Dr. Peter Greenwald Oral History 2008 B
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National Cancer Institute
Would you begin this interview by describing Dr. DeVita as a physician, a scientist, administrator?
PG: Yes. Vince DeVita is a very strong scientist, particularly in the clinical area. He led in the development of therapies for Hodgkin's and other lymphomas. He also was a strong and dynamic leader in the sense that he would listen to input and act forcefully when necessary. He believed in openness and open advisory groups. He believed that unless you could convince an advisory group that this was a good direction, you might want to rethink the direction yourself. But at the same time, he would make decisions and follow through on them, both about people and about programs.
All aspects of research--basic discovery, clinical trials, and research on public health applications--are part of science. And I wanted to do research that led directly to public benefit. To be successful, I needed to change the whole climate, the whole staff, and I didn't feel I could do that under Dr. Upton, even though I liked him as a kind and sensitive person. But I felt that with Vince DeVita's backing, I would be able forcefully to change the nature of cancer control.
VH: There was a broader issue within NIH in that period, too, if I recall correctly. There was argument over the value of funding basic science versus targeted research, and there was considerable push-pull as to where the money ought to go. This issue at NCI may have been bigger because NCI had more money.
PG: Yes. Congress provided a line item for cancer control to assure that we would apply the knowledge gained through research. But through the ‘70s and into the early ‘80s, the definition of cancer control was very fuzzy. Cancer research leaders who wanted cancer control money would say, "Cancer control is rehabilitation; cancer control is something else, spend the money on what I want," and cancer control as a field wasn't going anywhere. It didn’t have a clear mission. I felt a big missing link was that there was almost no cancer prevention. I saw many studies of epidemiological associations and rodent carcinogenesis, which were important, but the emphasis was on discovering relationships; there was no human intervention—a critical element for the work to be prevention. Etiology, to me, was knowing; prevention was doing, doing with a scientific basis in a way that would reduce the occurrence of cancer, and that's what I wanted to build.
VH: Before we get into the details of what you were doing, I want to discuss one side issue here. When you were setting up this division, they named you as Editor in Chief of the Journal of the National Cancer Institute, and you served from 1981 to 1987. Did you seek this responsibility, or was it assigned to you? And would you explain to me how you managed to edit a major journal, and set up and run a new division at the same time?
PG: Vince DeVita mentioned to me that the job was open. I said I'd love to be editor. I felt several things. Number one, as an editor of a journal, you're forced to look at areas of research that you otherwise might not pay attention to, and that that helped in getting a broad vision and being integrative in the way you thought about things. I felt that was part of our role as leaders, as members of the Executive Committee of the National Cancer Institute, so I wanted to become editor because I thought it would pull me away from my strong focus to a broader focus that would be of benefit. Of course, it meant longer work hours, but there was very good staff, very good associate editors. John Bailar [John C. Bailar III, M.D., Ph.D.] had been editor before me, and, for those times, he had installed a good computer system that facilitated the management of the journal. I had some associates, such as Betsy Weisburger [Elizabeth K. Weisburger, Ph.D.], who were dedicated to working on it hard, so I could manage the journal. Being editor also brought a level of prestige to our division because people who wanted their research published knew that "Oh, well, you know, Greenwald as editor of JNCI must be an important person, so I'm going to pay attention to him."
VH: Thank you. Now, back to cancer prevention and control, your first task when you got here was to lead a re-thinking of organizational aims and processes and structure. Would you tell me about the process and how you did it?
PG: First of all, I did it with our Board of Scientific Counselors. In other words, I involved them. Lester Breslow [Lester Breslow, M.D.] was the chair. He was an internationally respected public health leader and we were very much in agreement about what was needed. I actually decided myself what we would do. Number one, I defined phases of cancer control. I defined cancer control as a science. I wrote a few papers about it, and defined five steps, phases of cancer control, and said, "We're going to step one, and when we reach a point where we have enough evidence, we go to step two (by shifting funds) to step three, and it was all moving toward applications for public benefit.
There was also a part of this that we never told anyone about, but Joe and I would talk about it, and that was that we were funding people to do applied research. They were in the universities and public health departments, but we knew that the people we funded were the activists who were raising hell and promoting anti-smoking legislation and policies that we could not do as a government agency. Those people were the ones who actually moved society. They got smoke-free environments, they changed Clean Air Acts. For example, if you're in a public building and it had five changes of air an hour, if you allowed smoking, you would need more air exchanges per hour because you had to have lower particulate levels, and that would raise heating costs and air conditioning bills. So non-smoking policies for indoor air were implemented. We would support policies that we knew would force a change in smoking behavior across populations, and that could have a major impact. Joe Cullen later left to head a cancer center in Colorado.
VH: What time period are we talking about?
PG: We're talking about from about 1982-83 up into the early 90s. There was one other thing we did. You know that Dr. Koop, Chick Koop, or C. Everett Koop, [M.D.] lived next door to Harriet and me and for the eight years he was Surgeon General for the U.S. Public Health Service. He was a leader in tobacco control. He had come into the Federal government under Reagan [President Ronald Reagan]. At first, he was not liked by most people at NIH because he'd done a movie of rubber babies in the ocean, an anti-abortion film. But then his honesty and integrity came through in dealing with tobacco and with AIDS. He became a national hero. The Reagan group wanted to get rid of him but couldn’t because he was so widely respected. Koop only had a staff of five, I believe, and he did not have the capability of doing the background research for his talks about tobacco. He just didn't have the staff. So what Joe Cullen, mainly, and I did was to help Koop with his tobacco work. I said, "Joe, don't tell me the details, but use our support contracts, and get all his background work done." We would spend about $300,000 a year getting background information, so Koop, with his wonderful public ability, would talk about tobacco control, and he became the preeminent national and international leader in that effort.
