When US President Richard M. Nixon declared war on cancer in his 1971 state of the union address, his inspiration was the idea that millions of dollars thrown into the development of new and better chemotherapies would mean an end to the ancient scourge. It did not take long for even the most hawkish advocates of heavy investment in chemotherapeutic drug development to admit that victory was far in the future.

John Cairns, a microbiologist now retired from the Harvard School of Public Health, was a leading early critic of the Nixon war on cancer, which he said put too much hope into treatment, and too little study into epidemiology. Still, some successes in treatment and early detection may have helped drive the breast cancer death rate down, he now thinks, but even doing the math, cancer by cancer, does not provide all the answers. "Stomach cancer has disappeared for reasons nobody knows and lung cancer has rocketed upward for reasons everyone knows," Cairns says.

After more than three decades of this war, epidemiologists report significant progress in a few areas, such as childhood cancer, but more blanks than magic bullets in the arsenal. "The overall picture is that a reduction in the frequency of malignant invasive cancer seems to be substantially the largest contributor to a recent decline in mortality," says John C. Bailar III, epidemiologist and professor emeritus of the University of Chicago, who was also a vocal early critic of the war on cancer. "Early detection has also had a significant impact on some kinds of cancer. Treatment, not so much," he adds.

Veterans of the cancer war argue for the long view, in which incremental advances add up. "The history of cancer discoveries is checkered because of too much hype, the latest thing making the cover of Time magazine and that sort of thing," says Joseph V. Simone, chair of the Institute of Medicine's National Cancer Policy Board. "Anyone in the field a long time believes it is a step-by-step process, slow and frustrating."

CANCER POLITICS Frustrating, too, are the politics of cancer, says Vincent J. DeVita, who chaired the National Cancer Legislative Advisory Committee (NCLAC), which was charged with helping to strategize a comprehensive national plan to re-energize the war on cancer. The committee's work was controversial from the first, as advocacy groups and scientists, practitioners and researchers jostled for position at the table, explains DeVita, a former National Cancer Institute director who stepped down as director of the Yale Cancer Center in July. There were fears that cancers that hit political hot buttons would get favored status, or that the push to get fast results would mean less money for basic research. Many such chronic controversies were resolved over time.

The most vital issue--the need for a central national oversight function to make sure all parts of an expanded cancer science community were working together and getting what they needed--was not resolved, according to DeVita. "The big issue was how a national cancer program should be structured. We said, 'The landscape has changed on this since 1971 and the National Cancer Institute is no longer the only game in town,' " DeVita recalls. "Now the [Centers for Disease Control and Prevention] has to play a major role, and the Army has a major research program, and, of course, one has to bring industry in."

That approach, DeVita says, "raised a lot of anxiety." He chaired a subcommittee that conceived of a structure similar to what is now the Department of Homeland Security, in which an oversight agency would implement a comprehensive plan that assured all segments of the cancer research and treatment community were served. "The lid came off," DeVita says. "People got very upset and I viewed it as people being afraid their position in the structure would be altered." The concept got only a few lines in the final report, and has not surfaced in legislation based on NCLAC's work.

"We have moved into a new era of science, referred to as goal-directed research and the tools involved are very powerful, but they are rarely in one place," DeVita notes. "They are spread across a number of universities, some are in foundations and some are only in universities. This doesn't mean you abandon individual science, but you need to put the pieces together, to mobilize in a unified fashion."

At the time the NCLAC subcommittee argued for its umbrella cancer strategy function, there was no such thing as a Department of Homeland Security, no model anywhere in the government for an agency that could direct strategy to a common goal. The panel's report went to the White House a few days before the attacks of Sept. 11, 2001 captured the nation's attention, and set the public health agenda off on a different course.

A coordinated cancer research agency is not part of that agenda, DeVita says. "The major advocacy groups are dead set against it and the reason is that they don't want to see their own relative position in the hierarchy changed," he says. "This is not giving people what they paid for in $48 billion spent on cancer over the years."

