Colorectal Cancer: New Treatments, Improved Prognosis

Colorectal Cancer: New Treatments, Improved Prognosis
New drugs show promise, but more research needs to be done.
By R. Morgan Griffin
FeatureReviewed by Brunilda Nazario, MD

While colorectal cancer remains one of the most deadly cancers in the U.S., researchers are making steady progress against this disease. New drugs allow people with even the most advanced metastatic disease to live longer. Admittedly, there's no cure, and the improvements -- which can add several months to a patient's life -- may seem modest.

But for people living with advanced colorectal cancer -- and their loved ones -- small improvements make a huge difference. And experts are confident that treatment will keep getting better.

"I think the attitude has changed among doctors, especially when it comes to metastatic colorectal cancer," says Paulo M. Hoff, MD, an oncologist at the MD Andersen Cancer Center at the University of Texas in Houston. "We used to have a pessimistic view. But now we're seeing more patients with metastatic cancer responding to treatment. They are also responding well for a longer time."

"We have more tools than ever before to treat colorectal cancer," says Leonard Saltz, MD, leader of the colorectal disease management team at Memorial Sloan Kettering Cancer Center in New York. "What we're doing now is learning how to use them most effectively."
A Turning Point in Treating Colorectal Cancer

For decades, medications for colorectal cancer were limited to two drugs, 5-fluorouracil and leucovorin. But in 1996, things began to change.

* In 1996, the FDA approved Camptosar (irinotecan) for people with metastatic colorectal cancer that had recurred or spread beyond the colon. (Metastatic means that the cancer has spread to other parts of the body.)

* In 2002, the FDA approved the use of Eloxatin (oxaliplatin) in combination with 5-Fluorouracil and Leucovorin.

The new drugs improved survival to an extent. For example, one study published in the New England Journal of Medicine in 2004 found that adding Eloxatin to standard chemotherapy boosted survival among patients with advanced disease by 11%.
Advances in Targeted Therapies for Colorectal Cancer

Next, in 2004, came targeted therapies. Avastin (bevacizumab) and Erbitux (cetuximab) are monoclonal antibodies, a new generation of cancer drugs that can specifically target cancer tumors.

The problem with traditional chemotherapy is that it can't be focused. The drugs go through the body, affecting both cancerous cells and healthy cells alike. Targeted therapies affect the specific mechanisms that allow cancer cells to grow. As a result, they may have fewer side effects.

Avastin is modeled after the antibodies that naturally protect the body. It blocks the effects of a substance in the blood that helps tumors grow new blood vessels. This substance is called vascular endothelial growth factor (VEGF.) By preventing the creation of new blood vessels in the tumor, the cancer is "starved." Erbitux blocks the effects of a different growth factor called epidermal growth factor (EGF).

Studies have shown that these drugs do help. A 2004 article published in the New England Journal of Medicine found that Avastin, when combined with 5-Fluorouracil and Leucovorin and Camptosar for metastatic cancer, could increase life expectancy by about five months. Another 2004 article in the New England Journal of Medicine looked at people who were no longer responding to Camptosar. By adding Erbitux to Camptosar, the doctors were able to significantly slow down the progression of the disease, compared to using Erbitux alone for treatment.

But there are some drawbacks to these new drugs. For one, they are both only approved for people with metastatic cancer. They haven't yet been shown to work in earlier stages of the disease. And, they are still associated with side effects. In addition, Avastin seems to increase the risk of heart attacks and strokes, which makes it unsafe for some people, and prompted the FDA to request an additional warning to be added to the product labeling.
Fine-Tuning Chemotherapy for Colorectal Cancer

With more drugs to use for colorectal cancer, doctors are now trying them in new combinations and sequences.

Experts have developed a number of regimens that combine the benefits of different drugs. For some time, IFL or the "Saltz Regimen" (Irinotecan, 5-Fluorouracil and Leucovorin) was a primary treatment. But new regimens have eclipsed it, Hoff tells WebMD.

"IFL has largely been abandoned in the U.S.," says Hoff, "It's considered a little more toxic and less effective than FOLFOX (Folinic Acid, Fluorouracil, Leucovorin, and Oxaliplatin) and FOLFIRI ( Folic Acid, Leucovorin, Fluorouracil, and Irinotecan)."

In people with metastatic cancer, these regimens may be combined with Avastin or Erbitux. Many other combinations, including the use of Avastin and Erbitux at the same time, are being tested in clinical trials.

Researchers are also studying whether Avastin and Erbitux could be used in earlier stages of the disease, when the chances of actually curing the cancer are much higher. However, the results of those trials are a ways off, says Hoff.
A Dramatic Rise in Costs

The key problem with the new targeted therapies is their price.

"Avastin and Erbitux are outrageously expensive," says Anthony Back, MD, an oncologist at the Fred Hutchinson Cancer Research Center in Seattle.

The numbers show an explosion in the cost of treating colorectal cancer because of these drugs. One year's worth of treatment with the combination of Erbitux and Camptosar for metastatic colon cancer would add up to $161,000, according to an article published in the New England Journal of Medicine in 2004. Overall, the article noted that the costs for the first eight weeks of standard treatment for advanced colorectal cancer have risen 340 times over the past 10 years.

For people with insurance that covers medication, the actual costs may seem irrelevant. But even the co-payments for these drugs add up.

"Some people have 20% co-pays for these medications," says Back. "Over the course of therapy for metastatic cancer, that adds up to tens of thousands of dollars out of their own pockets." The high cost of drugs could force a person to make the impossible choice between extra months of life and financial ruin for his or her family.

