Colorectal Cancer
by C. Andreadis, M.D., Medical Oncologist

Epidemiology

Colorectal cancer is one of the most common human malignancies. It is estimated to be the 3rd most frequently diagnosed cancer in men and the 2nd most common type of cancer in women. The lifetime risk of developing this disease is approximately 5%. Globally, more than 1,200,000 patients are diagnosed with colorectal cancer every year, while more than 600,000 deaths occur because of this disease.   

Colorectal cancer incidence and mortality rates vary worldwide. It is more frequent in Australia, N. Zealand, Europe and North America and less common in Africa and South and Central Asia. 

Colorectal cancer is rare (3%) before the age of 40. After the age of 40, the incidence increases respectively with every successive decade of life.

Colorectal cancer frequency is influenced by various socio-economic factors:

  • Poor socio-economic status has been related with an increase of up to 30% in the incidence rates of colorectal cancer
  • Lack of natural activity, unhealthy diet, smoking, obesity and absence of regular screening have been described as possible risk factors of colorectal cancer incidence rates increase.  

Colorectal cancer mortality rates show significant reduction during the last decades. This can be attributed to many factors, such as: the early detection and removal of polyps, the early diagnosis of colorectal tumors, and more drastic treatments applied both on the adjuvant therapy and on metastatic disease.

The 5-year survival rates of the patients, depending on the stage of the disease during diagnosis, can be observed in the Table 1:

 

Table 1. 5-year Survival according to the disease pathological stage

Stage

5-year survival (%)

1 (T1-2 N0)

93

2A (T3N0)

85

2B (T4N0)

72

3A (T1-2 N1)

83

3B (T3-4 N1)

64

3C (N2 disease)

44

 

Risk Factors

Many different risk factors (hereditary and environmental) contributing to the pathogenesis of colorectal cancer have been described.

Sporadic disease

In 70% of patients the disease is sporadic since there is not a family history. In this subgroup of patients colorectal cancer arises from adenomatous polyps that are transformed into dysplastic ones.

Polyps

The progression of polyps into colorectal cancer has been well studied and is considered a multi-stage process: initially mucosal cell hyperplasia takes place, followed by the transition to adenomatous and dysplastic polyps. Finally, malignant transformation and invasive neoplasia progressively occur.

The whole procedure from the previous to the next stage takes place under oncogene activation, tumor suppressor gene inactivation, and chromosomal deletion. Environmental and hereditary parameters can interfere with the beginning and the progression of the procedure.

The polyps rarely give symptoms (mainly bleeding). They are categorized as non-neoplastic and neoplastic. Their size ranges from some millimeters to some centimeters. Polyps larger than 1cm in diameter, with high-grade dysplasia and villous histology carry a greater risk of evolving into colorectal cancer; they should be removed, and the patients should be monitored regularly. The cancer incidence increases by 2.5-4.0 times for polyps of >1cm, and by 5.0-7.0 times, if more than one polyps coexist.

The polyps that are detected during colonoscopy ought to be excised and examined by a pathologist. There is up to 50% probability of more than one adenomatous polyp being found. 

Follow-up surveillance of patients with colon polyps varies from three to ten years and is dependent upon the following factors: the presence of a family history of cancer, the number of polyps that have been found, the size of the polyps and the polyps' histology.

In the case of multiple polyps located in the colon, the possibility of the existence of an intestinal polyposis syndrome should be taken into consideration.

 

Inherited disease

In a second subgroup of individuals that accounts for about 7-10% of the patients, the risk of developing colorectal cancer is directly associated with the presence of hereditary syndromes with or without colon polyp occurrence. The most common syndromes are listed in Table 2.

Familial adenomatous polyposis-FAP (Hereditary non-polyposis colorectal cancer-HNPCC).  The development of numerous (hundreds, even thousands) polyps in the colon is the typical manifestation of FAP syndrome. Gastric and ampullary polyps, desmoids tumors, osteomas, abnormal dentition, and abnormal retinal pigmentation can be found synchronously. Often, polyps develop from puberty. FAP is a hereditary syndrome, usually caused by mutations in the APC gene. If it is not diagnosed and treated accordingly, leads (by 100%) to invasive cancer. It is considered a rare syndrome, with a reported incidence that varies from one in 22,000 to one in 7,000 individuals. In 30% of the cases there is no a family history. First-degree relatives of patients with FAP, are advised to undertake colonoscopy from the age of 10-12. Treatment is total colectomy.

