Colon Cancer

Colorectal cancer, also called colon cancer or large bowel cancer, includes cancerous growths in the colon, rectum and appendix. It is the third most common form of cancer and the second leading cause of cancer-related death in the Western world. Colorectal cancer causes 655,000 deaths worldwide per year, including about 16,000 in the UK, where it is the second most common site (after lung) to cause cancer death. Many colorectal cancers are thought to arise from adenomatous polyps in the colon. These mushroom-like growths are usually benign, but some may develop into cancer over time. The majority of the time, the diagnosis of localized colon cancer is through colonoscopy. Therapy is usually through surgery, which in many cases is followed by chemotherapy.



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The first symptoms of colon cancer are usually vague, like weight loss and fatigue (tiredness). Local (bowel) symptoms are rare until the tumor has grown to a large size. Generally, the nearer the tumor is to the anus, the more bowel symptoms there will be.



Symptoms and signs are divided into local, constitutional and metastatic.

Local symptoms

* Change in bowel habits
o Change in frequency (constipation and/or diarrhea),
o Feeling of incomplete defecation (tenesmus) and reduction in diameter of stool, both characteristic of rectal cancer,
o Change in the appearance of stools :
+ Bloody stools or rectal bleeding
+ Stools with mucus
+ Black, tar-like stool (melena), more likely related to upper gastrointestinal eg stomach or duodenal disease
* Bowel obstruction causing bowel pain, bloating and vomiting of stool-like material.
* A tumor in the abdomen, felt by patients or their doctors.
* Symptoms related to invasion by the cancer of the bladder causing hematuria (blood in the urine) or pneumaturia (air in the urine), or invasion of the vagina causing smelly vaginal discharge. These are late events, indicative of a large tumor.

Constitutional (systemic) symptoms

* Unexplained weight loss, probably the most common symptom, caused by lack of appetite
* Anemia, causing dizziness, fatigue and palpitations. Clinically, there will be pallor and blood tests will confirm the low hemoglobin level.


Metastatic symptoms

* Liver metastases, causing :
o Jaundice.
o Pain in the abdomen, more often the upper part (epigastrium or right side of the abdomen
o liver enlargement, usually felt by a doctor.
* Blood clots in the veins and arteries, a paraneoplastic syndrome related to hypercoagulability of the blood (the blood is "thickened")

Risk factors
The lifetime risk of developing colon cancer in the United States is about 7%. Certain factors increase a person's risk of developing the disease. These include:

* Age. The risk of developing colorectal cancer increases with age. Most cases occur in the 60s and 70s, while cases before age 50 are uncommon unless a family history of early colon cancer is present.
* Polyps of the colon, particularly adenomatous polyps, are a risk factor for colon cancer. The removal of colon polyps at the time of colonoscopy reduces the subsequent risk of colon cancer.
* History of cancer. Individuals who have previously been diagnosed and treated for colon cancer are at risk for developing colon cancer in the future. Women who have had cancer of the ovary, uterus, or breast are at higher risk of developing colorectal cancer.
* Heredity:
o Family history of colon cancer, especially in a close relative before the age of 55 or multiple relatives
o Familial adenomatous polyposis (FAP) carries a near 100% risk of developing colorectal cancer by the age of 40 if untreated
o Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome
* Long-standing ulcerative colitis or Crohn's disease of the colon, approximately 30% after 25 years if the entire colon is involved
* Smoking. Smokers are more likely to die of colorectal cancer than non-smokers. An American Cancer Society study found that "Women who smoked were more than 40% more likely to die from colorectal cancer than women who never had smoked. Male smokers had more than a 30% increase in risk of dying from the disease compared to men who never had smoked."
* Diet. Studies show that a diet high in red meat and low in fresh fruit, vegetables, poultry and fish increases the risk of colorectal cancer. In June 2005, a study by the European Prospective Investigation into Cancer and Nutrition suggested that diets high in red and processed meat, as well as those low in fiber, are associated with an increased risk of colorectal cancer. Individuals who frequently eat fish showed a decreased risk.However, other studies have cast doubt on the claim that diets high in fiber decrease the risk of colorectal cancer; rather, low-fiber diet was associated with other risk factors, leading to confounding. The nature of the relationship between dietary fiber and risk of colorectal cancer remains controversial.
* Physical inactivity. People who are physically active are at lower risk of developing colorectal cancer.
* Virus. Exposure to some viruses (such as particular strains of human papilloma virus) may be associated with colorectal cancer.
* Alcohol. See the subsection below.
* Primary sclerosing cholangitis offers a risk independent to ulcerative colitis
* Low selenium.
* Inflammatory Bowel Disease. About one percent of colorectal cancer patients have a history of chronic ulcerative colitis. The risk of developing colorectal cancer varies inversely with the age of onset of the colitis and directly with the extent of colonic involvement and the duration of active disease. Patients with colorectal Crohn's disease have a more than average risk of colorectal cancer, but less than that of patients with ulcerative colitis.
* Environmental Factors. Industrialized countries are at a relatively increased risk compared to less developed countries or countries that traditionally had high-fiber/low-fat diets. Studies of migrant populations have revealed a role for environmental factors, particularly dietary, in the etiology of colorectal cancers. Genetic factors and inflammatory bowel disease also place certain individuals at increased risk.
* Exogenous Hormones. The differences in the time trends in colorectal cancer in males and females could be explained by cohort effects in exposure to some sex-specific risk factor; one possibility that has been suggested is exposure to estrogens . There is, however, little evidence of an influence of endogenous hormones on the risk of colorectal cancer. In contrast,there is evidence that exogenous estrogens such as hormone replacement therapy (HRT), tamoxifen, or oral contraceptives might be associated with colorectal tumors.