VH: So you paid for Dr. Koop's tobacco control efforts, and Tony Fauci [Anthony S. Fauci, M.D.] paid for his AIDS efforts.
PG: We helped. We provided the backup so that he could do what he was terrific at. He needed staff work, and he didn't have it within the Public Health Service.
VH: In the 1983 paper that you mentioned earlier, “Cancer Control Research Directions and Opportunities,” you laid out several premises. First was that the scientific method applied to cancer control, as much as to other research areas. The second was that the pursuit of excellence in science has primacy over other considerations. And the final premise was that we must build on our strengths across the spectrum from etiology to treatment. At this point in time, these premises seem obvious, but they must not have been when you arrived. Can you tell me how difficult it was to convince people of their truth?
PG: They were not only not obvious, they were in a sense denied. By that I mean that cancer control--the block of money in the NCI budget ($30 million at first)--was defined as money that couldn’t be used for research. To me, it should've been defined as money that could be used for what we now call translational research, for making the bridge from discovery to public benefit, whether it is patient benefit or public health benefit. Also, that cancer control itself is a subject of research, applied research. It needs the same criteria of evidence and rigorous thinking and careful interpretation and scientific debate that you need in every other area of science.
VH: Did you get much push back at NCI?
PG: I got support. Vince DeVita was great. He said, "Go to it." He supported whatever we wanted to do. I would explain it. He'd agree. We'd go ahead. And so the push back actually came more in the administrative area. I walked into a situation where I had a staff of about 100. I was not satisfied with the overall quality of the staff, except for a small number of excellent people. What I did was to call people in individually and say, "Explain to me what you're doing, why, what you expect to accomplish over the next year. I'm going to hold you accountable for that." As a result, we went from 100 down to about 40. That was very tough, getting people to resign or move in the Federal Government, but afterwards, we built up to about 200. And the same situations arose as we shifted our budgets around. One example: We had a behavioral medicine program, which I terminated. I support behavioral research, but I terminated that program. The reason was that the main focus of the program was giving money to university psychology departments to support little psychology projects with their students. I didn't see how that would help progress against cancer. I wanted behavioral science, but I wanted it to improve behavior of institutions, behavior of policy makers, as well as behavior of individuals, but things that really counted. We supported studies into the eating behavior, tobacco control, focused where we knew there was a mission related orientation to it.
VH: It seems to me that you're defining cancer prevention as a subset of cancer control. In other words, cancer control includes more than cancer prevention includes.
PG: Right. That is the way the budget came. I wanted to focus primarily on prevention. My heart was in prevention. But there were parts of the budget that went beyond prevention in the program that I thought were important. I'll give you a couple of examples. We started in 1983 a community clinical oncology program. Actually, Vince and some of the community oncologists were eager to have this. This is basically a network of physicians, nurses and their health support staffs across the country that were seeing patients. What Vince wanted and what the treatment people needed was more patients going into clinical trials. Our community oncology program provided that. So we set up a whole network that greatly increased the number of patients entering NCI-sponsored clinical trials. And over time, we proved that the quality of the participation was at least as good as at our major cancer centers, sometimes better, which cancer research physicians had been skeptical about.
But I had a secondary motive. And that was that I thought--I couldn't prove it absolutely, but I thought--that when doctors all across the country took part in trials, they saw them as their own trials. As the results came in, they believed the results, because they were their trials. You were a leg up in the diffusion and adoption of new medical knowledge that was a way of continuing medical education that would help patients all over the country. We pretty much showed that this was true for the doctors taking part. I had hoped it would diffuse into the hospitals and other doctors in the community. I'm not really sure how well it worked beyond the doctors in the program. We had an additional component that had to do with research on symptom management built into the community clinical oncology program. That was an important aspect of cancer control, but not cancer prevention.
VH: You noted in that same article that Bell Laboratories served as a model program to you for channeling successful basic research into effective applications. And at NIH, people felt very strongly about basic research, which we've said. You had to recruit people for your new efforts. I want to list some names of those you hired and ask you to comment on them and what they did for you: Jerome Yates, Joe Cullen, who you've already mentioned, and Ed Sondik.
PG: Okay, they were all different. Joe Cullen was a behavioral scientist. A very talented, outgoing person who organized the national community against tobacco, and did a very effective job. Jerry Yates [Jerome W. Yates, MD], was a clinical doctor. He'd been at Roswell Park [Roswell Park Cancer Institute, Buffalo, NY]. He was an excellent, very honest clinical doctor, and savvy about clinical trials and building up the Community Clinical Oncology Program (CCOP). Later, Leslie Ford took over doing that. Jerry went on to be head of research for the American Cancer Society and later moved back to Buffalo.
We made all these estimates, and we put it out there, big goals. Then we ran into the problem of needing to apply it. We got ridiculed. People said, "You set these goals and you haven't done anything." The problem with this was something that you mentioned. What does NIH see as its mission? My view was we never tried to reach the goals. We laid out the goals, but it required an aggressive national effort to achieve the goals, to implement them. Nobody wanted to implement. Nobody wanted to put NIH money into that. The money was never allocated. I came from a public health background. I'd been in New York State for 12 years, in the health department, primarily. I knew that you could implement things like that, but the effort at NIH was almost completely focused on basic research and to some extent, clinical trials, but not public health applications of the research.
