Research and passion are paying off in cancer research.

By Kathy LaTour

In the hour it takes you to read this magazine, 156 Americans will hear, “It’s malignant.” During the course of this day, 1,500 will die of cancer. And tomorrow, the numbers start again.

Billions have been spent on cancer since the passage of the National Cancer Act in 1971, the country’s official declaration of war on cancer. But cancer has proved to be a stealthy enemy, and the so-called war now can most aptly be equated with the real war on terrorism. In this new kind of war, the enemy has rewritten the rules; soldiers are now lost in the general population, and to the old-war tactics have been added new approaches, such as attacking the root causes and infiltrating enemy “cells” to locate and disable the mastermind.

It’s also a war that some say needs a more coordinated approach, a criticism being addressed by Andrew von Eschenbach, MD, director of the National Cancer Institute (NCI), a position the Cancer Act named as the commander-in-chief of this war. Dr. von Eschenbach must oversee not only basic research to understand how cancer develops and grows, but also how to turn that research into diagnostic tools and treatment, and how to deliver those treatments to the population—all while looking for ways to prevent cancer and help survivors live with cancer. It’s a massive job since every aspect must be evaluated and funded appropriately.

And add to this war the allies in the private sector: survivors of cancer, now almost 10 million strong; advocates who are raising money themselves and demanding a voice in this battle; and private industry, which is active in drug and diagnostic development.

Winning the War?

Today, depending on whom you ask about where we are in the war on cancer, we have made great progress, no progress or some progress. But the answers are all inadequate since it’s like the old axiom about the blind men and the elephant—it depends of what part of the animal you are touching as to what you perceive—and no one can really see the big picture.

And the truth, according to those on the front lines, is that we have made remarkable progress in some areas, less in others and little in others.

Those who say we have made great progress are looking at victories after years of painstaking research into not only chemotherapy drugs, but also molecular, genetic, immunologic, infectious, environmental and lifestyle components, all of which have revealed that cancer is actually hundreds of diseases instead of one.

The “Annual Report to the Nation on the Status of Cancer, 1975-2001” was compiled by the NCI, Centers for Disease Control and Prevention, the American Cancer Society and the North American Association of Central Cancer Registries. The report, which was delivered at the annual American Society of Clinical Oncology (ASCO) meeting in June, indicates that overall cancer incidence rates dropped 0.5 percent annually from 1991 to 2001, while death rates from all cancers dropped 1.1 percent each year from 1993 to 2001. A child diagnosed with cancer now has a greater than 75 percent chance of survival, and 70 percent of cancer patients under age 15 are treated in pediatric cancer treatment centers.

When the Cancer Act passed some 30 years ago, the overall five-year survival rate for all cancers was about 50 percent compared to 64 percent today. Survival rates presented by the American Cancer Society’s Facts and Figures 2004 (see chart, page 28) show increases in five-year survival for every cancer across three decades.

A number of researchers expect survival to increase even further because of new targeted drugs, high-tech detection devices and combination therapies.
The no-progress voices chime in with their own interpretation of statistics, citing increases in a number of cancers. And, while mortality has decreased for a number of cancers thanks to advanced treatments, it doesn’t change the fact that incidence is up for some of the most deadly.

Robert Wittes, MD, physician-in-chief at Memorial Sloan-Kettering Cancer Center and former director of the Division of Cancer Treatment and Diagnosis at the NCI, says statistics can be misleading.

“The progress over a decades-long period has been measurable, and it has not been as great as everyone would like nor as great as what many people in the field expected. But you must remember that drug discovery prior to the 1990s was largely empirical, based on the ability of compounds or natural extracts to slow or stop the growth of tumors in dishes.”

And these, Dr. Wittes says, added up to improvement in certain tumor types, remarkable progress in some tumor types, but not too much progress in common tumor types.

Detractors would say today’s progress is due in part to prevention and early detection as much as treatment, a comment no one disputes. In fact, Dr. von Eschenbach says this is why any war on cancer has to include three areas of focus: prevention through averting or delaying; elimination through early detection and eradication; and control of the cancer through treatment options that reduce it to a chronic state instead of a deadly one.

