Ethical behaviour, uncompromising professionalism, exemplary, innovative, cancer care. Singapore Oncology Consultants

Tailoring Treatment According to the Cancer Genes

Dr Tan Yew Oo
Medical Oncology Centre
Singapore Oncology Consultants
Gleneagles Hospital
Singapore

1. Introduction

Colorectal cancer is cancer of the large intestine (colon and rectum). The incidence of colorectal cancer has ranked second for both males and females in Singapore since 1983 and since 2003-2007 it has overtaken lung cancer as the leading cause of cancer incidence among Singapore males. It accounts for 17.8% of cancers in males and 14.5% in females, and is the most frequent cancer when both genders are combined (7277 cases in 2003-2007 compared to 5696 cases of lung cancer in the same period). The age-standardized incidence rate in Singapore Chinese is the highest among Chinese populations around the world and has exceeded those of whites in the US. They are also inching towards the rates in Australia, NSW, a region with one of the highest age-standardized incidence rates in the world. Among the ethnic groups, Malays and Indians have a risk between 20-60% that of Chinese. The age-specific rates for colorectal cancers begin to increase sharply in the 40-45 year age group and continues to rise after 50 years old.

2. What is colorectal cancer and what causes the cancer?

Most cases of colorectal cancer begin as non-cancerous (benign) polyps on the surface of the colon which can become cancerous over time. Polyps can appear mushroom-shaped or some can be flat recessed into the wall of the colon or rectum. Common types of intestinal polyps include adenomas, hyperplasic polyps and inflammatory polyps following a bout of ulcerative colitis. They develop when there are errors in the way cells grow and repair the lining of the colon. Most polyps remain benign, but some have the potential to turn cancerous. Removing them early prevents colorectal cancer. Yet, when colorectal cancer is found early, it is highly curable. This type of cancer occurs when abnormal cells grow in the lining of the large intestine (colon) or rectum.

3. What are the risk factors for colorectal cancer you can’t control?

Your risk of colorectal cancer depends on genetics and lifestyle. Factors you can’t control include:

  • Age – most patients are older than 50
  • Polyps or inflammatory bowel disease
  • Family history of colorectal cancer
  • History of ovarian or breast cancer

4. What are the risk factors for colorectal cancer you can control?

Some factors that raise the risk of colorectal cancer are within your control:

  • Diet high in red, processed, or heavily cooked meats
  • Being overweight (excess fat around the waist)
  • Exercising too little
  • Smoking or drinking alcohol

5. What are the signs and symptoms?

  • Are there early warning signs for colorectal cancer?
  • There are usually no early warning signs for colorectal cancer. For this reason it’s important to get screened. Detecting cancer early means it’s more curable.
  • What are the symptoms?
  • As the disease progresses, patients may notice blood in the stool, abdominal pain, a change in bowel habits (such as constipation or diarrhea), unexplained weight loss, or fatigue. By the time these symptoms appear, tumors tend to be larger and more difficult to treat
  • If testing reveals a possible tumor, the next step is a biopsy. During a colonoscopy, your doctor will remove polyps and take tissue samples from any parts of the colon that look unusual. This tissue is examined under a microscope to determine whether or not it is cancerous.

6. Stages of colorectal cancer

What are the different stages in colorectal cancer?
If cancer is detected, it will be “staged”’ a process of finding out how far the cancer has spread. Tumour size may not correlate with the stage of cancer. Staging also enables your doctor to determine what type of treatment you will receive.

  • Stage I – cancer has not spread beyond the inside of the colon or rectum
  • Stage II – Cancer has spread into the muscle layer of the colon or rectum
  • Stage III – Cancer has spread to one or more lymph nodes in the area
  • Stage IV – Cancer has spread to other parts of the body, such as the liver, lung or bones. This stage does NOT depend on how deep the tumour has penetrated or if the disease has spread to the lymph nodes near the tumour.

7. What are the treatments available?

Can it be cured?

When colorectal cancer is detected early, it can often be cured
The descriptions of the most common treatment options for colorectal cancer are listed below

Is surgery always required?

The most common treatment for colorectal cancer is surgery to remove the tumor, called surgical resection. Part of the healthy colon or rectum and nearby lymph nodes will also be removed. While both general surgeons and specialists may perform colorectal surgery, many people consult specialists who have additional training and experience in colorectal surgery. A surgical oncologist is a doctor who specializes in treating cancer using surgery, and a colorectal surgeon has additional training beyond general surgery.

Some patients are able to undergo laparoscopic colorectal cancer surgery. This type of surgery involves smaller incisions and the recovery time is often shorter than standard colon surgery and the results can be as effective as conventional colon surgery in removing the cancer.. Less often, a person with rectal cancer may need colostomy and this is a surgical opening or stoma through which the colon is connected to the abdominal surface to provide a pathway for waste to exit the body; such waste is collected in a pouch worn by the patient. Sometimes the colostomy may be temporary to allow the rectum to heal but it may be permanent. With modern surgical
techniques and the use of radiation therapy and chemotherapy before surgery, most people treated for rectal cancer do not need permanent colostomy.

Some patients may be candidates for surgery on the liver or lungs to remove tumours that have spread to these organs. An alternative is to use radiofrequency ablation (RFA; energy in the form of radiofrequency waves to heat tumours). Not all liver or lung tumours can be treated with this approach. In some cases, RFA can be done through skin, in others RFA can be done during surgery. While this can allow preservation of liver and lung tissue that might be removed in regular surgical resection, there is also a chance that some portions of the tumour will not destroyed using this technique.

