Vermont Woman: Dr. Krag, I understand that you were a farmer before you were a surgeon. That was quite a leap. Or was it?
I always knew I wanted to be a doctor. But first I wanted life experience. So I worked on farms and outdoor jobs all over the country and in many parts of the world first.
VW: What did your father think of this? How did this shape you?
Even though my father thought my life plans were rather sketchy, he was always positive. It must have been very challenging for him. They sent me to Denmark at the age of 15 to work on a relative’s cargo ship. When the ship needed extensive repairs, I took off through northern Europe, hitchhiking with little money and no plan. They found out about it later. I think of my son doing that now, and it kind of takes my breath away.
VW: How were you brought up? How did your father influence your decision to become a doctor?
My father was a gerontologist. He was one of the first physicians in the U.S. that focused his life on caring for the elderly. I was born in Washington D.C. because he worked for the U.S. Public Health Service, setting up some of the first programs for the elderly post-WWII. His later practice in rural California was based out of the home. Like any home-based work it always involved the family.
This gave a front line view of what it was like to be a doctor. He was such a caring person and he is my role model for how to be a physician.
I grew up surrounded by elderly people needing care, tagging along on house calls and visiting patients in nursing homes. I also heard his frustrations with the lack of medical knowledge about solutions that should have been known. He knew I wanted to change things, and reinforced that a physician is in a powerful position for change. I have never looked back.
VW: Can you describe your education?
I did not enter college with a sterling academic record. I clearly remember answering the admissions officer’s question: Why should he let me in? I told him, so that I could prepare to be a physician and do research to design better care for patients. I encouraged him to take a chance. That worked for him.
Surgery seemed to offer the greatest flexibility to take on significant problems. And in that area, cancer was clearly one of the biggest unsolved problems.
Cancer hits good people doing good things. It happens when they are young, when they are taking care of children or at the peak of their career. I took the opportunity during my surgical residency to do a fellowship in surgical oncology at UCLA. That was a phenomenal experience that helped form the structure of all my subsequent research. There was a group of people that worked every day, knowing that curing cancer was completely possible. It was so exciting.
I joined the teaching faculty at University of California, Davis. I immediately went to work starting a lab and doing experiments. It was a fantastic starting point and everything and anything was possible. However, the Chairman of our surgery department, otherwise known as the boss, saw me in the lab 24/7 and wanted me to look more toward my personal development as a surgeon. He said that I would never cure cancer. So [I should] focus more on things that would help me out personally and head to the operating room.
I know that he meant well, but that meant that pursuing research would always butt up against leadership’s plans for my career. Sooner or later I would have to leave that institution.
VW: Would you describe your intention to find a cure for breast cancer realistic? You must have believed you could, because you committed your life to it.
A cure for breast cancer is absolutely realistic. It has to be. Nature is so beautiful that it could not have purposefully built in the mistake of cancer. It is only a matter of hard work, clever thinking and financial resources.
VW: You arrived in Burlington in 1991. How did you come to choose Burlington and what was the state of Vermont’s breast cancer diagnosis and care?
My brother Martin is an orthopedic surgeon here at Fletcher Allen Health Care. He specializes in fixing problems with the spine. In the late 1980s my wife and I visited Vermont for the first time to attend my brother’s wedding. During this visit we met members of the Department of Surgery and we learned how beautiful the state of Vermont is. These connections ultimately led to moving to Vermont.
I was the first fellowship-trained surgical oncologist in the state of Vermont. There was no organized breast center. Shortly after my arrival in 1991 several surgeons who did breast surgery either retired or moved, leaving a large number of women without solid follow-up. The problem was that in preceding years a large number of women with breast cancer had participated in a clinical trial in which long-term monitoring was a big deal.
In this clinical trial, one group of women were assigned to have a lumpectomy (partial mastectomy) and no concomitant radiation therapy. By 1991, we knew that the recurrence rate of cancer in the breast without radiation treatment was very high and approached 50 percent. These patients were like a time bomb waiting to go off.
I took time off from my research to organize, along with staff from pathology, radiology and medical oncology, to create one of the nation’s first breast cancer centers, so that women’s breast cancer care would be facilitated with a coordinated plan. The center was designed not only to provide highly efficient and organized care, but especially designed to focus on developing new treatments. Today the FAHC Breast Cancer Center serves the majority of Vermont women who get breast cancer.
VW: Didn’t the FAHC Breast Cancer Center become a model nationwide?
Yes. Breast Centers like the outstanding one at FAHC are the normal way women are managed across the United States. It is hard to understate the value of organized efforts to control this disease. A short two decades has led to this phenomenal transition.
Every day that I see patients in the FAHC Breast Center I mentally compare this to the day when there was no organized care and follow-up and realize what a wonderful setup this really is. I never take that for granted.
VW: What is your current assessment on the state of breast cancer?
Breast cancer is, of course, a phenomenal problem. There is almost no person untouched by a personal experience with breast cancer, or by a friend’s or relative’s. All women are deeply affected just by the need to be screened. It is at least an annual event. What a reminder! It is not like the joy of remembering an anniversary or birthday.
The complications related to this disease are profound and include loss of life, surgery with immediate physical changes to the body, radiation therapy with long-term changes, and side effects from drugs, which can last a lifetime. But today, the majority of women never get breast cancer. For those that do, the great majority is cured. This can be done with much smaller surgery than even 10 or 15 years ago.