 

Table 2. Common Familial Colon cancer syndromes. Implicated genes and estimated risk

Syndrome

Distribution of polyps

Malignant potential

Age of 1st fecal occult blood test

Genes

FAPa

Colon

90%

Teens

APC

Lynch (HNPCCb)

Proximal colon

40-80%

Coloscopy from age of 20 y

MLH1, MSH2, MSH6, PMS2, EPCAM

Peutz-Jeghers

Stomach, small bowel, colon, ovary

39%

>45 y

STK11

Juvenile polyposis

Stomach, small bowel, colon

none

None

BMPR1A, SMAD4

a: FAP: Familial adenomatous polyposis
b. HNPCC: Hereditary nonpolyposis colorectal cancer

 

Lynch syndrome–LS (hereditary non-polyposis colorectal cancer-HNPCC). LS is a familial syndrome associated with high risk of colorectal cancer development (usually located in the right colon) and with other cancers at different parts of the body (endometrium, ovaries, bladder, ureter, stomach, biliary tree, pancreas).

LS is responsible for 3-5% of colorectal cancers. Mutations of the genes MLH1, MSH2, MSH6, PMS 1, PMS2, with subsequent loss of stability of the Mismatch Repair (MMR) system, form the biological basis of this syndrome. The role of the DNA MMR system is to maintain genomic integrity by correcting base substitution mismatches and small insertion-deletion mismatches that are generated by errors in base pairing during DNA replication.

About 7-10% of family members with LS were found to have >1 cancer during diagnosis (synchronous colorectal cancers). It is underlined that LS patients with a history of previous colon cancer have an increased chance of developing a new metachronous colorectal cancer. It has been observed that metachronous colorectal cancer was developed in 20-40% of LS patients with colorectal cancer that did not get a subtotal colectomy. The cumulative risk of metachronous colorectal cancer development to LS patients that underwent a partial resection for the first tumor was 16% in 10 years, 41% in 20 years and 62% in 30 years.  

Diagnosis of colorectal cancer at a younger age (<40 years) is a typical feature of the syndrome. The prognosis of colorectal cancer in patients with Lynch syndrome is better than in patients with sporadic cancer.

The clinical criteria (Modified Amsterdam and revised Bethesda Criteria) that are used for the identification of LS are outlined in table 3. A detailed family history of all neoplasms is required. A research for Lynch-related tumors is conducted in patients that satisfy the Bethesda criteria. The tumors are examined for MSI analysis with PCR, or/and loss of MMR proteins with IHC (MLH1, MSH2, MSH6, PMS2). If Immunohistochemistry (IHC) MMR protein expression is found normal, molecular genetic testing is not needed. In case of pathological expression of an MMR protein genetic germline testing is performed. When the test results are positive, proving the diagnosis of Lynch syndrome, the patients and their families ought to receive special counseling and therapeutic treatment.

Table 3. The Amsterdam II criteria and the revised Bethesda Guidelines

A. Amsterdam II clinical criteria for families with Lynch syndrome

  1. At least 3 relatives with an HNPCC-associated cancera (colorectal cancer, cancer of the endometrium,, small intestine, ureter or renal pelvis);
  2. Two or more successive generations affected; One or more relatives diagnosed before the age of 50 years;
  3. One should be a first-degree relative of the other two;
  4. FAP should be excluded in cases of colorectal carcinoma;
  5. Tumors should be verified by pathologic examination

a. Hereditary Nonpolyposis Colorectal Cancer (HNPCC)-related tumors include colorectal, endometrial, stomach, ovarian, pancreas, bladder, ureter and renal pelvis, biliary tract, brain (usually glioblastoma as seen in Turcot Syndrome), sebaceous gland adenomas and keratoacanthomas in Muir-Torre syndrome, and carcinoma of the small bowel.

