Colorectal cancer

Accounts for approximately 13% of all cancers.

Worldwide, ranks third in incidence with 1,350,000 new cases and nearly 700,000 deaths annually.

746,000 new cases every year in men and in women 614,000 new cases each year, worldwide.

In 2022 there was an estimated 1.4 million colorectal cancer survivors.

Worldwide accounts for 9.4% of total cancer mortality.

Incidence 25% higher in males.

Incidence difference greatly between countries.

Asia accounts for half of the new cases, deaths and five-year prevalence for colorectal cancer, with studies suggesting individuals with Chinese, Japanese, and Korean ethnicity may be more susceptible to colorectal cancer.

Colon cancer accounts  for 150,000 new cases each year in the US.

The third most common cancer in US, and second leading cause of cancer related deaths in adults.

Estimated 53,000 cancer deaths in the US in 2024.

Approximately 30% of patients with stage 1 to III colorectal cancer experience recurrences after curative intent surgical resection of the primary tumor.

The incidence of colon and rectal cancer is decreasing is the result of cancer prevention, earlier diagnosis to screening, and dairy treatment modalities.

Almost 150000 patients in the US will receive a diagnosis of colon cancer annually and approximate 30-35% of these patients have regional lymph node metastases consistent was the IIIA-C colon cancer.

Second most prevalent cancer in the world behind breast cancer.

Third most common cancer in the US.

Early detection affects overall survival: 5 year survival 91% among persons with localized disease and 14% among those with metastatic disease.

Increased rates are largely due to obesity or physical inactivity.

Estimated approximately half of all colorectal cancer cases and deaths are attributable to modifiable risk factors, such as physical activity, smoking, and diet and are potentially preventable.

Diet influences the composition of the gut microbiome , and a western style diet and obesity lead to gut dysbiosis and chronic intestinal inflammation, which can promote colorectal tumorigenesis.

A cumulative lifetime exposure to excess weight may account for a large share of colorectal cancer risk, and halting and reversing the increase in prevalence of overweight and obesity may have a potential to prevent a large share of colorectal and possibly other cancers.

Colorectal cancer is associated with reductions in gut bacteria that produce short chain fatty acids, which preserve intestinal immune homeostasis.

A plant base diet promote beneficial gut microbes that are anti-inflammatory, whereas a western style diet promotes inflammation and then increase risk of coal rectal neoplasia.

Obesity in women is associated with increased risk, nearly doubled, of early onset colorectal cancer.

The risk of developing Colorectal cancer before age 50 years is nearly double for women who are obese and elevated for those who are overweight compared with women with normal body mass index.

Women have a lower overall incidence of colon cancer than men, but have a higher incidence of right-sided colon cancers, which have the worst outcomes.

Second leading cause of cancer death in the Western world.

Approximately 20-30% of colorectal cancer are potentially linked to genetic factors, and hereditary colorectal cancer syndromes constitute 3-5% of all colorectal cancers.

Death rate for colorectal cancer increases with age.

Age is considered the major unchangeable risk factor for sporadic colon cancer: nearly 70% of patients are greater than 65 years of age and this disease is rare before the age of 40 years.

De novo stage IV colon cancer accounts for approximately 22% of new cases of colon cancer and has an overall five-year survival of approximately 14%.

Third leading cause of cancer death in the world.

Second most common cancer diagnosed in women and the third in men.

4.7% of US population is diagnosed with CRC.

Currently more than 1 million survivors.

There has been a 3.1% annual reduction in new cases over the past 10 years.

Incidence in patients younger than 50 years is increasing, and most markedly among those younger than 35 years by approximately 2% per year.

Colon cancer incidence has increased by 1.3% per year since the mid-1990s, and rectal cancer has increased by 2.3% per year.

There has been a steady decline in the incidence of colorectal cancer in people 50 years and older, and average 51% increase in CRC incidence in patients younger than 50 years since 1994.

Presently one in 10colon  cancers and one in four rectal cancers will be diagnosed in individuals under the age of 50.

Annual incidence rates have increased by more than 1.5% for more than a decade among patients 20-49 years old, and now comprise 10-18% of newly diagnosed patients.

Predominantly a disease of the elderly with a median age of 72 years, and 28% of patients are older than 80: median age has recently shifted to 66 years with increasing incidence at younger ages.

72% of the US population with colorectal cancer are aged 65 years or older.

A heterogeneous disease that include 3 major forms: hereditary, sporadic and colitis associated.

Since 1998, the age-standardized incidence rates for the US population has decreased by an annual average of 2.8% in men and 2.2% in women (ACS).

The overall incidence has been increasing since 1992 among adults ages 20 to 49 years by 1.5% per year in men and 1.6% per year in women(ACS).

The highest percentage increases occur in patients 20 to 29 years of age with 5.2% increase from man in 5.6% increase for women(ACS).

Approximately 20% of cases are associated with familial clustering,

Tumor dissemination occurs by two routes: systemic route through the bloodstream leading to liver or lung metastases and a local route through the peritoneal cavity.

More than 10% of patients with Colorectal cancer have synchronous peritoneal metastases and in about 25% of these cases there are no other distant metastasis.

The natural history of metastatic colorectal cancer with peritoneal metastases is different from metastatic colorectal cancer involving other systemic sites.

Metastatic peritoneal disease is associated with worse survival waves impaired with other metastatic sides even after complete surgical resection, and this poor outcome is explained by a limited response to systemic chemotherapy.

Peritoneal metastases are difficult to detect with present day imaging.

Approximately 30-50% of patients will have liver metastases.

90% occur sporadically from somatic mutations and are mainly due to environmental factors, with no apparent association with hereditary of familial factors.

CRC tumorigenesis is associated with significant genetic disorders such as mutations in suppressor genes and oncogenes resulting in the transformation of normal intestinal epithelium towards malignancy.

CRC development is commonly initiated by mutations in the adenomatous polyposis  coli tumor suppressor gene.

The familial adenomatous polyp poses carcinogenesis is related to chromosomal instability.

The Lynch syndrome is related to microsatellite instability for its pathogenesis.

Colorectal cancers driven by the microsatellite instability pathway respond to immune checkpoint inhibitors, whereas tumors driven by chromosomal instability are not.

First-degree relatives of patients with colorectal adenomas or invasive colorectal cancers are an increased risk.

Anatomic subsite analysis reveals increases in tumors in the distal colon, 1.5% for men and 2.3% for women, and rectum primaries 3.5% for men and 2.9% for women.

Increasing incidence of colorectal cancer in younger patients speculated to be due to increased obesity, which is a strong risk factor and also increase consumption of red and processed meats, however, such tumors have not been associated with typical risk factors of diabetes and obesity.

Sporadic early onset CRC more commonly develop in distal colon and rectum with a continuous increaed incidence from the proximal colon to the rectum.

Increasing incidence in young people may be due to increased rates of obesity, as increased abdominal girth and decreased physical activity are reported to be associated with increased risk of colon polyps, a precursor to malignancy (Giovannucci E et al).

Early onset CRC are clinically, pathologically, and molecularly distinct from traditional CRC.

Inverse relationship between physical activity and colorectal cancer development, with an overall relative risk of 0.76 based on a meta-analysis of 52 observational studies (Wolin KY et al).

In the Health Professionals Follow-up Study the overall mortality in a cohort of 668 men with stage I-stage III colorectal cancer a value weighted by physical activity categories: more physical activity was associated with lower risk of colorectal cancer specific and overall survival (Meyerhardt JA et al).

Overall the incidence of colorectal cancer has been decreasing from 66.3 cases per 100,000 population in 1985 to 46.4 cases to 46.4 cases in 2005, as a result of screening and early detection and removal of polyps.