In general, the side effects of surgery include pain and tenderness in the area of the operation. The operation may also cause constipation or diarrhea, which usually goes away after a while. People who receive a colostomy may have irritation around the stoma. The doctor, nurse, or a specialist in colostomy management (called an enterostomal therapist) can teach the patient how to clean the area and prevent infection
What about radiation and chemotherapy?

Radiation therapy is the use of high-energy x-rays to kill cancer cells and is commonly used for treating rectal cancer because this tumour tends to recur locally. A radiation therapy regime (schedule) usually consists of a specific number of treatments given over a specific time. External beam radiation uses a machine to deliver x-rays to the site of the body where the cancer is located. Radiation treatment is given five days a week for several weeks and may be given at the hospital.

For rectal cancer, radiation therapy may be used before surgery (called neoadjuvant therapy) to shrink the tumor so that it is easier to remove or after surgery to destroy any remaining cancer cells, as both have shown value in treating this disease. One recent study found that pre-operative radiation therapy in combination with chemotherapy showed greater benefit compared with the same radiation therapy and chemotherapy given after surgery. The main benefits included a lower rate of the tumour coming back in the area where it started, fewer patients that needed permanent colostomies, and fewer problems with scarring of the bowel in the area where the radiation therapy was administered.

Chemotherapy is often given at the same time as radiation therapy (called chemoradiation therapy) to increase the effectiveness of the radiation therapy. Chemoradiation therapy is often used in rectal cancer before surgery to avoid

Chemotherapy is the use of drugs to kill cancer cells. Systemic chemotherapy is delivered through the blood stream, targeting cancer cells throughout the body. Chemotherapy is usually given by a medical oncologist in the doctor’s office or outpatient clinic. A chemotherapy regimen (schedule) usually consists of a specific number of cycles given over a specific time. Chemotherapy for colorectal cancer is
usually given into a vein, although some chemotherapy can be given as a pill.

Chemotherapy may be given after surgery to eliminate any remaining cancer cells. In some situations, for rectal cancer, a doctor will give chemotherapy and radiation before surgery to reduce the size of a rectal cancer and lower the chance of cancer returning.

Currently, six drugs are commonly used for the treatment of colorectal cancer in Singapore and they include fluorouracil (5-FU), capecitabine (Xeloda), irinotecan (Campto), oxaliplatin (Eloxatin), bevacizumab (Avastin) and cetuximab (Erbitux). The last two drugs are “targeted drugs”. 5-FU is often given by continuous infusion and may require a central line either in the form of Port-a-Cath or Hickman line. Many new drugs are in clinical trials and may provide future options. Some common treatments are:

  • 5-FU infusion
  • 5-FU infusion with leucovorin, a vitamin that improves the effectiveness of 5-FU
    Capecitabine, an oral form of 5-FU
  • 5-FU infusion with leucovorin and oxaliplatin (FOLFOX)
  • 5-FU infusion with leucovorin and irinotecan (FOLFIRI)
  • Irinotecan alone
  • Capecitabine with either irinotecan or oxaliplatin

Any of the above with either cetuximab or bevacizumab

The most common chemotherapy given for colorectal cancer may cause vomiting, nausea, diarrhea, or mouth sores. However, medications to prevent these side effects are available. Because of the way drugs are given, these side effects are less problematic than they have been in the past for most patients. In addition, patients may be unusually tired, and there is an increased risk of infection. Neuropathy (tingling or numbness in feet or hands) may also occur with some drugs. Hair loss is an uncommon side effect with the drugs used to treat colorectal cancer. Medications are available to ease most side effects, including nausea, neuropathy and diarrhoea. Most side effects usually go away once treatment is finished. If side effects are particularly difficult, the dose of drug may be lowered or a treatment

Targeted therapy is a treatment that targets specific genes, proteins or tissue environment that contributes to cancer growth and survival. These drugs are becoming important in the treatment of colorectal cancer.

Anti-angiogenesis therapy is focused on stopping angiogenesis, a process of making new blood vessels. A tumour needs the nutrients found in blood vessels to grow and spread, the goal of antiangiogenesis therapies is to “stare” the tumour. One such drug is bevacizumab (Avastin), a monoclonal antibody given with chemotherapy and it improves survival for patients with advanced colorectal cancer.

Another strategy is to give epidermal growth factor receptor (EGFR) inhibitor which is effective in shrinking or stabilizing the growth of colorectal cancer. Cetuximab (Erbitux) is a monoclonal antibody that blocks EGFR and it is usually given with chemotherapy. Recent studies show that cetuximab (Erbitux) is not effective in patients with tumours that have specific mutations (changes) to a gene called kras. Doctors using this drug should send the tumour for kras gene mutation and cetuximab (Erbitux) should be given to patients with tumours with non-mutated (sometimes called wild type) kras genes.

Chemotherapy can be given as adjuvant (preventive) after surgery or in advanced stage of cancer.

Colorectal cancer can spread to distant organs such as liver, lungs, peritoneum (tissue lining the abdomen) or to a woman’s ovaries. A combination of surgery, radiation therapy and chemotherapy (with targeted therapy) can be used to slow the spread of the disease and in many cases, can temporarily shrink a cancerous tumour. With metastatic colorectal cancer, it is particularly important to talk with doctors who are experienced in treating this disease. There can be different opinions about how to treat colorectal cancer, particularly in which combination of drugs. With current chemotherapies and targeted drugs, the median survival of patients with advanced colorectal cancer is more than 26 months.

8. Can Colorectal Cancer be prevented?

Can benign polyps removed by colonoscopy – When is this necessary?

Yes, colonic polyps are routinely removed by polypectomy during colonoscopy and sent for histopathology analysis. It is a simple surgery done during the procedure with minimal side effects.