B. The revised Bethesda Guidelines for testing colorectal tumors for microsatellite instability

  1. Colorectal cancer diagnosed under the age of 50 years.
  2. Presence of synchronous, metachronous colorectal, or other HNPCC associated Tumors, regardless of age.
  3. Colorectal cancer with the MSI-Hb histologyc diagnosed in a patient who is less than 60 years old.
  4. Colorectal cancer diagnosed with one or more first-degree relatives with an HNPCC-related tumor, with one of the cancers being diagnosed under the age of 50.
  5. Colorectal cancer diagnosed in two or more first or second degree relatives with HNPCC-related tumor, regardless of age.

b. MSI-H = high microsatellite instability (in tumors)
c. Presence of tumor infiltrating lymphocytes, Crohn's-like lymphocytic reaction, mucinous/signet ring differentiation, or medullary growth pattern.

There was no consensus on whether to include the age criteria in point (3) above; participants voted to keep age of 60 years in the guidelines.

 

Familial disease

In the third subgroup are patients diagnosed with colorectal cancer which have a positive family history of colorectal cancer, but without any evidence of hereditary disease. The reasons behind their disease are not well understood. Data from epidemiological studies report that having a first degree relative diagnosed with colorectal cancer increases the risk of developing colorectal cancer by 1.7 times compared to the corresponding risk of the general population.

 

Other risk factors contributing to the pathogenesis of colorectal cancer
  • Diet: Many studies have shown that an increased intake of fat and calories, and a low fiber (fruits, vegetables and grains) diet are related to a high risk of colorectal cancer. Increased consumption of red meat and excessive use of alcohol are important risk factors. On the other hand, increased absorption of calcium, vitamin D and regular aspirin use seem to decrease the probability of developing cancer. It is worth mentioning that there are several studies that do not confirm the above observations.
  • Inflammatory bowel disease: The risk of colorectal cancer is increased in patients with ulcerative colitis and Crohn's disease. Chronic inflammation is believed to promote carcinogenesis. Reactive oxygen and nitrogen species produced by inflammatory cells can affect the regulation of the genes that encode factors which prevent carcinogenesis, transcription factors or signaling proteins.
  • Ulcerative colitis: Ulcerative colitis is a proven risk factor for colorectal cancer development. About 1% of colorectal cancer patients have a history of ulcerative colitis. The risk of developing neoplasia depends upon the duration and the extent of the disease. A longer duration of colitis is associated with an increased risk of colorectal cancer, while it is relatively rare in individuals that have been suffering for less than 8 years from colitis. Patients with ulcerative colitis are recommended to undertake colonoscopy often (every 6 months) and sometimes, especially if they are considered to be at high risk, they should undergo a proctocolectomy when they have had the disease for a period of >8 years.
  • Crohn’s disease: Crohn’s disease is also related to an increased risk for colorectal cancer, but to a smaller degree than ulcerative colitis. With Crohn’s disease the risk increases by 1.5-2 times
  • Abdominal radiation: A history of abdominal radiation because of a previously diagnosed neoplasia (eg, prostate cancer, childhood malignancy), increases the risk of colorectal cancer.
  • Race: It is well known that African-Americans have higher colorectal cancer incidence and mortality rates than white Americans. This statistical variation led the American College of Gastroenterology and the American Society for Gastrointestinal Endoscopy to recommend the onset of colonoscopy screening in African Americans at the age of 45.
  • Other factors: In the literature there are many other conditions correlated with a small increased risk of colorectal cancer. Among these the most important are: renal transplantation, obesity, heavy alcohol use, acromegaly, tobacco smoking, diabetes mellitus, etc

 

Clinical Symptoms

The symptoms of colorectal tumors are mainly induced by the tumor’s growth in the intestinal tract, the tumor’s invasion into the surrounding tissues, and by (microscopic or excessive) blood loss. When metastases are present, symptoms from the affected organs are also added to the clinical presentation of the disease.

 

Local disease symptoms

Most common symptoms involving the colon are: abdominal pain (44%), changes in bowel habits (43%), hematochezia (loss of fresh blood from the colon) or melena (black tarry stools) (40%), fatigue (20%), anemia (11%), weight loss (6%).

The abdominal pain might be chronic or acute and can be attributed to intestinal luminal obstruction (ileus) or intestinal perforation and peritonitis. In these cases, the patient is urgently subjected to surgery, during which a tumor in the intestinal tract is discovered.

Changes in bowel habits are also frequent and may involve constipation (that did not exist before) or alternating constipation and diarrhea.

Hematochezia is another symptom of colon tumors. Iron deficiency anemia is caused by loss of small amounts of blood and it is more characteristic of tumors located in the right colon.