So what does it all mean and where exactly are we? To understand the present and the future, it’s necessary to start at the beginning.

The Past – 1971

Cancer is an insidious disease that begins with one mutated cell, which, for reasons we have only begun to understand, begins to multiply exponentially, eventually taking over healthy organs. It is also a disease that, according to anthropologists, has been with us since early man.

Stopping cancer began in earnest with the National Cancer Act of 1971, which infused new power and money into the National Cancer Institute, founded in 1937 as a division of the National Institutes of Health.

Many thought the war would be over in only a few years based on successes in the use of chemotherapy drugs in the late ’60s, an assumption that was reasonable for its time, says Dr. Wittes.

“There had recently been the demonstration that complete remissions were possible in large percentages of patients with acute leukemia, Hodgkin’s disease and certain of the non-Hodgkin’s lymphomas. A similar picture was emerging in cancers of childhood. And some data suggested that combinations of cytotoxic drugs might do some of the same things for certain adult solid tumors like testicular and perhaps breast cancer.”

Like all new ideas, the National Cancer Act had its opponents, but Vincent DeVita, MD, Amy and Joseph Perella Professor of Medicine at the Yale Cancer Center and a former director of the NCI, says he wasn’t surprised when the Act passed since he knew that activist, lobbyist and Washington insider Mary Lasker had pushed the Act and worked tirelessly for its passage. Dr. DeVita knew Lasker as a good friend of one of his patients. He later won the Lasker Award, given by The Lasker Foundation, for his work in Hodgkin’s disease.

“This was an amazing woman. She created a foundation and became involved in health issues. She understood politicians and knew how to network,” Dr. DeVita recalls.

Indeed, when support for the Act stalled, Lasker called her friend Ann Landers and asked her to do a column encouraging the American public to let Washington know they wanted the Act. It was the only open letter to the American public Ann Landers ever wrote, and the deluge of responses is said to have tipped the scale toward the Act’s passage.

Lasker was perhaps the first of the cancer advocates, a group that has become a powerful lobby of hundreds of thousands who have helped to drive research and, perhaps more importantly, access for those facing cancer.

At the time the Cancer Act was passed there were only three cancer centers in the United States, and important discoveries had come slowly, including understanding the structure of DNA in 1953, the first chemotherapy cure of a solid tumor in 1955 and approval of new chemotherapy drugs in the ’60s.

Dr. DeVita says that those who expected the Cancer Act to produce immediate results didn’t understand that the money generated by the Act prompted two waves, the first being funds to create an infrastructure to increase research, which meant money for laboratories across the country that would attract bright new people and provide the tools needed for many of today’s discoveries.

“The labs took two or three years to set up. Probably 80 percent of the funds went to the lab side in the basic biology,” Dr. DeVita says. “Investment from that wave has just been hitting the shores. The second wave went into what we had and making it better: technology, radiotherapy, chemotherapy. ”

Dr. DeVita also points to the Cancer Virus Program, which was an NCI special initiative that was routinely criticized.

“It generated seven Nobel prizes and delivered most of the information on the cells’ signaling systems we are using today,” he says, adding that one of the goals set in those early years of the Act was to reduce cancer mortality by 25 percent.

“Have we done that? No, but if you look at the benchmarks, we have hit them and I think that when we can measure 2000, we will have reduced mortality by 15 percent.”

But despite an overall decrease in cancer incidence and mortal-
ity, Americans keep dying, a fact not lost on Dr. von Eschenbach, himself a cancer survivor, whose plan to eliminate suffering and death from cancer by 2015 has been called overly ambitious by some and doable by others.

The greatest challenge, says Dr. von Eschenbach, is managing what he calls the “portfolio” of the pieces, which include discovery, development and delivery while also focusing on prevention and early detection.

“Basic science is about discovery, but it’s also about rapidly translating what we learn into interventions so that patients can benefit as quickly as possible,” he says. “Connecting and integrating the nation’s research portfolio is perhaps the NCI’s greatest challenge. NCI must use its leadership position to bring together and coordinate all aspects of healthcare, including academic institutions and industry, to streamline the system.”