VH: I’d like to come back to your stop-smoking and tobacco control program. I have always wondered why it took so long for tobacco to be understood as addictive and for some chemical, like that in the patches and the chewing gum, to be available to help people quit smoking. Did your division have any kind of involvement in making that happen?
PG: To some extent. We focused on preventing the onset of smoking by children or delaying it, and to some extent on cessation. If you can keep children away from smoking beyond high school--up to age 20 or so--most wouldn't start at all. So that was a goal, to prevent smoking by school children. But as a cancer prevention program, that would take decades to have an impact because children wouldn't reach the cancer-risk age group for a long, long time. So we thought you also needed a smoking cessation program to have an impact early enough that we would see it. And yet, we knew that it took many years after a smoker stopped for the risk to come down significantly. Risk seemed to level off at the level where it was when a smoker stopped. Risk wouldn't get worse, but it took fifteen years or so to decline. In fact, today there are slightly more lung cancers occurring in people who are former smokers than current smokers because the former smokers are older and lung cancer takes a long time to develop. We did not test smoking prevention drugs, although some of that is done by other NIH institutes. There was an effort at behavioral approaches and at what kind of messages to get out.
One conclusion of tobacco control experts is that it's important for a doctor to ask a patient if he or she wants to quit. Ninety percent want to quit. The doctor needs to give the person a strong message that he/she should quit. A follow-up appointment should be set for the patient to come in and tell you how he/she is doing. Your nurse or someone else on the staff should call up the patient a few times and say, "How's it going?" These were things that might take you from a 15 percent to a 20 or 25 percent sustained cessation, where patients would quit for a year or more, but it was far from perfect.
VH: Were you all addressing the issue of why it wasn't doing any better?
PG: A little. One problem was competing against the billions of dollars in marketing tobacco.
More recently, there is a drug called varenicline or Chantix by Pfizer that inhibits nicotine from reaching the receptors in the brain, and there are several vaccines that are in clinical trials now that do a similar thing. These may help people to stop smoking. But at that point in the1980s, there was a little work from Ernst Wynder’s group, but most was aimed at understanding the mechanisms of how tobacco harms you and behavioral approaches to prevention and cessation.
VH: I don't want to spend too much time on this, but there is also the argument that was going on whether or not smoking was an addiction.
PG: Whether we call it habituation or addiction, people get hooked.
VH: Let's move from smoking to chemoprevention. You said that you had been contacted by Michael Sporn about this. Now I think the public would love to think that they could take a pill that would prevent cancer, but that isn’t chemoprevention. Would you define chemoprevention broadly and explain how it works and what you all did?
PG: Yes. I see chemoprevention as utilizing medical approaches to lowering your risk for cancer. Obviously, it's not total prevention, but it's the same as what heart disease people mean when they say prevention. It improves your chances of staying healthy; it lessens your risk. Initially, Michael Sporn, working with retinoids and Lee Wattenburg [Lee W. Wattenburg, M.D.] at the University of Minnesota, working with cruciferous vegetables-- Brussels-sprout type vegetables, and the chemicals in them. Sporn and Wattenburg had evidence in animal models (mice) that you could prevent some cancers--quite a few— with chemoprevention. They were saying that we should look at this clinically. At NCI, I built the first clinical program. It included preclinical development and testing to early phase human clinical research. We looked at the array of potential chemicals that might have benefits and figured out how to move them forward. Some were drugs and some were food compounds, vitamins, minerals, other bioactive food compounds.
We started a process that would lead us into the trials. We set aside monies and issued requests for applications to get a community of scientists working on those trials, mainly aiming toward early (phase II) studies. At the same time about 1983, we started two very large trials. One was in Linxian, China. Actually, the idea came from NCI epidemiologists, Bill Blot [William J. Blot, Ph.D.], and Phil Taylor [Philip R. Taylor, M.D.]. They thought about it before I came on the scene. We jumped in and worked on a large vitamin and mineral study of what we thought, initially, was cancer of the esophagus. Linxian, China was the place that had the highest rate of esophageal cancer in the world. It turned out to be cancer of both the esophagus and the upper part of the stomach. We ended up showing that a combination of selenium, vitamin E and beta carotene cut the stomach cancer rate by about a fifth. One thing I wanted to do was get a big trial rolling before other results came in, so that even if the first results were negative, people wouldn't say, "Oh, there's nothing to that field." I wanted to be sure the field would take hold.
At the same time, we thought that beta carotene, which was being promoted as having health benefits by the vitamin pill industry, could be preventive against lung cancer, and that vitamin E had some possibilities of being preventive in reducing the risk of lung cancer in smokers. So we got together with Finnish scientists, excellent scientists. One of them, Olli Heinonen [O.P. Heinonen, M.D.] had been a classmate of mine at Harvard School of Public Health and was a leader of public health in Finland. We designed a trial in 29,000 heavy smokers that could be done very efficiently through what were old TB clinics around Finland. We did an intervention trial that we thought might prevent some lung cancer. Years later, there was a very interesting outcome, which was not what we expected. That was that beta carotene made things worse for smokers.
Of the group on beta carotene, roughly six men--they were all men--per thousand per year developed lung cancer. Of those on placebo, about five per thousand per year developed lung cancer, a difference of one per thousand per year--which is a 20 percent increase. Actually, the increase was a 16 percent higher rate of lung cancer for the men who got beta carotene. In my view, the most astute physician, or the best epidemiologist, could never pick up that tiny difference in practice (one per thousand per year). It took a very well-designed, top-of-the-line, randomized clinical trial to show this. This has great public health importance, and it was the first study that suggested, "Hold on, now. Taking large doses of one vitamin or another doesn't necessarily mean you're going to be better off. You might be harmed” You need evidence before you go promoting high dosage supplement use.
