Six years ago, I (Vincent) was diagnosed with life-threatening prostate cancer that would have killed most men. I survived because I was able to call on colleagues to deliver aggressive surgery outside the standard of care (hormone therapy) for my type of disease. Without a doubt, the operation saved my life.
What happened in my case should be how things happen as a matter of course, but it’s not. That more people than necessary continue to die from cancer has nothing to do with ‘the failed war on cancer’ – a familiar refrain in the press – or a lack of scientific tools, which have begun to accumulate at a breathtaking pace. Rather, obstacles take the form of not using the tools we already have to cure more; a reluctance to drop outdated beliefs; bureaucratic battles among physicians and medical groups; and outdated regulation by the US Food and Drug Administration (FDA) whose policies hinder the innovations wrought by cancer drug‑development in recent years. These issues are well‑known to doctors and researchers, but many are reluctant to talk about them overtly for fear that they could damage their colleagues or their chances of getting a grant or drug application approved.
When I was a child in the 1940s, long before I had any notion of becoming an oncologist, Aunt Violet, my godmother and a frequent visitor in my household, stopped coming over. My parents ceased talking about her, too. It was as if she had disappeared. Several months later, my father told me that she was sick and that she wanted to see me.
We went in, and I sat on the living‑room floor, playing with the toy car Aunt Violet had given me. I looked up when I heard the bedroom door open. Aunt Violet was quiet, gaunt and sad. Her skin looked yellow next to her white chenille bathrobe.
I was only six, but I knew something was terribly wrong. Years later, I learned that she’d had cervical cancer. Her case had apparently been so advanced by the time she was diagnosed that there was little her doctors could do. There wasn’t much that could be done for most people with cancer in those days, even if it was caught early. The main treatments were surgeries that were often disfiguring or toxic doses of radiation. Those treatments helped only the lucky few whose cancers were discovered before they had spread. There were no drugs to fight cancer then. And barely more than a third of people diagnosed with it survived. It was such a dreadful diagnosis, in fact, that many people, including my parents, couldn’t bring themselves to utter the word.
Two decades after my aunt’s death, as a newly minted doctor, I started work as a trainee at the US National Cancer Institute (NCI). There, I saw a lot of people who looked just like Aunt Violet had at the end of her life. Gaunt. Sad. Yellow.
The study of cancer was a stagnant field, a no-man’s-land populated by only a handful of doctors and researchers regarded by most of their colleagues as nuts, losers, or both. That’s what I thought, too. As late as the 1960s, the respected chief of medicine at Columbia University refused to let his medical trainees make rounds on the cancer wards, lest their careers be tainted by the futility they would encounter there.
And so it would have continued, if not for work initiated by a handful of mavericks on the same NCI wards where I landed as a trainee in 1963. Their research, in which I took part, led to the first use of a combination of drugs – known as combination chemotherapy – to treat and, increasingly, to cure childhood leukemia. Learning from them, I came up with a combination chemotherapy regimen that cured 80 per cent of people with advanced Hodgkin’s disease.
On 23 December 1971, in front of a throng of journalists, a jubilant President Richard Nixon signed the National Cancer Act, launching the war on cancer – an unprecedented $100 million federal research effort. Today more than 40 years have passed, and the country has spent more than $100 billion on the war on cancer. I have now seen that war from every possible angle: as a researcher, clinician and the longest-serving director at the NCI; as physician‑in‑chief at Memorial Sloan Kettering Cancer Center (MSKCC); as director of Yale University’s Cancer Center; as president of the American Cancer Society (ACS); and, most recently, as a patient myself.
I say we’re winning. People still get cancer, and people still die from it. But thanks to this concentrated effort, far more people survive than was true when the war was launched. By 1990, the overall mortality rate of all kinds of cancers in the US had begun to decline. By 2005, the absolute number of people in the US dying of cancer had declined even as the population, including the elder population, grew. (Risk of cancer is higher in the elderly).
Childhood leukemia is now almost completely curable. Hodgkin’s disease and several types of advanced lymphomas are almost completely curable. Mortality from colon cancer has dropped by 40 per cent in the past two decades. Mortality from breast cancer has dropped by about 25 per cent; for prostate cancer, by 68 per cent.
