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Cancer: the hope, the hype & the reality

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    Cancer: the hope, the hype & the reality

    Cancer: A Realistic Assessment

    The statistics are grim, but oncologists are hopeful

    Cancer will kill some 555,000 Americans this year. Among the victims so far: Dan Case, older brother of AOL Time Warner (AOL ) Chairman Steve Case. An investment banker in Silicon Valley, Dan died in June at age 44 of a brain tumor, a year after it was detected. "When Dan was diagnosed, I was very surprised to learn that no one knows what causes brain cancer or how to cure it, despite decades of work," says Steve. Instead of waiting passively for the inevitable, the Cases founded Accelerate Brain Cancer Cure last year, aiming to apply "results-driven strategies" to research. Steve now realizes no one organization, company, or government initiative can stop this scourge. As he told a Senate committee a few weeks before his brother died: "The only way we can find a cure is by working together."

    Case's frustration is understandable. The three-decade-old War on Cancer has cost the federal government more than $50 billion for research, and private industry has kicked in billions more. But the body bags keep piling up, and the statistics are even worse than had been assumed: The National Cancer Institute (NCI) discovered in October that incidents of the five most common cancers, thought to have leveled off since 1997, have done the opposite. Once the figures were revised, rates of lung, breast, prostate, colon, and skin cancers all steadily increased. Today, one in three people will develop cancer in his or her lifetime, and half of them will die within five years of diagnosis. In 10 years, cancer will likely surpass heart disease as the leading cause of death in the U.S.

    There's no way to gloss over these grim numbers. Remarkably though, most oncologists feel hopeful rather than helpless. Cancer treatment is finally on the verge of a transformation. This is no premature pronouncement about a cure. To be frank, most doctors in this field no longer use that term. Instead, oncologists envision a more realistic--and attainable--containment strategy. They're convinced that within five years it may be possible to use a windfall of new, precisely targeted drugs to keep cancer in check while patients live longer and relatively symptom-free lives, much as insulin is used to contain diabetes.

    This is no pipe dream. Over a dozen new drugs have been accepted by the Food & Drug Administration for expedited review, each meant to replace chemotherapy. "We'll start to see an impact, and by that I mean prolonging of life, in the next five years," says Dr. Lee M. Ellis, an oncologist at M.D. Anderson Cancer Center in Houston. Further out, the outlook is more heartening. "Within 15 years, we should see major changes in many cancers resulting from the treatments we're working on now," says Dr. Robert C. Young, president of Fox Chase Cancer Center in Philadelphia. "That's lightning speed in cancer research."

    Patients may feel they've heard all this before. Back in the 1980s, interferon and interleukin-2 were heralded as magic bullets, only to produce little or no impact. The latest drugs are far more promising, but they must contend with cancer's nefarious tendency to develop resistance to almost any drug.

    Still, oncologists are confident that this time they won't be disappointed. The past several years have yielded a wealth of insights into the mechanisms that turn healthy cells into killing machines. Researchers now have the understanding they need to gum up the works of these cancer cells. Some 170 pharmaceutical and biotech companies are running clinical trials for over 400 innovative cancer drugs--far more than for any other disease category. As these drugs wend their way through the testing process, stories from the front lines of patient care signal that cancer could one day be a disease we can live with, not die from.

    Ann Marie Reynolds, a 45-year-old nurse living near Albany, N.Y., had a persistent cough in August, 1999. Never having smoked, she wasn't unduly concerned. After a few weeks, she went to her doctor, and the news was about as bad as it can get: Reynolds had an advanced case of lung cancer. This disease is responsible for far more deaths than any other type of cancer--and less than 10% of its victims are non-smokers. In the next 12 months, Reynolds tried four different toxic chemotherapy drugs. Nothing worked, and by November, 2000, there were tumors in her liver. Her lungs were so blocked that she needed oxygen almost constantly.

    Reynolds, however, is one of cancer's lucky ones--and perhaps, a harbinger. In January, 2001, she entered a clinical trial for AstraZeneca (AZN ) PLC's Iressa, a targeted therapy meant to stop tumor cells from spreading while leaving healthy cells alone. "There wasn't much hope. I knew the realities," Reynolds says. Still, she made the trip to Memorial Sloan-Kettering Cancer Center in Manhattan, oxygen tank by her side. Within a week of starting the daily pill, she could breathe on her own. In a few months the initial tumor shrank; it has yet to grow back. The only side effect was a severe, acne-like rash that cleared up after two months. "It's wonderful," she says. "For the first time since I was diagnosed, I feel hope. I'm considering going back to work."

    Stories like that highlight the complications of cancer research as much as the triumphs. On Sept. 24, an FDA advisory panel recommended Iressa for approval, based on a clinical trial showing it shrank tumors in 10% of advanced-stage lung cancer patients. That's considered a significant result in such sick patients, even though there's no evidence the drug prolongs life.