Estimated age standardized incidence and mortality rates, respectively R. 29.6% and 12.4% in Europe, 29.2% and 8.8% in the US and 12.9 and 6.6% in Asia (Ferlay J et al).

In Asia in incidence has been increasing the last couple of decades.

Kills approximately 600,000 people annually worldwide (Ferlay J et al).

Number of deaths from this disease decreasing over the last 15 years.

Incidence rates as low as 3 per 100,000 in Africa and as high as 43 per 100,00 in North America, Europe, Australia and Japan.

Alaska native people have among the world’s highest rates of colorectal cancer with an incidence rate more than twice that of US whites 90.9 versus 41.1 per thousand persons, respectively.

Migrant groups develop incidence rates similar to adopted countries within one generation.

Incidence in the U.S. as high as 54 per 100,000 population.

Accounts for about 15% of all cancer related deaths in the U.S.

Lifetime risk is 1 in 17(about 4%) affecting men and women alike with 90% of cases after the age of 50 years.

75% of patients with CRC have sporadic disease: Highlighting the potential impact of diet and environmental influences on the overall incidence of and mortality of CRC


Most CRC cases for sporadic as a direct result of environmental stimuli.

CRC risk factors include: obesity, smoking, alcohol consumption, western diet, and diabetes: all of which modify the gut microbiotome.

Lifetime risk in industrialized nations is 5% and stable or decreasing (Bretthauer).

Incidence increasing in developing countries.

As many as 15% of such cancers occur in patients younger than 50 years of age.

Only 0.1% of all colorectal cancers occur before age 20, and 1% occur between 20 and 34 years of age.

In younger patients, colorectal cancer presents more commonly with stage III or IV disease (O’Connell JB et al).

The annual incidence increases from 10 cases per million at age 20 years to 100 cases per 1 million at the age of 45 years.

Colorectal cancer represent the third leading cause of cancer related deaths in the United States for men between ages 20 and 39 and the fourth leading cause of cancer related death for women in the same age group.

Lifetime risk for U.S. women and men are comparable at 5.1% vs. 5.5%, respectively.

Patients with a personal risk of adenomatous polyps are at increased risk of developing CRC, as are patients with a history of CRC with a relative risk ranging 3-6.

Colon cancer mortality in the US is inversely correlated with solar radiation.

There is a threefold increase in colon cancer risk in people who have a 25 (OH)D level less than 20 ng/mL.

African Americans have a 19% higher incidence and 39% higher mortality compared to other racial groups in the US (Polite BN).

Colorectal cancer surgery in the elderly mortality 2-16%

Goal in resection of early stage colon cancer is attaining R0 resection.

Patients who achieve R0 resection s compared to R1 and R2 have significantly improved long-term survival (R classification).

Traditionally, open resection of the colon tumor is employed, with end-end anastomosis of the uninvolved free margins.

Laporosopic resection for early stage disease decreases morbidity with similar outcomes and node sampling.

Laporoscopic resection provides similar outcomes in locally advanced disease.

Right sided lesions are treated with right colectomy and primary ileocolic anastomosis.

Outcome is worse for right-sided colon cancers than left side of colon cancers, and overall survival after curative surgery for right-sided colon cancer is better in patients whose surgery lead to a lymph node yield of 22 or more.

For patients with obstructing masses, the Hartmann procedure is the most commonly performed procedure, involving an ostomy with subtotal colectomy and subsequent ostomy reversal.

Surgery for patients with invasion into surrounding structures requires multivisceral resection.

Despite optimal primary surgical resection with or without adjuvant chemotherapy, up to 50% of early stage CRC patients will have disease relapse, and most of those patients will die of their disease.

Most patients with stage II CRC are not treated with adjuvant chemo therapy.

A ctDNA guided approach to the treatment of stage II colon cancer reduced the adjuvant chemotherapy use without compromising recurrence free survival (Tie J).

Patients with stage II colon cancer who have ctDNA  detected after curative intent surgery are 18 times as likely to have a relapse as patients with no detectable ctDNA.

The optimal time after surgery to check ctDNA is unclear and ranges between two and six weeks.

Approximately 10-15% of patients have residual disease after surgery.

Most patients with stage III CRC receive adjuvant chemo therapy despite more than 50% being cured by surgery.

Approximately 30% of the patients receiving adjuvant chemotherapy for stage III colorectal cancer experience recurrence.

Adjuvant chemotherapy for stage IIICRC decreases the probability of cancer recurrence by approximately 10 to 20%, depending upon the treatment regimen selected.

The key clinical pathologic features associated with high risk CRC recurrence include poorly differentiated or undifferentiated histologic findings, lymphatic or vascular invasion, bowel obstruction, less than 12 lymph nodes examined, perineural invasion, localized perforation, or close, indefinite positive margins, and tumor budding.

Adjuvant chemo therapy for patients with stage III colon cancer demonstrated noninferiority of three months versus six months of therapy.

Patients who have an intestinal perforation have increased surgical complications, infections, and lowered 5 year survival.

Colorectal cancer surgery 30 day mortality 1.3% for elderly and 0.6% for younger patients.

Five-year survival for patients with advanced, metastatic disease is low, at about 8 to 12%.

Colorectal resections mortality 3%.

Third most commonly diagnosed cancer and second leading cause of cancer deaths in the U.S.

First-degree relatives of patients with newly diagnosed adenomas or invasive carcinoma are at increased risk for colorectal cancer.

75% occur with no known predisposition, approximately 6% associated with hereditary predisposition and 25% represent familial disease.

Familial clustering of colorectal cancer accounts for 25_30% of CRC CASES.

Certain families have a strong clustering of disease and across the population, unaffected people with one or more relatives affected are at greater risk.

Younger patients tend to present with more advanced disease, but it is not clear whether stage for stage the prognosis differs from older individuals.

Young age is modestly associated with poorer progression free survival but not overall survival or response rate in treated patients (Blanke CD et al).

Young patients with colon cancer receive significantly more postoperative systemic chemotherapy at all stages, but experience only minimal gain in survival compared with older counterparts who received less treatment (Kneuertz PJ et al).

Represents approximately 11% of all new cases of cancer.

If first degree relative has colorectal cancer their risk increases by approximately two fold, and if the relative is diagnosed at an age younger than 45 years the risk is increased approximately by four fold.

Lifetime risk 6% for development and 2.6% estimated lifetime risk of colorectal cancer death.

Lifetime risk for developing CRC is about 4.3% for men and 4% in women.

Incidence increases after the age of 40 and progressively rises with age.

Hereditary cancer syndromes and other disposing factors account for less than 20% of colon cancers and persons under the age of 40 years.

Hereditary CRC syndromes are associated with early onset of disease, some with risk of extra clonic cancers.

Genetic susceptibility to TRC includes: The Lynch syndrome, familial adenomatous polyposis, MUTYH-associated polyposis, juvenile polyposissyndrome, Cowden syndrome and Peutz+Jeghers syndrome.

Approximately half of all cases are age 70 or older at diagnosis.

African-Americans have an increased risk compared to whites, and also have an increased mortality rate.

5-year survival in the U.S. is 63% and currently only 38% of patients are diagnosed when the cancer is localized to the bowel wall.

About 25% patients present with stage IV cancer.

5 -year relative survival for stage IV disease is <13%.

The 10 year survival for patients in stage I disease is about 90%, but for patients with inoperable stage IV disease and is presently about 5%.

50-60% of patients are diagnosed with metastatic disease and have a five year survival rate of 12%.

First line progression free survival for metastatic disease has remained largely unchanged over the last decade, and any improvements in survival is probably the result of incremental benefits of subsequent lines of therapy.