Alcohol

The WCRF panel report Food, Nutrition, Physical Activity and the Prevention of Cancer: a Global Perspective finds the evidence "convincing" that alcoholic drinks increase the risk of colorectal cancer in men.

The NIAAA reports that: "Epidemiologic studies have found a small but consistent dose-dependent association between alcohol consumption and colorectal cancer even when controlling for fiber and other dietary factors. Despite the large number of studies, however, causality cannot be determined from the available data."

"Heavy alcohol use may also increase the risk of colorectal cancer" (NCI). One study found that "People who drink more than 30 grams of alcohol per day (and especially those who drink more than 45 grams per day) appear to have a slightly higher risk for colorectal cancer." Another found that "The consumption of one or more alcoholic beverages a day at baseline was associated with approximately a 70% greater risk of colon cancer."

One study found that "While there was a more than twofold increased risk of significant colorectal neoplasia in people who drink spirits and beer, people who drank wine had a lower risk. In our sample, people who drank more than eight servings of beer or spirits per week had at least a one in five chance of having significant colorectal neoplasia detected by screening colonoscopy.".

Other research suggests that "to minimize your risk of developing colorectal cancer, it's best to drink in moderation"

On its colorectal cancer page, the National Cancer Institute does not list alcohol as a risk factor: however, on another page it states, "Heavy alcohol use may also increase the risk of colorectal cancer"

Drinking may be a cause of earlier onset of colorectal cancer.

Treatment

The treatment depends on the staging of the cancer. When colorectal cancer is caught at early stages (with little spread) it can be curable. However when it is detected at later stages (when distant metastases are present) it is less likely to be curable.

Surgery remains the primary treatment while chemotherapy and/or radiotherapy may be recommended depending on the individual patient's staging and other medical factors.


Surgery

Surgeries can be categorised into curative, palliative, bypass, fecal diversion, or open-and-close.

Curative Surgical treatment can be offered if the tumor is localized.

* Very early cancer that develops within a polyp can often be cured by removing the polyp (i.e., polypectomy) at the time of colonoscopy.
* In colon cancer, a more advanced tumor typically requires surgical removal of the section of colon containing the tumor with sufficient margins, and radical en-bloc resection of mesentery and lymph nodes to reduce local recurrence (i.e., colectomy). If possible, the remaining parts of colon are anastomosed together to create a functioning colon. In cases when anastomosis is not possible, a stoma (artificial orifice) is created.
* Curative surgery on rectal cancer includes total mesorectal excision (lower anterior resection) or abdominoperineal excision.

In case of multiple metastases, palliative (non curative) resection of the primary tumor is still offered in order to reduce further morbidity caused by tumor bleeding, invasion, and its catabolic effect. Surgical removal of isolated liver metastases is, however, common and may be curative in selected patients; improved chemotherapy has increased the number of patients who are offered surgical removal of isolated liver metastases.

If the tumor invaded into adjacent vital structures which makes excision technically difficult, the surgeons may prefer to bypass the tumor (ileotransverse bypass) or to do a proximal fecal diversion through a stoma.

The worst case would be an open-and-close surgery, when surgeons find the tumor unresectable and the small bowel involved; any more procedures would do more harm than good to the patient. This is uncommon with the advent of laparoscopy and better radiological imaging. Most of these cases formerly subjected to "open and close" procedures are now diagnosed in advance and surgery avoided.

Laparoscopic-assisted colectomy is a minimally-invasive technique that can reduce the size of the incision and may reduce post-operative pain.

As with any surgical procedure, colorectal surgery may result in complications including

* wound infection, Dehiscence (bursting of wound) or hernia
* anastomosis breakdown, leading to abscess or fistula formation, and/or peritonitis
* bleeding with or without hematoma formation
* adhesions resulting in bowel obstruction (especially small bowel)
* adjacent organ injury; most commonly to the small intestine, ureters, spleen, or bladder
* Cardiorespiratory complications such as myocardial infarction, pneumonia, arrythmia, pulmonary embolism etc

Chemotherapy

Chemotherapy is used to reduce the likelihood of metastasis developing, shrink tumor size, or slow tumor growth. Chemotherapy is often applied after surgery (adjuvant), before surgery (neo-adjuvant), or as the primary therapy (palliative). The treatments listed here have been shown in clinical trials to improve survival and/or reduce mortality rate and have been approved for use by the US Food and Drug Administration. In colon cancer, chemotherapy after surgery is usually only given if the cancer has spread to the lymph nodes (Stage III).

