• 2/8/2006
  • Pittsburg, PA
  • Amy Dockser Marcus
  • Pittsburg Post-Gazette.com

A series of clinical trials are opening this year to explore a newly discovered window of time when cancer treatments may work more effectively.

While newer drugs along with chemotherapy and radiation have improved cancer survival rates in recent decades, doctors have long debated why the treatments don’t work even better. Even the latest generation of medications — so-called “smart drugs” that target a tumor or its blood supply — often prolong life by only a few months.

Now cancer researchers are investigating the idea that there is a narrow period — following treatment with certain smart drugs — when changes in the body allow chemotherapy or radiation to be particularly effective. If oncologists can identify and exploit this window, it could lead to improved survival rates. And because the window involves changes in blood vessels, the effort could have implications for other diseases affected by blood vessels, such as macular degeneration and heart disease.

At research facilities around the country, including Dana-Farber Cancer Institute and Massachusetts General Hospital, researchers are recruiting patients with ovarian cancer, head-and-neck cancers, brain cancer and sarcoma to participate in several small trials that will explore this window. Studies will use investigational drugs from Novartis AG and AstraZeneca PLC, as well as existing smart drugs like Genentech Inc.’s Avastin, and Nexavar from Bayer Pharmaceuticals Corp. and Onyx Pharmaceuticals Inc. Some funding and drugs are being provided by the National Cancer Institute.

The researchers will closely monitor the progress of various regimens, combining the smart drugs with chemotherapy and radiation. The aim is to pinpoint when the body is most receptive so that chemo or radiation can be concentrated during that window.

Doctors are always on the lookout for ways to make current treatments more effective, and this window isn’t the only method being tested. Other efforts include research at Duke Comprehensive Cancer Center, where researchers in 2002 reported using heat therapy to help deliver chemotherapy drugs more effectively inside a tumor. In the trial, of 21 women with breast cancer, the therapy was shown to help shrink the women’s tumors.

But this new window idea has generated excitement because it would allow drugs to better attack cells not only in the site of the original tumor, but in other parts of the body if the cancer has spread. And it allows a more effective use of smart drugs that promises to make them even more potent weapons against cancer.

The idea centers around a tumor’s blood vessels, which deliver oxygen and nutrients to the tumor and allow it to grow. Some smart drugs, like Avastin, are believed to fight cancer by stopping a tumor’s ability to make new blood vessels. Doctors know that these drugs work best in combination with chemotherapy, but they have struggled to understand why. Ironically, these same blood vessels are also the main delivery system for getting chemotherapy to the tumor.

Studies in rectal-cancer patients and in mice have offered a clue. Researchers found that for a short period of time after a smart drug was given, the blood vessels actually worked better than before. This allowed for more effective delivery of chemotherapy, and increased the tumor’s response to radiation treatment — improving survival.

Essentially, this window turns the blood vessels that once nurtured the tumor into a potent weapon against it, says Rakesh Jain, ame of the new upcoming trials involve a small group of patients, now totaling 18, who have rectal cancer. In a 2004 article published in Nature, Christopher G. Willett, now of Duke University Medical Center, and colleagues from the Massachusetts General Hospital reported that a single infusion of Avastin helped the tumor’s blood vessels deliver chemotherapy drugs and radiation more effectively to the cancer.

Osman Salman, 43 years old, of Hickory, N.C., who was diagnosed in 2004 with rectal cancer, said he enrolled in a trial testing the idea of a treatment window in order to improve his chances of long-term survival. He also hoped that if Avastin helped the chemotherapy and radiation work more effectively, his tumor would shrink enough that it could be surgically removed without complications. One of the most difficult complications that many rectal-cancer patients face is the possibility of a permanent colostomy. Mr. Salman, who just completed his treatment, said he believed the trial “saved me from that fate.”

His doctor, Dr. Willett, said it is too early to tease out how much of the outcome of Mr. Salman and other patients is due to administering treatment during the window period. But he said the new trials getting under way reflect the excitement researchers feel over this window.

“The biology of each cancer can be different,” says Dr. Willett, “but one would hope that what we find can potentially be applied to other cancer sites.”

It is already being applied in clinical trials that are set to start this year. Some of the cancers researchers are focusing on, such as head-and-neck tumors, were chosen because they are easily accessible for surgeons and can be closely monitored. James W. Rocco, who will head a proposed head-and-neck cancer trial at the Massachusetts General Hospital and the Massachusetts Eye and Ear Infirmary that hopes to enroll as many as 40 patients, said the aim of the trial is to help doctors pinpoint exactly when the window opens.

The researchers will take frequent biopsies of the tumors, including before the drug is taken, eight hours after taking the drug, 48 hours later, five days later and 28 days later. They hope that the frequent measurements will enable them to “plot out” the window as it opens and then closes, Dr. Rocco said. They plan to use an experimental drug made by AstraZeneca, called AZD2171.

While the patients in the new trial will be those whose cancer has come back and for whom usually only palliative care to treat pain and other symptoms is typically given, Dr. Rocco said the idea is to eventually use it in patients who are not as sick, where the potential benefits are even greater.