Potential mechanism of action of anti-VEGF therapy

Now that bevacizumab is approved as front-line therapy for colorectal cancer in combination with intravenous 5-FU, ongoing laboratory experiments are attempting to determine its mechanism of action. Most believe it is anti-angiogenic; however, recent papers from Harvard and Massachusetts General Hospital have shown that anti-VEGF therapy can normalize the tumor vasculature.

Normal vasculature is efficient, whereas abnormal tumor vasculature is inefficient. Rakesh Jain demonstrated that approximately five days after anti-VEGF therapy was administered to a mouse, abnormal tumor vasculature became more normalized (Winkler 2004). From a laboratory perspective, I believe a biphasic response occurs with anti-VEGF therapy. Initially, it may help the delivery of chemotherapy, and in the long term it may be truly anti-angiogenic.

Jain has hypothesized that an early window of opportunity exists for enhancing the uptake of chemotherapy or oxygen for radiation therapy. One of the advantages of bevacizumab is that it has a long half-life. After administering one dose of bevacizumab, the half-life is approximately 20 days, so if bevacizumab is combined with intravenous 5-FU, FOLFOX, FOLFIRI or other agents, we’re likely to hit that window of opportunity, resulting in true enhancement of the effects of chemotherapy.

Bevacizumab in combination therapy

At ASCO 2004, it was reported that bevacizumab improved the efficacy of 5-FU/leucovorin in patients with first-line metastatic colorectal cancer who were not ideal candidates to receive irinotecan (Kabbinavar 2004, 2005a, 2005b). The study did not reach its primary endpoint in overall survival because too few patients were enrolled; however, approximately a four-month improvement in overall and progression-free survival was seen, which was statistically significant and similar to that seen in other trials.

Giantonio presented data demonstrating that bevacizumab improved the efficacy of FOLFOX (Giantonio 2005a, 2005b). Clinical trials have also shown that anti-VEGF therapy — bevacizumab being the most studied — also improves the effects of IFL (Hurwitz 2004). We assume it would also improve the efficacy of FOLFIRI. Since we aren’t sure of the mechanism of action of anti-VEGF therapy, we don’t know whether bevacizumab would be better with one agent versus another.

One interesting study reported at the ASCO GI meeting this year is BOND-2, which is a randomized Phase II trial of cetuximab/bevacizumab/irinotecan versus cetuximab/bevacizumab in irinotecan-refractory colorectal cancer (Saltz 2005a, 2005b). It will be interesting to see whether bevacizumab can improve the effects of cetuximab — two biologic agents — without any chemotherapy in the second-line setting.

Combination of anti-VEGF therapy with chemotherapy to enhance the effects of radiation therapy in the neoadjuvant rectal cancer setting

To most patients, sphincter preservation is extremely important. Many patients will accept a therapy with a higher risk of recurrence in order to maintain sphincter function and avoid a colostomy. In residency, I learned that life with a colostomy is greatly overrated. Patients will travel far and consult with numerous surgeons in order to find one who will try to save their sphincter. Unfortunately, if a tumor clearly involves the sphincter, little can be done to save the sphincter mechanism.

For these reasons, the advent of neoadjuvant chemoradiation therapy followed by sphincter preservation surgery is critically important. In a clinical trial conducted by Willett at Massachusetts General Hospital, bevacizumab was used with 5-FU to enhance the effects of radiation therapy preoperatively (Willett 2004a). In 2004, Willett published in Nature Medicine photos of the responses that were obtained with this novel regimen (1.1, 1.2; pages 8-9). All six patients had a near-complete response, and there was just a little ulcer remaining where the tumor was before.

The concept of adding bevacizumab is being expanded upon by Willett and other institutions, such as MD Anderson and Sloan-Kettering. At ASCO in 2004, Willett presented follow-up data with approximately 11 patients, and they all appear to have a better gross clinical response than we would expect with only microscopic patches of tumor cells remaining (Willett 2004b).

The overall analysis hasn’t been done, and this is a very small number of patients. However, we should follow this in the future and see if with a larger number of patients we continue to observe this excellent pathologic response to the combination of anti-VEGF therapy, chemotherapy and radiation therapy.

Laparoscopically assisted versus open colectomy

Laparoscopic surgery is safe when performed by an experienced surgeon. From a patient’s perspective, it is critical to use a surgeon who has been trained in this technique or has performed at least 50 cases. Many of us in academic centers don’t typically see patients with early-stage tumors, and for that reason have fewer patients undergoing laparoscopically assisted colectomy than in community practices.

Laparoscopically assisted colectomy has taught us that we can remove the colon through a smaller incision, and we believe patients recover better with smaller incisions. When performing an open colectomy, we now make smaller incisions and use retractors more efficiently. However, a study published in the New England Journal of Medicine, which randomly assigned patients to laparoscopically assisted versus open colectomy, reported a surprising variability in the length of incisions in both groups, ranging from two or three centimeters, respectively, to 35 centimeters (Clinical Outcomes of Surgical Therapy Study Group 2004).

While I believe the open technique is safer, I respect the opinions of the physicians who are experts in laparoscopic surgery. Laparoscopically assisted colectomy is preferable in some cases, such as in an elderly patient with a poor performance status who has a small tumor in the sigmoid colon or right colon. The laparoscopic surgery requires more time in the operating room, but an experienced surgeon can perform these cases relatively quickly.

I am more comfortable with the open technique because it allows me to palpate around the abdomen. We can do a laparoscopic ultrasound of the liver and run the bowel, but to me, nothing compares to that tactile sensation. Sometimes I can feel a lymph node at the base of the mesentery that can’t be seen, or I feel things on the liver that I may not see with a laparoscope. Tactile sensation is important to get a good feel for the location of the tumor, the lymph nodes and anything else that may be going on in the abdomen.

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Dr Ellis is a Professor of Surgery and Cancer Biology at The University of Texas MD Anderson Cancer Center in Houston, Texas.