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Form & Function

Changes in cancer care

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By John Milne

Milne, a freelance writer in Concord, N.H., is a former Cancer Center patient; he received a stem-cell transplant for lymphoma in 1998 —which he wrote a feature about for our Summer 2001 issue.

Actor John Wayne once defined cancer the way one of his movie characters might refer to an adversary. "I licked 'The Big C,'" rasped Wayne in the 1960s. The remark made cancer "a thing you could shoot down, like a cattle rustler," wrote Wayne's biographer, Garry Wills.

There's a reason "The Big C" entered the American dialect; it resonated with the concept of cancer as a life-or-death struggle. Patients "battled" their disease. Those who came through treatment were "survivors." Behind the saber-rattling metaphors was a stark reality: Medical treatments for invasive cancer can be uncomfortable, painful, and, to a degree, risky. Radiation, surgery, and high-dose chemotherapy change the body as they save the patient's life. Their aftereffects can even lead to new diseases, some of them life-threatening.

In the 21st century, the metaphor may need to change from war to containment. After decades of research, drugs are being developed that manipulate the actual chemistry of the cell. For a few cancers, this new biochemistry can reduce a malignant tumor to an inert mass. Other cancers can be controlled with a few pills a day. Cancer is on the way to becoming a chronic disease—like diabetes.

"This is a very exciting time for cancer medicine," says Burton Eisenberg, M.D., the new deputy director of Dartmouth's Norris Cotton Cancer Center. "Finally, a black box is opening, telling us a lot more about the genetic foundations of cancer and increasing the number of new compounds that will fight cancer at the molecular level."

Eisenberg's office is on the top floor of the new addition to the Cancer Center—an expansion that is part of this transformation in cancer treatment. Previous discoveries in cancer biochemistry came largely from basic-science and private-sector laboratories. Eisenberg believes the new breakthroughs will take place in integrated cancer centers such as Dartmouth's, where laboratory discoveries can take a more direct path to patients. At the same time, practical feedback obtained in the clinics can easily inform and guide the researchers' scientific efforts. "This will permit better communication between the people who work with the test tubes and the people who conduct that actual practice," he says. "In the past, doctors didn't know how to talk to scientists and vice versa."

The Cancer Center's expansion also dovetails with a recent decision by the National Cancer Institute. The NCI has assigned a top priority to research "into the genetic, molecular, and cellular basis of cancer" and to making new drugs and therapies more quickly available to patients. The U.S., says NCI Director Andrew von Eschenbach, M.D., stands "at that defining moment in history when a surge of new technologies and the fruits of many years of investigation will yield, over the next two decades, unimagined leaps forward in our understanding of cancer and our ability to control and eliminate it."

During the second half of the 20th century, cancer treatments were broadsword-crude but increasingly effective. Surgery removed cancerous tissue—or sometimes the entire organ containing that tissue. Radiation killed cancer cells—though its beams often passed through and damaged other organs, too. Chemotherapy showed remarkable success at destroying fast-growing cancer cells—as well as other fast-growing cells in the body; that's why chemo patients lose their hair and get mouth ulcers.

But what happens to patients after treatment ends? There hasn't been enough data to draw firm conclusions but, according to the NCI, "what is clear is that most of our current treatments, although benefiting the patient overall, will produce some measure of adversity." In August, the Institute of Medicine issued a report noting that aftereffects of treatments for various childhood cancers include heart problems, learning disabilities, osteoporosis, kidney damage, and infertility. Patients have paid a price for survival.

One such price is an effect known as "chemo brain." A team of Dartmouth researchers headed by Tim Ahles, Ph.D., and Andrew Saykin, Psy.D., has discovered much of what's known about this phenomenon—a post-chemo decline in the capacity for tasks requiring concentration or the ability to change focus quickly. Even when such factors as depression and age are taken into account, roughly one in four recipients of chemotherapy reports frustrating mental declines. "We're convinced there are long-term cognitive differences," Ahles says, even though the affected population is "a subgroup and . . . probably a minority." A likely explanation, revealed by new imaging methods, is startling, says Saykin: "Chemotherapy can influence brain structure."

Concern about these aftereffects is emerging because only now are there enough long-term survivors—almost 10 million, according to the American Cancer Society—to count and study. "We were so busy trying to cure their problems," Eisenberg says, "that we didn't take into account what life would be like after their cure."

Just as the weaknesses in the old strategies were becoming apparent, some new cancer drugs started showing promise. In 2003 alone, the number of approved drugs designed to attack cancer at its genetic and molecular roots rose from two to more than half a dozen. These drugs stop the uncontrolled cellular growth that characterizes a tumor by introducing proteins into the cell itself. One may countermand a too-prolific protein. Another may prevent a rogue protein from entering a cell, like putting a dummy key in a car's ignition so the real key can't be used to start the engine.

Above: Murray Korc, left, chair of medicine, moved his lab into the new Cancer Center. Below: William Kinlaw, left, and a pair of colleagues. Both images: Flying Squirrel Graphics

The most successful of these new drugs, imatinib mesylate (better known by the brand name Gleevec), works like a dummy key in a rare cancer of the gastrointestinal tract called GIST, or gastrointestinal stromal tumor. GIST resists chemotherapy and radiation, and surgical removal of the stomach or small intestine is usually ineffective. A protein called KIT may be the culprit. From its location on the surface of the cell, KIT turns on and off as it signals a cell that it is time to reproduce; GIST, however, makes KIT signal the cell to multiply without end. Eisenberg, who participated in clinical trials of Gleevec before coming to Dartmouth, explains that the drug creates a protein that blocks KIT from entering a receptor on the cell surface. "It stops the proliferation of the signal to make the cell abnormal," he says.

Gleevec appears to be effective against chronic myeloid leukemia (CML), too. The drug does have some side effects. They're not trivial, Eisenberg says, but are far milder than the pain, nausea, and aftereffects of powerful chemotherapies. Doctors also anticipate less physical weakness, which increases the risk of infection. Furthermore, administration is easy—Gleevec can be taken as a pill. "The concept of cancer as a chronic disease is becoming realistic," Eisenberg says, "because we finally understand how a cell is growing and changing."

But, cautions NCI official Anthony Murgo, M.D., "we're not ready to discard the traditional approaches" of chemotherapy, radiation, and surgery. "Although we'd like to mitigate the side effects, the benefits still outweigh the risks." Gleevec and the other newfangled compounds have been successful with cancers such as GIST and CML because each has a single cellular Achilles' heel. Many cancer cells, Murgo says, require that two or more proteins be neutralized.

But the conceptual shift is already so significant that cancer terminology may need to be revised, Eisenberg says. Today, cancer is defined as "in remission" or the patient as "cured," based on x-rays or CAT scans showing elimination of the tumor. Yet some molecular interventions leave once-malignant cells in the patient, inert and immobilized. Under the old definition, cancer would still be present. New detection methods such as PET (positron-emission tomography), which can show molecular chemical activity, may be required. "As long as that tumor is in an inert condition, if that protein is no longer available" to signal the cell to reproduce, Eisenberg says, "then that patient can live with it without much effect."

Many questions remain: Why do some lung cancer drugs work in some patients but not others? If Gleevec erases a tumor, can patients stop taking the pills? Will there be unanticipated aftereffects from these new therapies? The answers, Eisenberg believes, are likely to come from "an institute like this one, where . . . our understanding of the biology of cancer can come out of the lab and into the clinic."

At that point, patients may no longer have to lick the Big C, for its six-shooters will have been taken away.

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