Clinical Research News

Colorectal Cancer: Reducing Recurrence, Making Surgery Safer

We hear a lot about the benefits of laparoscopic surgery today, and for good reason. Patients clearly recover faster than after open surgery, experience less pain, and have better cosmetic results. Ninety percent of colorectal surgeries are performed laparoscopically at the Colorectal Care Program at NewYork-Presbyterian Hospital/Columbia University Medical Center. Yet even minimally invasive surgery inflicts trauma on the body. Investigators in the Section of Colon and Rectal Surgery are aggressively working to reduce this downside of surgery through a host of cuttingedge studies.

Colon cancer is the third most common cancer in the U.S., affecting over 130,000 people and responsible for 57,000–60,000 deaths per year. In 80–90% of cases, the diseased portion can be successfully removed surgically.

Laparoscopic Colon Resection

Compared to open surgery, patients tolerate laparoscopic surgery better than they do open surgery. It shortens patients' stay in the hospital by one to two days, reduces the need for pain medication, promotes faster bowel recovery, and allows 85% of patients to walk the day following surgery. Some of the complications associated with surgery are related to being in bed, immobility, and narcotics; laparoscopic surgery avoids or limits these detrimental factors.

Despite the benefits of laparoscopic surgery, however, minimally invasive procedures still place significant stress on the body. Research at the Laparoscopic Physiology Laboratory has demonstrated that after surgery, the body primes itself for wound healing in order to repair the tissue damaged during the procedure. Angiogenesis, the formation of new blood vessels, is an important part of the wound healing process. Unfortunately, the conditions that are conducive to surgical wound healing, especially angiogenesis, are also ideal for tumor growth. "Up to a month after surgery, blood levels of Vascular Endothelial Growth Factor (VEGF), an important stimulant of angiogenesis, are notably elevated. This increase may stimulate the growth of any tumor cells remaining in the patient after the surgery. This is true after both laparoscopic and traditional "open" or big incision surgery. Even in the hands of the best surgeons, cancer cells remain in up to 40% of patients. The presence of residual tumor cells, in combination with elevated levels of VEGF and other tumor stimulatory proteins, provides a recipe for metastatic tumors in the following years.

Both open and minimally invasive surgery are associated with increased blood levels of this protein which encourages tumor growth. In a key study scheduled to be published in November 2006 in the Annals of Surgery, the team determined that the level of VEGF rises twice as high in the first three days after open surgery when compared to results after laparoscopic surgery. A second study of laparoscopic colon cancer patients determined that despite the delayed increase in VEGF levels after surgery, VEGF levels remained elevated for at least three weeks. Since cancer patients with higher pre-surgery levels of VEGF have a worse prognosis than those with lower VEGF levels, it is safe to assume that blood levels matter," said one investigator. Armed with this observation, his team is now working to develop drug therapies to tackle the problem posed by rising VEGF levels.

In another study, the team is using genomics to understand both the beneficial and detrimental effects of major surgery. Using a DNA microarray, they will determine how surgical trauma affects the expression of over 43,000 genes in key immune cells found in the bloodstream. By identifying which genes are up- or down-regulated, the researchers hope to identify targets for anti-cancer therapy and also to find ways to limit the negative impact of surgery. They also hope to find other protein "markers" that may reveal which patients are at high risk for operative complications or a poor outcome. This study, organized by Columbia University, involves the Cleveland Clinic, the Ferguson Clinic in Michigan, and the University of Vermont.

Yet another line of study has focused on the search for "safe" chemotherapy that can be used before and immediately after surgery. Traditionally, chemotherapy has been administered six weeks after surgery to target any cancer cells that might remain after the operation. Physicians have avoided giving chemotherapy during the month or two immediately after surgery because of fears that its toxic effects would prevent the body from healing during this vulnerable time. Now, a compound called granulocytemacrophage colony-stimulating factor (GMCSF), given for three days before and four days after laparoscopic colon surgery, has been shown to ameliorate the impact of the VEGF increase that occurs after surgery. GMCSF may prevent the VEGF from stimulating cancer growth. Although it was initially thought that GMCSF would improve immune function after surgery, in fact, this drug was found to have a greater impact on angiogenesis. Importantly, GMCSF was well tolerated and did not appear to cause any complications.

"The advent and development of minimally invasive surgery has altered forever the manner in which major abdominal surgery is performed. The next step, I believe, is to find safe drugs that can be given immediately before and after cancer resection that will decrease tumor recurrence rates and improve survival." A second anticancer drug trial, testing the effects of a drug called cetuximab when given three weeks before and three weeks following surgery, is planned for early 2007.