So much of the mortality declines come from refinement of old technology: mutilating surgeries, such as the radical mastectomy, have given way to more refined ones that still get the job done; radiotherapy equipment has become more refined, allowing radiotherapy to be delivered to the tumour without killing the normal tissue surrounding it; drugs have been developed to prevent nausea and vomiting, the bane of the existence of chemotherapists, so people can tolerate drug treatment.
And the best is yet to come. We have the critical mass of usable knowledge to get us the rest of the way, to bring about the end of cancer as a major public health issue in the next decade.
Part of the reason for the remarkable progress is a series of three paradigm shifts in our thinking about cancer. The first was the recognition that combination chemotherapy could cure advanced cancer. That led to the decline in mortality of the leukemias and the lymphomas in which the original work was done. And it gave birth to the use of adjuvant chemotherapy – cancer drugs paired with surgery and/or radiotherapy – that led to the decline in mortality of common cancers such as those of the breast and the colon.
The second paradigm shift resulted from research that validated targeted therapy – drugs developed for and aimed at specific molecular lesions that characterise certain cancers. This kind of targeted therapy could convert a previously fatal leukemia into a chronic disease that did not reduce the patient’s lifespan. This finding is now being applied to common tumours such as lung cancer and melanoma.
The third paradigm shift was in understanding how we could unlock the immune system. Now immunotherapy – turning the patients’ immune defences against cancer – can work in a majority of patients. Though recent, this finding has already had a major impact on patients with advanced melanoma, formerly a tumour highly resistant to treatment, and very advanced leukemias and lymphomas and even the difficult‑to-treat lung cancers.
All of these shifts have not only helped to cure cancer and to extend lives but also changed the experience of having cancer. For many patients, brutal treatments such as disfiguring amputations are a thing of the past. Culturally, everything has changed. Where once, as in Aunt Violet’s day, the word cancer couldn’t be uttered, now ribbons, shirts and plastic bracelets all announce a person’s cancer status, or their relationship with someone who has the disease.
The paper showed that all kinds of cancers share six important traits: go after those traits, and we can have effects on many kinds of cancers
In March 2011, in the scientific journal Cell, I noticed the article ‘Hallmarks of Cancer: The Next Generation’. It stopped me cold. For one thing, one of the authors was Robert Weinberg. Anything with his name on it gets my attention. A founding member of the Whitehead Institute for Biomedical Research and a professor of biology at MIT, Weinberg did some of the original work showing that specific genes, called oncogenes, could cause cancer in rodents. This laid the foundation for our fundamental molecular understanding of the disease.
The paper on the hallmarks of cancer was not just any paper. Eleven years earlier, Weinberg and his co-author, Douglas Hanahan, published an article in the same journal called ‘The Hallmarks of Cancer’, in which they wrote about six traits that all cancer cells have in common. The new study updated and extended the work of the earlier study. It painted a big picture: if all kinds of cancers share six important traits, then that dramatically shrinks the number of targets we have to attack to fight cancer. Go after those six traits, and we can have effects on many kinds of cancers.
Weinberg’s first paper is the most cited paper in the history of Cell. It is that critical to the current thinking on cancer. In the second paper, published in 2011, Weinberg and Hanahan had refined their descriptions of the original hallmarks using information gleaned from animal studies and biochemical assays, or measurements, that didn’t exist a decade ago. And they added two new ones. I knew when I picked it up that it was going to be a riveting paper, and it was.
To recap their points, using technical language, the eight hallmarks of all cancer cells include: sustained proliferative signalling; evasion of growth suppressors; resistance to cell death; avoidance of immune destruction; the ability to induce angiogenesis (generating blood vessels that bring a blood supply); the deregulation of cellular energetics; the ability to enable replicative immortality; and the activation of invasion and then, of metastases.
Now let me translate.
A cancer cell starts as a perfectly normal adult cell packed tightly, shoulder to shoulder, with other similar cells. They can talk to each other by communicating through their contact points, like pressing a buzzer on an intercom. Depending on which organ the cells are in, the signals generally say: Sit still, do your job, make proteins, excrete waste, but, as much as you might like to, don’t even think about dividing.
