Long-Term Survivors Offer Clues to Cancer Therapies : Medicine: At least 50% of patients with the disease will be cured. Scientists are asking why some beat the odds.
“Make the next six months the best of your life,” the doctor told Jerilyn Ross.
It was August, 1979. Ross, 33, had just learned the grim news: Cancer cells from a malignant melanoma surgically removed seven months earlier had migrated to a lymph node under her arm. Her doctors were pessimistic. Melanoma, a skin cancer that often starts as a black mole, does not respond to drugs or radiation, and can be deadly once it spreads.
More than 15 years later--and about to celebrate her 48th birthday--Ross is cancer-free.
In 1974, Natalie Spingarn, 52, was diagnosed with breast cancer. By 1977, it had metastasized, or spread, to her spine. By 1979, it was in her bones. In 1982, she developed cancer in the other breast. “You have one year, maybe two,” her doctor told her in 1982.
Twelve years later--and 20 years after her initial diagnosis--she is still going strong.
An estimated 8 million Americans have survived cancer, and at least 50% of those who develop the disease will be cured. To be sure, most of these are people in whom the cancer is detected early. Stories of spontaneous remission are extremely rare, and cases of long-term survival after metastasis also are much less common.
Nevertheless, they exist.
The question is, why? Why do some people beat the odds while others with similar medical profiles succumb? In recent years, scientists have begun paying greater attention to the question, believing the answers could provide valuable insights into the body’s response to cancer--and to cancer therapies--and help lead to new approaches to fighting the disease.
“There are some very interesting clues that come out of chance observations in medicine, particularly from these long-term survivors who have beaten the odds,” said Dr. Harmon Eyre, an oncologist who is chief medical officer for the American Cancer Society. “They should never be overlooked.”
Scientists now are examining all of these questions in trying to design strategies against a disease that is the second-leading cause of death among Americans--after heart disease--but probably the one dreaded the most.
The field “is exploding,” said Dr. Steven A. Rosenberg, a National Cancer Institute researcher who has devoted virtually his entire career to seeking ways to use and strengthen the body’s own defenses against cancer. “I think it’s become one of the most exciting areas in cancer research.”
In some of these success stories, the reason for a good outcome could be as basic as the skill of the medical team--the surgeon who operates, the chemotherapist who calculates the doses of drugs and administers them or the radiologist who delivers the radiation. It could also depend on the destination sites of metastasized cells--if they spread to the bones, for example, an individual can live for many years with cancer; if they end up in vital organs, death can be swift.
But some of the answers also may be found in the complexities of the body’s genetic makeup or its immune system--that is, how the body’s defenses respond to the presence of alien cells. Or answers may come from how the body tolerates chemotherapy; doses can be made strong enough to kill tumors if the patient can withstand the onslaught of a drug’s often-toxic side effects.
“There is a subset of people who have an unusually good response under usually unfavorable circumstances,” said Dr. Sam Broder, NCI director.
As to why this happens, “it’s a complicated question,” Broder said. “Experts have postulated that some have better immune systems that can synergize with the chemotherapy or hormones that are used. Or that they are resistant to (drug) side effects. Or, by the luck of the draw, the tumor is just unusually sensitive to the (drug) agents. . . . Every person’s response is variable.”
But, he adds in a note of caution, “the biologies of different cancers are different. A diagnosis of lung or pancreatic cancer is a very bad diagnosis. It is important to have no illusions about this. Basically there are certain cancers that are very difficult--or impossible--to treat.”
Lately, a growing emphasis has been placed on trying to home in on the various ways in which the body naturally responds to cancer and in seeking ways to strengthen those responses. Most researchers believe that the body almost always tries to mount some kind of a response, but the battle often typically favors the cancer.
In recent years, scientific and medical journals periodically have reported research that reveals intriguing clues about the body’s relationship to the onset and spread of cancer.
Late last month, for example, Dr. Michael O’Reilly and Dr. Judah Volkman, researchers at Children’s Hospital in Boston, announced they had identified a hormone-like factor in animals that appears to check the growth of secondary tumors formed by metastasizing cells, often the tumors that ultimately cause death. They have also found preliminary evidence that this chemical exists in humans.