VW: I know that back in the nineties so many brave Vermont women with breast cancer volunteered in clinical trials. Can you comment on their contribution and your subsequent research?
Many strong-willed women volunteered to participate in clinical trials that they knew would be of no benefit to them, but might help others down the road. It was in this context that I started injecting radioactive tracers (safe radioactivity) into the breast cancer to map the path of cancer to lymph nodes. Prior to this time, the lymph nodes under the armpit were simply removed completely in almost every patient. This was painful, with a recovery back to normal function that took months and sometimes never. Life-long problems resulted, such as lymphedema, which is permanent swelling of the arm.
The tracer showed me where the very first lymph node was that received drainage from the breast cancer. It seems so logical now, but to be able to identify the individual lymph node that was the first to receive cancer cells was like magic. It still is amazing to be able to make a small one-inch incision and dive deep into the armpit and accurately pull out one or two lymph nodes. Our team proved that when these first few lymph nodes were clear of cancer, then the rest of the lymph nodes were almost always clear of cancer.
The next step was to prove that removing only a few nodes was as effective a cancer treatment as the conventional complete removal. To accomplish this task takes a very large clinical trial, in which groups of women with breast cancer are randomized to get one of two treatments. Then over many years it can be observed which treatment is best. It was daunting to even consider taking this on.
There had not been any meaningful surgical trials for breast cancer in nearly twenty years! The procedure was very dependent on the skill of the surgeon, and like any good experiment, it is important that things are done consistently so that you can be confident of the results.
After long discussions with my family, I decided to request funds from the National Cancer Institute to do this trial. This meant a commitment of at least 10 years. I knew that if a trial were not done, surgeons would just go ahead and do this procedure. It would be chaos, and we would never know if this procedure was as good a cancer treatment as the conventional, more radical surgery.
Outstanding colleagues at University of Vermont became partners in this effort. In particular, this involved Seth Harlow, who became the head of training for all U.S. surgeons who participated in this trial. How to train more than 250 surgeons across North America and make sure that every case they did was done correctly? This was a mind-boggling task.
Most people in the community do not know Taka Ashikaga, but he is the person who masterfully applied statistics to the design of this trial. Donald Weaver is the pathologist here, who made sure that all the other pathologists in the country did the correct pathological assessment of the lymph nodes. Our small team here in Vermont drove this trial for the entire country.
This summer marks the final closure of this effort, which lasted almost 20 years. The trial was the largest surgical trial ever done in breast cancer patients. It proved definitively that taking out only a few nodes was just as effective a cure as the radical procedure, which removed all the lymph nodes. Today more than one million women in the US alone have had this procedure done. It is now the preferred method around the world, including Europe, Australia, China, India and Japan. From the first article we published on how to do this, there now are more than 4,600 subsequent articles.
VW: What exactly is cancer?
Cancer is a complicated disease. The cells that make up a cancer are different among themselves. I spent years peering down a microscope at living cancer cells, and it is simply obvious that cancer cells exist as a type of multinational population. How can it be that a single drug could kill all of the different cells? Well, with few exceptions, it is not possible.
Also every time a cancer cell divides into two child-cells, the children—no surprise—are different than the parents. This means that cancer does not only exist as multiple targets, but the targets are moving.
There is ample evidence that our immune system has the capacity to respond to these multiple targets. And it does. For a while. But then the mechanisms that are supposed to turn off a normal immune response kick in. This normal turning off of the immune system prevents eradication of the tumor.
VW: So is breast cancer all about those lymph nodes?
I think so. And here is why. It is the lymph node receiving drainage from a tumor that has the special immune cells that react to the tumor. This means that the tumor-draining lymph node is very important. These immune cells also have the ability to take on all the complex population of different cancer cells.
The idea is that the special immune cells in this lymph node begin to respond to a cancer. If it went well, the immune cells in this lymph node would greatly expand their activity to go fight the cancer. But this does not happen. It is like they are ready to run out and do it, but then they are shut down. The cancer probably does this by very complicated means, but the main point is that it happens. It is like turning down the volume knob.
VW: And you want to turn the volume knob way up, right?
Right. Way, way up. Much research is being done to try to give drugs to stimulate the immune cells, but we are taking a different approach. Our work with breast cancer lymph nodes has shown us how, using the radioactive tracer, we can very accurately find and remove the lymph node that is responding to the cancer. What a wealth of immune cells right in this lymph node!
We have learned how to grow these immune cells in the lab. I mentioned earlier that one of the reasons that the immune system does not eradicate the cancer is because the cancer shuts off the immune response. But in the lab, we do not have these constraints. We can grow these cells up, as much as we want.
VW: What does this mean?
It means that we can find the special immune cells that have been exposed to a cancer and have learned how to fight it. We can grow these cells up, which will turn up the volume of the response. You can guess what is next. We will give this back to the patient. That is precisely what we intend to do. We are ramping up to accomplish this in patients with cancer.
Even though the idea of boosting a patient’s own immune cells is a straightforward idea, the details of pulling this off are very complicated. That is where our dedicated research team comes in. We are currently working with the U.S. Food & Drug Administration to get the treatment plan approved so that we can begin trials.
VW: How long do you anticipate the new trials to take?
We are now thinking in terms of many months, rather than many years.
VW: If you get the results you expect, will you have achieved your lifelong dream of eradication of cancer?
Won’t that be amazing!