 

Metastatic disease symptoms

For about 20% of the patients, the diagnosis for colorectal cancer is concurrent with the presence of metastatic disease. Metastasis takes place through the lymphatic system, the blood vessels, by contiguous and transperitoneal routes.

The most common sites for metastatic spread are the lymph nodes, liver, lungs, and peritoneum. Uncommon sites are the bones and the brain.

Metastatic disease symptoms are dependent upon the location of the metastases: in case of liver metastases, a feeling of heaviness in the upper abdomen, pain in the right hypochondrium or jaundice (in advance disease) may occur. Common symptoms and signs of lung metastatic disease are cough, pleural effusion, while hemoptysis and dyspnea are rarer. In patients with peritoneal carcinomatosis abdominal pain and ascites may be present.

 

Diagnosis

Colorectal cancer is detected mainly during colonoscopy performed due to the presence of symptoms, or during routine screening.

Colonoscopy is the most appropriate examination for the diagnosis of colorectal cancer. Usually, the malignancy appears as a large irregular mass that originates from the mucosa. Sometimes the lesion may be flat or depressed. During colonoscopy biopsies are taken from the tumor, for the clarification of the histological classification. Rarely (about 5% of the cases) colonoscopy is unable to detect the tumor, due to poor bowel preparation, tortuous colon, bowel obstruction, etc. When the size of the tumor is very large and it is impossible to examine the colon beyond the tumor, a second colonoscopy post surgery is needed to view the entire colon and to exclude the presence of a second tumor or polyp.

Some other methods such as the air contrast barium enema and CT colonography, are used in more specific cases.

Digital rectal examination (DRE) also assists in the diagnosis of colorectal tumors. The DRE provides more information to the surgeon, such as the tumor’s size, its mobility etc. The CT scan, the magnetic resonance imaging (MRI) and the endoscopic ultrasound scan are also necessary for the staging of colorectal tumors. Imaging tests, such as CT or MRI scans of the abdomen and chest are required to exclude or to confirm metastatic disease. CT scan of brain or bone scanning are not mandatory and are conducted only in the presence of suspicious symptoms. PET scan is not considered as a routine examination during preoperative staging and is only necessary in specific cases.

 

Tumor markers

The tumor marker levels of CEA and Ca 19-9 are determined in all patients, although their diagnostic value is questionable. For this reason they are not recommended as a screening test. Nevertheless, CEA has a prognostic value since preoperative levels of CEA >5 ng/ml have been associated with a worse prognosis compared to normal levels. Preoperative increased CEA levels in IIB-stage patients constitute for many researchers a strong reason to recommend postoperative chemotherapy. Moreover, abnormally elevated CEA levels after surgery suggest incomplete resection of the tumor and residual disease which requires treatment.

It is possible that CEA can be also found increased in other pathological conditions, such as other diseases of the gastrointestinal tract (gastric ulcer, diverticulitis, liver diseases, obstructive pulmonary disease, diabetes mellitus, etc.)

CEA measurement is considered valuable in patient-monitoring post surgery and also in assessing the response to chemotherapy in patients with metastatic disease.

 

Staging

Two systems are used for the colorectal cancer staging: the ΤΝΜ system (preferred) and Astler-Coller modification of the Duke's.

The ΤΝΜ (Tumor-Node-Metastasis) system analyzes the degree of the primary tumor invasion, the number of the lymphnodes involved, and the presence or not of metastases.  

 

Table 4. Staging table by ΤΝΜ

Primary tumor (T)

TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ: intraepithelial or invasion of lamina propria

T1

Tumor invades submucosa

T2

Tumor invades muscularis propria

T3

Tumor invades through the muscularis propria into the pericolorectal tissues

T4a

Tumor penetrates to the surface of the visceral peritoneum

T4b

Tumor directly invades or is adherent to other organs or structures

Regional lymph nodes (N)

NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis in 1-3 regional lymph nodes

N1a

Metastasis in 1 regional lymph node

N1b

Metastasis in 2-3 regional lymph nodes

N1c

Tumor deposit(s) in the subserosa, mesentery, or nonperitonealized pericolic or perirectal tissues without regional nodal metastasis

N2

Metastasis in 4 or more lymph nodes

N2a

Metastasis in 4-6 regional lymph nodes

N2b

Metastasis in 7 or more regional lymph nodes

Distant metastasis (M)