VH: I was trying to remember when the dietary supplements program got started. It was designed so there would be no FDA [Food and Drug Administration] regulation. But there would continue to be an impetus from the commercial side to convince the public that dietary supplements were good things.
PG: Right. And because of the way the Food and Drug Administration legislation is written, the FDA does not have authority to insist on efficacy before the marketing of products for supplements, vitamins and minerals. They don't have the authority, and there were people in Congress from states that had supplement industries and who insisted on that kind of legislation.
VH: This brings us back to the need to communicate to the public why you need to run a clinical trial, because there is a great deal of public trust that if “they” put it out there on the TV, it's bound to be true.
PG: Right. It's a distortion. The same thing is happening with antioxidants. The public has been taught the word “antioxidants.” To me, there is probably no such thing. They're all redox systems. The same chemical can be anti-oxidant in one microenvironment, and pro-oxidant in another. With beta carotene maybe in the aerated lung where you have tobacco carcinogens, the beta carotene was pro-oxidant. You have to really understand the chemistry. You don’t want to oversimplify and then hype something where there's little evidence.
VH: Indeed. In your 1996 article in Scientific American about chemoprevention, it suggested to me that the surface has really just been scratched in this area. Can you tell me where it stands now?
PG: Yes, I think the surface still has just been scratched. I say that because we have a lot of leads--many, many. It's almost the opposite problem of cancer treatment. In treatment, the problem is finding drugs that are very effective. There are only a few drugs a year coming out of an enormous effort. What we have in prevention is that a lot of drugs or bioactive food compounds that look like they potentially could have benefits. We don't have the resources to follow through and test them all in clinical research. We have very few clinical trials in cancer prevention. They're all expensive, and they take many years. Some of them are $100 million trials. To me, that's not expensive because if you look at the aggregate investment, it's small compared to other fields. But if you look at each individual trial, what we have are people saying, "Oh, my gosh, look how many labs you could fund for that money." They almost want us to prove the efficacy of a prevention effort before we do the trial, and that's impossible. So I think our investment is small, and the potential in the field is enormous. We're also looking at how best to get buy-in by industry, how to get buy-in at NCI and NIH. That varies according to who is the director of NCI. The current director does not like large trials. He prefers NCI to invest in basic sciences, early discovery. This limits our getting new large clinical trials in place. It's always been uphill, but it was a lot easier under Vince DeVita, a lot easier with Sam Broder, both of whom understood the need for a strong clinical trials program. But starting with Klausner [Richard D. Klausner, M.D., NCI director 1995-2001], it's been a bit of a problem.
VH: Let’s talk about the diet and cancer branch which was established in 1983. I’d like to know who headed this effort and that it started out with your knowing that diet and eating behaviors are thought to be related to approximately one-third of all cancers. Tell me about this program.
PG: Okay. Although many of us thought about this earlier, in 1981, two eminent British epidemiologists, Richard Doll and Richard Peto, under a contract from NCI, looked at avoidable causes of cancer and published The Causes of Cancer: Quantitative Estimates of Avoidable Risks of Cancer in the United States Today. That's where the estimate of roughly a third--within broad boundaries of uncertainty--but roughly a third of all cancer has dietary determinants. The last time I saw Doll, which was ten or twelve years ago, before he died, he put the bounds at 40 to 60 percent of cancer related to diet (and I would say eating behavior and exercise). That came largely from looking at international differences, at effects of migration. When people move from one country to another, they – or especially their children – take on the risk of the place to which they move. The most logical explanation of this is change in lifestyle, with diet as the biggest factor. So we had this rough estimate of about a third. We have some general epidemiologic data, not a lot of basic nutritional science, some debates in the nutrition community over dietary fat and other factors. The first thing we wanted to do was to get some sound research going. Two people who did this in my division were Dr. Ritva Butrum [Ritva Butrum, Ph.D.] and Carolyn Clifford [Carolyn K. Clifford, Ph.D.]. Ritva was very dynamic in coming forward with requests for applications and set asides, where we put money aside just to get people doing research on diet and cancer. That built up the program. Then we became involved with some public issues. One was fiber, and the other was fat. I'll take one at a time.
Within less than a year, there were billions of gross impressions with the Five A Day label. An example of a gross impression is one person seeing a stamp on a plastic bag in the market one time, or seeing one ad in a magazine. And 80 percent of the supermarkets in the country were using this message. It was all over the country. From our evaluation, I think it improved the understanding, although it's still hard to get kids to eat their vegetables.
VH: One related question. Did your division have any input to the development of the food pyramid publicized by the U.S. Department of Agriculture (USDA)?
PG: Not the recent one. In fact, I don’t like it. No food is shown on the current pyramid display. You can’t tell what you should be eating. Also, individual variability may be a fact, but you look at the current pyramid and you don’t know what you're supposed to do. We’ve had mixed relations with the USDA, some of it outstanding with Beltsville scientists who are interested in health. They have some good labs, and we collaborate.
The data indicate no significant statistical association, but when you look at the trend over time, you see no change between the intervention and control groups for about four years. And then those on low fat start to do slightly better—they have a lower incidence of breast cancer--and the improvement increases toward the time when the trial is stopped. When you look at the trend line, you think, "That's a study that needs a longer follow-up." It might be that there was a benefit early in carcinogenesis, but you need to wait longer before you can see the effect.