Discovery – Basic Research

Dr. von Eschenbach says that any discussion of where we are with treatment must really begin with the early 1990s, when researchers began understanding the fundamentals of cancer at the molecular level and the impact such knowledge will have on every aspect of cancer prevention, detection, treatment and control.

Rather than one seminal moment, Dr. von Eschenbach points to the “gradual illumination” that has occurred with the understanding of the genetic abnormalities driving the unregulated growth, and the fact that there are tumor suppressor genes. This, combined with the ability to image in a way that allows us to see the biology and biochemistry of the cancer, means it’s time for the next step—a multipronged approach that recognizes that cancers, indeed each individual cancer, may have multiple factors that must be addressed in order to shut down the process.

Chemotherapy drugs, still a valuable component of this new approach, are being joined by what are called targeted therapies and with incredibly complex imaging and diagnostics that give an even greater picture of individual cancers.

“These things we call targets are actually usually proteins inside cells that are linked together functionally with other proteins into pathways,” explains Dr. Wittes. “And those pathways are linked together to form networks, information flow networks. It’s analogous to a circuit diagram of a complicated electronic instrument such as a television set.”

Trying to fix a television without knowing the circuit diagram, Dr. Wittes says, is impossible.

“Right now the problem of controlling cancer is that we only know some of the circuit elements inside the cancer cell, a very complicated ‘device.’ We can go after those, but we don’t know others and how they are related. For many important cellular functions there seem to be multiple pathways that stimulate it, and so if you knock one out, the others may still be there, and the cancer cell may not care much. How many do you have to knock out for the cell to feel the effect?”

Herbert Hurwitz, MD, director of the cancer program in experimental chemotherapy and GI cancers at Duke Comprehensive Cancer Center in Durham, North Carolina, likens treating cancer to controlling weeds in a garden, where the weeds are different from each other and different from the healthy parts of the garden.

“In the healthy flowers and shrubs some have pink petals and some have brown and some are specked. In the past, people were working with the best tools they had to keep the weeds under control, and the best weed killer we had was a chemical that had lots of side effects for the healthy part of the garden. Now we are developing ways to be more specific,” he says. In other words, it’s not necessary to burn down the garden to get rid of the weeds.

Dr. Hurwitz says that a top goal is finding more effective, better-tolerated treatments that allow us to just do a little weeding now and then while keeping the rest of the garden healthy.

Perhaps the most successful of the new targeted therapies that illustrates Dr. Hurwitz’s analogy is Gleevec® (imatinib), which targets a particular mutation in patients with chronic myelogenous leukemia and has shown success in patients with gastrointestinal stromal tumor (GIST).

But Dr. Wittes explains that Gleevec’s success with GIST is not as dramatic since it benefits about half of those treated for many months but doesn’t, in most cases, make the tumor go away completely.

Targeted therapies that interfere with one or more factors or pathways include antiangiogenic drugs that cut off the blood supply and others that basically interrupt the growth signal within the cell. Two of these antiangiogenic drugs, Avastin® (bevacizumab) and Tarceva® (erlotinib), were recently shown to improve or stabilize disease in 85 percent of 40 patients with advanced non—small-cell lung cancer who were given a combined regimen of the two.
The response rate was about 20 percent, while overall median survival was 12.6 months.

While these findings were heralded at the recent ASCO meeting, the results, like those for many of the new targeted therapies, received criticism for only extending life by a matter of months, a fact that researchers such as Drs. Hurwitz and Wittes say misses the point because it’s understanding that there will be multiple drugs used in myriad combinations that will provide the full answer.

In addition, most new drugs are tested on the sickest patients, those whose other options have run out, and researchers agree that when they are tested on healthier patients, a greater benefit can be seen. In addition, the use of the drugs gives researchers another clue about how and why they work.

For example, Iressa™ (gefitinib), a targeted therapy approved in 2003 for use in lung cancer, was criticized for only working in 10 percent of patients. Yet not even a year after its approval, clinicians found a genetic abnormality in the 10 percent for whom it worked.