M0

No distant metastasis

M1

Distant metastasis

M1a

Metastasis confined to 1 organ or site (eg, liver, lung, ovary, nonregional node)

M1b

Metastases in more than 1 organ/site or the peritoneum

 

Stage

T

N

M

Dukes

MAC

0

Tis

N0

M0

--

--

1

T1

N0

M0

A

A

 

T2

N0

M0

A

B1

2A

T3

N0

M0

B

B2

2B

T4a

N0

M0

B

B2

2C

T4b

N0

M0

B

B3

3A

T1-T2

N1/N1c

M0

C

C1

 

T1

N2a

M0

C

C1

3B

T3-T4a

N1/N1c

M0

C

C2

 

T2-T3

N2a

M0

C

C1/C2

 

T1-T2

N2b

M0

C

C1

3C

T4a

N2a

M0

C

C2

 

T3-T4a

N2b

M0

C

C2

 

T4b

N1-N2

M0

C

C3

4A

Any T

Any N

M1a

--

--

MAC: Modifided Astler-Coller
Τ4a: tumor penetrating the intestinal tract; T4b: tumor invading into the surrounding tissues.

 

Pathology

The vast majority of colorectal neoplasms are adenocarcinomas. According to the degree of tumor differentiation these are stratified as grade 1 (well differentiated), grade 2 (moderately differentiated), and grade 3 (poorly differentiated). Other, less common histological subtypes of colorectal carcinomas include squamous cell carcinoma, adenosquamous carcinoma, medullary carcinoma, undifferentiated carcinoma, etc. Some rare types of tumors are the malignant lymphoma, the Kaposi sarcoma and the carcinoid tumors.

According to their microscopical features, morphological subtypes of adenocarcinomas include the mucinus adenocarcinomas and the signet-ring cell carcinomas. These distinct histopathological types display differences in clinical features and survival outcomes. Mucinous adenocarcinomas have been found to correlate with more advanced stage lesions, with poorer pre- or post- operative chemotherapy outcomes. Moreover, signet-ring cell carcinomas have been associated with worse prognosis.

 

Treatment Strategies

Initial management of colorectal cancer involves the precise localization of the primary tumor, histological diagnosis (after performing endoscopy and taking a biopsy) and accurate staging. It is essential that the therapeutic strategy is determined by a multidisciplinary team of experts. All decisions should be undertaken through collaborative discussions at oncology board meetings.

It must be noted that 75-80% of the patients exhibit localized (tumor located only in the intestine) or regionally spread (in the lymph nodes) cancer. For these patients, surgical intervention is the cornerstone of curative therapy. The surgeon proceeds by fully removing the primary tumor, the surrounding lymph nodes and any adjacent lymph node and vascular pedicles. The technique differs according to the sites of the primary tumor or any other lesions in the intestinal tract (eg. right colectomy, extended right colectomy, transverse colectomy, left colectomy, sigmoid colectomy, subtotal and total colectomy).

 

Surgery

Surgical resection of the colon for cancer should achieve at least a 5cm margin of normal bowel on either side of the tumor. In the case of invasion of adjacent organs by the tumor, an extended en block resection is performed to avoid any residual disease. It is recommended that at least 12 regional lymph nodes should be removed and examined for accurate pathologic staging and prognosis. When incomplete lymphadenectomy (dissection of fewer than 12 lymph nodes) has taken place, adjuvant chemotherapy is required even if the lymph nodes are metastasis free.

In the case of localized rectal cancer, pre-operative concurrent chemo/radiotherapy is a common management strategy.  It is primarily advised for patients with T3 and T4 tumors (Table 4). Neoadjuvant chemoradiotherapy in this category of patients has been associated with lower rates of long term toxic effects, as well as a reduced percentage of local recurrence. Also, neoadjuvant chemoradiotherapy may be considered for patients of a smaller T stage, with suspected metastatic regional lymph nodes during screening tests.

Surgical treatment in rectal cancer initially aims towards the preservation of the sphincter. The success of this effort depends on the location of the tumor on the rectum and more importantly on the distance of the lesion from the sphincter. If the sphincter cannot be preserved, then a permanent colostomy is essential. In case of superficial malignant lesions on the rectum (low-risk T1 rectal cancer) transanal endoscopic microsurgery procedure is performed.