The substance, called angiostatin, apparently is a natural drug that circulates in the bloodstream after being produced by large primary growing tumors, such as those in the breast and colon. The hormone is apparently one of the body’s defenses against a tumor spreading, and it appears to slow the growth of blood vessels to secondary tumors.
Cancer experts say they hope the newly discovered substance--if it can be produced through biotechnology--can be used to help the body’s chances in this battle.
“If cancers don’t grow beyond a millimeter in size, they won’t kill you--and to grow, they need blood vessels,” Eyre said. “Find a way to block the vessels, and people could live with cancer for many years.”
Rosenberg has also searched for years for evidence of the body’s natural ability to fight cancer. He became hooked on the approach in 1968 after encountering a patient whose stomach cancer apparently had disappeared spontaneously a dozen years earlier.
In 1956, the Massachusetts man had received a hopeless prognosis: He would die within several months from an untreatable gastric tumor. When Rosenberg found him alive years later, he at first was convinced there had been some mistake, a misdiagnosis perhaps. But a scrutiny of the patient’s records proved there had been no mistake. The man’s cancer had simply vanished on its own.
The man’s body had cured its cancer. But how?
Transfusing the man’s blood into another dying cancer patient failed, but it set Rosenberg on a quest to determine ways in which the body’s immune system could be harnessed in the cancer battle.
He and his colleagues at the NCI have spent most of the last decade studying the body’s immune response to melanoma and kidney cancer, two malignancies long recognized as highly responsive to immunogenic factors.
Rosenberg has treated more than 1,200 patients with several different kinds of experimental immune-based therapies, with a mixed success rate. About one-third of the melanoma patients showed tumor shrinkage. And about 10% of all the patients treated--most of them individuals who likely would have died within several months--have experienced long-term remissions.
“When you get a long-term response like that, the chances are very high it (cancer) will never recur,” he said.
Because there have been some spectacular successes amid many failures, Rosenberg is also focusing on trying to discover why some patients do not respond. If the answers are determined, he says, they could be used to alter or fine-tune the therapies.
His early experiments involved doses of Interleukin-2, a chemical produced by the immune system that now can be mass-produced, and the use of lymphokine-activated killer (LAK) cells, another type of immune system cell, in conjunction with IL-2.
Last spring, he and his NCI colleagues reported that they had identified a gene in normal cells that produces a protein capable of stimulating the body to defend against melanoma.
This immune response--also discovered by Rosenberg in 1988--involves certain immune cells found in tumors, known as tumor-infiltrating lymphocytes, or TIL, that can attack and destroy tumor cells.
He said he believes that the gene, known as MART-1, or the protein itself could serve as the basis of a melanoma vaccine. Such a vaccine could be given to people who already have the disease, or, eventually, even to those identified to be at risk.
The beauty of such an approach, he says, is that therapy directed against melanoma could cause minimal side effects because skin pigment cells are not necessary for any life function.
In yet another approach, researchers are studying genes in cancer cells to try to pinpoint how and where a cancer will spread. How a cancer spreads is considered critical to a patient’s prognosis.
“We know that cancers vary greatly in their metastatic potential and growth rate, and we know this is under control of the genes in the cancer cells themselves,” he said. “We know that it takes a whole series of mutations in the genes in order for a full-fledged cancer to develop. Some of these mutations will determine how aggressively it spreads, and where it goes.”
For some types of cancer--breast cancer, for example--there are several generally recognized patterns of spread, he says.
“The first is a local recurrence in the same breast,” he said. “A second is spread to the bones and not much elsewhere. A third involves visceral organs like the liver and the lungs, in which case, it tends to be rapidly fatal.”
Determining the mechanism possibly could yield a way to predict the route of the cancer or even to manipulate the spread to make it less deadly.
With cancer, “the fact that there are long-term survivors, particularly in circumstances where the outcome would not typically be considered favorable, should be stimulus for further research--and should provide some measure of optimism,” Broder said.