Patients with metastatic colorectal cancer originating of the left side of the colon survive longer than those with originating right sided lesions.

Right-sided colon cancer defined as cancer of the cecum and the ascending colon up to the hepatic flexure.

Left-sided colon cancer comprised of cancer of the splenic flexure and regions distal to the splenic flexure, including the rectum.

Sidedness suggests differences in the molecular genetics that drive tumors arise in different locations of the colon.


About 2% of breast cancers have mismatch repair deficient to microsatellite instability.

Right side of colon cancers are found in older and more likely in female patients, and are initially seen with more advanced tumor stage,and are more likely to blefye poorly differentiated.

Right-sided colorectal cancer patients with stage III and high-risk stage II cancers have a worse disease free survival than patients with left-sided tumors (Saunders M).

Right-sided colon tumors more frequently harbor BRAF mutations, have a higher tumor/node/metastases stage a presentation, and have a worse prognosis compared with left-sided colorectal tumors.

Anatomic location of primary tumors in the colon correlate with survival in the metastatic setting: left?sided tumors may exhibit superior survival compared with right?sided tumors.

The Oncotype Recurrence Score (RS) assay is a clinically validated predictor of recurrence risk in patients with stage II colorectal cancer (CRC).

CDX2?negative stage II CRC tumors are associated with a lower rate of disease?free survival than CDX2?positive stage II CRC tumors.

Recurrence score is higher in right?sided tumors,and gradually decreased across the colon with cecum having the highest score and the sigmoid, lowest score

Right?sided tumors exhibited more CDX2?negative tumors.

Right?sided colorectal tumors may display worse prognosis compared with left?sided tumors in Mismatch repair proficient stage II CRC.

Young patients with stage II colorectal cancer do not benefit from adjuvant chemo therapy.

MMR-Deficiency rate is approximally 10%-20% and stage I, II, III colorectal cancer and 4% in stage IV colorectal cancer.

Primary tumor location should be taken into account for recurrence risk assessment and consideration of adjuvant treatment.

8-10% of patients with colorectal cancer have a BRAF mutationsn and 80% of those are BRAF V600E mutations.

BRAF mutations are more common in women and elderly patients with colorectal cancer.

KRAS and BRAF genes are the main causes of both primary and acquired resistance to anti-EGF for agents, and their testing is predictive biomarkers is mandatory, traditionally by PCR or next generation sequencing.

BRAF lesions are predominantly right sided and large primaries.

BRAF Mutation is present in 8-10% of metastatic colorectal cancers, and is located in the EGFR signaling pathway, is a factor of poor  prognosis and it seem predominately in women, the right colon, and with extra hepatic involvement.

BRAF mutation is a marker of resistance to anti-EGFR drugs.

BRAF lesions are associated with mismatch repair deficiency, tend to have a higher grade, a greater rate of peritoneal disease, and more expensive lymph node metastasis.

BRAF mutant CRC With metastases in that phase III BEACON trial the triplet combination of BRAF inhibitor encoreafenib and MEK inhibitor binimetinib, and the EGFR had significant activity.

BRAF mutant CRC treatment with BRAF inhibitors and six taxman resulted in superior outcomes.

Patient with left-sided cancer is receiving bevicizumab have a median in overall survival of 38.7 months and 34 months for right-sided lesions.

For left-sided lesions treatment with cetuximab has a median overall survival of 40.3 months compared with right sided lesions at 18.4 months.

For left-sided RAS wild-type lesions EGFR based therapy should be considered.

Bevacizumab is considered for patients with RAS mutation.

With RAS wild type, consideration is given to cetuximab or panitumumab.

Before first line treatments or patients should have testing for microsatellite instability or mismatch repair deficiency, RAS  mutation status, and BRAF  mutation status.

Additional molecular test to be considered include HER2 amplification, NTRK fusions, and RET fusions in the first line setting.

The microbiome is different on the right side and the right side has a different embryological origin than the left side of the colon.

Inappropriate antibiotic exposure may be linked to an increased risk of colon cancer by alterations in the microbiome.

Gut microbes interact with a host immune system and can influence the antitumor immune response.

Patients with colorectal cancer have reduced bacterial diversity, as compared with healthy persons.


Studies  have shown an association between antibiotic use and an increased risk for colon cancer.


A Swedish population study from more than 40,000 colorectal cancer patients and 200,000 cancer-free control persons, found that moderate use of antibitotics increased the risk for proximal colon cancer by 9% and that very high antibiotic use increased the risk by 17%.

Increasing evidence indicates that dysbiosis of the intestinal microbiota is closely related to colorectal cancer (CRC). 

Studies have identified Streptococcus bovis, enterotoxigenic Bacteroides fragilis, Fusobacterium nucleatum, Enterococcus faecalis, Escherichia coli, and Peptostreptococcus anaerobius as CRC candidate pathogens. 

EGFR targeted agents do not seem to provide as much benefit for patients who have right-sided primary tumors.

Patients with the right-sided tumors generally appear to benefit more from chemo therapy combined with bevacizumab.

The AGITG MAX trial did not show that the side of primary site had any impact of Bevacizumab on progression free survival.

Few cancers occur in the transverse colon.

Without treatment the median survival for metastatic disease is about 1 year.

Median overall survival for metastatic colorectal cancer from first line treatments has reached 30 months.

Over the past 2 decades 5-year survival has increased from 50-63%.

Patients with colorectal cancer require intensive surveillance since the risk of a second primary ranges from 0.3-3.6%.

There are four molecular subtypes into which most CRC can be categorized based on their genomic signature:CMS1, CMS2, CMS3, CMS4.

CMS1-accounts for approximately 14% of all CRCs, of which approximately 12% are sporadic and the remaining have inherited disease.

CMS1 is characterized by hypermutation, marked the levels of BRAF mutation and high immunogenicity.

CMS1 precursor lesions are serrated polyps, Which are accompanied by low transforming growth factor beta micro environment.

Serated pathway to colorectal cancer has the following characteristics: proximal colon location, high BRAF mutation rate, impaired DNA mismatch repair, tumor microenvironment with lymphocytic infiltration, hyper methylation of island CPG, and loss of tumor suppressor function.

When hypermethylation or mutation to the promoter regions of the DNA miss patch repair genes occurs, microsatellite instability arises.

CMS1 Disease is characterized by a mutation rate that is high and is also associated with a low copy number for the affected genes.

CMS1 subtype tumor microenvironment has a relative lack of proliferative supporting cancer associated fibroblasts as well as the presence of immunity promoting cells such as natural killer cells, CD8 cytotoxic T lymphocytes and CD4 activating type 1 T-helper cells.

CSM1 tumors do tend to have a lower rate of relapse, but if relapse does occur they are associated with a worse survival.

CSM1 tumors have a five-year survival rate of 73%.

CSM2 subtype makes up the largest number of colorectal cancer patients at approximately 39%.

CSM2 cancers are thought to arise from the canonical-to-carcinoma pathway.

CMS2 has WNT/MYC pathway activation.

CMS2 tumors are associated with a high degree of chromosomal instability, often with aneuploidy, gains and/or losses of large portions of chromosomes and loss of heterozygosity.

CMS2 Tumors have a high somatic copy number alterations and more frequent copy number losses in tumor suppressor genes and copy number gains in oncogenes.

At the time of diagnosis 39% of CMS2 colorectal cancer patients present with stage III disease.

The standard of care with stage III colorectal cancer has been to administer six months of FOLFOX or CAPOX.

The standard of care with stage Roman noodles three colorectal cancer has been to administer six months for fox or K packs.