 

Laparoscopic surgery

Laparoscopic surgery for colorectal cancer is not a routine procedure. Up to date studies suggest that it should be performed safely only by experienced surgeons, in patients that have not undergone any laparatomy in the past and under specific circumstances. These include tumours not locally advanced and tumours that do not cause bowel obstruction or perforate the colon wall. When these circumstances are met, laparoscopic surgery presents no significant differences to open surgery in terms of complications or risk of future relapse.

 

Polypectomy

Colon polyp removal during endoscopy is a common procedure. Many studies have confirmed that colonoscopic removal of adenomatous polyps prevents death from colorectal cancer. In case of in situ carcinoma, polypectomy is considered adequate only when the resection margins are free from the presence of malignant cells. However, when poorly differentiated carcinoma, lymph node invasion, presence of cancer in the incision tumor margins and infiltration of muscularis propria are found, then endoscopic resection is insufficient therapeutic approach and there is need for a wider part of the bowel to be resected.

 

Adjuvant chemotherapy

Adjuvant chemotherapy is the chemotherapy administered after surgery. The aim of adjuvant chemotherapy is to eradicate any microscopic residual disease and to prevent micrometastases. In this manner, the risk of recurrence and distant metastases is lowered and survival is prolonged.

Adjuvant chemotherapy is administered to all stage 3 patients and in a subgroup of high risk stage 2 patients. However, it is not recommended for stage 1 disease.

For stage 2 disease, there is conflicting evidence from studies concerning the benefit of adjuvant chemotherapy. Many research trials have taken place in an effort to clarify low and high risk groups. Across the literature, clinical parameters and biological markers have been analyzed as predictive factors, determining which patients may be considered as high risk and will benefit from adjuvant chemotherapy. Some of these clinical features include: cases where fewer than 12 lymph nodes have been removed or examined, poorly differentiated tumors, lymphatic or neural invasion, bowel obstruction or perforation, large tumors (T4N0), tumor incision margins infiltrated by malignant cells. Many researchers also include elevated preoperative CEA levels (>5 ng/mL).  

In addition to the clinical parameters described above, recent studies have taken place to identify biological parameters predictive of clinical outcome to distinguish and determine high-risk patients that would benefit from adjuvant chemotherapy. Markers that have been investigated are the following: thymidylate synthetase (TS) overexpression, K-ras, BRAF, and p53 mutations, microsatellite instability (MSI)/deficient mismatch repair, hypermethylation affecting extracellular matrix pathway genes, gene expression arrays (ColoPrint, Oncotype DX Colon Cancer Assay, ColoGuideEx), as well as identification of circulating tumor cells by molecular methods. To date none of the above markers alone can be used to predict the benefit of adjuvant chemotherapy. The only exception is the presence of microsatellite instability (MSI) which has been correlated with a good prognosis and with chemoresistant tumors to fluoropyrimidines. Stage 2 patients with MSI-H do not benefit from adjuvant chemotherapy and chemotherapy does not recommended.

Many studies confirm that stage 3 patients benefit from adjuvant chemotherapy. Therefore, chemotherapy is highly recommended for these patients, as meta-analyses show a reduction of the risk of relapse by 30% and morbidity by 22-32%.  

It is advised that chemotherapy should initiate immediately after patient recovery but no longer than 2 months after surgery, for an approximate duration of 6 months. Delayed onset of chemotherapy may be detrimental on overall patient survival.  

The recommended regimen is FOLFOX or XELOX (Table 5) for six months. In cases of severe side effects the course of chemotherapy can be modified (eg. combination of 5-FU/LV or treatment with capecitabine alone). Targeted therapies [for Vascular Endothelial Growth Factor (VEGF) or Epidermal Growth Factor (EGFR)] are not administered, since in several randomized trials these agents failed to demonstrate any benefit in the adjuvant setting.

 

Metastatic disease

Patients with colorectal cancer may be diagnosed with synchronous (20%) or metachronous metastases (30%). Metastases may be singular or multiple and in an individual or numerous organs. The most common sites include the liver, lungs, lymph nodes and peritoneum.  

Patients with metastatic disease ought to be investigated extensively for the possibility of metastasectomy. Subjects that meet the criteria should undergo resection of metastatic lesions to increase survival. Liver metastasectomies have been most widely performed and have yielded a 5-year recurrence free survival rate of 20%. Resection of extrahepatic lesions is less frequent; however there is clear evidence that it benefits survival.