VH: How do these studies compare with the Framingham Heart Study? Do we need that kind of long term study to understand if dietary fat does have a causative effect on breast cancer?
PG: We need a study of years longer than the Women’s Health Initiative. A longer follow-up study is underway. I can give you another example from this trial. Let’s take the hormone part and use an imaginary example. Let’s say that there's an effect on cognitive function of estrogen use, and the time to event is many years longer than the time-to- event for heart attacks. Say it's twenty years later, you either have a benefit or harm to your brain. You won't know that if you don't do a very long-term follow-up. And there's no bio-marker study or other quick way of shortening that time line. Once you make this enormous investment to do the trial at all, the investment for continued follow up after the intervention has stopped is fairly small but very important. There are always people who say, "Why do you have to go any further? Let's stop the study." But in my view, you want the long-term follow-up. You get a lot out of it, and sometimes in these add-on studies that were not part of the main plan, but which look at the person as a whole in other disease categories have valuable findings.
VH: In some respects, it's just like finance: it is difficult to convince people that a big investment now will pay off over time when people only want to know what they will get in a short period of time.
PG: Right. Also, with preventive interventions, I worry about adverse events that occur late.
In cancer therapy, especially for late stage cancer, you don't want bad side effects, but you're willing to take the risk to pretty large extent. In prevention, you don't want that risk; you want to absolutely minimize adverse events. Prevention and treatment are coming close together with adjuvant therapy, that is, treatment of early-stage disease. So, for example, with localized breast cancer, when many women now have a lumpectomy and radiation, you have to treat many to have a clear benefit for some. When the survival is very good, to show an additional benefit, you need a large population and a long-term study, and you don't want much toxicity. So the challenge is not so different between therapy of early cancers where treatment is very effective and prevention.
VH: In 1983, you created the Community Clinical Oncology Program, or CCOP [pronounced C-COP]. And in 1996, you had 51 programs in 30 states, funded by the CCOP, and there are now at least 214 hospitals involved. Tell me about how this is helping the expansion of prevention, as well as therapy.
PG: Part of our aim was to increase the number of patients on trials. We now contribute to about a third of all patients on cancer treatment trials that are run by the Federal Government. So CCOP contributes a huge proportion. But my division does not drive what drugs are being tested. That's our Division of Cancer Treatment and Diagnosis. Several of our large cancer prevention trials have been run through the CCOP, the Community Clinical Oncology Program. I can describe the breast cancer prevention trials, then the prostate cancer trials, then those for colorectal cancer prevention.
We sponsored the trial in over 13,000 women. It was run as a cooperative agreement with the NSABP, who ran the trial. Healthy women who did not have cancer but had the risk of a 60-year old (even though they may have been younger) were randomized to take Tamoxifen or a placebo. This trial showed a 49-percent reduction in the occurrence of new breast cancer in the Tamoxifen group as compared to the control group; so we prevented about half of breast cancer using this estrogen receptor modulator called Tamoxifen. There were a few side effects, a little more endometrial cancer, though none fatal, and as with every estrogenic compound, more blood clot problems, some of which were serious. On balance, most women were better off taking Tamoxifen. The NSABP and we had proved definitively for the first time that a medical approach can prevent some breast cancer.
VH: How is this going go interface with the rise of individualized genetics? I mean, will you be able to say this woman will benefit from Tamoxifen but that one may not?
PG: That’s hard to answer because there are not enough women who have the BRCA-1 or BRCA-2 genes or other, not yet proven, genes that raise breast cancer risk for us to say whether these women benefit or not. There are little hints that they might to some extent, but we don't have the answer from this study. NIH promises “personalized medicine,” but we are not there yet. I think of it as “stratified medicine.” That is, you can stratify into risk groups. For example, there is a group of breast cancer patients with the HER2 gene amplified. About 20 percent of breast cancer patients have this amplified gene that has a bad outcome. You can aim for treating those with a particular therapy. So there may be groups that we can address. You're not going to treat each individual as a special case, but if you're in those groups, you might get a different therapy or prevention than someone else. We may be able to do innovative studies using biorepositories, the bloods that were collected and the white cells in large clinical trials, to identify people with various risks and targets for new drug development.
The follow-through on the breast cancer studies, however, is interesting. The next thing that happened while the Tamoxifen study was going on was a study of a drug called Raloxifene. Raloxifene was being used for osteoporosis, to prevent progression of osteoporosis and to prevent fractures. There was a study called MORE, Multiple Outcomes of Raloxifene Efficacy, that showed that women on Raloxifene not only had improvement and fewer fractures, they also had less breast cancer, 60 or 65 percent less, something around there. Women with osteoporosis aren't particularly at high risk for breast cancer. If anything, their estrogens are a little low. But we now had two drugs that seemed to have benefits in preventing breast cancer. We decided we needed a head- to-head comparison, to try to see which one works better for whom. So we started another trial, again with NSABP in the lead, called the STAR trial, Study of Tamoxifen and Raloxifene, in over 19,000 women. The outcome was that the two drugs were equivalent in reducing breast cancer occurrence. When you looked at the adverse events and the overall picture, in general, the Raloxifene looked a little better, and the company then got Raloxifene approved by the Food and Drug Administration for reducing breast cancer risk in post-menopausal women. This past Mother's Day, the drug company started an advertising campaign. This showed the women with a towel around them saying, "If you want to prevent breast cancer and osteoporosis, raise your hand."
VH: Yes, I’ve seen the ad and tried to figure out what it meant.
PG: It’s an odd ad. They're marketing the drug for osteoporosis in women at risk for breast cancer, and it helps against both. So that was fine.
