New Advances in Colon Cancer

Over the last few decades, colon cancer has been a frustrating disease for patients and physicians.  It is the third most common cancer in the United States and is the third leading cause of cancer mortality.  In the past, successful treatment with surgery was the only hope for cure.  If the disease recurred, the ability to control the cancer with additional surgery, radiation, or chemotherapy was severely limited.  5-fluorouracil (5-FU), a DNA-disrupting drug developed over forty years ago, had a response rate of only 15-20% -- and even then, responses were incomplete and of short duration.  Addition of leucovorin (a folic acid derivative) to 5-FU improved the response rate somewhat.  However, dozens of other chemotherapy drugs were tried over the ensuing decades, and nothing proved superior to 5-FU.  In a word, there was a long period of stagnation during which there seemed to be little progress against the disease.

Surgeons were the first to make additional inroads.  Tumors in the rectum could be cured more readily if pre-operative chemotherapy and radiation were given, and some progress was made in anal sphincter conservation and avoidance of colostomies.  Interestingly, operating on metastatic tumors in the liver, or even the lung, was met with some success.  Some patients could even be cured by such technically difficult surgery. 

More recently, some successful systemic therapies finally have arrived on the scene.  Irinotecan and oxaliplatin were the first.  Combining these agents with 5-FU, oncologists started to see response rates greater than 50% in metastatic disease.  In addition, some of these responses were of long duration.  Whereas responses to 5-FU alone might last for only a few months, the combination therapies sometimes produced good-quality remissions in excess of two years.  For the first time it felt like there was actually progress in the treatment of this disease.

As is customary in oncology, the question was raised whether using combinations of drugs earlier in the course of the disease might be helpful in preventing disease recurrence (adjuvant chemotherapy).  After all, this concept had proven useful in breast cancer.  As it turns out, adjuvant chemotherapy, particularly with oxaliplatin, indeed has been successful in improving the likelihood of surgical cure.  Patients with stage III disease (lymph nodes involved at initial surgery) are routinely offered such therapy currently.

A newer approach to intravenous 5-FU therapy has been an oral agent, capecitabine.  In some cases this has allowed patients freedom from prolonged intravenous infusions of 5-FU. 

Most recently, a class of drugs called monoclonal antibodies has come along.  Agents such as bevacizumab, cetuximab, and panitumumab target a substance called epidermal growth factor.  They work by inhibiting this substance and probably by altering blood vessel growth in a tumor.  When added to conventional chemotherapy, they appear to improve the response rate in the metastatic setting, and hopefully in the adjuvant setting as well.

Not surprisingly, all newer agents bring with them additional toxicities and significant economic costs.  In some cases irinotecan causes marked problems with diarrhea, and almost always causes hair loss.  Oxaliplatin causes a unique kind of neuropathy characterized by extreme cold sensitivity in the hands, feet, and mouth, making it unpleasant to touch cold objects or to drink cold liquids.  Capecitabine can result in a troubling redness and scaling of the palms and soles.  The monoclonal antibodies can cause hypertension, infusion reactions, rashes, electrolyte imbalances, and serious bowel perforations. Drug costs for six months of treatment with 5-FU, oxaliplatin, and bevacizumab can exceed $75,000.

Nonetheless, it is encouraging and exciting to know that we have more to offer colon cancer patients in 2007.  We have every reason to be optimistic that more advances are in the pipeline heading our way.