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Prevention and early detection of colon cancer are still keys to a cure, but now advances in the treatment of metastatic colorectal cancer are making even disease that has spread a beatable form. As recently as 1997, the average survival for patients with metastatic colorectal cancer was one year. In the last 12 years the FDA has approved six new agents for the treatment of metastatic colorectal cancer, and we have made significant strides in surgical resection of liver metastases for these patients. The result is a current average survival of 2-2.5 years, with more patients with metastatic disease able to be cured of their cancers. For patients who are not curative candidates, more trials have focused on limiting side effects of therapy to allow a better quality of life.

Among the newly approved agents, three are targeted or biologic. The latest cancer research has focused on development of anti-cancer therapies that specifically target how cancers manipulate themselves and their environments to allow for tumor growth. Bevaciuzmab is an antibody that targets the vascular endothelial growth factor, limiting blood vessel growth that feeds the tumors. Data suggest that bevacizumab also allows for more traditional chemotherapies that, given in combination, penetrate more into the tumor for better cancer cell kill.

Cetuximab and panitumumab are antibodies that target the epidermal growth factor receptor, which in colorectal cancer cells has been shown to be involved with increasing and perpetuating tumor cell growth. Both of these drugs have been shown to cause tumor shrinkage and to stabilize tumor growth. The targeted agents also do not show the typical chemotherapy side effects. They do not affect patients' hair and usually do not cause nausea or vomiting. However, there are other side effects, including hypertension, slow wound healing and rash.

The new targeted agents are often used in combination with chemotherapy agents, such as 5-fluorouracil, capecitabine, oxaliplatin and irinotecan. These combination treatments create a better chance of causing tumor shrinkage. Prior to the new agents' availability, response rates, or rates of tumor shrinkage with chemotherapy, were about 20 percent. Now rates run in the 50-70 percent range. With these increased response rates, we have been able to convert many patients with metastases limited only to the liver to candidates for curative surgery. Patients with metastatic colorectal cancer who go for surgical resection of their disease have cure rates in the 30 percent range. In addition, surgical resection techniques have become more aggressive, allowing for even more candidates to undergo potentially curative surgery.

For patients who are not curative surgery candidates, many trials have examined how to minimize side effects without sacrificing efficacy of treatment. Studies have addressed building in chemotherapy holidays to treatment, where patients receive the full regimen of three or four agents for the first two-to-three months of treatment and then move to only one or two agents for a period of time. This approach has shown a significant decrease in side effects and the same efficacy in controlling the cancer. One trial suggested that patients who have these chemotherapy holidays may have even longer stabilization of their disease -- the decrease in side effects led to better tolerance of therapy. Other studies have looked at using one chemotherapy agent at a time, rather than three or four agents together, to minimize side effects and allow for better quality of life. It appears from these studies that this is a viable treatment option.

Research is now focusing on two things: bringing more targeted agents into clinical trials and figuring out whether a patient's tumor might respond better to one therapy than another. This concept of "tailored therapy" would allow patients to get the most effective regimen for their particular tumor faster. We have already seen some progress on this front. Recent studies found that patients whose tumors have a mutation in the K-ras gene will not respond to treatment with the epidermal growth factor inhibitors. Therefore, these patients should be spared the potential side effects of a treatment that will be ineffective. Most current clinical trials include studies of patients' tumor samples and blood to continue to build on this concept of picking the right treatment for the patient's tumor.

The significant progress we've seen for patients with metastatic colorectal cancer would not have been possible without the patients who participated in clinical trials and proved that new treatments worked better than standard therapies. Patients who want to participate in clinical trials for colorectal and other cancers can turn to resources right here in Nashville. It is only through these clinical trials that we will be able to keep making leaps forward in improving cure rate and survival for patients with metastatic colorectal cancer.


Johanna C. Bendell, SB, MD, is the director of GI cancer research and associate director of drug development at the Sarah Cannon Research Institute. She practices at Tennessee Oncology, a leading provider of oncology services in Middle Tennessee. www.tnoncology.com

SCRI is one of the largest clinical research programs in the nation, conducting community-based clinical trials in oncology, cardiology, gastroenterology and other therapeutic areas through affiliations with a network of nearly 500 physicians in 23 states. Additionally, SCRI offers management, regulatory and other research support services to drug development sponsors and strategic investigator sites across the country. www.sarahcannonresearch.com.

Tags:

5-fluorouracil, bevacizumab, capecitabine, cetuximab, colon cancer, irinotecan, Johanna Bendell, metastatic colorectal cancer, oxaliplatin, panitumumab, Sarah Cannon Research Institute, targeted agents, Tennessee Oncology

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