The majority of CMS2 colorectal cancer patients (59%) have lesions that occur on the left side of the colon.

With CMS2 subtype hire survival rates, 35 months, after relapse.

The five-year survival rate for CME2 colorectal cancer is 77%, the best of the four different colorectal cancer subtypes.

CMS3 the metabolic subtype of disease, typically has chromosomal instability but with lower somatic copy number alterations then those found in the CMS2 or CMS4 subtypes.

CMS3 has KRAS mutations and metabolic dysregulation.

Approximately half of patience with metastatic colorectal cancer harbor a KRAS or NTAS  tumor gene mutation: both are considered negative predictive biomarkers for anti-epithelial growth factor receptor monoclonal antibodies.

The only patients with KRAS while tight metastatic colorectal carcinoma are eligible for EGF are monoclonal antibodies.

30% of CMS3 tumors characterized as hypermutated

The MSI observed is intermediate in nature being less than that found for CMS1 but greater than the levels found in CMS2 and CMS4.

CMS4 is a mesenchymal, stroma-rich subtype.

Colorectal tumors based on the CMS classification are either hyper mutated or ultramutated (16%) or non-hypermutated (84%).

High tumor mutation burden is associated with mismatch repair deficiency (MMR-D) and a high level of microsatellite instability (MSI).

KRAS mutations are present in every colorectal tumor subtype however they are most frequently found in patients with CMS3 disease at 68%.

Molecular profiling is critical in front line metastatic colon cancer: it is needed to know the MSI, RAS, BRAF, HER2 and MTRK profile.

The high percentage of KRAS mutations in CMS3 colorectal cancer limits therapeutic options for this sub type of disease, as monoclonal antibodies targeting the epidermal growth factor receptor, such as cetuximab, have limited effectiveness against KRAS driven cancers.

Patients with KRAS type metastatic colon cancer with the left sided disease benefit from the addition of anti-EGFR in therapy to chemotherapy, whereas those with right sided disease receive no significant benefit from this addition.

Only the presence of RAS activating mutations (KRAS/NRAS), present in 30-45% of metastatic colorectal cancer, has proven to be a negative predictive biomarker of response to anti-EGFR.

No predictive biomarkers of response other than RAS exist, and includes BRAF, HER2 amplification, microsatellite instability, and ALK/ROS/NTRK fusion/rearrangements.

Approximately 3% of CMS3 colorectal cancer patients have a high copy number for HER2.

Human epidermal growth factor receptor that is a cell surface protein composed of an extracellular domain, a transmembrane domain and an intracellular domain with tyrosine kinase activity.

CMS4 is characterized by microsatellite stability, low methylation, chromosomal instability, very low levels of hypermutation, and very high levels of somatic copy number alterations.

CMS4 cancer adjuvant chemotherapy has no benefit.

Metastatic CMS4 disease is often EGFR Inhibitor resistant, independent of KRAS mutation status.

Patients with early-stage MSI cancer have better prognosis compared with those with microsatellite stable disease.

Testing for MSI currently recommended for most patients after a diagnosis of colorectal cancer, both for hereditary syndrome screening and for the prognosis and treatment implications.

Patients with microsatellite instability-high and/or mismatch repair deficient metastatic colon rectal cancer benefit less from conventional chemotherapy than those with microsatellite stable/mismatch repair proficient metastatic colon rectal cancer.

Microsatellite instability-high/mismatch repair deficiency is a predictive marker of response to treatment with anti-program death checkpoint inhibitor therapy.

Stage II cancers are associated with a low local recurrence rate and are generally not candidates for adjuvant chemo therapy.

Patients with stage III MSI tumors do not benefit from fluorouracil monotherapy, however they are responsive to FOLFOX therapy.

Patients with MSI-H have less benefit from conventional chemotherapy and historically have a shorter survival in those with microsatellite stable disease.

Genetic testing reveals that CRCs have a median of 76 non-silent mutations (Science, 2007).

The genesis is multifactorial and includes genetic, familial, dietary, lifestyle, and environmental factors.

Four stages are proposed to the progression of colorectal cancer: the first, genetic and epigenetic alterations underlying the colorectal epithelial compartment and promotes cancer progression by a clonal growht of abnormal cells.

The second stage to colorectal cancer is the progression at the molecular and morphologic levels.

The third stage involves the loss of genomic stability, resulting in cancer formation.

The fourth stage is the emergence of clinical cancer syndrome as eveidenced by late-stage colorectal cancer.

In societies where Western diets have become more common, there is a parallel increase in the incidence of colorectal cancer.

A low-fat diet accounting for 20% of energy intake reduces the risk of colorectal cancer.

Eating tree nuts associated with a reduction in the recurrence rate and deaths from stage III Colon cancer.

Among long term colorectal cancer survivors, regular use of nonsteroidal anti-inflammatory drugs after colorectal cancer diagnosis is significantly associated with improve survival in patients with KRAS wild-type tumors.

Evidence exists that red meat, especially processed meat is linked to increased risk of colorectal cancer.

Foods containing dietary fiber linked to decrease risk.

Decreased risk probably related for garlic, milk and calcium intake.

Carcinogenesis occurs over a number of years and is related to combination of gene alterations which include APC, p53, tumor suppressor genes and Ki-ras oncogene.

Patients with left-sided colon cancers that are Ras and BRAF wild-type have an improved outcome if an EGFR targeted therapy is used in the frontline setting.

The median survival for left-sided lesions was 12 months and right side lesions 23-24 months in patients with BRAF mutations treated with Bevacizumab.

70-90% of patients have lost a portion of chromosome 17p or 18q or both.

Process of tumorigenesis noted as the polyp-carcinoma sequence, and generally takes over 8-12 years to develop.

A multistep disease with a biological heterogeneity that results from an accumulation of genetic and epigenetic variations.

The polyp-carcinoma process is accelerated in the familial adenomatous polyposis (FAP) and hereditary nonpolypoid colorectal cancer (HNPCC), the two major forms of hereditary colorectal cancer.

Sporadic type makes up 85-90% of cases.

Thought to originate in the multiple potential stem cells located in intestinal crypts from which polypoid precursor lesions and metastatic cancer can develop.

Carcinogenesis is characterized by genetic and at the genetic alterations.

The majority of genetic alterations are harmless mutations.

Approximately 15 mutations drive functionally important processes during carcinogenesis.

Driver mutations can affect cell proliferation, migration, differentiation, adhesion, apoptosis, DNA stability and repair.

Pathways that are frequently affected include wingless-type MMTV integration site family (WNT), transforming growth factor/bone morphogenetic protein/SMAD, P53, tyrosine kinase receptors and Phosphoinositide 3 kinase (PI2K) signaling pathways (Sjoblom T et al).

The same genetic changes seen in hereditary cancers are altered in sporadic cases with key signaling pathway dysregulation in the Wnt/Beta-catenin, tumor growth factor-beta receptor, Notch and hedgehog signaling pathways.

Transforming growth factor beta-(TGFb) plays a role in tumor progression, invasion and metastases.

40-60% of patients have p53 mutations.

Adiponectin levels are inversely associated with risk of colorectal cancer.

There is epidemiological and biological evidence suggesting adiposity, hyperinsulinemia, altered glucose homeostasis an elevated insulin growth hormone axis abnormalities may impair the prognosis of colorectal cancer.

High-risk features include high-grade or poorly differentiated tumors, histological subtypes, including mucinous and signet-ring, presence of miscroscopic invasion into surrounding blood vessels and nerves, penetration through the visceral peritoneum or into surrounding structures, removal of fewer than 12 lymph nodes for pathological review, extension of tumor beyond the lymph node capsule, tumor deposits in pericolic fat not contiguous with the primary tumor and not associated with lymph nodes (Stage INc), and obstruction and/perforation secondary to the tumor.