NCLAC's work produced the National Cancer Act of 2002, which bogged down in Congress last year and was reintroduced in May as the National Cancer Act of 2003. The legislation calls for more money for the NCI and a refinement of the grant mechanism, as well as a network of state cancer efforts linked to an expanded CDC effort, to help make sure that new advances get to patients fast.

Spearheaded by Sen. Dianne Feinstein (D-Calif.), the 2002 legislative revamping of the cancer war would have authorized $4.8 billion for the NCI in fiscal year 2003, up from the $4.6 billion the agency received and the $4.77 billion the Bush Administration is requesting for fiscal year 2004. Successive annual increases spelled out in the legislation would have taken NCI to $7.1 billion by the 2007 fiscal year.

Both the 2002 and 2003 versions included a cancer research loan repayment program and higher salaries for postdoctoral researchers, measures aimed at luring more talent to the field. Instead of the 4,500 research grants NCI hands out each year, the cancer agency should fund at least 6,400 grants, or 40% of applications, the bill's backers maintain.

FOLLOWING THE MONEY While the latest cancer war plan begins its push through Congress, however, appropriations measures that will parcel out the dollars for the coming fiscal year show almost flat funding for government-sponsored cancer research. Contrast that with the boom in bioterrorism spending, which went from $305 million in 2001 to $4.3 billion in 2003, moving up fast on the NCI's $4.6 billion budget for 2003.

"The president's initiative on bioterrorism is at the very best a mistake and at the very worst a cynical maneuver to build support for the war on Iraq," says Hillel Cohen, assistant professor in the department of epidemiology at Albert Einstein College of Medicine. "It transfers resources from an undernourished public health system to a military and police-oriented agenda for public health."

According to an analysis by the Oncology Nursing Society, both House and Senate versions of fiscal year 2004 funding plans shortchange cancer prevention and early detection programs in particular. That is particularly tough news to critics of treatment-heavy cancer policy who say the numbers speak for more prevention and less toxic treatments.

"The main effort--the war on cancer by better chemotherapies, better drug treatment regimens--has not done what we had all hoped and expected they would do and it's time to start getting behind the things that are working in spite of ourselves," Bailar says. Campaigns against smoking, rather than treatment, account for the big drop in lung cancer rates, after decades of rising mortality in that category, he adds.

The happy homemaker may be a better icon than the warrior for what passes as progress in the war on cancer these days, the plodding transformation of the killer into a chronic condition. Good nutrition and clean living, boring and tedious though they may be, promise more widespread success than arsenals of magic bullet therapies. Stop people from smoking and cancer rates drop by about one-third, cancer epidemiologists agree. Cut obesity and chances are an even more dramatic impact is recorded, they say.

"We're putting all this money into chasing will-of-the-wisps with chemicals, and there's no sign we're getting anywhere," asserts Bruce Ames, a University of California, Berkeley, molecular biologist and co-director of the NFCR Center for Genomics and Nutrition. "We're spending incredible amounts of money to try to identify hypothetical risks and not putting money into nutrition for the poor, which we know is a big risk."

This year cancer-connected obesity research is getting $34.19 million, compared to the $185 million being spent on research into breast and cervical cancer. That is a long step down from the $65 million that the Oncology Nurses Society maintains that the United States should be spending to track the connection between obesity and cancer.

"It is well established that the most effective protection for the public health is good food, clean air and water, jobs that pay a decent wage," says Cohen of Albert Einstein. "These are the things that make the biggest difference between people who get sick and die and those who don't. Yet the simple approach of improving access to adequate nutrition is usually overlooked in funding."