Usual chemotherapy regimens that are used for metastatic colorectal cancer are listed in summary in Table 5.

 

Table 5. Common regimen used for the treatment of metastatic colorectal cancer

Regimen*

Drugs

Schedule

FOLFIRI

Irinotecan
Leucovorin
Fluorouracil

Every two weeks

FOLFOX

Oxaliplatin
Leucovorin
Fluorouracil

Every two weeks

XELIRI

Irinotecan
Capecitabine

Every three weeks

XELOX

Oxaliplatin
Capecitabine

Every three weeks

IROX

Irinotecan
Oxaliplatin

Every three weeks

FOLFOXIRI

Irinotecan
Leucovorin
Fluorouracil
Oxaliplatin

Every two weeks

5FU/LV

Leucovorin
Fluorouracil

Weekly, or

every two weeks, or

every three weeks*

Capecitabine

Capecitabine

Every three weeks

* There are many variations of most regimens in terms of dose and schedule

 

A combination of the following targeted pharmacotherapy treatments with conventional chemotherapy presents the most novel advance in the management of metastatic colon cancer in the last few years:

Bevacizumab is a humanized monoclonal antibody which inhibits Vascular Endothelial Growth Factor-A (VEGF-A) that stimulates angiogenesis during carcinogenesis. Many randomized phase III trials and meta-analyses have shown that Bevacizumab enhances overall survival (HR = 0.84; CI: 0.77-0.91; P < 0.00001) and progression-free survival (PFS) (HR = 0.72; CI:0.66-0.78; P < 0.00001).

Cetuximab is an Epidermal Growth Factor Receptor (EGFR) inhibitor also used for the treatment of metastatic colorectal cancer. It is a chimeric (mouse/human) monoclonal antibody. Panitumab is a fully human monoclonal antibody specific to the EGFR. Anti-EGFR therapy has been found in many trials to be effective in patients with KRAS-wild type colorectal cancer when combined with chemotherapy (FOLFOX or FOLFIRI). Meta-analyses have indicated improvement of overall survival as well as of progression-free survival rate, when this is added to first-, second- or third line chemotherapy regimens. KRAS and NRAS mutations screening is essential before the treatment with anti-EGFR therapy, since anti-EGFR antibodies are not administered to KRAS or NRAS mutated colorectal cancer patients.

Afilbercept, a fusion protein, is an inhibitor of Vascular Endothelial Growth Factor (VEGF), in combination with FOLFIRI as second line therapy, in a clinical phase III trial was proved to benefit overall survival and progression-free survival.

Regorafenib, an oral multi-kinase inhibitor (for VEGFR1, VEGFR2, VEGFR3, PDGFRβ, Kit, RET and Raf-1), was found in a recent randomized phase III trial to statistically increase overall survival as well as progression-free survival.

 

Common chemotherapy toxicities (side-effects) of anticancer therapy

Specific side-effects correlate with different chemotherapy schemes. Usual toxicities include:

  1. Hematological (leucopenia, anaemia, febrile neutropenia, thrombocytopenia, bone marrow suppression fever),
  2. Gastrointestinal (nausea, vomiting, diarrhea, constipation, dry mouth, stomatitis),
  3. Cardiovascular (angina, ischemic cardiac disease, arrhythmias, thromboembolic disorders, arterial hypertension, syncope),
  4. Neurological (neuritis, numbness, tinnitus, headaches, sleep disorders),
  5. Dermatological (hand-foot syndrome that include pain, tenderness, redness, swelling, blistering, or peeling skin on hands or feet, acne rash, alopecia, itch),
  6. Others  (anorexia, fatigue, fever, swallowing difficulty, visual disturbance, muscular pain, laryngeal spasm)

 

Screening methods for colorectal cancer

During screening, the following tests are administered:

  1. Guaiac-based fecal occult blood test (gFOBT) and fecal immunochemical test (FIT). gFOBT is a cost-effective and easy analysis. However, it has a large percentage of false positive results. Polyps do not affect this test. On the contrary, FIT is more expensive, but with a greater sensitivity and a smaller percentage of false positive and negative results. These tests are recommended annually.
  2. Sigmoidoscopic examination. In a large study, it was shown that sigmoidoscopy with a flexible sigmoidoscope every 3 to 5 years can reduce the incidence of colorectal cancer (in both the distal and the proximal colon) as well as the mortality rate (in the distal colon only). The above finding has also been confirmed by a number of meta-analyses. Therefore, many medical associations (National Cancer Institute, the American College of Surgeons, American Cancer Society, etc) advise the performance of sigmoidoscopic examination every 3-5 years in all asymptomatic individuals aged over fifty.
  3. Colonoscopy. This test offers the advantage of fully examining the colon, as well as of removing any adenomatous polyps. One drawback is the long bowel preparation that is required and the need for rehydration. It is suggested that this examination is repeated every 10 years after the age of fifty.
  4. CT colonography has a similar sensitivity to optical colonoscopy, but also requires a long bowel preparation. In case of pathological findings, colonoscopy needs to be performed. One of the disadvantages is the radiation that is omitted.
  5. Double-contrast barium enema. This test is usually performed in cases where it is difficult or impossible to conduct colonoscopy. One limitation is the lack of ability to locate half of the polyps sized>1cm. For this reason, its use has been dramatically reduced.
  6. Digital examination. It has no proven benefit and is not recommended, given that all previous screening methods also examine the rectum.

Screening is not recommended for people >75 years old.

 

Prevention

In order to prevent and diagnose colorectal cancer early, each individual’s personal data is assessed in order to estimate the risk of development. Prevention is achieved through the screening tests that were described above. Endoscopy allows polyp removal and thus, reduces the incidence frequency of colorectal cancer.

In high-risk persons (those suffering from FAP, Lynch syndrome, inflammatory bowel disease) colonoscopy and all other screening tests should be initiated at a younger age.

Diet rich in fiber, calcium and poor in fat has been found to prevent the conversion of polyps to malignant cancer.

Several epidemiological studies have shown that aspirin (at a 325mg dosage) reduces the formation, the size and the number of polyps. It also seems to minimize the frequency of colorectal cancer.

Other elements with potential beneficial effect in colorectal cancer prevention are folic acid, folate, Vitamin B6 (pyridoxine), magnesium, garlic, fish consumption, antioxidants, etc.

 

Summary

  • Colorectal cancer is one of the most common human malignancies. It is estimated that it is the third most frequently diagnosed cancer in men and the second most common type of cancer in women. The lifetime risk of developing this disease is approximately 5%.
  • Colorectal cancer mortality rates show significant reduction during the last decades.
  • Colorectal cancer frequency is influenced by various socio-economic factors. Many different risk factors (hereditary and environmental) contributing to the pathogenesis of colorectal cancer have been described.
  • The symptoms of colorectal tumors are mainly induced by the tumor’s growth in the intestinal tract, the tumor’s invasion into the surrounding tissues, by (microscopic or excessive) blood loss and from the affected organs in case of metastatic disease.
  • Colorectal cancer is detected mainly during colonoscopy performed due to the presence of symptoms, or during routine screening. During colonoscopy biopsies are taken from the tumor, for the clarification of the histological classification.
  • The vast majority of colorectal neoplasms are adenocarcinomas.
  • The tumor markers CEA and Ca 19-9 are determined in all patients, although their diagnostic value is questionable. They are not recommended as a screening test. Nevertheless, pre-treatment CEA level has a prognostic value. CEA measurement is considered valuable in patient-monitoring post surgery and also in assessing the response to chemotherapy in patients with metastatic disease.
  • Surgical intervention is the cornerstone of curative therapy for patients with locoregional disease. Adjuvant chemotherapy is given in almost all stage 3 patients and in a high-risk subgroup of stage 2 patients. Stage 2 patients with MSI-H do not benefit from adjuvant chemotherapy and chemotherapy does not recommended.
  • In the case of localized rectal cancer, pre-operative concurrent chemo/radiotherapy is a common management strategy. It is primarily advised for patients with T3 and T4 tumors.
  • Chemotherapy is the appropriate therapeutic approach for patients with metastatic disease. A combination of conventional chemotherapy with modern targeted pharmacotherapy treatments seems to be more effective. All patients ought to be investigated extensively for the possibility of metastasectomy. Subjects that meet the criteria should undergo resection of metastatic lesions to increase survival.

 

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