    Still, negative news may cause the FDA to reject the drug when it considers Iressa in January. In Japan, where Iressa was approved this summer, 39 deaths from pneumonia have been associated with the drug. And in August, a separate trial found that newly diagnosed lung cancer patients who received Iressa in combination with chemotherapy didn't respond at all. "This is exactly the opposite of what everyone expected, which is that Iressa given early would get a better response," says Eric Dupont, CEO of Canadian biotech AEterna Laboratories Inc. (AELA ).

    The disappointing results were a blow to the whole field of cancer-drug development--and hardly the first one. Last May, Protein Design Labs Inc. (PDLI ) reported that 36% of leukemia patients responded to its drug Zamyl, but failed to live longer than those on standard chemotherapy. In September, trials of Genentech Inc.'s (DNA ) Avastin failed to show improved survival. ImClone Systems Inc.'s (IMCL ) controversial drug Erbitux seems to help some colon cancer patients, but the trial data have been called into question.

    What's going wrong? "When targeted therapies work, they are really helpful," says Dr. Mark G. Kris, in charge of Iressa trials at Sloan-Kettering. "But they don't work for everybody." That is the catch-22 facing companies struggling to come up with new cancer weapons. Although trial after trial shows that targeted therapies can be highly effective for a small subset of patients, there is no easy test to identify them. If the wrong patients end up in a clinical trial, success rates could be too low to win a nod from the FDA.

    From a business perspective, drugs that address only a small demographic may seem problematic. But the drug industry has shrugged off this worry--virtually all the cancer drugs in human trials are targeted therapies. The companies reason that patients who do improve on a given drug may take it for the rest of their lives. That translates into a lot of revenue: Iressa costs $3,000 a year in Japan. Analysts do not expect payers to balk at those prices, given the alternatives. The National Institutes of Health estimate that cancer costs the U.S. $60 billion annually in direct medical costs (including $8.8 billion for drugs) and a further $120 billion in lost productivity due to illness and premature death.

    Big Pharma and biotech firms alike are pushing ahead with targeted therapies. Novartis (NVS ) has 10 cancer drugs in development, and "from 2005 onwards, our new launches are almost exclusively oncology products," says development head Jorg Reinhardt. Biotech companies are even more heavily invested because most targeted therapies stem from biological rather than chemical discoveries. "We expect the cancer sector to be the fastest-growing in biotech, given the rate of innovation," says analyst Dr. Mark Monane of Needham & Co.

    Those innovations are based on two decades of painstaking progress in deciphering the molecular underpinnings of cancer. Scientists have identified a dozen or so genes, along with the hundreds of different signals they emit--often referred to as pathways--that turn a normal cell malignant. Transforming these discoveries into treatments has been arduous. "Drug development takes forever," laments Genentech CEO Arthur D. Levinson. On average, it takes 15 years to go from lab to market--and the first genes associated with cancer were discovered only 20 years ago. Still, hundreds of different methods for blocking cancer signals have been developed. "The good news is that there appear to be a limited number of pathways that underlie the development of most tumors," says Dr. Bert Vogelstein, oncology professor at Johns Hopkins University Medical Center. "But just as there are many ways to skin a cat, there are many ways to inactivate a pathway."

    Unfortunately, choosing the right point of intervention is just one challenge. Cancer cells can learn to evade the smartest therapy. The cancer community overlooked this fact in April, 2001, when the FDA approved the first targeted therapy, Gleevec. Novartis' drug blocks the action of a single defective gene responsible for chronic myeloid leukemia (CML), a rare cancer of the blood. It was heralded as a near-miracle because 80% of patients improved. Then came the rude awakening: CML cells in some patients quickly mutated until they were resistant to Gleevec.

    Just as infectious-disease specialists keep trying new antidotes to drug-resistant microbes, however, cancer specialists are hopeful that an arsenal of targeted therapies will be able to overcome drug-resistant cancer cells. In an ideal future, an oncologist will analyze a patient's tumor, determine which cellular mechanisms drive its growth, and choose the drugs designed to shut them down. As soon as one drug stops working, the patient would switch to another. It's not a cure, but this prospect may be as good as it gets for cancer. As long as the pool of drugs can be constantly replenished, many patients may be able to hold illness at bay indefinitely.

    First, though, drug developers must figure out how to get a targeted therapy to work on more than 10% to 15% of patients. The lowest response rates are for victims of solid tumors that start in the lung, colon, breast, or prostate, which make up 50% of all cases. These cancers, unlike CML, are caused by multiple defects. "Gleevec was an important step forward in demonstrating how to take a single genetic alteration and translate it into a new drug," says Homer L. Pearce, vice-president of cancer research for Eli Lilly & Co. "The treatment of solid tumors is going to be very different."

