Successes and Struggles in the War on Cancer

Your career in medicine and oncology thus far has been truly inspiring. Among many other positions, you’ve been the Director of the Yale Cancer Center and the National Cancer Institute as well as Physician in Chief at Memorial Sloan Kettering. Can you speak to your view on cancer and patient outcomes through these experiences?

Things have changed so much since I came into the field over 50 years ago. Morbidity was severe, if patients survived. Take breast cancer, for example. Before, surgeons would take everything off the chest wall, they even opened the chest wall, nothing worked. You could go as wide and as deep as you wanted to, but it didn’t change the mortality. Originally, it was thought that solid tumors, like breast cancer, spread directly to the surrounding areas, and if you took that tissue out “en bloc” you’d be able to get all the disease eventually. But, actually, that was not the case. The cancer spread early through the lymphatic system and blood stream. It was really only surgically curable in a small number of patients.

Vincent T. DeVita, Jr., MD, Amy and Joseph Perella Professor of Medicine (Medical Oncology) and Professor of Epidemiology (Chronic Diseases), Yale School of Medicine, New Haven, CT

Since then, with all the advances, mortality rate for breast cancer in this country has dropped by 30 percent and the morbidity has very much diminished. In fact, that was the mandate of the War on Cancer, “to support research to reduce the incidence, morbidity and mortality of cancer.” The same has been seen with colon cancer in which mortality has dropped 48 percent and a lot of morbidity from treatment has decreased, in part because we are catching it earlier with colonoscopy. Disease by disease, we see the same sort of trend. Quality of life has gone up, fewer people die, and they’re more comfortable for the remainder of their lives if you can’t cure them.

Cancer treatment, such as chemotherapy, can still be very intense and taxing for patients. How should we be balancing quality of life in our care practices?

I think sometimes there’s an illusion in which people think you can increase the quality of life and not worry about the outcome. You can’t do that. You should try to cure the patient first before worrying about the quality of life. It’s like saying that a new treatment is too expensive. You don’t worry about the expenses when you’re developing a new treatment. If it works, then the price will come down eventually. Quality of life is important, but you should not sacrifice the ability to save a life for this. That’s a decision the patient should make. Very often, it’s not the patient complaining about their quality of life, it’s the doctor saying the toxicity is too much. If you were to tell patients that you can either have the toxicity or leave this world a lot earlier, patients will most always tell you they’ll take the toxicity. But, if you say there’s nothing I can do for you, then it’s a different story. When you cure the disease, then you can begin to refine the treatment and make it easier to take.

What then is your perspective on palliative care?

I’m a big supporter of good palliative care. Good palliative therapy should start when the patient is first diagnosed with cancer. Anticipating the difficulties they could have and getting them ready for what will happen should be part of palliative care. If they don’t understand what’s in store for them, then patients will be stunned by it. If you consider palliative therapy in this way, then you’re always trying to make the patient understand and you should start preparing them earlier for what they have to deal with. We should be honest with patients. Unfortunately, in today’s hectic health care environment, communication is the first thing that’s sacrificed. Because doctors must see so many more patients than before – they see a patient for five or seven minutes – you can’t explain much in that time, so often they don’t.

How have cancer death rates changed both nationally and worldwide with improved treatments and diagnostic strategies?

We’re doing very well in this country, but others are not. Quite often, countries in Europe lag behind us. When I saw patients in consultation in Italy, if you’re in Milan or Rome, everything is fine like in the US, but 20 miles outside of the cities, awareness and knowledge is much lower. I was dealing with a therapy that cured patients with Hodgkin’s disease, but doctors in small towns were not really aware of these therapies. One thing the Cancer Act did in the US was make what we had in larger cities available throughout the country.

The War on Cancer began with a philanthropist, Mary Lasker, who was convinced that if we put in a big enough effort into cancer, we could get rid of it. She got the Congress to pass the Cancer Act. It was signed by Richard Nixon in December of 1971. The mandate was to support research to reduce the incidence, morbidity, and mortality of cancer. And it succeeded. Eighty-five percent of funding went into basic research while the remaining fifteen percent went into clinical programs. Incidence and morbidity rates in the US began to decline overall in 1990 and 1991, although mortality rates for childhood leukemia and Hodgkin’s lymphoma began to decline as early as the 1970s. Since then, the mortality of those two diseases has dropped by 80 percent. Mortality rates for breast cancer dropped about 30 percent; for colon cancer 48 percent; for prostate cancer almost 60 percent. Even lung cancer mortality rates are declining largely due to smoking cessation.

