By Clifton Leaf
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Changing the way we think about cancer
Strange as it may seem, much of our failure in fighting cancer--and more important, much of the potential for finally winning this fight--has to do with a definition. Some 2,400 years ago the Greek physician Hippocrates described cancer as a disease that spread out and grabbed on to another part of the body like "the arms of a crab," as he elegantly put it. Similarly, medical textbooks today say cancer begins when the cells of an expanding tumor push through the thin protein "basement" membrane that separates them from another tissue. It's a fancy way of saying that to be cancer, a malignant cell has to invade another part of the body.
Michael Sporn, a professor of pharmacology and medicine at Dartmouth Medical School, has two words for this: "Absolute nonsense!" He goes on: "We've been stuck with this definition of what cancer is from 1890. It's what I was taught in medical school: 'It's not cancer until there's invasion.' That's like saying the barn isn't on fire until there are bright red flames coming out of the roof."
In fact, cancer begins much earlier than that. And therein lies the best strategy to contain it, believes Sporn, who was recently named an Eminent Scholar by the NCI: Let's aggressively find those embers that have been smoldering in many of us for years--and douse them before they become a full-fledged blaze. Prevent cancer from ever entering that deadly stage of malignancy in the first place.
Sporn, who spent more than three decades at the NCI, has been struggling for many years to get fellow researchers to start thinking about cancer not as a state of being (that is, an invasive group of fast-growing cells) but as a process, called carcinogenesis. Cancer, as Sporn tells it, is a multistage disease that goes through various cell transformations and sometimes long periods of latency in its progression.
Thus, the trick is to intervene earlier in that process--especially at key points when lesions occur (known to doctors as dysplasias, hyperplasias, and other precancerous cell phases). To do that, the medical community has to break away from the notion that people in an early stage of carcinogenesis are "healthy" and therefore shouldn't be treated. People are not healthy if they're on a path toward cancer.
If this seems radical and far-fetched, consider: We've prevented millions of heart attacks and strokes by using the very same strategy. Sporn likes to point out that heart disease doesn't start with the heart attack; it starts way earlier with the elevated blood cholesterol and lipids that cause arterial plaque. So we treat those. Stroke doesn't start with the blood clot in the brain. It starts with hypertension. So we treat it with both lifestyle changes and drugs. "Cardiovascular disease, of course, is nowhere near as complex as cancer is," he says, "but the principle is the same." Adds Sporn: "All these people who are obsessed with cures, cures, cures, and the miraculous cure which is still eluding us, they're being--I hate to use this word, but if you want to look at it pragmatically--they're being selfish by ignoring what could be done in terms of prevention."
The amazing thing about this theory--other than how obvious it is--is that we can start applying it right now. Precancerous cell changes mark the progression to many types of solid-tumor cancers; many such changes are relatively easy to find and remove, and others are potentially reversible with current drugs and other treatments.
A perfect example is the Pap smear, which detects premalignant changes in the cells of the cervix. That simple procedure, followed by the surgical removal of any lesions, has dropped the incidence and death rates from cervical cancer by 78% and 79%, respectively, since the practice began in the 1950s. In countries where Pap smears aren't done, cervical cancer is a leading killer of women.
Same goes for colon cancer. Not every adenomatous polyp in the colon (a lesion in the organ's lining) goes on to become malignant and invasive. But colon cancers have to go through this abnormal step on their way to becoming deadly. The list of other dysplasia-like conditions goes on and on, from Barrett's esophagus (a precursor to cancer there) to hyperkeratosis (head and neck cancers). Obviously, doctors are already doing this kind of testing with some cancers, but they need to do it much, much more.
Some complain that the telltale biomarkers of carcinogenesis, while getting more predictive, still are far from definitive, and that we should wait until we know more. (Sound familiar?) Researchers in heart disease, meanwhile, have taken an opposite tack and been far more successful. Neither high cholesterol nor hypertension guarantees future cardiovascular disease, but they're treated anyway.