He retaliated by lowering my personnel report rating. We have something called the COER, the Commissioned Officer Effectiveness Report. It's your personnel report if you’re in the U.S. Public Health Service. Niederhuber turned to Al Rabson [Alan S. Rabson, M.D.], his deputy, who is well liked, but who at this point is a pathetic old man who just wants to hang onto his job. So Al Rabson wrote me up as mediocre compared to other officers. He told me on the phone that it was because Dr. Niederhuber was still “mad at me” for speaking out and giving my scientific opinion that we wanted to do a trial that might demonstrate that we can prevent up to 70 percent of post-menopausal breast cancer. The COER may not really matter, because those who get it know me. The NCI director didn’t want to do the trial because he wanted to put the money in his own pet projects. That fight about resource allocation is still going on.
VH: Which illustrates clearly that scientific priorities are not things easily agreed upon.
PG: Right. But you have a problem when you have a director whose management style is very centralized, top down; he’s the expert on everything. And that's who we have now.
VH: In December 1983, when you were setting up the new Division of Cancer Prevention and Control, you wanted to base its activities on scientific data. And the first thing that I saw that you did was to develop something called a Prevention Trials Decision Network, the PTDN, as a means to formalize the prioritization and evaluation process. There was also the End Points and Biomarkers Committee. Would you talk about those two and what was going on here?
PG: We wanted to build criteria of evidence and logic that would fit cancer prevention. So we defined some of these things. We started to work with them. Some of it was very practical, and some sort of faded away. We used the Prevention Trials Decision Network for a while, but there weren't enough different trials to need a formal structure. We ended up going case by case, gathering people who were expert in the various fields, and arguing each trial as we went along. There was one committee set up. I'm not sure what the name of it was. It was chaired by Barry Kramer [Barry Kramer, M.D.], and co- chaired by Bernard Levin (it's spelled L-E-V-I-N, but he pronounces it Levine) [Bernard Levin, M.D.], who was head of prevention at M.D. Anderson Cancer Center. They
What we have found is that biomarker validation is a costly and long-term process. It's not easy. There is much wishful thinking about biomarkers, but to really work them out so they're useful and proven is not so easy, and it takes time. Our Early Detection Research Network is set up to do that, and it's a unique, highly respected national program.
VH: Another one of the overarching programs that I see in this period is the SEER program, Surveillance Epidemiology and End Results. Would you talk a little more about it?
PG: SEER is the cancer registry system that was already established before I joined NCI. Brenda Edwards [Brenda K. Edwards, Ph.D.], who is a meticulous statistician and excellent manager of science, was heading this program when I came in 1981, and she still is the leader. SEER provides the data for U.S. cancer statistics. I didn't have to do much except support what Brenda and her staff already were doing, except to help them to expand SEER. We wanted to make sure that we covered enough of the major population subgroups so there would be enough Hispanics, enough African Americans, Asian Americans, and native Americans. Also, we wanted to do special studies where the registry was used to identify patients in defined geographic areas—studies that would give specific information about health outcomes. There is a field of research called Outcomes Research.
The cancer registry program was expanded with CDC [Centers for Disease Control and Prevention] supporting some non-SEER state registries. A lot of states-- most of them--now have some sort of cancer registry system. I had a rule of thumb that you should spend at least as much on use of the data as you do on collecting the data and publishing annual reports. SEER did that in the sense that all of NCI was using it, especially the epidemiologists. But in many places, the means have become the ends; a state may have a registry, but they just collect data and don’t use it very effectively.
VH: Along with expanding SEER, you created a special population studies branch and a minority-based program too.
PG: Initially, about 1983 or so, Lou Sullivan [Louis W. Sullivan, M.D.] was a member of my Board of Scientific Counselors. He was president of Morehouse [Morehouse School of Medicine] in Atlanta, Georgia. A very skilled public health physician, Claudia Baquet [Claudia R. Baquet, M.D.], was running our minority program. Claudia and Lou made a strong case that we needed an African American initiative. They called it the National Black Leadership Initiative on Cancer. They developed it. I watched and supported them, but they were the leaders, Lou Sullivan and Claudia Baquet. They got the historically black medical schools and some other groups into science, the science of applications of knowledge, and built a strong network across the country. After that, in 1989, Lou Sullivan was named DHHS Secretary. He still called back every week when he was DHHS Secretary to talk to Claudia, and so we had an ongoing connection. They were outstanding, and they kept moving this program forward. It worked well. Claudia is now at University of Maryland.
This was our chief method of addressing disparities. We aimed to attract minority scientists who would be leaders in cancer control and not just fund one-shot deals that would end when the money ran out. We wanted something more permanent. Drs. Baquet and Sullivan were very savvy. We used the National Black Leadership Initiative on Cancer as a model to build the Hispanic Leadership Initiative on Cancer, and an Appalachia Initiative. These helped to address disparity issues.
VH: And speaking to disparity issues, you made a very interesting statement that I noted: "Research is underway that will help standardize the way in which health care providers assess health quality of life for minority populations." Why is assessing health quality of life for minority populations different from assessing the health quality of life for the majority population?
PG: I don't think it's different in what you want to accomplish. There are cultural differences in perception and understanding, such as whether going to a hospital is a benefit or a place to die. There are differences in access to care, and there still are prejudices. These are diminishing, but we still see prejudices about how people are perceived and what kind of therapy they'll get according to who they are. And although it's been changing over time, there were issues over cultural sensitivity, understanding, and access.
VH: Are the different programs, for example, for trying to reach one minority teenage population with stop smoking messages from another?
