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Why we're losing the war on cancer [and how to win it]

By Clifton Leaf
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Originally published in the March 22, 2004 edition of Fortune, Why We're Losing the War on Cancer describes the battles of cancer patients and officials.

It's strange to think that I can still remember the smell after all this time. The year was 1978, not long after my 15th birthday, and I'd sneaked into my brother's bedroom. There, on a wall of shelves that stretched to the ceiling, were the heaviest books we had in our house--24 volumes of the Encyclopedia Britannica. The maroon spines were coated in a film of dust, I remember. The pages smelled as if a musty old pillow had been covered in mint.

I carefully pulled out the volume marked HALICARNASSUS TO IMMINGHAM and turned to the entry for Hodgkin's disease. It took forever to read the half-dozen paragraphs, the weighty book spread open on my lap like a Bible. There was talk of a mysterious "lymphatic system," of "granulomas" and "gamma rays," as though this disease--the one the doctor had just told me I had--was something out of science fiction. But the last line I understood all too well: Seventy-five percent of the people who got it would die within five years.

As it turns out, I did not die from Hodgkin's, though the cancer had already spread from my neck to my lungs and spleen. I lost my spleen to surgery and most of my hair to chemotherapy and radiation. But I was lucky enough to get into a clinical trial at the National Cancer Institute that was testing a new combination therapy--four toxic chemicals, together called MOPP, plus those invisible gamma rays, which flowed from an enormous cobalt 60 machine three stories below ground. The nurses who stuck needles in my arm were so kind I fell in love with them. The brilliant doctor who tattooed the borders of an imaginary box on my chest, then zapped me with radiation for four weeks, had warm pudgy hands and a comic look of inspiration, as though he'd thought of something funny just before entering the exam room. The American taxpayer even footed the bill.

Most of all, of course, I was lucky to survive. So it makes the question I am about to ask sound particularly ungrateful: Why have we made so little progress in the War on Cancer?

The question may come as a shock to anyone who has witnessed a loved one survive the dread disease--or marveled at Lance Armstrong powering to his fifth Tour de France victory after beating back testicular cancer, or received a fundraising letter saying that a cure is within our grasp. Most recently, with media reports celebrating such revolutionary cancer medicines as Gleevec, Herceptin, Iressa, Erbitux, and the just-approved Avastin, the cure has seemed closer than ever.

But it's not. Hope and optimism, so essential to this fight, have masked some very real systemic problems that have made this complex, elusive, relentless foe even harder to defeat. The result is that while there have been substantial achievements since the crusade began with the National Cancer Act in 1971, we are far from winning the war. So far away, in fact, that it looks like losing.

Just count the bodies on the battlefield. In 2004, cancer will claim some 563,700 of your family, friends, co-workers, and countrymen. More Americans will die of cancer in the next 14 months than have perished in every war the nation has ever fought ... combined. Even as research and treatment efforts have intensified over the past three decades and funding has soared dramatically, the annual death toll has risen 73%--over one and a half times as fast as the growth of the U.S. population.

Within the next decade, cancer is likely to replace heart disease as the leading cause of U.S. deaths, according to forecasts by the NCI and the Centers for Disease Control and Prevention. It is already the biggest killer of those under 75. Among those ages 45 to 64, cancer is responsible for more deaths than the next three causes (heart disease, accidents, and stroke) put together. It is also the leading disease killer of children, thirtysomethings--and everyone in between.

Researchers point out that people live a lot longer than they used to, and since cancer becomes more prevalent with age, it's unfair to look just at the raw numbers when assessing progress. So when they calculate the mortality rate, they adjust it to compare cancer fatalities by age group over time. But even using this analysis (in which the proportion of elderly is dialed back to what it was during the Nixon administration), the percentage of Americans dying from cancer is about the same as in 1970 ... and in 1950. The figures are all the more jarring when compared with those for heart disease and stroke--other ailments that strike mostly older Americans. Age-adjusted death rates for those diseases have been slashed by an extraordinary 59% and 69%, respectively, during the same half-century.

Researchers also say more people are surviving longer with cancer than ever. Yet here, too, the complete picture is more disappointing. Survival gains for the more common forms of cancer are measured in additional months of life, not years. The few dramatic increases in cure rates and patient longevity have come in a handful of less common malignancies--including Hodgkin's, some leukemias, carcinomas of the thyroid and testes, and most childhood cancers. (It's worth noting that many of these successes came in the early days of the War on Cancer.) Thirty-three years ago, fully half of cancer patients survived five years or more after diagnosis. The figure has crept up to about 63% today.

Yet very little of this modest gain is the result of exciting new compounds discovered by the NCI labs or the big cancer research centers--where nearly all the public's money goes. Instead, simple behavioral changes such as quitting smoking have helped lower the incidence of deadly lung cancer. More important, with the help of breast self-exams and mammography, PSA tests for prostate cancer, and other testing, we're catching more tumors earlier. Ruth Etzioni, a biostatistician at Seattle's Fred Hutchinson Cancer Research Center, points out that when you break down the Big Four cancers (lung, colon and rectal, breast, and prostate) by stage--that is, how far the malignant cells have spread--long-term survival for advanced cancer has barely budged since the 1970s (see charts opposite).