"The benefits of these drugs are so dramatic that we can't deny people from getting them," says Damian Augustyn, MD, spokesperson for the American Gastroenterological Association. "But the costs will put an enormous strain on the health care system."

Saltz agrees. "It doesn't take an economist to see that these prices are unsustainable," he tells WebMD.

Although your insurance company may bear the brunt of these costs now, experts worry that even insured patients may be affected eventually. As the drugs become more widely used, their price tag could make insurance companies attempt to limit their use.
A Dramatic Rise in Costs continued...

"With prices this high, I'm sure the insurance companies will start erecting barriers to patients trying to get these drugs," says Back. "These companies just can't afford it."

Saltz worries that it's already happening. He says some insurance companies are relying on "debunked" science -- namely, the EGF receptor test, which was thought to predict whether a person would be helped by Erbitux.

"The EGF receptor test is a bad test," he says. "Studies have shown that it has no predictive or prognostic value and should not be marketed. But insurance companies are using it as a way to deny people treatment with Erbitux."

Hoff agrees that the current test is a problem. "It's just not sensitive enough," he says. "We just don't have the data to justify using it to exclude people from treatment."

Augustyn, who is also chief of gastroenterology at California Pacific Medical Center in San Francisco, hopes that competition from other pharmaceutical companies might drive the prices down. But it will still be many years before any similar drugs can be tested, approved, and sold.
Surgery Remains the Standard of Care for Early Colorectal Cancer

While new drugs may get the most attention, surgery remains the standard treatment for people in the earlier stages of colorectal cancer. In recent years, minimally invasive -- or "keyhole" -- surgery has become a popular choice.

With this approach, the procedure is done by the surgeon through a small incision using special instruments and a laparoscope, a long flexible tube with a camera and light attached. The surgeon performs the operation while looking into a monitor. This minimally invasive approach allows for smaller incisions, less pain after surgery, and quicker recovery.

A 2005 study published in The Lancet found that laparoscopic surgery worked as well as traditional open surgery for some colon cancer patients, but more studies looking at long term outcomes are needed.

"There's definitely a trend toward using laparoscopic surgery for colon resection," says Augustyn. "We're finding that 80% or more of colon cancers can be done that way."

However, The Lancet study also found that for rectal cancer, laparoscopic surgery has not been shown to be as effective as open surgery.

Hoff points out another problem with the keyhole approach. "While we have evidence that laparoscopic colon surgery is safe and probably as good as open surgery, that's only true if the surgeon is experienced with the technique," he says. "Not all surgeons are."

Hoff also thinks that people can have inflated ideas about the benefits of keyhole surgery. "Laparoscopic surgery is still surgery," he tells WebMD. "You're still getting a piece of the colon removed and you'll still need recovery time. While the hospitalization may be a little shorter, it's not a big difference."
Treatment Before Surgery for Colorectal Cancer

Traditionally, chemotherapy and radiation have been used after surgery. This approach is called adjuvant therapy. The goal is to kill any cancer cells that might have survived the operation.

But doctors are also using an approach called neoadjuvant therapy -- treatment before surgery. The advantage is that the treatment can make the tumor smaller and easier to remove surgically.

"There's growing acceptance that using chemotherapy and radiation before surgery is more convenient and gives better results," Hoff says. "It's a trend that's gaining momentum around the world, but especially in the U.S."
Keeping Treatment Advances in Perspective

While these advances in treatment are cause for enthusiasm, none of them are the magic bullet that researchers hoped to discover.

Saltz points out that the average life expectancy for someone with metastatic colon cancer in 1995 was about 11 months. Now in 2006, using the best treatments, it's about two years.

"There are two ways to look at those numbers," says Saltz. "You could say that it's great that over the last decade, we doubled the life expectancy of someone with metastatic colon cancer. On the other hand, you could also say that over the last ten years, all we managed to do was add about twelve months. Both statements are true."

But experts agree that while the steps may be frustratingly small, we are still moving forward. They may not be flashy, but some of the most important advances may come in the details -- tinkering with different dosages, treatment regimens, and combinations of drugs. Hopefully, with time and research, all of these smaller steps may add up to something big.

SOURCES: American Cancer Society web site. American Gastroenterological Association web site. Damian Augustyn, MD, American Gastroenterological Association spokesperson; chief of gastroenterology, California Pacific Medical Center in San Francisco. Anthony Back, MD, affiliate member of the Fred Hutchinson Cancer Research Center, Clinical Research Division; associate professor, University of Washington. Cunningham, D., New England Journal of Medicine, July 22, 2004; vol 351: pp 337-345. Erlinger, T. The New England Journal of Medicine, June 3, 2004; vol. 350: pp 2335-2351, Andre et al. JAMA, 2004; vol 291: pp 585-590. Paulo M. Hoff, MD, associate professor, GI Medical Oncology, MD Andersen Cancer Center at the University of Texas; deputy chair, GI medical oncology. Hurwitz, H., New England Journal of Medicine, June 3, 2004; vol 350: pp 2335-2342. Guillou, P. The Lancet, May 14-20, 2005; vol 365: pp 1718-26. Levin, B., "Colorectal Cancer," ACP Medicine: Oncology V, January 2006. National Cancer Institute web site. Leonard Saltz, MD, attending physician and leader of the colorectal disease management team, Memorial Sloan Kettering Cancer Center. Schrag, D., New England Journal of Medicine, July 22, 2004; vol 351: pp 317-319. FDA web site.