    The required approach in such cases will almost certainly be a drug cocktail. Targeted therapies will initially be used with chemotherapy, and eventually with one another. Dr. Dennis Slamon, a leading researcher at the University of California at Los Angeles, is already testing Genentech's Herceptin, a breakthrough breast cancer drug approved in 1998, in combination with two of Genentech's experimental targeted therapies, Avastin and Tarceva.

    Such cocktails will face their own special hurdles. Longtime competitors will not easily agree to join forces to test their experimental therapies together. Even if they do, the FDA has rarely allowed experimental drugs to be tested in combination, preferring to see a drug prove efficacious as a stand-alone. "The FDA has to get more realistic," says Dr. Eric P. Winer, director of the breast cancer unit at Dana-Farber Cancer Institute in Boston. "Most new drugs are not designed to be home runs on their own, and they should not be judged as though they are."

    The more clinicians work with targeted therapies, the more convinced they are that no drug on its own can win; there are simply too many pathways tumors can use to spread through the body. To complicate matters, the same paths are used for normal cell division. It's only when a cell starts to divide uncontrollably that the paths facilitate a killing machine.

    It is the normal and continuous renewal of the body's cells that sets the machine off (table). As cells divide and die--a balancing act that occurs millions of times over--tiny mistakes are made and copied into the two sets of genes that control the process. Another set of cleanup genes corrects these mistakes, but over time they can become overwhelmed. The longer a person lives, the more defects pile up--until a gene goes haywire. The balancing act is disrupted, and cells multiply out of control.

    Targeted therapies aim to reintroduce balance. First, a patient's defective pathways are identified, then the proper antidote, or antidotes are administered. "I can imagine a scenario where five pathways are significant," says Dr. George D. Demetri, a medical director at Dana-Farber. "If you block all five, you have major containment--but you have to hit all five." That prospect, he admits, is humbling, but it can be done.

    There are four leading contenders among the many containment strategies:

    STARVING THE TUMOR. Melanie McDaniels of Londonderry, N.H., is a typical 22-month-old--except that she has a brain tumor. She started having seizures at five months, in June, 2001. Childhood cancer is not the death sentence it once was--about 50% are cured--but it is the second leading cause of death, after accidents, in children under 15. Melanie's prognosis was grim after two operations failed to stop the tumor's growth. "We thought it would be hopeless. What could possibly fix this?" recalled her father, Paul, who left his job to care for his daughter.

    Last November, in a last-ditch effort, Melanie's mother Amy got in touch with Boston's Children's Hospital. Dr. Mark W. Kieran, director of pediatric neuro-oncology at nearby Dana-Farber, enrolled Melanie in a clinical trial of four powerful drugs meant to shut down the blood supply to the tumor, essentially starving it to death. One of the four was Thalidomide, the drug that caused horrific birth defects when taken by pregnant women in the 1960s. It has since reemerged as a cancer drug because of its ability to stop blood vessel growth. The treatment requires a weeklong hospital stay every 21 days while Melanie receives the infusions. "We decided that, if anything, it might carry her along till they found something that would work," says Paul. But the little girl surprised everyone. Her tumor stopped growing, and she's now running around like any other toddler.

    Treatments that block blood-vessel growth are called anti-angiogenesis drugs. The group as a whole has had more failures than successes, but there is still a firm belief that cutting off cancer's blood supply can stop it in its tracks. More than 40 anti-angiogenesis drugs are in clinical trials, and they are likely to end up being more complementary than competitive. Dr. Judah Folkman of Children's Hospital, father of the angiogenesis field, says that as tumor cells mature, they call on multiple pathways to encourage blood vessel growth. "By using more than one of these agents, we might be able to block the full angiogenic output of the tumor," he contends.

    Genentech's Avastin is the furthest along of this group. It may be having problems, however, because it blocks only one pathway, the protein VEG-F. Another drug in this class, AEterna's Neovastat, hits at least four anti-angiogenesis pathways. Neovastat doubled the survival of kidney-tumor patients in early clinical trials and is now in phase-3 trials against kidney and lung cancer and multiple myeloma. AEterna expects to seek FDA approval late next year.

    BLOCKING GROWTH. The largest category of targeted therapies in development block proteins that encourage cell growth. All cells need such growth factors, but cancer cells take far more than their fair share. The most common, epidermal growth factor (EGF), is found in large amounts in more than 50% of solid tumors. At least 14 anti-EGF drugs are in clinical trials, including Iressa and ImClone's Erbitux, but none has yet proved its worth unequivocally. Specialists place the blame, in part, on the difficulty in determining exactly which patients are most receptive to an anti-EGF drug.