A few cancer researchers have made great strides in finding more early warning signs--looking for protein "signatures" in blood, urine, or even skin swabs that can identify precancerous conditions and very early cancers that are likely to progress. For instance, Lance Liotta, chief of pathology at the NCI, has demonstrated that ovarian cancer can be detected by a high-tech blood test--one that identifies a unique "cluster pattern" of some 70 different proteins in a woman's blood. "We've discovered a previously unknown ocean of markers," he says. And it's potentially a mammoth lifesaver. With current drugs, early-stage ovarian cancer is more than 90% curable; late stage is 75% deadly. Early results on a protein test for pancreatic cancer are promising as well, says Liotta.
Yes, the strategy has costs. Some say wholesale testing of biomarkers and early lesions--many of which won't go on to become invasive cancers--would result in a huge burden for the health-care system and lead to a wave of potentially dangerous surgeries to remove things that might never become lethal anyway. But surely the costs of not acting are much greater.
Indeed, it is an encouraging sign that Andy von Eschenbach, director of the NCI, and Elias Zerhouni, who leads the NIH, are both believers in this strategy. "What our investment in biomedical research has led us to is understanding cancer as a disease process and the various steps and stages along that pathway--from being very susceptible to it, to the point where you get it, and ultimately suffer and die from it," says von Eschenbach, a former urologist who has survived prostate and a pair of skin cancers. So, he says, he wants to lead the NCI on a "mission to prevent the process from occurring in the first place or detect the occurrence of cancer early enough to eliminate it with less morbidity."
How to win the war
There has been talk like this before. But the money to fund the assault never came. And several cancer experts interviewed for this story worry that the new rhetoric from the NCI, while encouraging, has yet to move beyond lip service.
For the nation finally to turn the tide in this brutal war, the cancer community must embrace a coordinated assault on this disease. Doctors and scientists now have enough knowledge to do what Sydney Farber hoped they might do 33 years ago: to work as an army, not as individuals fighting on their own.
The NCI can begin this transformation right away by drastically changing the way it funds research. It can undo the culture created by the RO1s (the grants that launched a million me-too mouse experiments) by shifting the balance of financing to favor cooperative projects focused on the big picture. The cancer agency already has such funding in place, for endeavors called SPOREs (short for specialized programs of research excellence). These bring together researchers from different disciplines to solve aspects of the cancer puzzle. Even so, funding for individual study awards accounts for a full quarter of the agency's budget and is more than 12 times the money spent on SPORE grants. The agency needs to stop being an automatic teller machine for basic science and instead use the taxpayers' money to marshall a broad assault on this elusive killer--from figuring out how to stop metastasis in its tracks to coming up with testing models that better mimic human response.
At the same time, the NCI should commit itself to finding biomarkers that are predictive of cancer development and that, with a simple blood or urine test (like PSA) or an improved molecular imaging technique (PET and CT scans), can give patients a chance to preempt or control the disease. For that matter, as a nation we could prevent tens of thousands of cancers--and 30% of all cancer deaths, according to the NCI--by getting people to stop smoking. This all-too-obvious observation was made by every researcher I interviewed.
Alas, this is not a million-dollar commitment. It's a billion-dollar one. But the nation is already investing billions in research, and that doesn't even include the $ 64 billion a year we spend on treatment. To make the resource shift easier, Congress should move the entire federal war chest for cancer into one bureaucracy, not five. Cancer research should be managed by the NCI, not the VA and Pentagon.
Just as important, the cancer leadership, the FDA, and lawmakers need to transform drug testing and approval into a process that delivers information on what's working and what's not to the patients far faster. If the best hope to treat most cancer lies in using combinations of drugs, we're going to have to remove legal constraints and give drug companies incentives to test investigational compounds together in shorter trials. Those should be funded by the NCI--in a process that's distinct from individual drug approval. One bonus for the companies: If joint activity showed marked improvement in survival, the FDA process could be jump-started.
"It's going to require a community conversation to facilitate this change," says Eli Lilly's Homer Pearce. "I think everyone believes that at the end of the day, cancer is going to be treated with multiple targeted agents--maybe in combination with traditional chemotherapy drugs, maybe not. Because that's where the biology is leading us, it's a future that we have to embrace--though it will definitely require different models of cooperation."
When clinical trials begin to offer patients more than incremental improvements over existing drug treatments, people with cancer will rush into the studies. And when participation rates go up, it will accelerate the process so that we can test more combinations faster and cheaper.