Dr. Wittes says Iressa represents an example of when the glass is half full—not half empty.

“We now have an idea of who that 10 percent is that Iressa works for. It didn’t take long after the general availability of Iressa to find out that there were a set of lesions in the Iressa target and if any of those mutations are present, there is a better chance of the drug working. We still don’t know why. But I think the lesson that we have learned with Iressa is going to apply to the great number of molecular targeted drugs that come along.

“You can take a look at Iressa and say, ‘Boy is that disappointing because there was a lot of hype about it and it benefits only a small minority of all patients with lung cancer and it doesn’t benefit them for long.’ Or you can say, ‘This is a start, and we had a target, and it was rational to go after the target and it appears to help a subset of the total population.’ And now investigators are beginning to sort out who that subset may be.”

From Research to Treatment

Translating the past decade’s new discoveries into usable treatments has meant a massive influx of information. Indeed, according to The New York Times, the Pharmaceutical Research and Manufacturers of America reported 395 cancer drugs currently in clinical trials.

Susan Braun, president and CEO of the Susan G. Komen Breast Cancer Foundation, has watched the information mass crest during her eight years as head of the country’s largest breast cancer advocacy group and largest funding source for breast cancer outside the government. In fiscal year 2003, Komen funded $23 million of cancer research in an overall budget of $96 million, which also went to community outreach programs focused on education, screening and treatment services.

“A top breast cancer physician recently told me that he can no longer keep up with all the basic science and all clinical information emerging about breast cancer. He had to choose to follow only the basic science. There is just too much information, ” Braun says.

Braun, like many in the cancer community, says calling it the “war on cancer” no longer applies because of the multiple forms of cancer and the complexity within each tumor type.

“When we talk about cancer, we have to be more specific. We know pretty well what causes some cancers; for others—like breast and prostate cancer—we need to learn a lot more. Cancer is not a single disease with a single cause and a single cure. It is a complex array of diseases and the ways to intervene are complex and will grow even more diverse.”

It’s the era that Dr. DeVita calls big science and big questions. “We have tools we never dreamed we would have. We can measure genes and their function using gene microarrays and other powerful tools. Very few institutions have all of the resources in one place. It’s looking at the gene families associated with drug resistance, and I am going to find that out from tissue of people who are resistant and that takes collaboration and coordination for goal-directed research.”

Dr. DeVita says he would like to see more flexibility in funding from the government to look at new issues that are harder to fund. He has found that the more flexible funding comes through philanthropic organizations and the pharmaceutical industry, which he says gets undue criticism.

“I can see it from their side,” says Dr. DeVita, who sits on the board of ImClone Systems Inc. “It costs a lot of money to develop a drug, and a company that goes bankrupt is of no use to any of us. And look around the world. The drugs come from U.S. drug companies. The process works. Yale can discover a drug but not develop it. ”

Dr. Wittes says pharmaceutical companies have become instrumental in research and discovery but much of their research remains proprietary and not available to other researchers.

“They have no impetus to publish and lots of reason not to, so we don’t know much of what they are doing. The way companies operate is with a responsibility to shareholders for return on investment. That is their bottom line and they will do all they can to enhance that stand.”

Ironically, Ellen Stovall, president and CEO of the National Coalition for Cancer Survivorship (NCCS), began treatment for Hodgkin’s disease on the day Richard Nixon signed the National Cancer Act. NCCS, the oldest survivor-led advocacy organization working on behalf of people with all types of cancer and their families, advocates for quality cancer care for all Americans.

As one of her first tasks upon taking over leadership of NCCS in 1992, Stovall was assigned to be a part of an examination by a subcommittee of the presidentially appointed National Cancer Advisory Board to look at the National Cancer Program and what was needed.

“The report said we need a coordinated effort among all the agencies that were engaged in conducting research in 1994,” says Stovall, adding that the National Cancer Program was so vast and involved so many agencies and organizations that the absence of coordination was a serious impediment to making serious advances in cancer research.

One answer, Stovall says, is providing incentive for collaboration in the same way people are rewarded for personal success.

