Breakthroughs reported in controlling colon cancer

Of the thousands of drug studies presented at the recent meeting of the American Association for Cancer Research (AACR) in Washington, D.C., two took center stage as "genuine breakthroughs in colon cancer treatment and prevention." First, international scientists cited the biologic panitumumab (Amgen) for extending progression-free survival in advanced cancer patients. Then they hailed new research on celecoxib's (Celebrex, Pfizer) potential to prevent colon cancer-despite concern about heart-related side effects.

Treating colon cancer

Results from a pivotal phase III study of the new targeted compound panitumumab bring hope to metastatic colorectal cancer patients failing on standard chemotherapy, according to a new report. Panitumumab is the first fully human monoclonal antibody that blocks epidermal growth factor receptor (EGFR).

In the multinational, open-label study, 463 patients with metastatic colorectal cancer not helped by standard chemotherapy, including oxaliplatin (Eloxatin, Sanofi-Aventis) and irinotecan (Camptosar, Pfizer), were randomized to receive 6 mg/kg panitumumab plus BSC every two weeks or BSC alone.

Those on panitumumab showed a 46% drop in tumor progression rate versus those on BSC alone. At week 24, nearly four times as many panitumumab patients were alive and progression-free compared with those on BSC. At week 32, twice as many patients on the new agent were alive and progression-free.

Noteworthy as well: Some 75% of the BSC patients entered a crossover arm to receive panitumumab after their disease had recurred. Despite the setback, treatment with the new biologic showed a clinical benefit in these patients. There was a 9% partial response and one complete response, and in 32% of the patients, the disease stabilized.

Although panitumumab resembles cetuximab (Erbitux, ImClone) in being an EGFR inhibitor, Peeters emphasized that "the former is fully human, while the latter is a hybrid monoclonal antibody-part mouse." Thus, he said, unlike cetuximab, panitumumab does not require pretreatment with steroids or antihistamines to manage infusion reactions.

Peeters summed up: "The results of trials involving the use of panitumumab alone and in combination with other therapies for various cancers may confirm the use of humanized monoclonal antibodies as a great step forward in cancer treatment."

Panitumumab received fast-track designation from the Food & Drug Administration in July 2005. Amgen is currently preparing a Biologics License Application (BLA) for the agent's use in advanced colorectal cancer patients who have failed standard chemotherapy.

Preventing colon cancer

Dramatic research presented at the AACR meeting confirmed that Pfizer's COX-2 inhibitor celecoxib can help stop the growth of precancerous polyps (adenomas) in the colon and thus prevent colorectal cancer among high-risk patients. But continued concern about possible heart damage dampened some experts' enthusiasm about the drug's promise in average-risk patients.

Two major long-term clinical trials concluded that the overexpression of the COX-2 enzyme is related to the spread of colorectal tumors. "COX-2 inhibitors may reduce the occurrence of precursor colorectal adenomas in patients with a family history of the disease," researchers explained. "The drugs also may prevent sporadic colorectal tumors."

Both trials found that sustained, higher doses of celecoxib for nearly three years reduced precancerous polyp formation with the greatest benefit for those at highest risk of polyp recurrence.

The randomized double-blind Adenoma Prevention with Celecoxib (APC) study enrolled 2,035 patients. Of these, 679 received placebo, 685 received 200 mg of celecoxib, and 671 took 400 mg of celecoxib, all doses given twice daily. At one year colonoscopy was performed in 90% of participants and again, in 76%, three years later.

After a year, a 61% incidence of precancerous polyps occurred in patients on placebo, while celecoxib use reduced the chances of developing polyps by 45% in high-risk cancer patients. At 33 months, however, APC investigators discovered a two-to threefold increase in serious adverse cardiovascular events ranging from stroke to death in patients on celecoxib, and the trial was stopped.