Overexposed

When Maureen Reagan first noticed a spot on the back of her right thigh more than five years ago, she wasn't too concerned. But then it started looking "gushy," as she put it--and Reagan knew it was time to see a doctor. When she did, in the winter of 1996, the nuisance became a grim diagnosis: malignant melanoma. After surgery and a year of wrenching treatment with the drug Interferon, Reagan was optimistic. But last fall the melanoma was back. By spring, doctors had detected the cancer in her groin, right arm, liver and a rib; by July, it had invaded her brain. Despite aggressive treatment and a crusading spirit, Reagan died last week at home. During her battle against melanoma, she made a point of going public and warning others. With better awareness, she wrote in The Skin Cancer Foundation Journal in 1999, "we can stop this epidemic dead. It's really very simple."

Doctors could not agree more. The incidence of skin cancer has been on a worrisome upward trajectory in this country, affecting more than 1 million Americans a year. Melanoma--the least common, but most deadly form of the disease--strikes at more than twice the rate (14.3 cases per 100,000 people) it did three decades ago. Like Reagan, John McCain has struggled publicly with melanoma. He was first diagnosed in 1993; last year, in the middle of the Republican convention, doctors found a recurrence, removed the lesion--and McCain returned to the festivities with a bandage on his head. Melanoma is one of the most common cancers in Americans between the ages of 25 and 29--when other leading cancers, like lung and colon, rarely occur. This year, the American Cancer Society estimates, 51,400 people will be diagnosed with melanoma and 7,800 will die from it. But doctors say those numbers could be slashed if Americans knew more about how to protect themselves against the disease--and if they were better informed about how to detect it in its earliest stages, when the odds for long-term survival are excellent. The hunt is on for better ways to attack melanoma and even stop it in its tracks. But for now, says Dr. Charles M. Balch of the American Society of Clinical Oncology, "the biggest advance we can make is to heighten public awareness."

The vast majority of skin cancers are "non-melanomas"--either basal-cell carcinomas (which make up about 75 percent of skin cancers) or squamous-cell carcinomas (about 20 percent). Both are harmless as long as they're detected early and removed. In rare circumstances, the lesions do what all cancer cells can do if left untreated: grow uncontrollably. Basal-cell carcinomas, which usually appear on the head, neck and hands, can destroy surrounding tissue and even bone, though the lesions are almost never fatal. Squamous-cell carcinomas can be more vicious: occasionally, patients die from the disease.

Melanomas, however, are by far the most dangerous. Caught early and removed, they are almost 95 percent curable. Yet once they've grown deeper into the skin--sending cancerous cells spinning off into distant parts of the body--melanomas can kill within months. A difference of just a couple of millimeters in the thickness of a mole "is really the difference between life and death," says Dr. Darrell Rigel, of the New York University Medical Center.

Scientists are working hard to understand precisely how melanoma is triggered. Although the link between the sun and all forms of skin cancer is widely accepted, it is more clearly established in non-melanomas than it is in melanoma. Scientists have discovered that when ultraviolet light hits basal and squamous cells, it leaves nifty little molecular signatures in the cells' DNA. But those same genetic mutations have not been detected in melanoma. And melanoma has other characteristics that make its connection to the sun more confounding: in extremely rare instances, the cancer is found in parts of the body never exposed to the sun, like the mouth and soles of the feet.

Still, the circumstantial evidence is overwhelming. Melanoma patients almost always report a history of intense sunburns early in life. Reagan was part of the baby-oil and sun-reflector generation. "I did that myself and always had a year-round tan," she wrote. As a young man, McCain says he got burned on purpose, just to achieve the tan that came later. Melanoma rates have increased worldwide as sunbathing and skimpier clothing have become more popular. The disease is also geographically linked to the sun: the highest rates in the world are in Australia, where a fair-skinned population lives close to the equator. One recent study of World War II POWs found that those who served in the Pacific were three times as likely to die later from melanoma than vets in Europe. And there is even some extremely preliminary molecular evidence making the link between sun and melanoma: researchers at Philadelphia's Wistar Institute announced in March that when human skin grafted onto mice was exposed to ultraviolet light, some animals developed full-blown melanomas.

