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Colon cancer treatment has come a long way in 20 years
January 04, 2010It has been pointed out to me that whenever I have written about colon cancer, I have written about screening, prevention and colonoscopies. I have been remiss because there is an exciting story to tell. In the last 20 years, we've gone from one drug to five and the cure rate for stage III cancer has jumped from 40 to 66 percent.
When I started my cancer training in 1990, we had no chemotherapy that changed the chances of curing a patient after primary surgery and only one 30-year-old drug, 5-FU, with hit and miss benefit for patients with metastatic disease. Three months later things changed with a national alert. In early cancers that had spread as far as lymph nodes, an unlikely combination of 5-FU and a drug previously used only to deworm sheep had cured one-fourth of the 60 percent of patients who otherwise would have died of relapse.
At the same time another regimen, 5-FU and the vitamin folinic acid, was also in clinical trials in early cancers. But it was being compared to no treatment, and no treatment was no longer ethical, so it was abandoned and a new trial, the dewormer regimen vs. the vitamin regimen, was begun. Five years later, 5-FU/folinic acid won out by a small margin and became the new standard.
Meanwhile, in 1994, a new drug, the first in nearly three decades, irinotecan, was approved for the treatment of metastatic colon cancer. Initial regimens were quite toxic, but as our familiarity with it has grown, an optimal regimen of 5-FU, folinic acid and irinotecan (FOLFIRI) was developed, and best supportive care defined.
Things were quiet until 2002, when oxaliplatin, a drug that had been approved in Europe for nearly six years, found its way through the FDA process to patients in America. It has little impact as a single agent, but as FOLFOX, (5-FU, leukovorin and oxaliplatin), it proved a very active combination in metastatic cancer and further studies quickly led to the approval of FOLFOX as optimal therapy for treating patients with potentially curable disease as well.
Next, in February of 2004, two lab-made antibodies, Avastin and Erbitux, came to market. Avastin was approved for first line therapy in combination with FOLFOX for advanced colon cancer, and has since been approved for many other cancers. Its anti-tumor activity appears to be through blocking a cancer's ability to develop and grow a blood supply. Its one disappointment, unveiled just this past spring, is its failure to improve the cure rate over FOLFOX alone in early stage disease.
Erbitux has a storied history that demonstrates how much we have yet to learn. First, and perhaps most famously, it is the drug that quite literally put its CEO and Martha Stewart in jail for insider trading when in December of 2001, it first applied for and failed to receive FDA approval. When it did get approval, it was as an end-stage therapy drug to be given with irinotecan in patients who had already failed FOLFIRI. Its ability to resurrect an irinotecan response was impressive, but response rates were really underwhelming; its price tag was very high, and it didn't get much play.
Erbitux, however, is seeing a renaissance. It acts by blocking a growth factor protein that is often over-activated in colon cancer, though many colon cancers also have mutated downstream proteins that negate the impact of Erbitux. When studies have been reassessed and patients with these mutations are removed from the analysis, it is apparent that Erbitux is very active in the rest of the patients.
Finally, in 2005, Xeloda, a drug that is both new and old, was approved for colon cancer therapies. Xeloda is an oral drug that our bodies promptly metabolize to our old friend 5-FU. FOLFOX and FOLFIRI are complicated regimens that include 72-hour intravenous infusions of 5-FU. An oral substitute, in selected patients, can be significantly more convenient.
Twenty years, one drug to six drugs, and what does it mean to patients? In 1990, the average patient with metastatic colon cancer lived 11 months. Today, patients routinely live greater than two years and the incidence of patients surviving more than five years has increased from 1 percent to 10 percent. In early stage cancers with positive lymph nodes, or stage III, we have gone from 40 percent cure rates to 66 percent, and in spite of an aging population, fewer Americans are dying of colon cancer today than in 1990. And that is something to write about.
Dr. Ward is a medical oncologist at Puget Sound Cancer Centers. He can be reached at (425) 775-1677.