Dr. Wittes says the NCI has a lot of initiatives that call for collaborative research, which vary from the Specialized Programs of Research Excellence (SPORE) program in the translational interface to the large clinical trials. The NCI established SPORE in 1992 to promote interdisciplinary research and to speed the exchange between basic and clinical science to move basic research findings from the laboratory to applied settings involving patients and populations.

“They are slow, and it is ponderous and it takes a long time to get things done. But it’s not as if everyone is wandering 16 different directions. Whenever you get some kind of national effort that exists over a number of years, it’s not possible to make things run on a dime,” says Dr. Wittes.

Started last summer in a pilot program, the cancer Biomedical Informatics Grid (caBIG) will eventually link all 50 NCI-designated cancer centers, providing what Dr. von Eschenbach says will be one tool that brings all the pieces together in an integrative information grid either from the laboratory or the clinic.

“caBIG is essentially creating the World Wide Web for cancer research. It will take the avalanche of cancer information and turn it into useful knowledge,” Dr. von Eschenbach says. “With over 40 cancer centers involved as a pilot, we have never been at a more exciting juncture in cancer research. Common tools and a shared language will result in an explosion of exciting new ideas.”

Dr. von Eschenbach says that other aspects under review include clinical trials, which the NCI is looking at restructuring to better test individualized targeted interventions.

“For example, we will need to integrate imaging tools that can detect, within 24 hours, whether we have shut off a pathway. ”

But Dr. Hurwitz says he is seeing other collaboration in a number of ways through the web, through industry support, conferences and other venues for brainstorming. “Finding a successful treatment is complicated. Even though there are lots of problems in drug development, at the end of the day, the process is guided by caring and smart people who are trying to do their best.”

Delivery – From the Lab to the Patient

Stovall says the NCCS, as a patient advocate organization, has focused on finding areas where there is agreement, such as the need for increased participation in clinical trials (see Speaking Out), and creating collaborations.

Stovall says the next goal should be getting quality care into clinical practice and finding a way to reward doctors for providing care, an area Braun agrees with.

“We are all wound up about research and clinical trials, which are critically important, but pragmatists will tell you that the higher hurdle occurs after a new intervention has been proven,” says Braun.

Braun gives the hypothetical example of finding an accurate test that would tell which patients would respond to a specific treatment—but the treatment is accurate for only 30 percent of patients.

“In the real world, for this very effective intervention to be available for the appropriate patients, we need a well-informed provider network, available diagnostics and accurate pathology, all of which must be adequately reimbursed. Then we have to battle against barriers to access that exist because of economics, education or ethnicity. ”

A big question, and one that haunts all those in the cancer community, is who will pay for the new targeted therapies, which are significantly more expensive than the older treatments in a system that is already taxed.

The Other Pieces – Prevention & Early Detection

Some of the greatest strides in the reduction of cancer incidence have come from prevention. The introduction of the Pap test has reduced cervical cancer significantly and smoking cessation programs are known to reduce lung cancer, one of the most deadly cancers. Lifestyle changes in eating habits and exercise will also play a larger role in cancer reduction as more proof emerges of their importance.

But why do some people get cancer and others don’t? Dr. von Eschenbach says it ’s an obvious question that needs to be answered.

“We have to understand cancer susceptibility and stratify patients according to risk and tailor opportunities to change risks having do with diet, exposure to sunlight or other factors. Some people are more susceptible because they have defects. We need to know what they are and overcome those. ”

Dr. von Eschenbach says that as we live and age, exposure to environmental factors must also be considered as well as a way to counteract those exposures. “We have a study under way right now to look at men at risk for prostate. How can selenium and vitamin E protect a man from prostate cancer?” (See Research to Consider)

Ways to find premalignant changes are also in the works, says Dr. von Eschenbach. “We need tests where we can take one drop of blood and look at the protein patterns and see if a cancer is in the body and what it is. As we speak there is research under way looking at proteomics for the detection of cancer—particularly for ovarian cancer.”

Says Dr. von Eschenbach: “We need to focus on the fact that the pace of progress has accelerated and we need to take that to the next step. Every minute, one American is dying of cancer, and that is unacceptable.”