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Research... and Hope

More precise therapes aim to spare the body's healthy tissue

By RachelK. Sobel

In his prime, Joe Haley could lift 150-pound boxes, one after another, as a cargo loader for Southwest Airlines. With his sturdy 6-foot-1 frame, he could hoist even the most cumbersome luggage. But since his diagnosis of cancer of the liver more than a year ago, his robust body has rapidly withered away. There's no more washboard stomach; gone are the bulging quadriceps. "I probably can't even walka mile now," says the 36-year-old father of two.

Ironically,it wasn't the cancer that wreaked havoc on his health. The treatment did. "He had no symptoms from the disease at first. All theside effects came from going to doctors," says David Van Echo, his oncologist at the University of Maryland-Baltimore. Of course, without chemotherapy, Haley would have died. But with it, he has wasted away from fevers, nausea, and fatigue.

Like millionsof other patients, Haley encountered the age-old conundrum of traditional cancer therapies, chemotherapy and radiation. They are thankfully potent, but at times too potent. Not only do they annihilate cancer cells; they wipe out healthy ones, too. This leads to devastating side effects. For decades, researchers have pondered ways to soften these repercussions without diluting the treatments' strength. They've varied dosage schedules to improve tolerance and designed drugs to counter nausea. But now, scientists have begun to take a vastly different approach to the toxicity problem: Aim treatments directly at tumors and spare healthy tissue along the way. In dozens of hospitals across the country, doctors are vigorously experimenting with novel "vehicles"–such as glass beads and magnetic particles–to deliver treatments right to the cancer.

Such a remedycan't come soon enough for Haley. Early this summer, conventionaloptions abruptly ran out when chemotherapy poisoned his kidneys.Surgery, though potentially curative, was no alternative, becausegolf-ball-size tu- mors had already invaded too much of his liver.Standard radiation was out, too. External X-ray beams strike toobroadly and would destroy his remaining normal tissue.
In late summer, however, Haley's hope was rejuvenated. He becamethe first patient to undergo radioactive glass bead therapy sinceits FDA approval earlier this year. (The device's approval was basedonly on safety; its effectiveness will be evaluated at several universityclinics.) These minuscule beads are packed with a radioactive elementand sent on a one-way trip straight to the liver. There, they emitradiation for as long as a month to tumors just millimeters away.After the radioactive element has decayed, the beads remain harmlesslylodged in the liver.

On paper, thebeads look promising. They harness the potency of radiation while leaving the rest of the body unscathed. What's more, the radioactive dose has the potential to be much greater than a typical one, since the beads' rays hardly affect normal tissue. In the end, if enough radiation can be packed into the tiny beads, "no tumor willsurvive–period," says Van Echo, also the director of new-drug development at the University of Maryland's Greenebaum Cancer Center.

Chemical magnetism.While some doctors are trying to steer radiation to its target, others are striving to do the same with chemotherapy. UCLA's Scott Goodwin has just the gadget in mind. He is shuttling chemotherapy directly to tumors with miniature magnetic vehicles–tiny medicine-coatedparticles, made of iron dipped in doxorubicin, a strong anticanceragent. Once injected into the bloodstream, these particles gravitatetoward the tumor by the pull of a magnet, the size of a large soupcan, positioned over the tumor site for 15 minutes. "The particlesare actually pulled through the blood-vessel wall out into the tumoritself," says Goodwin, principal investigator of the trial."Then you get a slow release of the drug inside the tumor tissue."

Whether this technique will prove superior to traditional treatments is yet to be determined. So far, preliminary results with liver cancer suggest it might also be used in the lungs, pancreas, and brain. The treatment minimizes side effects such as hair loss and nausea. And it leaves a stockpile of toxic drugs in the tumor for a few days with minimal effect on rest of the body. This is a welcome change from standard chemotherapy, where only a fraction of the drug dose congregates at the desired tumor site; the rest circulates in the bloodstream and unnecessarily harms healthy tissues. So, there are legitimate reasons to think the magnetic transporters might be more effective, says Goodwin, but "that's a long ways from saying that we know it's better."

Reason to believe.For Doris Drennen of Sandusky, Ohio, an experimental targeted therapy indeed provided a better option. After radiation, chemotherapy, and mastectomy, Drennen thought she had squelched her breast cancer. But a plum-size lump soon surfaced. Her doctor injected the tumor locally with an experimental viscous gel because the tumor had only popped up in one place. Treating the whole body would have been like "killing something with a sledgehammer when, in the schemeof things, it's the size of a grain of rice," says Richard Leavitt, an oncologist and vice president for gel-producer Matrix Pharmaceutical of Fremont, Calif.

The tumor shrankin a matter of weeks, thanks to the gel's clever cocktail of ingredients.The gel contains chemotherapy blended with epinephrine, which constrictsblood vessels surrounding the tumors. The taut blood vessels trapthe chemotherapy at the site for hours, or even days. As as result,drug concentration can be 10 to 1,000 times higher than with bloodstreamadministration.

With encouragingclinical results like Drennen's, the company plans to apply for FDA approval later this year. More than 450 patients have been treated so far for melanoma, breast, colon, liver, and esophageal cancer, among others. And for head and neck cancer patients, nearly 1 out of 3 saw tumor size shrink by at least half. "Many of thesepatients had failed standard chemotherapy, but this actually worked," says Glenn Mills, professor of medicine at Louisiana State University Health Sciences Center at Shreveport.

Several othertargeting methods have already been approved by the FDA, but doctors are still trying to figure out how to effectively use them. Some scientists, for instance, are experimenting with cryosurgery, which entails freezing cancerous tissue to destroy it. Others are investigating radiofrequency (RF) ablation–poking tumors with probes tosear the cancerous tissue away with intense heat. "We knowRF is safe in the liver, but we want to look at other organs, likethe prostate gland, kidneys, and lungs," says Steven Curley, a professor of surgery at the University of Texas M. D. Anderson Cancer Center.

Although thesenovel technologies have roused hope, they do have limitations. For one thing, they aren't the ultimate cure for cancer. "I findit appealing to stick something right into tumors and kill them,but it's just not practical for most tumors. They're widespread," says David Golde, physician in chief at Memorial Sloan-Kettering Cancer Center. Ninety percent of all cancer deaths are due to metastatic cancer, but these new approaches aim only for localized tumors. In the long term, Golde banks on strategies such as vaccines (box) or gene therapy that home in on cancer cells lurking anywhere in the body.

Still, theseinnovative delivery systems could help a host of needy patients. If cancer is caught early, patients can get rid of the disease with targeted therapy before it spreads. Even some advanced cancers stay confined to limited areas and thus are candidates for localized treatment. This year, 15,300 new liver cancer cases will turn up in America and the vast majority will remain in the liver. Colon cancer that spreads to the liver–which affects 20,000 to 40,000people annually–also tends to stay put.

Joe Haley'scancer, it turns out, only plagues his liver. Since the glass bead radiation therapy, his liver functions have improved dramatically, his energy has escalated, and his tumors have gotten less tender–asure sign of shrinkage. "For the first time in a year,"he says excitedly, "I was able to take my kids out to the mall for sundaes."