Even when people think they're protecting themselves, they may not be. Sunscreens offer good defense against burns, but some scientists believe they may be contributing to skin-cancer rates--not because they don't work, but because people use far too little, then bake in the sun far too long. A survey of sunbathers in Galveston, Texas, published in May found that three quarters of those who used sunscreens still went home as pink as a Hawaiian sunset. "People think this little bit of cream can block that big ball of fire in the sky," says Dr. Kathy Fields, a San Francisco dermatologist. "No way." Men, who have the highest rates of skin cancer, are the worst offenders: in the Texas survey, only one third used sunscreen, compared with three quarters of the women.

Although skin cancer is most prevalent in middle age, doctors say they are now seeing more cases in younger patients, even though the numbers are still statistically small. The cancer can even occur in teens. Matthew Brady, now 19, spent summers riding his boogie board on the New Jersey shore, then developed a melanoma at the age of 14. "They cut a steak out of my back," he says. Protecting kids is critical, say doctors, because about 80 percent of lifetime sun exposure happens by the age of 18. "If skin cells are damaged as a child, it causes a cancer clock," says Dr. Paul Nghiem, of the Dana-Farber Cancer Institute in Boston. "The earlier and heavier the damage, the faster the cancer clock ticks."

Australia is years ahead when it comes to safeguarding its children. Neck-to-knee surfer outfits in funky designs are standard in kids' beachwear. Playgrounds are covered with sun canopies, and primary schools have strict "no hat, no play" rules. While the incidence of melanoma in Australia is still dangerously high, rates in younger groups are finally beginning to drop. And after years of increasing in all Australians, rates among women appear to be hitting a plateau and rising less sharply in men.

Americans are much less aware--especially when it comes to knowing the warning signs. Individuals should check themselves routinely, since family doctors usually don't take the time to do full-body skin exams. But in a random phone survey of 1,001 Americans conducted by the American Academy of Dermatology, half of all men and one third of women did not recognize the word melanoma. Only one quarter knew what to look out for--and fewer than half actually did self-exams. It was Shelby Morgan's boyfriend (now husband) who first noticed a mole on her back. By the time the itchy black spot was removed a year and a half later, the cancer had spread to her lymph nodes. "I cried and I cried and I cried," says Morgan, 29, of Orlando, Fla., whose odds of surviving five years are about 50/50. Had it been removed sooner, she says, "I probably would have saved myself."

Scientists are now testing new technology to see if they can make detection more sophisticated--especially for high-risk patients who have a large number of irregular moles. Digital cameras can take a picture of a lesion, magnify it, then store it on a hard drive so the image can be compared from visit to visit--much like doctors use "baseline" mammograms. One experimental device even compares detailed information about the lesion to a database of benign and cancerous moles, then predicts the likelihood of cancer. Most high tech of all: a picture so precise it might one day be sent as a digital biopsy through the computer to a pathologist for immediate diagnosis.

Detection equipment will do nothing for patients fighting the disease right now--they desperately need better treatment. Some of the most promising advances are in battling non-melanomas. A drug called Imiquimod, used to treat genital warts, cleared up superficial basal-cell carcinomas (flat and scaly, they typically appear on the upper body) in about 90 percent of patients in a pilot study. If the results are as good in a larger trial, patients might be spared the traditional burning, scraping or surgery. Another experimental compound, Dimericine, may even prevent non-melanomas from forming in the first place. The drug has been tested in people with xeroderma pigmentosum (XP), a condition that makes patients highly susceptible to skin cancers. Those who used the lotion for a year had a 30 percent decrease in basal-cell carcinomas and a 68 percent decrease in actinic keratoses--lesions that are precursors to squamous-cell carcinomas. (President George W. Bush had three removed last week.) And the National Cancer Institute (NCI) is also launching a trial of the arthritis drug Celebrex, which appears to prevent polyps from developing into colon cancer, to see if it might stop actinic keratoses from becoming squamous-cell carcinomas.