And the new cases keep coming. Even with a dip in the mid-1990s, the incidence rate has skyrocketed since the War on Cancer began. This year an additional 1.4 million Americans will have that most frightening of conversations with their doctor. One in two men and one in three women will get the disease during their lifetime. As a veteran Dana-Farber researcher sums up, "It is as if one World Trade Center tower were collapsing on our society every single day."

So why aren't we winning this decades-old war on terror--and what can we do now to turn it around?

That was the question I asked dozens of researchers, physicians, and epidemiologists at leading cancer hospitals around the country; pharmacologists, biologists, and geneticists at drug companies and research centers; officials at the FDA, NCI, and NIH; fundraisers, activists, and patients. During three months of interviews in Houston, Boston, New York, San Francisco, Washington, D.C., and other cancer hubs, I met many of the smartest and most deeply committed people I've ever known. The great majority, it should be said, were optimistic about the progress we're making, believing that the grim statistics belie the wealth of knowledge we've gained--knowledge, they say, that will someday lead to viable treatments for the 100-plus diseases we group as cancer. Most felt, despite their often profound misgivings about the way research is done, that we're on the right path.

Yet virtually all these experts offered testimony that, when taken together, describes a dysfunctional "cancer culture"--a groupthink that pushes tens of thousands of physicians and scientists toward the goal of finding the tiniest improvements in treatment rather than genuine breakthroughs; that fosters isolated (and redundant) problem solving instead of cooperation; and rewards academic achievement and publication over all else.

At each step along the way from basic science to patient bedside, investigators rely on models that are consistently lousy at predicting success--to the point where hundreds of cancer drugs are thrust into the pipeline, and many are approved by the FDA, even though their proven "activity" has little to do with curing cancer.

"It's like a Greek tragedy," observes Andy Grove, the chairman of Intel and a prostate-cancer survivor, who for years has tried to shake this cultural mindset as a member of several cancer advisory groups. "Everybody plays his individual part to perfection, everybody does what's right by his own life, and the total just doesn't work."

Tragedy, unfortunately, is the perfect word for it. Heroic figures battling forces greater than themselves. Needless death and destruction. But unlike Greek tragedy, where the Fates predetermine the outcome, the nation's cancer crusade didn't have to play out this way. And it doesn't have to stay this way.

'A very tough set of problems'

Nuclear fission was a mere eight months old when the Panzers rolled into Poland in September 1939, beginning the Second World War. Niels Bohr had announced the discovery at a conference on theoretical physics at George Washington University. Three years later the crash program to build an atomic device from a uranium isotope began in earnest. And within three years of that -- Aug. 6, 1945 -- a bomb named Little Boy exploded over Hiroshima.

NASA came into existence on Oct. 1, 1958. Eleven years later, two men were dancing on the moon. Sequencing the entire human genome took just 18 years from the time the idea was born at a small gathering of scientists in Santa Cruz, Calif. Go back as far as Watson and Crick, to the discovery of the structure of DNA, and the feat was still achieved in a mere half-century.

Cancer researchers hate such comparisons. Good science, say many, can't be managed. (Well, sure, maybe easy stuff like nuclear physics, rocket science, and genetics--but not cancer.)

And to be sure, cancer is a challenge like no other. The reason is that this killer has a truly uncanny ability to change its identity. "The hallmark of a cancer cell is its genetic instability," says Isaiah "Josh" Fidler, professor and chair of the department of cancer biology at Houston's M.D. Anderson Cancer Center. The cell's DNA is not fixed the way a normal cell's is. A normal cell passes on pristine copies of its three-billion-letter code to every next-generation cell. But when a cancer cell divides, it may pass along to its daughters an altered copy of its DNA instructions--and even the slightest change can have giant effects on cell behavior. The consequence, says Fidler, is that while cancer is thought to begin with a single cell that has mutated, the tumors eventually formed are made up of countless cellular cousins, with a variety of quirky traits, living side by side. "That heterogeneity of tumors is the major, major obstacle to easy therapy," he says.

Harold Varmus, president of Memorial Sloan-Kettering Cancer Center in New York City, agrees. "I just think this is a very tough set of problems," says Varmus, who has seen those problems from more angles than just about anybody. He shared a Nobel Prize for discovering the first oncogene (a normal gene that when mutated can cause cancer) in 1976. That crucial finding, five years into the War on Cancer, helped establish that cancers are caused by mutated genes. Later Varmus served as NIH director under Bill Clinton, presiding over a period of huge funding increases. "Time always looks shorter in retrospect," he says. "I think, hey, in 30 years mankind went from being almost completely ignorant about how cancer arises to being pretty damn knowledgeable."

Yet all that knowledge has come at a price. And there's a strong argument to be made that maybe that price has been too high.