Mucinous cell colorectal adenocarcinoma is characterized by more than 50% of the extracellular mucin and accounts for 10 to 20% of patients with colorectal cancer.: These patients having inferior  responses and shorter overall survival to chemotherapy based therapy and to anti EGFR therapy.

Tumor deposits are aggregates of tumor cells in the fat surrounding the bowel and is found in 20 to 25% of colon cancer patients: tumor deposits are an independent prognostic factor with a linear relationship between the number of tumor deposits and survival, and that prognostic accuracy is improved when tumor deposits and lymph node metastasis count are combined.

Increased adiposity is associated with increased colon-specific mortality.

Increased adiposity associated with worse disease free colon cancer survival among women.

Expression of adiponectin and adiponectin receptors are higher in colorectal carcinomas compared with normal colonic epithelium.

Over production of prostaglandin E2 linked to the development of colorectal cancer.

COX-2 important in carcinogenesis during transition from adenoma to malignancy and during invasion and metastasis.

COX-2 enzyme overexpressed in approximately 90% of patients and 40-90% of colon adenomas.

Coloeectal cancers exhibit a high level of cyclooxygenase-2 (COX-2) expression.

Fewer than 40% of cases are diagnosed early i.e. stages 0 to 1.

Approximately 56% of colorectal cancer patients present with locoregional and distant metastases.

Most common sites of metastases include the liver, lungs, retroperitoneal lymph nodes, peritoneum and bones.

The peritoneum is the initial site of failure in 10 to 20% of patients after curative resection and is involved in 40 to 70% of patients who present with advanced disease.

Hyperthermic chemotherapy is not effective for patients with primary peritoneal metastases (PRODIGE 7 trial).

In 5 to 8% of all patients with colon cancer and 10 to 35% will patients with recurrent disease, tumor recurrences are confined to the peritoneal surface only.

Patients with peritoneal carcinomatosis have a dismal median survival of 5 to 9 months and is considered equivalent to distant metastases.

Most important prognostic factor is the presence of lymph node metastases.

Recurrence rates increases from approximately 25% in patients with negative lymph nodes, pNo, to approximately 50% in patients with 4 or more lymph nodes with metastases (Wited).

Metastatic nodules in the pericolic or perirectal fat are considered lymph nodes metastases and should be included in N staging.

The removal and examination of fewer than 10 lymph nodes is considered an indication for postoperative adjuvant chemotherapy.

Studies demonstrate better survival for patients with more lymph nodes evaluated.

Advocated that surgical evaluation of 12 or more nodes acceptable for staging newly diagnosed colon cancer patient.

Improved survival in patients with higher number of lymph nodes examined is not due to diagnostic upstaging and remains unexplained.

Proportion of patients with lymph nodes metastases at the time of resection of the primary disease is 40-42%.

The greater the number of nodes examined is associated with a reduced 5-year hazard of death for both node negative and node positive cancers, and the protective association is more pronounced in node negative patients (Parsons HM et al).

Isolated nodal recurrences is uncommon in colorectal cancer.

Trend in increases in lymph node evaluation has not increased the population of node positivity (Parsons H et al).

Lymph node assessment is necessary to accurately stage disease and to provide maximal therapeutic benefit.

Approximately 40% of patients present with advanced local disease, stage III, which has a 5-year survival of BRAF mutation associated with poor prognosis.

BRAF mutations are present in 7% of metastatic colorectal cancers.

A study describing the prognostic impact of the SN-procedure in colon carcinoma after 5-year-follow-up: Only one patient had recurrent disease after a negative SN procedure with a disease-free-survival 96%, indicating patients that are lymph node negative after an SN-procedure have an excellent prognosis and do not need adjuvant treatment.

In 2006 patients with stage III colon cancer treated with optimal surgery and FOLFOX have a 75% likelihood that they will be disease free at 3 years, and most will be cured, compared to prechemotherapy era when surgery alone was utilized and 50% of patients remained recurrence free at 3 years.

5-year survival for patients with Stage II disease is 75%, with roughly 20% developing surgical disease recurrence.

75% of cases are diagnosed in people older than 65 years and incidence rates among persons aged 65-84 years are six times as high as among younger people.

2.3-5.8% of cases below the age of 45 years.

In the MOSAIC trial, all patients with stage III who received FOLFOX4 showed significant gains of 7.5% in DFS at 5 years and 4.2% in overall survival at 6 years.

FOLFOXIRI/Bevacizumab in advanced colorectal cancer improved progressive progression free survival at nine months: 68% versus 56% compared with FOLFOX/bevacizumab.

In the above study median progression free survival of what is 12 months and 10 months, respectively, representing a 20% reduction in risk with FOFOXIRI.

Approximately one third of newly diagnosed patients with colorectal cancer will die within five years because of cancer-related problems.

Overall survival for metastatic disease has increased from 6 months with supportive care to within range of 24 months with biologic and cytotoxic therapy.

Overall survival of metastatic colorectal cancer with modern therapy has reached 29 months of average (Venook A).

Right sided lesions associated with a greater delay in diagnosis, poorer prognosis, and poor response to EGFR receptor antibody treatment.

A range from 6 to more than 15 lymph nodes are needed for optimal staging.

The number of lymph nodes removed during surgery can affect patient survival with improved prognosis with removal of more nodes.

A study with 3200 patients with stage II disease treated with surgery and who had removal of more than 20 lymph nodes had a 14% 5-year survival advantage compared to those patients with removal of fewer than 11 lymph nodes, and a survival advantage in stage III disease of 23% if more than 40 lymph nodes were removed compared with 11 lymph nodes.

Stage I and Stage II tumors are curable by surgical excision and up to 73% of cases of Stage III disease are curable by surgery combined with adjuvant chemotherapy.

QUASAR trial involving 3,239 patients with predominantly stage II colon or rectal cancer treated with adjuvant 5FU/LR compared to surgery alone resulted in an absolute 3-4% survival benefit.

MOSIAC trial-the Multicenter Internaional Study of Oxaliplatin/5 Fluoracil/Leucovorin on the Adjuvant Treatment of Colon Cancer included 2,246 patients showed the addition of oxaliplatin to fluoracil/leucovorin regimen improved 5 year disease free survival from 67.4% to 73.3% and improved 6 year overall survival rates from 76%to 78.5%.

5-year survival rate of patients with Stage IIIB colon cancer treated with surgery and adjuvant chemotherapy is approximately 69% (ACS).

Stage IIA cancer has a 5-year survival rate of 89% while stage IIB has a 5 year survival rate 63%, and stage IIIA 89%.

NSABP C-07 Trial-2407 patients compared adjuvant oxaliplatin, fluoracil, and leucovorin against fluoracil and leucovorin:triple therapy improved 3 year disease free survival from 71.8% to 76.11% and an improvement in 4 year disease free survival from 67% to 73.2%.

Oncotype DX colon cancer assay is a valid indepenednet predictor od individualized recurrence risk for stage II colon cancer

Surgery alone is usually curative for stage II colon cancer but approximately 20-30% of patients will recur and ultimately died of metastatic disease: Stage II patients are a heterogeneous group with five-year overall survival rates ranging from 84.7% for stage IIA to 72.2% with stage IIB (Burke HB).

Clinical risk factors for stage II are T4 tumors the presence of venous or lymphatic invasion, presence of obstruction, perforation, poor differentiation and less than 10 lymph nodes examined are associated with higher risk of recurrence.

The risk of local-regional recurrence for patients with tumor adherence to surrounding tissues or with regional nodal involvement is greater than 30% when treated with surgery alone.

