Doctors thought combining two newer drugs that more precisely attack cancer would help people with advanced colon cancer. Instead, it made the cancer worse and the patients more miserable, a study found.

The surprising findings underscore the importance of doing rigorous studies before rushing to mix these expensive, new-generation drugs, the Dutch researchers and other experts said.

The doctors tried combining Erbitux and Avastin because lab tests and an earlier small study had shown promising results.

"This will stand out as a warning," said Dr. Cornelis Punt, the study's leader. "You have to do the randomized studies to see what really happens."

For the study, Eli Lilly & Co.'s Erbitux was added to standard treatment, which includes Genentech Inc.'s Avastin. Since both are "targeted" drugs and attack tumours in different ways, the thinking was that the combo would do a better job of keeping the cancer from growing.

But the results show "more is not always better," said Dr. Robert Mayer, of Dana-Farber Cancer Institute in Boston. He wrote an editorial published with the study in Thursday's New England Journal of Medicine.

What makes the results even more compelling, Mayer said, is that another similar study reached the same conclusion. That study, released in December, tested another targeted drug that works the same way as Erbitux.

"This is the first time we've seen harm by combining targeted therapies and it tells us we need to be cautious," said Dr. Jordan Berlin, a gastrointestinal cancer specialist at Vanderbilt-Ingram Cancer Center in Nashville, Tenn.

Results worse with combo

Berlin, who had no role in the research, stressed that the drugs do help patients, just not when given together.

Colorectal cancer is the second leading cancer killer in the U.S. The disease was expected to kill almost 50,000 Americans last year, although death rates are dropping because of screening and better treatment.

The research was done at hospitals throughout the Netherlands and led by Punt at Radboud University Nijmegen Medical Center.

The 755 study patients had colon cancer that had spread. They all received Avastin, also known as bevacizumab, and two chemotherapy drugs. Half of them also got Erbitux, also called cetuximab. They were followed for nearly two years.

The group that got Erbitux saw their cancer get worse sooner, the researchers found. On average, their cancer progressed after 9.4 months compared to 10.7 months for those who didn't get Erbitux. The Erbitux group also had lower quality-of-life scores.

The overall survival in both groups was about the same.

Punt said they are now trying to figure out why the combo didn't work; it could be an interaction between these two specific drugs, Erbitux and Avastin.

After the study began in 2006, it was shown that Erbitux didn't help colon cancer patients who had a specific gene mutation. The Dutch researchers said their study confirmed that — the worst results were in those with the mutation who got Erbitux.

Vanderbilt's Berlin said the results also show doctors need to be careful when using drugs "off-label."

Drugs are approved for specific uses but doctors can prescribe them for other purposes. Medicare has recently expanded its coverage for such use of some cancer drugs, which can cost thousands a month.

Off-label use "needs to be cautious and this proves it," said Berlin.

The study was supported by a network of Dutch researchers which receives grants from a cancer foundation and drug companies.

The two targeted drugs were provided by the companies that market them in Europe. Several of the researchers have consulted for cancer drug companies, as has the editorial writer and Berlin.