    Again, one way around this problem may be to administer a cocktail of growth blockers, and a number of other ways are under study. Similar to EGF is an insulin-like growth factor called IGF-1, which seems to affect growth and blood-vessel production. IGF drug development is still in its infancy, though ImmunoGen Inc. (IMGN ) in Cambridge, Mass., is expected to start human trials in the next two years.

    THE DEATH STAR. Cells of all living organisms are programmed to die at some point to make room for new cells, a process called apoptosis. In cancer, apoptosis stalls out, allowing tumor cells to live long past their sell-by date. Several biotech companies are testing drugs that trigger the gene responsible for this process, but they face a tough challenge: It's harder to turn a gene on than off.

    Millennium Pharmaceuticals Inc. (MLNM ) is trying a different tack by avoiding apoptosis genes altogether. Its Velcade drug, currently in phase-3 trials, blocks overprotective enzymes that prevent cells from dying. There's a lot of excitement in the cancer world about Velcade because it is one of the few targeted therapies that has not experienced setbacks. When tested against the blood cancer multiple myeloma, Velcade stabilized or reduced disease in 77% of 78 patients.

    However, the drug has yet to prove itself against solid tumors, which are far more common than blood cancers. For those, the most popular apoptosis target is the p53 gene, which plays a role in purging defective cells. P53 is inactivated in more than 50% of solid tumors, and at least four biotech outfits are developing drugs that would turn it back on. Advexin, for example, from Introgen Therapeutics Inc. (INGN ), uses a deactivated virus to deliver a working p53 gene to the patient. Advexin is in phase-3 trials against head and neck cancer and in early tests against lung cancer.

    LIFELONG PROTECTION. Cancer patients know all too well that they are never out of the woods. Cancer cells can reappear years after "successful" treatment, and recurrence usually kills. When John L. Willey, 57, was diagnosed with prostate cancer at age 40, he had his entire prostate and surrounding tissue removed, but 12 years later the cancer was back. The father of two sons, now 16 and 10, Willey decided to try buying time with a vaccine that would train his immune system to take out the tumor cells. He enrolled in a clinical trial at Johns Hopkins for GVAX, from Cell Genesys Inc. (CEGE ), and got two shots a week for eight weeks. So far, the cancer has not resumed its spread. "I know I have a disease that is incurable," says Willey. So he is lobbying for enrollment in a trial for a new, stronger version of GVAX.

    Immunotherapy is the great hope of many cancer specialists, and the most elusive: It is devilishly hard to get the body to defend itself against a homegrown enemy. Plenty of biotech startups are determined to find a way, and are responsible for some 70 vaccines in development. New York's tiny Antigenics (AGEN ) is a case in point: Its skin cancer vaccine, HSPPC-96, generated considerable buzz in October when data from a phase-1 trial showed that it eliminated tumors in 2 of 28 patients with advanced skin cancer, and stabilized the disease in three.

    These drugs have more safety hurdles to overcome than other treatments, however. Because cancer cells so closely resemble normal ones, there is a danger that a stimulated immune system will go after both. It doesn't help that many of the early candidates failed clinical trials. This year, however, 29 cancer vaccines are in late-stage trials. "I think several of these have a good chance of success," says Monane.

    Of course, all of these initial targeted therapies could wash out. But researchers insist that early failures should not discredit the entire field. "There could be a problem with the design of the clinical trial, or a drug may need to be tweaked to improve its effectiveness," says Dr. Geoffrey Duyk, chief scientific officer of Exelixis Inc., which has several drugs in preclinical development. "I think the biggest threat to the whole field of cancer research is people giving up too soon." One need only listen to patients to realize this truth.

    Perry Colmore, a 60-year-old former newspaper editor in Massachusetts, was diagnosed with breast cancer in 1987. She had one breast removed, and the second one in 1995 when the cancer returned. By then, the disease had spread to her lymph nodes. "I figured I was dying and was ready to give up," she says, "but a wonderful social worker convinced me to keep going." Colmore went through a brutal chemo regimen at Boston's Beth Israel Deaconess Medical Center, 35 rounds of radiation, and took tamoxifen, a hormone- based treatment, for six years. She also started meditating, gave up drinking, changed her diet, and moved from a Boston suburb to Martha's Vineyard. Six months ago, she started a clinical trial for Femara, a promising breast cancer drug from Novartis. She has suffered from multiple side effects from all these treatments, among them pleurisy, asthma, arthritis, and weight gain. Still, "asthma's a lot better than being dead," she says flatly. "It's pretty annoying that we don't have a a cure and we don't even know why we're getting cancer," Colmore admits. Nevertheless, "I have a feeling a lot of miracles are being worked."

    By Catherine Arnst
    With John Carey in Washington, Arlene Weintraub in Los Angeles, and Kerry Capell in London
    "Oh yeah life goes on
    Long after the thrill of livin is gone"

    John Cougar Mellencamp