Colorectal Cancer

Colorectal cancer originates in the colon or the rectum. Like all cancers, treatment options will vary depending on the severity or staging of the cancer. Below is a brief description of the stages:

❖ Stage 0: the cancer has not grown beyond the inner wall of the colon.

❖ Stage 1: the cancer has grown through several layers of the colon, but is still contained within the colon.

❖ Stage 2: cancer has grown through the colon walls and into nearby tissue. However, the lymphnodes are not affected.

❖ Stage 3: cancer has spread to the lymph nodes but has not spread to other organs.

❖ Stage 4: cancer has spread to distant organs.

As a note, because colorectal cancer originates as a tumor, it is staged using TMN staging criteria.

Treatments: Best Practices

Surgery

In the case of stage 0 colon cancers, only small abnormal growths called polyps need to be removed by a procedure called polypectomy. This is done through excision using a colonoscope so that the surgeon can see during the operation. If the tumor is too large, the surgeon will resort to colectomy. It is a very effective operation for early stage colorectal cancers (stage 02). It requires that the bowels be evacuated before the procedure. The surgeon will make an incision in the abdomen while the patient is put under with anesthesia. The portion of the colon that contains the cancer and small segments on either side will be removed. Usually, about a quarter of the colon is excised during this surgery. In addition to the segment of the colon, lymph nodes will also be taken out during the surgery if necessary. The two healthy segments are joined to complete the surgery.

Surgeries for rectal cancer are slightly different from the colon procedures. Local transanal resection is done with instruments inserted through the anus such that no incisions will be needed. This surgery is appropriate for early cancers (stage 0 or 1). If the cancer has occurred in the upper third of the rectum, a procedure called low anterior resection is performed. The operation removes this upper third, then joins the colon with the anus. This should return normal bowel control.

If the cancer occurs in the middle and lower third of the rectum, the procedure used is called proctectomy. The operation requires removal of the entire rectum. Afterward, the colon and anus are joined by a procedure called coloanal anastomosis. If all the lymph nodes in the area are to be removed, the surgeon will perform a total mesorectal excision (TME).

In cases of very advanced cancers where the tumor has spread into nearby organs like the bladder, prostate in men, or uterus in women, a pelvic exenteration may be necessary. This is a rather extensive surgery because all of the affected organs need to be removed. If the bladder removed, another procedure called an urostomy is needed. It involves making an incision in the abdomen to allow urine to exit the body into a pouch.

It is clear that there are many surgical options involved in colorectal cancer. The appropriate surgery requires knowledge of the location, size and stage of the tumor.

Chemotherapy

Chemo drugs are powerful drugs that can be harmful to healthy cells, so chemotherapy is usually given in cycles of about 2 to 4 weeks. There are two ways to give chemo drugs. Systemic chemotherapy is given as an injection or as a pill such that the drug is able to circulate throughout the entire body. Regional chemotherapy is given through an injection into arteries that go directly to the organ that contains the cancer. There are definitely reduced side effects associated with regional chemotherapy.

Drug used to treat colorectal cancer are:

❖ 5Fluoroouracil (5FU), usually given with the vitamin leucovorin

❖ Capecitabine

❖ Oxaliplatin

❖ Irinotecan

Common combinations used especially for metastatic cancers are:

❖ 5FUleucovorin, and oxaliplatin

❖ 5FU, leucovorin, and irinotecan

❖ 5FU, leucovorin, oxaliplatin, and irinotecan

❖ Capecitabine and oxaliplatin

Targeted Therapies

There are several types of targeted therapies for colorectal cancer, including drugs that target VEGF, EGFR, and kinases. VEGF (vascular endothelial growth factor) is a protein that allows cells to form new blood vessels, a process called angiogenesis. Angiogenesis inhibitors such as Avastin and Zaltrap are available and seem to be effective in treating advanced colon cancers when combined with chemotherapy.

EGFR, endothelial growth factor receptors, are overexpressed on the surface of cancer cells. When specific ligands bind to this receptor, the cell is told to grow. By blocking these receptors, the growth of the cancer can be controlled. Drugs that target EGFR are cetuximab and panitumumab.

Cetuximab is commonly combined with the chemo drug irinotecan and can be a first line treatment for metastatic colorectal cancer. If other treatments have been tried, or if the cancer is no longer responding to other drugs, panitumumab is used for advanced metastatic cancers.

Kinases are enzymes that are vital to signalling within the cell. They are involved in both the signaling that initiates cell growth and also in angiogenesis. Regorafenib is one of the drugs that inhibits these kinases and has been shown to prolong the life of patients marginally by about 6 weeks.

Radiation Therapy

The most common form of radiation therapy used is called external beam radiation therapy. Using a machine called a linear accelerator, radiation is directed to the location of the cancer after taking precise measurements of where it needs to be aimed. The procedure itself is painless and only lasts a few minutes. Doses are usually given 5 days a week for several weeks, but this can vary depending on whether the radiation is intended for adjuvant therapy or neoadjuvant therapy.

For rectal cancers, a good approach is endocavitary radiation therapy. It is done by inserting a device through the anus that delivers radiation for a few minutes. Four total doses are given, and each dose is given two weeks apart. This approach gives a targeted dose of radiation without affecting other tissues.

In brachytherapy, a pellet of radioactive material is inserted into the cancerous. The pellet is only left in the tissue for a short period of time and is then removed so that healthy tissue is not damaged. Seed particles are left behind for a longer term release of radiation which weakens over time. This type of therapy should only be administered once.

Research Pipeline

Imprime PGG

This drug is an immunomodulator being developed by Biothera. It works by enhancing immune cells’ ability to fight cancer cells. In addition, Imprime PGG directs these immune cells to the site of the cancer in large quantities. This mechanism of action is very clever because these cells make up about 60 percent of the body’s innate immune system. These cells are not normally involved in antitumor activity.

Recruiting these cells would then make a huge difference in the body’s ability to fight off cancer.

Imprime PGG is currently undergoing phase III trials in combination with cetuximab for treatment of metastatic colorectal cancer.

MEHD7945A, RG7597

This is a dual action IgG monoclonal antibody developed by Genentech. It targets human endothelial growth factor 3 (HER3) and EGFR. Its phase II trial is currently recruiting patients that have metastatic colorectal cancer. The trial will combine MEHD7945 A/RG7597 with cetuximab as well as the drug combination of 5FU, leucovorin, and irinotecan.

MORAb004202

This drug is also a IgG1 monoclonal antibody, but it being developed by a company called Morphotek. It acts by interacting with cell surface proteins called endosialin, or tumor endothelial marker 1 (TEM1). It also targets CD248 which is implicated in angiogenesis. A phase II trial is currently underway with patients that have metastatic colorectal cancer that have shown resistance to chemotherapy. The study is no longer recruiting and the preliminary results are expected shortly.

Centers of Excellence

❖ California Pacific Medical Center, San Francisco, California

❖ East Cooper Medical Center, Mt. Pleasant, South Carolina (renown for short average length of stay)

❖ Memorial Hospital, Chattanooga, Tennessee

❖UMass Memorial Medical Center, Worcester, Massachusetts

❖University of Texas MD Anderson Cancer Center, Houston, Texas

❖Memorial Sloan Kettering Cancer Center, New York, New York

❖Massachusetts General Hospital, Boston, Massachusetts

 

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