PG: I don't always think of it so much now as minority groups, but rather as the lower income, poorly educated. We now have now a large middle class of minority families, and they're the same as the white middle class in terms of health messages that reach them. Harold Freeman [Harold P. Freeman, M.D.] is a person who speaks a lot about that. He chaired the President's Cancer Panel [1991-2004] and worked with us. I think you have to look at who the group is that you really want to help impact. If you stratify the education level, it's the poor minorities plus poor whites who still suffer in health care.
VH: What about the differences within an ethnic group?
PG: Again, I'm not an expert, but for example, I think the mainly Puerto Rican Americans in Florida are different from the New York City Hispanics, are different from the Mexican Americans. So even within a group like Hispanics, there's a lot of variety. And if you take Native Americans, there are huge differences between some of the tribal areas. The same is true of African Americans—we have tremendous heterogeneity. In terms of genetics, when you look at the scientific details, these old ways of classifying population groups don’t make much sense.
VH: What implications does this have for cancer prevention efforts?
PG: It’s hard to generalize, but we want to aim for a common goal. A physician named Al Haynes [M. Alfred Haynes, M.D.] once served on our Board of Scientific Counselors. I asked him to chair the Board. He was the president of the Drew Medical School [Charles Drew University of Medicine and Science] in Los Angeles. I didn't realize it when I asked him, but I was told later that he was the first African American ever to chair an NCI advisory group. The point he kept stressing was, “We have the same goals as everyone else. We want to reach the same reduction of cancer rates, and we don't want a different goal that's less rigorous, but is going to cost more to reach it. You need more people working on this. You have to understand, cancer control in minority populations is intensive. You have to spend a lot of face time with people talking with them.” So it's a matter of how much investment it takes, how much thinking, how much community participation to really reach the same goal? It takes a lot more effort and costs a lot more, but it is important.
VH: In the mid 1980s, from '83 to '87, and then in the early 1990s, you served on the U.S. National Committee for the International Union Against Cancer [IUCC]. Would you tell me about this group and what your role was?
PG: I didn't have a big role. UICC is loosely tied to the American Cancer Society. It's a very large international group. They mainly try to apply information of cancer control and bring together people in different countries. It helps us to address global problems in cancer control. Usually some of the more advanced western countries are together, and the others are trying to learn from them. We tend to get involved by giving talks at international meetings and in training.
There was one initiative, it wasn't with UICC but with the World Health Organization (WHO). I don’t remember who was head of WHO at that time, but WHO had almost no tobacco control in its entire program. With Dr. Koop in the lead, we worked out that we, NCI, would pay for two staff to work in Geneva with the World Health Organization for two years, and then WHO would pick up the cost of building a tobacco control program. We did our part, and after the two years, they reneged. They didn't do it until they got a new WHO leader from Norway, Gro Brundtland [Gro Harlem Brundtland, M.D., WHO Director-General, 1998-2003]. She built a strong tobacco control program. But before that, they had almost nothing.
VH: In 1986, Vince DeVita resigned as NCI director and was replaced by Samuel Broder. Would you take just a minute and describe Dr. Broder's leadership style, his goals for the NCI, and how cancer prevention fit into those goals?
PG: Sam Broder was very bright. I liked him a lot. I still consider him a friend. He had developed AZT [the antiretroviral AIDS drug, azidothymidine], along with Burroughs Wellcome [Burroughs Wellcome pharmaceutical company] and did the early testing of AIDS treatment at the NIH Clinical Center. That gave him the reputation that led to his being named NCI director. Before that, his forte was clinical medicine, when he would troop around Building 10, the Clinical Center, with a lot of fellows, very bright, a good sense of humor, and well liked – I liked him on the NCI Executive Committee. We would debate things. He had no problem debating. He had this kind of Talmudic logic, but if you disagreed with him, there was no problem; and you still respected each other when the debate was over.
I would stand up for Bernie Fisher and say, "Sam, why don't you go to Congress and just say we had a problem, we took care of it, we're moving forward," and Sam would be furious with me. He'd say, "If you don't like the way NCI's being run, you can resign today, or you can go to the President and ask him to get my resignation." This happened about five times. Sam would be very excited and just go off the wall with it. He didn't carry a grudge afterwards, but that's what he said. Eventually, Bernie Fisher sued and won, and what I just said to you is in the legal transcript from when the lawyers interviewed me. Bernie knew it. I would talk to him during this period, as would Leslie Ford [Leslie Ford, M.D.], my associate director for clinical research and herself a leader in breast cancer research. We would say, "You know, all of us at NCI are not your enemies, Bernie.” It was very hard, especially on Bernie Fisher's wife and on his head statistician, Carol Redman [Carol K. Redman, Ph.D.], who just could not take it. She left Pittsburgh because of that. It put unfair pressure on one of the greatest men in the history of breast cancer research. That was terrible. If it wasn't for that, I would've said Sam Broder was a wonderful NCI director. In a way, I miss him because his style was good compared to some of the later directors. I see him occasionally now and he likes to say, "Now don't you miss me? You never thought you'd miss me, did you?"
VH: In 1989, you created the Applied Research Branch to focus on three areas of research: Health Services and Economics, Modeling and Statistical Methods, and Cancer Risk Assessment. Tell me about this branch and who headed it.