CELL SCIENCE AND THE BODY POLITIC Molecular biology is leading advances in epidemiology and in nutrition research, as well as in treatment. Examination of cellular-level changes tells how cancer grows, how nutritional deficiencies lead to chromosomal damage that invites malignant growth, and how to design drugs that target fatal DNA flaws. Cellular-level views of cancer argue for a truce among the warring factions, advocates of chemotherapy, nutrition, environmental investigation and others, says I. Bernard Weinstein, professor of medicine at Columbia University. "We should not polarize things too much, because if it turns out that people working on treatment discover things that can be used in prevention, we want to have open lines of communication," he adds.

Weinstein's research focuses on molecular epidemiology, which combines laboratory studies of tissues and body fluids with epidemiological investigation that weighs numbers of people, types of cancer, age, race, ethnicity, and mortality. "When we take samples in addition to collecting information, we see what the person was exposed to and whether events are happening that show causation," Weinstein says. "Closely related to that is identifying individual risk factors, some of which are inherited. We need to know why people vary in their susceptibility to cancer and this means merging with genetics."

Bruce Stillman, director of Cold Spring Harbor Laboratory, says genetics has just started to make its contribution to countering cancer. It can speed identification of drug targets and refine understanding of how nutrition and other environmental factors operate. Completion of the human genome project this year opens the way to creation of a library of data on the mutations and alternations that characterize cancer.

Across the United States, dozens of research groups are chasing gene-expression paths and protein patterns. But these are scattershot efforts that threaten to end in disappointed isolation unless collaboration similar to the one that accomplished the mapping of the human genome is put into place, Stillman says, echoing DeVita. "This is going to take a national coordinated effort and I don't see that happening," Stillman asserts. "The work is being done haphazardly at the moment and part of the problem is the mechanism of [National Institutes of Health] funding."

Stillman chaired the National Academy of Sciences "Big Science" committee, which studied the barriers to conducting large-scale research in biology. In a report released in June, the panel took cancer as the prototype of a disease challenge that called the type of concentrated research power that only a full-scale collaboration involving academia, industry, and government could deliver.

"It's against the culture of investigator-initiated research for someone to come in and take over to do something big like this," Stillman says. "But one of the lessons of the human genome project is that ultimately, everyone has to knuckle down to get it done."

Peg Brickley (pegbrickley@hotmail.com) is a freelance writer in Philadelphia.

	WINNERS AND LOSERS IN THE CANCER TREATMENT STAKES While chemotherapeutics still draw fire from prevention advocates, enthusiasm continues to run high among developers of dendritic cell vaccines, monoclonal antibodies, and other treatments based on cellular research. Roughly 350 cancer drugs are in clinical trials now. Some are mere tweaks on existing drugs, new combinations, or dosages. But some are products of structure-based design, targeting growth receptors or other weak spots on tumor cells. Center stage at the 2003 American Society of Clinical Oncology annual showcase of advances were Iressa and Avastin, prolonging life by a few months in lung cancer and colon cancer, respectively. "At ASCO there has never been such a high level of excitement," says Charles Bugg, CEO of BioCryst Pharmaceuticals, a Birmingham, Ala.-based structural drug design firm with an oncology candidate in clinical trials. "You do get a lot of news flow, or maybe it's hype, coming out of the biotech industry, but investors are learning to appreciate the long-term potential." Biotech scientists in the trenches temper their hopes with the reality that risks are high and regulators tough on new science headed to market. Vaccines using dendritic cells or T cells are theoretically impressive, for example, but they result in very costly individualized therapies, which means a limited market and maybe even a cold shoulder from the US Food and Drug Administration, says Maurice Zauderer, chief executive officer of Vaccinex, a University of Rochester spin-off. "Companies are afraid of FDA regulatory problems with therapy that is not standardized," Zauderer explains. "So a lot of companies instead of cell-based approaches are looking at biologics or antibodies." Fascinating science takes a back seat to reality in the market politics that dictate which therapies advance--antibodies--and which languish--vaccines. "Vaccines are very difficult to work with and companies are reluctant to take the risk," Zauderer says. "The industry likes antibodies, which have low toxicity. The FDA is comfortable with antibodies, so there's a strong push in the direction of building antibody-based therapeutics."