* Adjuvant (after surgery) chemotherapy. One regimen involves the combination of infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX)
o 5-fluorouracil (5-FU) or Capecitabine (Xeloda)
o Leucovorin (LV, Folinic Acid)
o Oxaliplatin (Eloxatin)

* Chemotherapy for metastatic disease. Commonly used first line chemotherapy regimens involve the combination of infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) with bevacizumab or infusional 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) with bevacizumab
o 5-fluorouracil (5-FU) or Capecitabine
o Leucovorin (LV, Folinic Acid)
o Irinotecan (Camptosar)
o Oxaliplatin (Eloxatin)
o Bevacizumab (Avastin)
o Cetuximab (Erbitux)
o Panitumumab (Vectibix)

* In clinical trials for treated/untreated metastatic disease.
o Bortezomib (Velcade)
o Oblimersen (Genasense, G3139)
o Gefitinib and Erlotinib (Tarceva)
o Topotecan (Hycamtin)

Radiation therapy

Radiotherapy is not used routinely in colon cancer, as it could lead to radiation enteritis, and it is difficult to target specific portions of the colon. It is more common for radiation to be used in rectal cancer, since the rectum does not move as much as the colon and is thus easier to target. Indications include:

* Colon cancer
o pain relief and palliation - targeted at metastatic tumor deposits if they compress vital structures and/or cause pain
* Rectal cancer
o neoadjuvant - given before surgery in patients with tumors that extend outside the rectum or have spread to regional lymph nodes, in order to decrease the risk of recurrence following surgery or to allow for less invasive surgical approaches (such as a low anterior resection instead of an abdomino-perineal resection)
o adjuvant - where a tumor perforates the rectum or involves regional lymph nodes (AJCC T3 or T4 tumors or Duke's B or C tumors)
o palliative - to decrease the tumor burden in order to relieve or prevent symptoms

Sometimes chemotherapy agents are used to increase the effectiveness of radiation by sensitizing tumor cells if present.

Immunotherapy

Bacillus Calmette-Guérin (BCG) is being investigated as an adjuvant mixed with autologous tumor cells in immunotherapy for colorectal cancer.

Vaccine

In November 2006, it was announced that a vaccine had been developed and tested with very promising results. The new vaccine, called TroVax, works in a totally different way to existing treatments by harnessing the patient's own immune system to fight the disease. Experts say this suggests that gene therapy vaccines could prove an effective treatment for a whole range of cancers. Oxford BioMedica is a British spin-out from Oxford University specialising in the development of gene-based treatments. Phase III trials are underway for renal cancers and planned for colon cancers.

Treatment of liver metastases

According to the American Cancer Society statistics in 2006, over 20% of patients present with metastatic (stage IV) colorectal cancer at the time of diagnosis, and up to 25% of this group will have isolated liver metastasis that is potentially resectable. Lesions which undergo curative resection have demonstrated 5-year survival outcomes now exceeding 50%.

Resectability of a liver metastasis is determined using preoperative imaging studies (CT or MRI), intraoperative ultrasound, and by direct palpation and visualization during resection. Lesions confined to the right lobe are amenable to en bloc removal with a right hepatectomy (liver resection) surgery. Smaller lesions of the central or left liver lobe may sometimes be resected in anatomic "segments", while large lesions of left hepatic lobe are resected by a procedure called hepatic trisegmentectomy. Treatment of lesions by smaller, non-anatomic "wedge" resections is associated with higher recurrence rates. Some lesions which are not initially amenable to surgical resection may become candidates if they have significant responses to preoperative chemotherapy or immunotherapy regimens. Lesions which are not amenable to surgical resection for cure can be treated with modalities including radio-frequency ablation (RFA), cryoablation, and chemoembolization.

Patients with colon cancer and metastatic disease to the liver may be treated in either a single surgery or in staged surgeries (with the colon tumor traditionally removed first) depending upon the fitness of the patient for prolonged surgery, the difficulty expected with the procedure with either the colon or liver resection, and the comfort of the surgery performing potentially complex hepatic surgery.

Poor pronostic factors of patients with liver metastasis include:

* Synchronous (diagnosed simultaneously) liver and primary colorectal tumors
* A short time between detecting the primary cancer and subsequent development of liver mets
* Multiple metastatic lesions
* High blood levels of the tumor marker, carcino-embryonic antigen (CEA), in the patient prior to resection
* Larger size metastatic lesions
Support therapies

Cancer diagnosis very often results in an enormous change in the patient's psychological wellbeing. Various support resources are available from hospitals and other agencies which provide counseling, social service support, cancer support groups, and other services. These services help to mitigate some of the difficulties of integrating a patient's medical complications into other parts of their life.

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