PG: It first was headed by Ed Sondik. Also, Larry Kessler [Larry Kessler, Sc.D], who later went to the FDA. Martin Brown [Martin L. Brown, Ph.D.] was an economist looking at health services; these and others were key people in the program. They were interested in health outcomes, how you evaluate them, how you use population data, like from the SEER registry, in a analytical way, and they were world class. A lot of their work helped groups like Medicare in thinking about how to make policy. They would contribute useful information. This is a strong group. Rachel Ballard-Barbash [Rachel Ballard- Barbash , M.D.] was part of it and, eventually, led it. Then under Rick Klausner, it got broken off into another division that he established. That's another big issue.
VH: That issue we'll get to in the next interview.
VH: The Preventive Oncology Branch, 1991. Tell me about its work.
PG: This training program actually was begun way before that, I think 1983 or '84. I wanted to start a training program where we would bring people in and train them to build the field for the future. We had an educator, a doctor of education, named Robert Burnite with whom I worked. We set up a training program which provided a summer course, and then set up a mentorship for two years or so. We aimed to build a new generation of physicians and scientists for cancer prevention. Later, we formed the program into an Office of Preventive Oncology, aimed at training. It eventually included a summer program with dozens of international people, plus postdoctoral fellowship program where physicians or Ph.D. scientists could be mentored in different areas of prevention across NCI.
VH: One of the very important prevention trials you did through the Community Clinical Oncology Program related to prostate cancer. I'd like to hear more about this study, especially the fact that you became a subject in it.
PG: Okay. That was the Prostate Cancer Prevention Trial. There's a drug called finasteride or “Proscar” that had been developed and used to treat enlarged prostates, which cause obstructive symptoms of urine output. The drug would shrink the gland and help improve urine flow. Testosterone is the main male hormone. In the prostate, it gets converted to a more potent hormone called dyhydrotestosterone (DHT), and the finasteride inhibits the conversion of testosterone to the far more potent DHT. So we and Merck [Merck & Co. pharmaceutical company] felt that it might be useful in preventing prostate cancer. We wanted to set up a trial, which we did, with another cooperative clinical cancer research group called SWOG, the Southwest Oncology Group. The trial was aimed at seeing if we could prevent prostate cancer with this drug. Because African American men have the highest rate of prostate cancer in the world, when we set up the trial, we wanted to over-sample African American men. Earlier, when we had started the breast cancer prevention trial, we had a hardboiled hearing in Congress, when NIH director Bernadine Healy, my colleague Leslie Ford, and I had to defend why we were giving a drug that we knew would have some side effects to healthy women. We went to Congress and defended it. In the prostate trial now we were going to over-sample black men, and the legacy of the Tuskegee syphilis study in black men meant that there would likely be questions about the possibility of doing of harm.
We never start a trial unless there's something called equipoise, that is, we don't know the answer. If we knew the answer, we wouldn't do the trial. There's a balance between what you think will work and what you're not sure about. So we were setting up a trial to over-sample black men, and we pictured the worst-case scenario: "Supposing it comes out wrong? How are you going to explain that you over-sampled black men, did harm?" The women and younger members of my staff said, "No problem, Peter, you go on the trial. And if it comes out wrong, you can go to Congress and say, 'Look, I knew the benefits and potential risks and I went on the trial myself, so there." So I was one of the 18,000 men who went on the trial. At the end of that seven years of intervention, no matter what your PSA [prostate-specific antigen screening test] was, you got a biopsy. I went through everything, including having my prostate biopsied, when my PSA was very low (favorable).
VH: Which wasn't very pleasant, I dare say.
PG: Well, true. But the biopsy was negative, so that was good.
VH: And what about the trial itself? What kind of results did you get?
PG: We showed that we could reduce the occurrence rate of prostate cancer by a quarter, a 25 percent reduction. We showed definitively we could prevent some prostate cancer. But there was a problem at the time of the first report of the study. While those on the drug finasteride had that 25 percent reduction, whether it was clinical disease developing during the seven years of intervention, or biopsy results at the end, the men on the finasteride who did develop cancer appeared to have slightly more aggressive cancers.
I'm pretty sure that's going to happen. And then we need an educational campaign.
VH: I'm going to stop today with one broad philosophical question for you. After the germ theory became so completely established in infectious diseases, the thinking of almost everybody was that there must be a single cause for everything, and of course they were looking for the single cause of cancer.
VH: Are we back now to a situation where we need to think about multiple causation? When you say you can prevent 30 percent of a type of cancer, it sounds like there must be more than one thing that's leading to these cancers.
PG: It is many more than one. I think of necessary causes and sufficient causes. So necessary means if you don't have that cause, you won't get the cancer. For example, human papilloma virus is a necessary cause of cancer of the cervix. There may be other-- probably are other contributing factors. Number of sexual partners. Some people even say smoking. There are multiple things that affect the environment and may contribute to whether you develop cervical cancer, hygiene possibly. But if you don't have the human papilloma virus, you won't get cervical cancer, so you can prevent it by vaccinating against the virus. You have to vaccinate early enough in life before a woman is exposed.
But now you take the diet-related cancers. They are not like tobacco where you smoke or you don’t smoke. Everyone's eating, and it's the relative amounts of calories and nutrients that may promote or inhibit cancer development. The relative amount probably can affect the microenvironment that allows the tumor to develop, grow or not grow. It's a very complex issue. I don't think it's likely we'll have a single cause for some cancers. We will for some; not for others. There are going to be some that are just part of your normal response to DNA damage. For example, if a cancer results from everyday exposure to cosmic rays, you can't really prevent it. We're going to have to learn how to deal with that. Detect it early, treat it effectively. Prevention is a partial answer, a very important one, I think the most important one. Prevention is under- supported, but it's not going to be a complete answer, and there's not one cause.
VH: With that, I'm going to stop for today, and thank you very much.