Given its deadly potential, doctors are most desperate to improve treatments for invasive melanoma, a wily and aggressive disease that responds miserably to chemotherapy and radiation. The drug Interferon boosts survival only modestly and can be highly toxic. Reagan once said it made her feel as if she had "a massive case of Asian flu." The NCI is now sponsoring trials in drugs that are showing promise in other cancers. One is Gleevec--a sophisticated new "smart bomb" drug--which has helped put certain patients with chronic myelogenous leukemia and gastrointestinal cancer into remission.

Researchers do know that melanoma is one of the most "immunogenic" of cancers, meaning the body's own immune system fights a strong battle against it; in rare cases, melanomas have even spontaneously disappeared. For years, scientists have been testing vaccines to boost and take advantage of that immune response. The vaccines (which are therapeutic, not preventative like a measles shot) contain fragments of melanoma cells called antigens, which are like little flags on the cell's surface tipping them off as foreign invaders. The hope is that by bombarding the body with melanoma antigens, the immune system will wake up and launch an attack. No vaccine has made it to market yet, and there have been stumbling blocks along the way. But those who have benefited so far propel the research forward. Rosemary Treese, 79, got the experimental vaccine Canvaxin--now in trials nationwide--13 years ago. Today, still cancer-free, she calls the therapy "the most fantastic thing in the world."

Ultimately, scientists hope to pinpoint the genetic steps that turn normal skin cells into cancer. If doctors knew exactly how a mole switches from benign to malignant or why one melanoma becomes more aggressive than another, they might be able to develop targeted therapies that could interrupt the process and stop the disease. That research is now going on, and already certain groups of genes have been located, but it is still too early to know when and if new compounds will make it to the clinic.

Maybe the best inspiration for covering up will come from people like Nicole Kidman and Angelina Jolie--who make pale skin look glamorous. Robin Coe Hutshing, who runs a beauty boutique in Santa Monica, Calif., says she has customers who are "these gorgeous creatures with milk-white skin that has never seen a ray of sun." That, she says, "is a whole fashion look in and of itself." Maureen Reagan probably wouldn't have cared how the message got out, as long as it did. "I don't want anybody else to go through this," she told a British magazine three years ago. "If you have to have a melanoma, find it early." A powerful mandate--and a legacy that might even save lives.

Photo: Why She's AT RISK: She's got it all wrong--over-oiled, undercovered and out in the noonday sun. Other risk factors: pale skin (Caucasians are far more vulnerable, though all groups are at risk), light eyes and hair, freckles, lots of moles, a family history, childhood sunburns and prior skin cancers.

Sometimes a mole is just a mole--but it can also be deadly. Basal-cell carcinomas often appear on the head, neck and hands; squamous on the face, ears, lips and mouth. In women, melanomas tend to be on the back and legs; in men, on the back and chest. But they can occur anywhere. Check yourself regularly from head to toe, be proactive about getting a diagnosis and ask your doctor for a full-body check every year.

· 800,000 new cases a year

· What happens: The least deadly form of skin cancer. It develops in cells that line the base of the epidermis. The cancerous cells clump together into clusters that almost never travel beyond the skin.

· What to look for: Comes in a variety of forms, including bloody, oozing sores that stay open for weeks; irritable, reddish patches; pearly bumps that can be pink, white or brown, or waxy, scarlike areas with poorly defined borders.

· 200,000 new cases a year

· What happens: Starts in the top layer of skin. The affected cells form a mass of tissue that usually doesn't spread to other body parts, but can be deadly when it does.

· What to look for: A crusty, wartlike growth with occasional bleeding that may grow rapidly in size, appearing often in areas damaged by burns, scars and sores. Most common in people chronically exposed to the sun.

· 51,400 new cases a year

· What happens: Cancerous cells can break off into fast-growing clusters and spread through the body via nearby blood vessels. The deeper the melanoma, the more likely it is to metastasize and kill.

· What to look for: Asymmetrical moles with uneven borders that tend to grow past 1/4 inch (the size of a pencil eraser) in diameter. Color is uneven, ranging from black to tan with regions of white, red or gray.

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