By Monica Zangwill, MD

“It was kind of like the hidden cancer, the embarrassing cancer until Katie Couric’s husband died,” says Michael Dunne, a 48-year-old police detective from Long Beach, New York, who was diagnosed with colon cancer in June 2002. Once Couric started talking about it, however, colon cancer news buzzed through the air.

Still, when Dunne was diagnosed he joined the more than 100,000 people diagnosed with colon cancer each year and 42,000 people with new diagnoses of rectal cancer. And colorectal cancer remains the third most common cancer in the United States, excluding skin cancers.

Yet, when Couric’s husband, Jay Monahan, died in 1998 there were essentially only two effective chemotherapies used in the United States for metastatic colon cancer. In the late 1990s and early 2000s, scientists worked hard to come up with more options. In 2003, much of this research began to pay off. New medicines and new combinations now show great promise in fighting colon cancer. And while none of the recent studies produced a cure for colon cancer, the news is hopeful.

“It’s an exciting time to be doing research in colorectal cancer because it seems like we are making progress every year,” says Richard Goldberg, MD, chief of hematology/oncology and associate director of the University of North Carolina’s Lineberger Comprehensive Cancer Center.

Chemotherapy: A Short History

Less then 10 years ago, the only chemotherapy treatment used for advanced colon cancer in the United States was 5-fluorouracil (5-FU). 5-FU, which is almost always given with leucovorin (also called folinic acid) to enhance its effectiveness, kills cancer cells by interrupting their DNA-making capabilities. But like many traditional chemo drugs, 5-FU can’t discriminate between healthy and unhealthy cells, so it damages many normal cells. Because of this, its side effects include low white blood cell count, diarrhea, and mouth ulcers.

Scientists struggled to find alternatives to 5-FU. Then, in the ’90s, Camptosar® (irinotecan), the first new drug seen effective against colon cancer in decades, entered the scene. The U.S. Food and Drug Administration (FDA) granted accelerated approval to Camptosar in 1996 with full approval coming in 1998 for treatment of advanced colorectal cancer. Camptosar blocks an enzyme called topoisomerase-1 that cells need to divide. However, like 5-FU, it damages some healthy cells, leading to side effects, including diarrhea and low white blood counts.

Pati Lanning was diagnosed with colon cancer in 1998 at age 47. She had the standard treatment of 5-FU/leuco-vorin after surgery. Then her oncologist suggested she try Camptosar, which had just finished clinical trials in colon cancer.

“I was sort of a guinea pig,” she says about her experience. “But I do feel lucky to have had the benefit of Camptosar even before it was actually approved. Who knows if Camptosar could have made the difference why I have not had a recurrence while a lot of my friends have.”

Camptosar was quickly integrated into standard colon cancer treatment in combination with 5-FU in a regimen called IFL, or the Saltz regimen. More recently, Camptosar is being given with 48-hour infusions of 5-FU/leucovorin (FOLFIRI regimen). This seems to improve efficacy while reducing side effects as compared to the Saltz regimen. Progress continued in 2001, when the FDA approved Xeloda® (capecitabine), an oral medicine that works similarly to 5-FU, for the treatment of metastatic colorectal cancer.

New Millennium Brings New Medicines

The story of new drugs for colon cancer continued in the early 2000s. The FDA approved Eloxatin™ (oxaliplatin) in 2002 for use in combination with 5-FU and leucovorin for patients with treatment-resistant colorectal cancer. And in January 2004, Eloxatin in combination with 5-FU/leucovorin (called the FOLFOX regimen) was approved for the initial treatment of advanced colorectal cancer. Eloxatin disrupts cells’ DNA and triggers cell death.

Research released in 2003 found FOLFOX is effective in the often hard-to-treat advanced colon cancers. FOLFOX was more effective than IFL and more effective than the combination of Camptosar and 5-FU (called IROX) in a clinical trial of 796 patients.

“In terms of response rate,” says Dr. Goldberg, who wrote and led the study in collaboration with the North Central Cancer Treatment Group, “there was a 31% response rate for IFL, a 34% response rate for IROX, and a 45% response rate for FOLFOX.”

In addition, patients treated with FOLFOX lived on average 19.6 months—five months longer than those treated with IFL, who survived an average of 14.8 months. While the side effects for all these combinations include diarrhea and fevers related to low white blood counts, people who received Eloxatin had the least severe reactions.

“Now I generally use the FOLFOX program as my first-line therapy for patients with advanced disease,” says Dr. Goldberg.

Recent data show the FOLFOX regimen is also more effective than 5-FU/leucovorin when used after surgery in patients with completely resected stage 2 and 3 colon cancer. The phase III trial, which included more than 2,200 patients, resulted in a 23% reduction in the risk of recurrence for the FOLFOX group.

Dunne, who has stage 4 colon cancer, considered his options when faced with choosing a chemotherapy course.

“When you get diagnosed,” he says, “it’s like the end of the world, and you start scrambling. You become very educated as fast as you can.” He chose FOLFOX and is hopeful it will provide good results.

While on the therapy, however, he has suffered through one of the side effects particular to Eloxatin called sensory neuropathy.

“It’s a tingling and numbness sensation in the fingers and the feet,” says Dunne. “And also the sensation of cold. Touching anything cold, you feel like you might have to drop it. You can’t even drink anything cold.” But it does wear off, he says.

“As a cancer patient, you always look at the glass half full instead of half empty. So I remain optimistic.”