At the time of diagnosis approximately 20-30% of all cases are diagnosed as Stage Dukes D.

Liver is the most common site of metastases.

Prognosis with liver metastases without treatment associated with a median survival of 5-13 months.

Median survival with metastatic disease now 20-24 months, and in patients with liver only metastatic disease there is a 30-50% chance of surviving for 5 or more years after the initial diagnosis (Day).

Five year survival decreases from stage I to IV, with 93% among stage I patients and 8% in stage IV disease (O’Connell JB et al).

Five year survival for patients with liver only metastases 51-58% in recent series.

Stage I and II disease have 93% and 83% 5 year survival rates, respectively, but account for only 40% of patients.

Resection of hepatic disease vs. non resection in a series of 252 patients resulted in a 5 year survival rate of 25% vs., 2% , respectively (Wagner).

In well selected patients with colon cancer 17-25% of patients my achieve cure after hepatic resection of metastases (Tomlinson).

Phase III studies reveals that with irinotecan +fluorouracil/LR (FOLIRI) or oxaliplatin + fluorouracil/LR (FOLFOX6) the median survival is 21.5 and 20.6 months, respectively.

Long term survival with liver metastases is poor with less than 5% of patients surviving longer than 5 years.

Higher vitamin D levels associated with better survival in metastatic colorectal cancer.

Women who consume higher levels of vitamin D – particularly from dietary sources – have a reduced risk of developing early-onset colorectal cancer, compared with those who have lower levels.


Mutational changes occur by chromosomal instability accounting for 85% of colorectal cancers.

Chromosomal instability causes changes in chromoso A repository of information on disease and medical conditions | Standard of Care mal copy number number and structure.

Chromosomal instability causes a physical loss of a wild type copy of a tumor suppressor gene, such as APC P53, ans SMAD family member 4 (Kinzler KW, Grady WM, Fearon ER).

In colorectal cancer inactivation of genes that normally function to maintain chromosomal stability during replication and account for most of chromosomal instability (Barber TD).

Amplification of gene copy number or gene rearrangement not involved in colorectal cancer causation.

Most common genomic instability in colorectal cancer is chromosomal instability.

Chromosomal instability is found in 65-70% of sporadic colorectal cancers and is associated with accelerated rate of gains or loses of large portions of whole chromosomes. I

Microsatellite instability also called replication error accounts for 15% of colorectal cancers.

Microsatellite instability (MSI) associated with a significant survival advantage independent of other prognostic factors, including tumor stage and is less likely to metastasize to regional nodes or distant organs.

Data suggests that mismatch repair deficiency, which is synonymous with microsatellite instability, have a poorer survival in patients receiving adjuvant 5FU among patients undergoing surgery alone.

When MSI is high and mismatch repair is deficient the expected 5-year survival in colorectal cancer is 90% vs less than 75% for a microsatellite stable profile.

Preoperative nivolumab plus ipilimumab appears safe and feasible for patients with early-stage colon cancer with mismatch repair-deficient (dMMR) tumors and in patients with MMR-proficient (pMMR) tumors. 

The combination produced produced pathological responses in 100% of patients with mismatch repair-deficient (dMMR) tumors and in 27% of patients with MMR-proficient (pMMR) tumors. 

This treatment is both safe and feasible, with few treatment-related AEs and without compromising surgery.

Among patients with dMMR tumors, pathological responses occurred in 100%, major pathological occurred in 95% and complete responses occurred in 60%.

Among patients with pMMR tumors, 27% had a pathological response, 20% had a major pathological response, and 7% had a partial response.

MSI tumors are frequently poorly differentiated, mucinous, diploid, located in the right colon, and have a large peritumoral lymphocytic infiltration, assoicated with a large primary lesion, and usually present with an eraly staged-disease, with a good prognosis.

The frequency of MSI is higher in early stage diseae than in later stage disease.

Patients whose tumors have high frequency MSI, that his lack or are deficient of MMR proteins, have better prognoses regardless of tumor stage.

Patients with low frequency MSI or tumors with microsatellite stability have poor prognoses and higher risk for recurrence.

Patients with deficient MMR and hgh MSI are not responsive to conventional chemotherapy.

MSI associated colon cancers do not show significant karyotypic abnormalities and are often diploid or nearly so.

Chromosomal instability associated cancers, in contrast to MSI associated cancers, are aneuploid and do not show instability at the nucleotide level.

Most colorectal cancers have chromosomal instability rather than MSI.

5-year survival with localized disease approximately 90%.

5-year survival for regional spread approximately 60%.

5-year survival for metastatic spread approximately 10%.

In a study of 140 patients who underwent curative surgery tumor cells using immunochemistry or cytological studies were revealed to be present in the peritoneal cavity in 22%, bone marrow in 64%: indicating nearly 2/3 of patients had tumor cells left in the body after curative surgery, but the presence of minimal residual disease had no independent prognostic significance in relation to established risk factors for tumor progression (Steinert).

Incidence and mortality declined substantially during the past 2 decades.

64% of recurrences detected first by CEA testing.

Approximately 70% of colorectal tumors consist largely of CEA negative cell lines, and they are documented to have scarce or no CEA secretion (CEA negative tumors constitute 49 to 75% of colorectal cancers).

In patients with negative baseline CEA, serum CEA is insufficiently sensitive in recurrence surveillance after treatment to improve oncologic outcomes.

First degree relatives have a two-to fourfold increased risk over the general population.

Individuals with two or more relatives with colorectal cancer have a three-to six-fold risk over the general population.

Serrated pathways are more prevalent in right sided lesions where BRAF mutations develop and CpG island hypermethylation occurs.

The conventional pathway, where mutations in KRAS, TP53, and APC occur most, is a left-sided phenomenon.

About 88% of cells of epithelial origin in colon cancers, and about 50% of the colon crypts in the epithelium within 10 cm adjacent to cancers  have reduced or absent expression of PMS2.

Patients with right-sided tend to be older and female, and to have tumors with BRAF,P1K3A and KRAS mutations, and have tumors classified as having microsatellite instability (MSI-H).

BRAF mutations may be associated with deficient MMR.

Patients with left-sided tumors are usually younger, have KRAS and NRAS wild type disease, and demonstrate amplification in epidermal growth factor receptor (EGFR) and HER2 as well as high EGFR ligand expression.

HER2 testing is reserved for individuals who have RAS wild-type tumors.

HER2 amplification is associated with up to 10% of cases involving the left sided colon and rectal primaries with RAS/RAF wild type disease.

HER2 amplification associated with complex, signaling cascade downstream with activation of MAP kinase, PI3K/mTOR and STAT3, reactivation pathways, leading to cell growth, proliferation, tumor, angiogenesis, and metastatic spread.

HER2 amplification has resistance to anti-EGFR inhibitors and decreased survival in patients were with HER2 positive of disease exposed to cetuximab or panitumumab.

The incidence of HER2 amplification is between 3.3 and 5% in metastatic CRC, and increases up to 10% in those with left-sided colon and rectal primaries with RAS/RAF wild type disease.

HER2 amplification is associated with signaling cascade down stream with activation of MAP Kinase, PI3K/mTOR and STAT3 pathways.

HER2 amplification confers resistance to anti-EGFR inhibitors, and inferior outcomes in patients exposed to cetuximab or panitumumab.

The impact of side is clear in metastatic disease with a worse prognosis for right-sided lesions, but is not the case for early disease.

The left side of the colon comes from the hindgut, whereas the mid gut gives rise to the right-sided colon.

Trend toward increased incidence of right-sided tumors and decreased incidence of rectal tumors since 1980.