To see which drugs truly have promise, however, we need to do one thing more: test them on people in less advanced stages of disease. The reason, once again, comes back to cancer's genetic instability--a progression that not only ravages the body but also riddles tumors with mutations. When cancer patients are in the end stage of the disease, drugs that might have a potent effect on newer cancers fail to show much progress at all. Our current crop of rules, however, pushes drug companies into this can't-win situation, where the only way out is incremental improvements to existing therapies. Drugs that might well help some cancer patients are now getting tossed by the wayside because they don't help people whom they couldn't have helped in any case. This has to stop.
Witness what has happened with the new class of drugs developed to fight the process called angiogenesis ("angio" refers to blood vessels, and "genesis" to new growth)--compounds designed to block the development of capillaries that supply oxygen and nutrients to tumors. Avastin is the best known, but there are some 40 anti-angiogenesis drugs in clinical trials.
This, by the way, is one of those big ideas that the cancer culture didn't take seriously, and would barely fund, for decades. The concept was pioneered 43 years ago by Judah Folkman, now a surgeon at Children's Hospital Boston. While studying artificial blood in a Navy lab, he was struck by a simple and seemingly obvious idea: Every cell needs oxygen to grow, including cancer cells. Since oxygen in the body comes from blood, fast-growing tumors couldn't develop without access to blood vessels.
Folkman later figured out that tumors actually recruited new blood vessels by sending out a protein signal. If you could turn off that growth signal, he reasoned, you could starve the tumors and keep them tiny. The surgeon submitted a paper on his experiments to various medical journals, but the article was rejected time and again. That is, until an editor at the New England Journal of Medicine heard Folkman give a lecture and offered to publish it in the Journal's Beth Israel Hospital Seminars in 1971--ironically, the year the War on Cancer began.
After decades of resistance, the cancer culture has finally come around to Folkman's thinking--as the reception greeting Avastin makes clear. Still, the biggest promise of anti-angiogenesis drugs will be realized only when doctors can use them to treat earlier-stage patients. That's because the drugs designed to choke the tumor's blood supply often take a far longer time to work than traditional toxic chemo--time that people with advanced disease and fast-growing cancers may not have. Doctors also need the freedom to administer such drugs in combination. Tumors recruit blood vessels through several signaling mechanisms, researchers believe, so the best approach is to apply several drugs, cutting off all routes.
Who knows? A new paradigm in treatment may emerge from Folkman's 40-year-old idea. Yet to make this simple and seemingly obvious shift, the entire cancer culture must change--from the rules governing drug approval to tort law and intellectual property rights. Science now has the knowledge and the tools; we need to act.
The good doctor
In the weeks since I finished my reporting and began writing this story, one image has stuck with me: a drawerful of letters. The letters belong to Eric Winer, a 47-year-old physician at Dana-Farber. He and I had been talking for close to an hour when he showed me the drawer.
It was late on a Friday evening, and Winer, still in the clinic, was describing the progress we were making in this war, his reedy voice cracking higher every so often. He was telling me of his optimism. That's when he mentioned the drawer: "That enthusiasm is very much tempered by the fact that we have 40,000 women dying of breast cancer every year. Um, and you know, I've got a file full of letters that are almost entirely from family members of my patients who died."
I asked to see it, and then asked again, and there it was, in the bottom drawer of his filing cabinet--two overstuffed folders of mostly handwritten notes. Once the letters go in, Winer confessed, he never looks at them again. "I don't go back," he said sheepishly. "My excuse initially was that if anyone wanted to say I was a bad doctor, I'd hold on to these things that people said about me. And I could prove that I wasn't."
If the walls of his office are any indication, there is no way Winer is a bad doctor. They are covered with loving mementos from patients. There is a picture of Tolstoy from a woman whose breast tumors were initially shrunk by Herceptin, but who died within five years. (Winer had once mentioned to her to that he had majored in Russian history at Yale.) There's a photo of the Grand Canyon taken by a young nurse who was determined to take a trip out West with her 10-year-old son before she died. The daughter of another patient even cornered Lance Armstrong and begged him to sign a neon-yellow jersey for Winer, who is an avid cyclist. It is the most prominent thing in his office.
No, it isn't just the patients in this War on Cancer who need renewed hope. It is the foot soldiers as well.
Additional reporting by Doris Burke