual treatment modality according to disease localization and extent, tumour biology and patient factors is able to maintain quality of life, enables long-term survival and even cure in selected patients by a combination of chemotherapy and surgery. (Source ESMO guidelines)

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