But, it’s too early to see the national impact of recent successes from immunotherapy and targeted therapy, for chronic myelocytic leukemia, advanced melanomas, and even advanced lung cancer but we will see the decline soon. It takes about six years for some of these advances to appear in the statistics. We still have some issues such as a lack of big cancer centers near patients in small towns, but they still have access to the treatments developed at major centers. The Cancer Act was one of the most important federal government programs to date. I tell the back story of the trials and tribulations of the War on Cancer in my recent book, The Death of Cancer I wrote with my daughter, Elizabeth DeVita-Raeburn.

Can you speak to the influence your work has had on the morbidity and mortality of cancer patients?

The purpose of our original studies is often misunderstood. We were working with Hodgkin’s disease, but ultimately, we were out to show chemotherapy could cure advanced cancer in adults using Hodgkin’s disease as a model. We were often asked if we knew the importance of what we were doing. We knew that if we could prove it, and it was a stretch to think that we could at that time, it would be important. I would say 99 percent of the people in the field at the time felt that you couldn’t cure cancer with drugs. They thought you could do it surgically in a small number of patients, or maybe with radiotherapy, but if you said you were trying to cure cancer with chemotherapy you were often derided and laughed at. So, we needed to have a model. We were certain if you put drugs together in clever ways, we should see a combinatory effect. In Hodgkin’s disease and leukemia, we provided proof of principle that you could cure advanced cancers using combination chemotherapy programs.

When we did MOPP, a four-drug combination for patients with advanced Hodgkin’s disease, it was expensive for its time, but nobody survived on the standard therapy of the day, so we didn’t worry about expense. With MOPP, we were able to cure 80 percent of people with advanced disease. I’ve received so many letters and emails from doctors and patients telling me of their experience with MOPP. It’s been very satisfying. It provided proof that if you had the right tools you could cure cancer.

The impact of demonstrating that drugs could cure cancer quickly spread to other tumors. After MOPP, we started to put together adjuvant treatments for breast cancer, that is using chemotherapy with surgery to destroy cells missed by the surgeon’s knife. The big US cancer centers, dominated by surgeons, did not want to be involved with this because it meant giving chemotherapy to patients whose tumors had apparently been removed; they thought we were crazy. So, we went to Italy. With Umberto Veronesi and Gianni Bonadonna in Italy and Bernard Fisher in the US, we set up the CMF and L-PAM chemotherapy programs. In the 1970s, each program was reported to successfully reduced mortality. They became the first adjuvant therapies in breast cancer and changed the morbidity and mortality equation enormously. Now, new therapies in breast cancer have come out that work even better. Two-thirds of the reduction in breast cancer mortality is due to adjuvant therapy, whereas only about a third is due to early diagnosis using screening with mammography. Adjuvant chemotherapy is now effective in many other solid tumors.

So, after proving that drugs could effectively be used as adjuvant therapy, surgeons could back off and use less radical surgery with lumpectomies instead of mastectomies. This caused enormous difficulty. Bernie Fisher, a surgeon, was castigated by his colleagues for showing that lumpectomy and adjuvant therapy, a simpler treatment, was equal or better than the more extensive and expensive radical mastectomy. He changed the morbidity of breast cancer by proving that you didn’t need to have radical surgery.

I remember going to a press conference in New York with the President of the American Cancer Society, who was himself a breast surgeon, when the first lumpectomy study was reported. He told reporters that we should not do anything other than a radical mastectomy until we could prove that radical mastectomies were not the way to go. But what kind of logic was that? We couldn’t prove it if we always did radical mastectomies – you must do something else to compare the two. Medicine is very slow to change. Treatment for breast cancer now compared to 50 years ago is much less intense. We have drugs preventing nausea and vomiting, and hair loss to name a few things that improve the quality of life for breast cancer patients. It ultimately took 75 years to get rid of radical mastectomy.

The benefit of growing older in your field is the perspective you gain. I’ve seen breast cancer as it used to be and I’ve seen it now and I’ve seen the steps along the way. And although I’ve bemoaned the fact that it takes so long to effect change, and you have to fight so many non-scientific battles to get there, we did get there. You just have to stay with it. Bernie Fisher is now 100 years old.¹ He had to fight a lot of these battles. With that perspective, you appreciate how difficult it can be to do some things and the kind of freedom to do research you have to have to be able to do it, to be able to think and focus on your goals. I’m oriented that way – that’s how I grew up in the field, that was my experimental approach. I was always interested in curing cancer.

You are one of the three editors of Cancer: Principles & Practice of Oncology, now in its 11th edition! Does this project reflect the evolution of the field?