Right-sided tumors more likely to develop in patients with a genetic predisposition to colon cancer, including Lynch syndrome or microsatellite instability.

Colon cancer with BRAF mutations, which have a poor prognosis, are more likely to occur on the right side.

P53 protein expression correlated with survival and tumor of the distal colon and rectal areas.

Excess body composition and hormonal factors associated.

Weight gain in middle age resulting in abdominal obesity increases risk of colon adenomas and colorectal cancer.

Associated with abdominal obesity and hyperinsulinemia.

Markers of insulin resistance such as C-peptide and insulin like growth factor binding protein-1 (IGFBP1) are directly associated with colorectal cancer risk.

Mutation of ras oncogenes found in approximately 50% of colorectal cancers that leads to more aggressive biologic behavior of the tumors.

All patients should have KRAS codon 12 and 13 mutation tests done before the use of epidermal growth factor receptor inhibitors.

Colorectal tumors harbor KRAS and NRAS mutations at these codons and mutations tend to be mutually exclusive suggesting functional redundancy.

HER1/EGFR overexpressed in up to 85% of cases and linked to increased aggressiveness and poorer prognosis.

There is a potential negative interaction of the fluoropyrimidine drugs in the context of concomitant oxaliplatin therapy with EGFR monoclonal antibodies.

KRAS mutations circumvent effect of EGFR blockade.

In the presence of KRAS mutation patients should not receive EGFR inhibitors either alone or with chemotherapy.

Multiple trials demonstrate either no benefit or inferior outcome with the addition of EGFR-directed therapy in the approximately 40% of advanced colorectal cancers activating KRAS mutations.

Patients with KRAS mutations in exon 2 do not have a response to anti-EGFR therapy and they have inferior outcomes if this therapy is combined with oxaliplatin containing chemotherapy regimens.

KRAS G12C mutation lesions respond to targeted therapies such as Sotorasib and adagrasib.

CAIRO2 trial conducted in the Netherlands evaluated 775 untreated patients with metastatic colorectal cancer randomly treated with capecitabine, oxaliplatin and bevacizumab (COB) vs. COB plus Cetuximab (Erbitux) with survival as the end-point and KRAS mutation also evaluated: addition of cetuximab to COB decreases progression free survival from 10.7 months in the COB group to 9.4 months in the COB-C group, overall survival and response rates did not differ.

The addition of cetuximab to FOLFIRI chemotherapy as first-line therapy in metastatic colon cancer improves survival in patients with KRAS wild type disease (Van Cutsem et al).

The addition of cetuximab in patients with KRAS wild type disease to chemotherapy resulted in significant improvements in overall survival with the median survival 23.5 versus 20 months, progression free survival median 9.9 versus 8.4 months and response rates of 57.3% versus 39.7% compared with FOLFIRI alone, confirming KRAS as a powerful biomarker predictor for cetuximab efficacy. (Van Cutsem E et al).

Presence of KRAS or NRAS predict for resistance to cetuximab and panitumumab for colrectal carcinoma.

CRYSTAL study -Cetuximab Combined with Irontecan in First-line Therapy for Metastatic Colorectal Cancer: addition of Cetuximab to FOLFIRI reduced risk of progression of metastatic colorectal cancer compared with chemotherapy alone.

In the CRYSTAL study objective response rate was 46%, median survival 19.6 months and median progression free survival 8.9 months in all patients, and a median overall survival of 23.5 months, with an objective response rate of 57%, and median progression free survival of 9.5 months in patients with KRAS wild type subpopulation.

The CRYSTAL study showed that with cetiximab with FOLFIRI patientS with left-sided cancers the survival was much better-28.7 months compared with 21 months with FOLFIRI alone..

Bevacizumab use in advanced colorectal cancer increases survival, its use with adjuvant chemotherapy treatment in colon cancer does not prevent recurrence of disease after surgery.

Bevacizumab added to first-line chemotherpay offers a modest clinical benefit.

Bevacizumab in combination with EGFR monoclonal antibodies in addition to chemotherapy is not recommended for colorectal cancer as it may have negative implications

Trials have established efficacy of the addition of bevacizumab to first line chemotherapy in metastatic colorectal cancer.

A meta-analysis of randomized control trials showed that the addition of bevacizumab to chemotherapy is associated with a higher incidence of treatment-related mortality than chemotherapy alone with hemorrhage, neutropenia, and GI perforation being the most common causes of fatality.

In randomized trials the benefits of bevacizumab is observed irrespective of KRAS mutational status.

CAIRO2 trial the addition of cetuximab to the COB regimen resulted in a significantly shorter progression free survival, particularly in patients with mutated KRAS tumors, but the addition of cetuximab did not improve outcome in the wild type KRAS tumors either.

Approximately 2-45% of colorectal cancer patients who undergo curative resection subsequently develop local tumor relapse or metastatic disease in lymph nodes, liver, lung and peritoneum.

Maintenance therapy is considered in patients who receive doublet or triplet chemotherapy in the first line setting; maintenance agents with bevicizumab plus capecitabine have similar or better outcomes with therapy as opposed to continuing aggressive first line therapy until unacceptable toxicity or disease progression (CAIRO study).

Lung metastases are the second most common site of metastases, occurring in 20-30% of colorectal cancer patients.

Liver metastases occur in about 60% of patients.

The liver is the most common site for metastases and is the cause of death in two thirds of patients.

About 30% of patients present with liver metastases, and 14.5% develop such lesions in the liver within 5 years of diagnosis.

Multidetector CT of the abdomen considered imaging modality of choice to detect liver metastases, while MRI best for problem solving in detection and characterization of small lesion in the liver.

PET and PET-CT scans are also sensitive to detecting liver metastases in colorectal cancer.

Ultrasound imaging of the liver may fail to detect up to 50% of liver lesions.

Sensitivity to detect liver metastases reduced by the presence of infiltration of fat into the liver.

Blacks are more likely to develop colorectal cancer, at a younger age, and more likely to die of colorectal cancer than are whites.

Black’s appear to have a more aggressive disease course and have a three fold increase risk of MSI-H tumors compared with European Americans.

Persons taking more than 2 tablets of aspirin per week for more than 20 years have half the relative risk of colon cancer, compared with those who took no aspirin.

Randomized trials of cardiovascular prevention with aspirin reduces the 20 year risk of colorectal cancer by 24% and of associated mortality by 35% (Rothwell PM et al).

US Preventative Services Task Force has concluded that aspirin reduces the risk of colorectal cancer by 40% and it should be prescribed routinely to patients with advanced colorectal polyps.

40-50% reduction in risk with use of nonsteroidal anti-inflammatory drugs (NSAIDs) suggesting mediation as inhibitors of cycloooxegenase-2 (COX-2) and prostaglandin production.

In metastatic cancer patients receiving indomethacin survive a median of 510 days compared to 250 days for patients receiving placebo.

Median survival with unresectable metastatic disease can now achieve a median survival of 18 months.

Patients with tumors that have lost 18q or lack protein expression have an inferior 5-year survival compared to those who retain both alleles.

Active drugs either in combination or as single agents include: 5FU/leucovorin, capecitabine, irnotecan, oxaliplatin, bevacizumab, cetuximab, panitumumab, ziv-aflibercept, ramucirumab, regorafenib, trifluridine-tipiracil, pembrolizumab and nivolumab.

Among patients with refractory metastatic, colorectal cancer, treatment with trfluridine-tipiracil and bevacizumab, resulted in longer overall survival than trifluridine-tipiracil alone(10.8 vs 7.3 months)(SUNLIGHT Study).

