Originally created 05/24/00

Cancer drugs show hazards as well as promise



NEW ORLEANS (AP) - Drugs designed to stop tumors by cutting off their blood supply have shown modest benefit in tests against three kinds of cancer, but have also raised concerns about possible dangerous side effects.

Angiogenesis inhibitors, as these drugs are called, are among the most closely watched new developments in cancer research. In animal studies, they sometimes dramatically reverse cancer, and hopes are high they will do something similar in people.

Several reports on mid-size studies of these medicines were reported at this week's annual cancer conference sponsored by the American Society of Clinical Oncology. Together, experts say, these studies offer proof that the concept is sound: Attacking tumors' ability to sprout blood vessels clearly inhibits cancer growth, even in terminally ill patients who have tried all of the standard cancer drugs.

However, these studies also show that these drugs can have a variety of unwanted side effects, some of which are fatal.

"These are drugs in every sense of the word," said Dr. George Sledge of Indiana University. "They have activity, and they have toxicity."

On Tuesday, doctors reported studies on drugs developed by Genentech and Sugen that are designed to block tumors' use of vascular endothelial growth factor, or VEGF. This substance is a key fuel that allows the cancer to grow new blood vessels and repair old ones. Without a new blood supply, cancers never get bigger than a pinhead.

As is usual at this stage of testing, the drugs were given only to people with spreading, incurable tumors, sometimes alone, sometimes in combination with standard chemotherapy medicines.

Doctors say that while no one was clearly cured, the anti-VEGF compounds did seem to slow the tumors' spread, at least for a few months.

"We have three common solid tumors - breast, colon and lung cancer - and this drug shows some evidence of clinical benefit in all three, the most common cancers we deal with. That's the real significance," said Dr. Russell DeVore of Vanderbilt University, referring to new results with the Genentech drug.

However, DeVore's study, conducted on 99 terminally ill lung cancer patients, also shows the drugs' potential hazards. Six patients developed sudden, catastrophic bleeding in their tumors, killing four of them.

"We were taken by surprise. This was not an expected side effect," DeVore said.

However, Dr. Nicholas J. Vogelzang of the University of Chicago called this bleeding "very exciting," despite its unfortunate consequences, since it suggests the treatment truly does appear to disrupt the tumor's ability to maintain a blood supply.

Other dangerous side effects of anti-VEGF treatment include high blood pressure and blood clots.

Dr. Lee Rosen of the University of California at Los Angeles tested Sugen's anti-VEGF drug, code-named SU5416, in combination with standard chemotherapy on 28 people with advanced colon cancer. The combination stopped cancer growth for an average of 9´ months, compared with six months for the usual therapy.

Of the 28, "25 are still alive, some as long as a year so far, and they are all doing very, very well," Rosen said. Although the study is small, "the data are very interesting and very promising. This really validates the target. By regulating VEGF, we seem to be doing something."

Doctors were pleasantly surprised in these studies to see evidence that the anti-VEGF drugs seem to make tumors shrink. In theory, they might have halted cancer's spread while doing nothing to make them go away.

The data from these studies are promising enough for Sugen and Genentech to begin large studies that will enroll several hundred cancer patients in an attempt to prove that the two drugs actually lengthen patients' lives.

"I continue to feel this is an enormously interesting way to treat patients with cancer," said Dr. Susan Hellman, Genentech's development chief. "Now we need to move into the next phase and see how much we will help patients and what the risks will be."

Much of the enthusiasm for blocking blood vessels came from optimistic coverage of the development of the drugs endostatin and angiostatin by Harvard's Dr. Judah Folkman, the field's pioneer.

Endostatin is in early testing at three hospitals, and participating doctors have been silent about the effects so far. At the meeting Monday, Folkman said he is "very pleased" with the results in Boston.

On the Net: Sugen: http:www.sugen.com

Genentech: http://www.gene.com



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