Yes. Just like the treatments, there was no cancer book that covered the whole field back then. The main book at the time was by Ackerman and del Regato. Ackerman was a pathologist and del Regato was a radiotherapist who was quite narrow-minded. He had a fit if you tried to give drugs to a radiotherapy patient. I was going to do a book on medical oncology, but I got a call from Steve Rosenberg, my chief of surgery at NCI, and he tried to convince me that we instead needed a book that covered the whole field. He would do the surgery part, I would do the medical oncology, and we’d find a radiotherapist. I agreed to do it. I ended up asking Sam Hellman, from Harvard, to join us. He initially thought we were out of our minds. Putting a big book together would be a big job and we were all very busy. But he agreed to join us as the radiotherapist and we published the first real multidisciplinary book in 1982. Our philosophy was to publish all existing positive work even if it had yet not been published in journals. Because by the time the book came out, that research would be published in a journal and we wanted the book to be fresh. Since I was at the National Cancer Institute, we had access to all new exciting work. So, the book was always ahead of its time and it chronicled all the changes in the field. Since it was a major source of information on cancer in those days we feel it had a major role in contributing to the decline in cancer mortality that ensued.

You’ve previously talked about the paper by Hanahan and Weinberg entitled “The Hallmarks of Cancer” which identifies eight areas that are good targets, not only for treatment but also for the prevention of cancer. Could you elaborate on this?

That is probably the most cited paper in medical literature. The first iteration was published in Cell and cited some 20,000 times. We asked the authors to update it as a chapter it in our book because it’s a unifying principle. The hallmarks of cancer, by definition, are the acquired characteristics of a cancer cell that it needs to survive, proliferate, and disseminate. Some of the therapies we have now are already attacking one or another hallmark – immunotherapy, for example, and most of the other treatments we use target the cancer cell’s ability to divide. The question is if we can use these hallmarks to either prevent cancer or to combine anti-hallmark treatments in different ways together.

We’ve made so much progress on the War on Cancer. What are the next steps?

I believe the War on Cancer has been a great success. But by some people’s definition, as long as anybody dies of cancer, you can’t declare success. That’s nonsense – you’re successful in steps along the way and progress will continue in steps. We would like to get to the point where we’re curing 90 percent of patients. Now we’re curing more than 50 percent of all cancer patients – it’s not trivial. If you included the hundreds of thousands of skin cancers of which we cure 95 percent (we exclude common skin cancers because they are easily cured, how logical is that?), then the percentage would be up way higher.

Metastatic melanoma ten years ago was universally fatal. Five to six years ago, we had an inkling that immunotherapy was working. Now, you can cure about 30 percent of advanced melanomas. I always thought melanoma would be the last tumor to fall because it is a very difficult, resistant cancer, but this percentage is going up. We know that patients respond to immunotherapy and targeted therapy. Now we’re trying to figure out how to use effective therapies together. This was unheard of just a few years ago. With Hodgkin’s and leukemia, I am still following patients 50 years later, who just made it onto the new program. We’re doing a 45-year follow-up on the original MOPP group; these patients have led normal lives and did not die from Hodgkin’s disease or the therapy. I like to encourage patients to hang in there because the next effective treatment may just be around the corner. There is also a lot of new options on the horizon.

Lately, I’ve been thinking about liquid biopsy research. It would be an enormous advance if we had a test that had 95 percent sensitivity and 95 percent specificity to tell you if cancer cells were or were not present. In the past, we would dream about it, but now it’s quite possible using liquid biopsy. We can analyze circulating DNA and identify the mutations from the primary tumor and follow them. If you have a test like this after you operate on a woman with breast cancer, you can do the test and if it says that there’s no cancer left then that’s it, you don’t give them adjuvant therapy at all, knowing with some comfort you got all the cancer cells. When you put a patient with advanced cancer into remission with chemotherapy and your follow-up with the test, when it goes to zero, you don’t have to give them anymore chemotherapy. It would change the field dramatically, overnight. For the first time, I actually feel like we’re now very close to doing it. Such is the impact of newly developed technology.

Finally, do you have any advice for those starting or thinking about careers in medicine and oncology?

Understanding a cancer cell is understanding developmental biology. Many of the hallmarks of cancer describe the cancer cell dipping into the bag of tricks of an embryo, for example altering energy metabolism in a cell and neovascularization. They’re turning on switches that were turned off after a growing embryo develops. The molecular biology revolution that we’re going through now was started by the War on Cancer. It makes this field maybe the most exciting field in medicine, so to anybody thinking about going into oncology, I would say good for you. It’s gotten to the point where I personally can’t keep up anymore, things are happening so fast.

Cancer used to be a field that nobody wanted to go into. I went into it partly because I had the option of going to the National Cancer Institute to do research or going to Vietnam, so I made the choice to stay at the NCI rather than dodge bullets. I originally wanted to be a cardiologist, but when I was at the NCI, things got so exciting that I just stayed. I don’t regret one minute of my time in the field, I only regret not being here for twenty more years to see the whole thing evolve into the control of cancer. But I have absolute certainty that it will happen. At some point, in the next ten to fifteen years, an enormous number of patients with cancer will become treatable and curable.