Patients with metastatic disease that receive combinations of therapy that include irinotecan or oxaliplatin plus 5FU/LV have a median overall survival of 21.5 months compared to 11-13 months with 5 FU monotherapy.

Combination and sequential treatment with fluoropyrimidines with irinotecan and oxaliplatin have approximately doubled expected median survival of patients with advanced disease compared with 5FU based therapy.

Three Regimens of Eloxatin Evaluation (TREE-2 study) evaluated the safety and efficacy of three oxaliplatin and fluoropyrimidine regimens, with or without bevacizumab in metastatic colorectal cancer-indicating that the addition of bevacizumab was well tolerated without markedly changing overall toxicity.

The TREE-2 study compared Oxaliplatin with fluoropyrimidine given as a continuous infusion, bolus or oral treatments with or without bevacizumab: overall response rates, time to progression and overall survival were improved over the same treatments without bevacizumab.

TREE-2 study revealed a median overall survival of previously untreated patients with metastatic colorectal cancer and oxaliplatin and fluoropyrimidine and bevacizumab to have a median overall survival of approximately 2 years.

OPTIMOX 2 study with FOLFOX (5FU, leucovorin, oxaliplatin) utilized treatment for 6 cycles for metastastic disease and then treatment was withdrawn to be restarted when progression occurred, and again discontinued when response occurred.

OPTIMOX 2 study revealed that a chemotherapy free period improved quality of life since patients were in remission and off chemotherapy.

OPTIMOX 2 study revealed a median chemotherapy free period of 4.6 months for all patients with 8 months for patients without adverse factors.

OPTIMOX 2 study revealed that the median progression free survival was higher for a continuously group on FOLFOX (OPTIMOX 1) at 38 months versus 30 months, but the duration of disease control was similar for both groups at 12-13 months.

OPTOMOX 2 study revealed a 30% inferior duration of disease control for patients with a chemotherapeutic break. You should

OPTIMOX approach stopping of stopping FOLFOX until regrowth of tumor is related with less neurotoxicity and the same efficacy compared to continuous therapy of FOLFOX.

FOLFOXIRI plus bevacizumab associated with a 4 month extended overall survival compared to FOLFIRI plus bevacizumab in metastatic colorectal cancer (TRIBE trial).

In the above study progression free survival for FOLFOXIRI plus bevacizumab was 12.3 months versus 9.7 months for the FOLFIRI plus bevacizumab regimen.

The TRIBE study show that the triple regimen of FOLFOXIRI plus Bevacizumab able to achieve progression free survival of approximately one year in patients with our RAS and BRAF mutations, who have a poor prognosis.

FOLFOXIRI: CPT-11 (150?mg?m?2) given on d1, Oxaliplatin (65?mg?m?2) on d2, LV (200?mg?m?2) on days 2 and 3 and 5-FU (400?mg?m?2 as i.v. bolus and 600?mg?m?2 as 22?h i.v. continuous infusion) on days 2 and 3.

XELOX (capecitabine plus oxaliplatin)vs, FOLFOX regimen essentially comparable PFS of 8 months and overall survival of 19 months, suggesting oral capecitabine is an appropriate alternative to IV 5FU for the first line treatment of metastatic colorectal carcinoma.

Irinotecan in patients failing 5FU by bolus increases median survival by 2-3 months in patients treated with best supportive care or 5FU by infusion.

Irinotecan plus 5FU/LR (IFL) as initial treatment for metastatic disease is twice as likely to decreased tumor size by 50% compared to 5FU/LR alone and extends median survival by about 2 months.

Median survival in clinical trials correlates with the percentage of patients who receive 5 FU, oxaliplatin and irinotecan in the course of their disease.

When patients receive 5 FU, oxaliplatin and irinotecan a median survival for metastatic disease of over 20 months can be expected.

Targeted agents directed against vascular disease growth factor (VEGF) pathway includE anti-VEGF monoclonal antibody Bevacizumab, both soluble VEGF decoy receptor aflibercept , and a multi-kinase inhibitor Regorafenib that targets tyrosine kinase receptors including the VEGF receptor.

Ramucirumab a monoclonal antibody targeting the VEGFR2 improves outcomes in metastatic colorectal cancer in combination with chemotherapy.

Regorafenib approved for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy.

Regorafenib, and its active metabolites, inhibit multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes, including those in the RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, Trk2A, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl pathways.

Regorafenib as a third line therapy demonstrated overall survival benefit compared to placebo, but it is largely attributed to durable stable disease rather than tumor response (CORRECT trial).

Ziv-afilbercept approved for use in combination with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) for the treatment of patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin containing regimen.

Ziv-aflibercept is a recombinant fusion protein consisting of vascular endothelial growth factor (VEGF)-binding portions from the extracellular domains of human VEGF receptors 1 and 2 that are fused to the Fc portion of the human IgG1 immunoglobulin.

In a retrospective analysis of 233 consecutive patients with metastatic colorectal cancer between 2000 and 2006 and did not undergo resection of the primary lesion and who were treated with standard chemotherapy 89% did not develop colon problems that required surgical care, 4% developed colon obstruction that was treated with stents or radiation rather than surgery, 7% required nonelective colon surgery for obstruction or perforation and 0.8 died from surgical intervention (Paty, P-ASCO 2009).

Postoperative radiation in patients with T4 non-metastatic colon cancer does not provide a survival advantage.

In a meta-analysis of 850 asymptomatic patients with stage IV colorectal cancer treated with primarily chemotherapy intestinal obstruction develop than 14% of patients and hemorrhage occurred in 3% (Scheer MG et al).

Up front surgery for patients with metastatic disease major disadvantage is delayed chemotherapy, was 12% of patients having major complications including up structuring, hemorrhage, infection and dehiscence (Scheer MG et al).

Resection of the primary tumor in the presence of metastases is not associated with an overall survival advantage and most patients can go to chemotherapy directly.

A clinical trial showed that in patients with colorectal cancer (CRC) and synchronous unresectable metastases, primary tumor resection followed by chemotherapy has no survival benefit over chemotherapy alone.

Among patients treated with curative surgery, intensive imaging or CEA screening each provided an increased rate of surgical treatment of recurrence with curative intent compared with minimal follow-up (Primrose JN et al).

In the above study no advantage occurred with combining of CEA and CT.

In the above study a survival advantage to any cancer surveillance strategy is small.

It is recommended that all patients who require a second line treatment undergogo molecular profiling for microsatellite instability and for alterations in genes including KRAS, BRAF, HER2 amplifications and NTRK fusions.

NTRK fusions are rare in colorectal cancer, less than 1%, and more common in right sided lesions, elderly females, and patients with nodal metastasis, conferring a poor prognosis.

NTRK fusion positive tumors respond to larootrectinib and entrectinib.

Approximately 50% of patients have our S/PREF wild type tumors.

Ramucirumab has been approved as second line treatment in combination with standard chemotherapy for metastatic colorectal cancer following progression on a first line bevacizumab contaniing regimen.

Microsatellite instability-high patients respond to nivolumab and pembrolizumab.

Patients with MSI-H phenotype or a dMMR immunohistochemistry seem to derive the most benefit from PD-1/PD-L1 inhibitors.

The addition of ipilmubab increases the response rate of nivolumab from 50% to 80% in miscrosatellite instability-high patients, and the combination is approved by FDA.

BEACON CRC : encorafenib, binimetinib/cetuximab – the BRAF/MEK combination significantly improved overall survival in patients with BRAF-mutated metastatic colon rectal cancer.

Concomitant use of PPIs with colorectal cancer treated with fluoropyrimidine based chemotherapy may be related to alterations in the gut microbiome altered immune milieu  within the tumor and interactions through transporters impairing survival.



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