Newest of the Newcomers: Approved Colon Cancer Drugs

A new drug just approved Feb. 26 to fight colon cancer may buoy Dunne’s hope. Avastin™ (bevacizumab) is the first antiangiogenesis drug to be approved for the treatment of advanced colorectal cancer.

“[Feb. 26] marks an important shift in the treatment of metastatic colorectal cancer, with the approval of an innovative treatment based on elegant science that targets cancer in an entirely new way,” says Arthur D. Levinson, PhD, chairman and chief executive officer of Genentech, the maker of Avastin.

Avastin works to reduce blood flow to growing tumor cells. Like all cells, tumor cells need the nutrients brought to them via blood vessels to grow. But because tumor cells are new growths, they need to stimulate new blood vessels to reach them.

Approval was based primarily on the results of a clinical trial reported in 2003 showing that Avastin combined with Camptosar/5-FU/leucovorin (IFL) extended the lives of people with metastatic colon cancer longer than similar patients who received only IFL. Those who received Avastin plus IFL survived a median of 20.3 months, while those who did not receive Avastin with the conventional chemotherapy survived a median of 15.6 months. Side effects of Avastin were modest, but those who got Avastin did tend to have more frequent high blood pressure. A rare complication also seen with Avastin was perforation of the intestinal wall.

With the news of Avastin’s beneficial effects in colon cancer, it became the first antiangiogenesis drug to show success in a randomized phase III study.

“That study prompted a great deal of interest in studying Avastin in other stages of colorectal cancer and in other diseases,” says Richard Schilsky, MD, professor of medicine, University of Chicago, and chairman of the Cancer and Leukemia Group B.

There are many steps involved in the angiogenesis process; one of them requires a protein called vascular endothelial growth factor (VEGF). It turns out that high levels of VEGF are produced by many colon tumors. Avastin is a monoclonal antibody that can bind to this VEGF protein, render it inactive, and thereby shut down the hungry tumor cells’ ability to stimulate blood vessel growth. Without proper nutrients brought to them by blood vessels, the tumor cells can no longer grow.

Clinical trials are under way to test Avastin with other stages of colon cancer and with other types of chemotherapy drugs. It is also being tested in other types of cancer, particularly kidney cancer (see CURE, Summer 2003), where preliminary data show it has some positive effects.

Another recently approved treatment for patients with advanced, metastatic colorectal cancer is ErbituxTM (cetuximab). Under their accelerated approval program, the FDA approved Erbitux on Feb. 12, 2004.

Erbitux is a monoclonal antibody that binds to a protein called the epidermal growth factor receptor (EGFR), which is involved in stimulating a cell’s growth. Some colon cancer cells have very high amounts of EGFR. Erbitux binds to EGFR on these cancer cells and slows their growth.

European investigators gave Erbitux with Camptosar or Camptosar alone to metastatic colon cancer patients who had already tried other chemotherapies, including Camptosar. The results showed Erbitux plus Camptosar was more effective in reducing tumor size than re-treatment with Camptosar alone. This data confirmed previous American studies. Side effects of Erbitux include acne-like rash, nausea, diarrhea, and fatigue.

With the approval of Erbitux and Avastin comes a significant step forward in the battle against colorectal cancer.

The Quest for Combination Treatments

While none of the new medicines provides a cure for colon cancer, having more choices greatly increases the options available to people with colon cancer, especially those with advanced disease. With more drugs available, doctors can more easily switch medicines if patients develop side effects. Also, combinations of several drugs are usually more powerful than single drugs alone.

To this aim, much of the current research in colon cancer hopes to determine the most effective chemotherapy combinations with the fewest side effects.

“Let’s take the drugs that are working and put them together and see if they will work better,” says Leonard Saltz, MD, oncologist, Memorial Sloan-Kettering Cancer Center, New York. In fact, investigators are currently looking at a whole range of combinations, including FOLFOX with Erbitux, Avastin with FOLFOX, and Avastin with XELOX (Xeloda and Eloxatin) (also called CAPOX). Other studies are combining Camptosar with Xeloda. Dr. Saltz is even planning a trial to combine Avastin and Erbitux, the two newly approved monoclonal antibody drugs, as treatment for colon cancer.

Looking for a Crystal Ball

As a police detective, Dunne knows the difficulty of making decisions without all the information. He also understands the many unknowns involved in treating cancer.

“Every human body is different and reacts differently to the medicine,” he says. “And that’s the tough call when picking treatment. Nobody has a crystal ball, but you try to make an educated choice.”

Oncologists agree that, currently, doctors don’t have enough information about how cancer grows to know who will respond to one chemotherapy combination and who might respond to another.

Dr. Saltz notes, however, that new research may provide the ability to target individualized therapy for patients. “Rather than just mix up a cocktail that works for everybody, investigators hope to try to figure out which drugs are going to make sense for which patient.”

This may be the crystal ball that could help doctors create specific combination chemotherapies for each patient based on factors such as the person’s body and tumor.

Continued Optimism

The encouraging news for current colorectal cancer patients is that with Avastin and Erbitux, there are potentially six active drugs to fight their tumors.

“Remember, in 1995 there was one,” says Dr. Saltz. “We are making enormous progress compared to what we’ve been able to accomplish before.” But, he is quick to add there is still a long way to go. “We’re hoping these drugs are the tip of the iceberg and that there are newer and hopefully better drugs coming behind them.”

For people like Dunne, rapid progress is hopeful. He feels OK between treatments and has an eye on learning more about possible alternatives if he needs them in the future.

Dunne feels staying focused and looking at the whole picture is most important. “It’s a battle, and from what I see and from every survivor story I’ve read, you have to be optimistic and believe in your treatment.”