President Nixon devoted exactly 100 words of his 1971 State of the Union speech to proposing "an intensive campaign to find a cure for cancer." The word "war" was never mentioned in the text, yet one would flare up in the months that followed--a lobbying war over how much centralized control the proposed national cancer authority would exert. Between the speech and the signing of the National Cancer Act that December, there was a "battle line between 'creative research' and 'structured research,' " as a news report headlined it. A massive alliance of virtually all the medical societies, the medical schools, the then--Big Three cancer hospitals (Memorial Sloan-Kettering, M.D. Anderson, and Roswell Park in Buffalo) said yes to federal money but wanted very little direction and only loose coordination from Uncle Sam.

On the other side was Sidney Farber, the Boston physician known as the godfather of cancer research. He wanted public backing for a massive, coordinated assault. "We cannot wait for full understanding; the 325,000 patients with cancer who are going to die this year cannot wait; nor is it necessary, in order to make great progress in the cure of cancer, for us to have the full solution of all the problems of basic research," Farber testified in congressional hearings that fall. "The history of medicine is replete with examples of cures obtained years, decades, and even centuries before the mechanism of action was understood for these cures--from vaccination, to digitalis, to aspirin."

Farber lost.

Today the cancer effort is utterly fragmented--so much so that it's nearly impossible to track down where the money to pay for all this research is coming from. But let's try anyway.

We begin with the NCI budget. Set by Congress, this year's outlay for fighting cancer is $ 4.74 billion. Critics have complained that is a mere 3.3% over last year's budget, but Uncle Sam gives prodigiously in other ways too--a fact few seem to realize. The NIH, technically the NCI's parent, will provide an additional $ 909 million this year for cancer research through the National Institute of Environmental Health Sciences and other little-noticed grant mechanisms. The Department of Veterans Affairs will likely spend just over the $ 457 million it spent in 2003 for research and prevention programs. The CDC will chip in around $ 314 million for outreach and education. Even the Pentagon pays for cancer research--offering $ 249 million this year for nearly 500 peer-reviewed grants to study breast, prostate, and ovarian cancer.

Now throw state treasuries into the mix--governors signed 89 cancer-related appropriations from 1997 to 2003--plus the fundraising muscle of cancer charities, cancer centers, and research hospitals, which together will raise some $ 2 billion this year from generous donors, based on recent tax forms. And finally, that huge spender Big Pharma. The Tufts Center for the Study of Drug Development estimates that drug companies will devote about $ 7.4 billion, or roughly a quarter of their annual R&D spending, to products for cancer and metabolic and endocrine diseases.

When you add it all up, Americans have spent, through taxes, donations, and private R&D, close to $ 200 billion, in inflation-adjusted dollars, since 1971. What has that national investment netted so far?

Without question, the money has bought us an enormous amount of knowledge, just as Varmus says. Researchers have mapped the human cell's intricate inner circuitry in extraordinary detail, identifying dozens of molecular chains of communication, or "signaling pathways," among various proteins, phosphates, and lipids made by the body. In short, scientists now know (or think they know) nearly all the biochemical steps that a healthy cell uses to multiply, to shut down its growth, and to sense internal damage and die at the right time--as well as many of the genes that encode for these processes. What's more, by extension, they know how these same gene-induced mechanisms go haywire in a cancer cell.

According to PubMed, the NCI's online database, the cancer research community has published 1.56 million papers--that's right: 1.56 million!--largely on this circuitry and its related genes in hundreds of journals over the years. Many of the findings are shared at the 100-plus international congresses, symposiums, and conventions held each year.

Yet somehow, along the way, something important has gotten lost. The search for knowledge has become an end unto itself rather than the means to an end. And the research has become increasingly narrow, so much so that physician-scientists who want to think systemically about cancer or the organism as a whole--or who might have completely new approaches--often can't get funding.

Take, for instance, the NCI's chief funding mechanism, something called an RO1 grant. The grants are generous, averaging $ 338,000 apiece in 2003. And they are one of the easiest sweepstakes to win: One in three applications is accepted. But the money goes almost entirely to researchers who focus on very specific genetic or molecular mechanisms within the cancer cell or other tissue. The narrower the research niche, it sometimes seems, the greater the rewards the researcher is likely to attain. "The incentives are not aligned with the goals," says Leonard Zwelling, vice president for research administration at M.D. Anderson, voicing the feeling of many. "If the goal is to cure cancer, you don't incentivize people to have little publications."

Jean-Pierre Issa, a colleague of Zwelling's who studies leukemias, is equally frustrated by the community's mindset. Still, he admits, the system's lure is powerful. "You get a paper where you change one gene ever so slightly and you have a drastic effect of cancer in the mouse, and that paper gets published in Science or Nature, and in your best journals. That makes your reputation. Then you start getting grants based on that," he says. "Open any major journal and 80% of it is mice or drosophila [fruit flies] or nematodes [worms]. When do you get human studies in there?"

Indeed, the cancer community has published an extraordinary 150,855 experimental studies on mice, according to a search of the PubMed database. Guess how many of them have led to treatments for cancer? Very, very few. In fact, if you want to understand where the War on Cancer has gone wrong, the mouse is a pretty good place to start.

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Additional reporting by Doris Burke
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