But, unbeknown to the soon-to-be cancer cell, some changes have been taking place behind the scenes. The cell genes that suppress unwanted, dangerous growth might have been altered by a mutation or by inheriting defective genes in a way that makes them unable to respond.
These cells aren’t cancerous yet, but they are primed to become cancer cells. These abnormalities can be inherited, as with some familial cancer syndromes, usually apparent from a careful family history. Or the abnormalities can occur because our genes are bombarded with materials that damage them (for example, chemicals in cigarette smoke that cause lung cancer) and bring about structural changes known as mutations (as occur in colon cancer). Or a cancer-causing virus captures the genes that control growth to allow the cell to replicate (as the papilloma virus does to cause cervical cancer).
Even then, cancer might never develop without a second incident – another mutation, or extra copies of the gene, or an abnormality in the controlling element of the gene to cause cancer. With a second incident, the cell receives a steady signal to grow and begins to divide. It continues, all the while looking back over its shoulder, fully expecting a rap on the head from the suppressor gene for disobeying orders. But if that suppressor is broken, the rap doesn’t come.
These are the first two hallmarks of cancer: sustained willy-nilly growth; and a deactivation of the braking system present in normal cells. Then the cancer cell is like a car rolling down a hill – all acceleration and no brakes.
The life of a budding cancer cell is not that easy; this is why we don’t all die of cancer as children. Many cells primed to become cancer do not progress to that stage. The would-be cancer cell must face immediate challenges if it is going to continue its course.
Evading the cell’s suicide mechanism is one. When we develop as embryos, we go through stages that mimic our distant ancestors. We develop gills for a time, for instance, and webbed fingers and toes. We don’t have them at birth, because Mother Nature put a cell-suicide system in place which signals cells that are not wanted to commit suicide. And the mechanism stays in place as we grow into adulthood, when it’s used to tell cells that have incurred dangerous cell damage to commit suicide. So it’s hardly surprising that a cancer cell might be one of the first to go – except that, with suppressors deactivated, some cells that have incurred damage can no longer be forced to commit suicide.
Next there is the immune system designed to recognise and destroy anything foreign and dangerous to the host. The immune system can ferret out rogue cells and send an army of assassin lymphocytes to kill them. This immune reaction can be dangerous in adults if the immune system goes after the wrong cells. So normal cells have a system to deactivate a harmful immune reaction. When this deactivation fails, we develop autoimmune diseases such as lupus and inflammatory arthritis. The budding cancer cell co-opts the immune system, inactivates it, and fools it into ignoring the cell.
These are the first four hallmarks of cancer cells: growth, deactivation of the braking system, the loss of the suicide mechanism, and the trickery of the immune system. They might not emerge exactly in that order, and what I’ve described could take place slowly, over months to years, but they are the essential elements that convert a normal cell to a cancer.
Like Patton’s Third Army, the cancer cell moves so fast that it runs out of fuel quickly if its supply line is not maintained. It needs a blood supply. So it co-opts the normal cells’ ability to form blood vessels, an ability normally used by adult cells to help heal wounds – a process called angiogenesis.
That blood can supply the nutrients the cancer cell needs. But the tumour also needs a source of building blocks for DNA synthesis to build new cancer cells. To get them, it reaches back into the bag of tricks normally available only to a developing embryo, and activates a form of energy metabolism referred to as aerobic glycolysis.
Humans derive their energy from two forms of metabolism: oxidative phosphorylation and glycolysis. Oxidative phosphorylation, the most efficient form of metabolism, takes place in the presence of oxygen carried by red blood cells in the bloodstream (that’s what ‘oxidative’ means). It results in the complete metabolism of nutrients to glucose; that glucose is then converted into water and carbon dioxide, which are easily excreted by the lungs and kidneys.
On the other hand, humans generally derive energy from less-efficient glycolysis only when oxygen is in short supply. Glycolysis is the metabolic system tapped by the muscles of long-distance runners, for example, after oxygen has been spent.
Very rarely, however, glycolysis can take place when oxygen is present. One of those rare instances includes the circumstance of the cancer cell, which prefers glycolysis, as inefficient as it is, because it burns glucose only incompletely, leaving parts of molecules behind that can be used to synthesise DNA and other large molecules that rapidly dividing cells need. The cancer cell, like the embryo, retains the ability to switch back and forth between the two forms of metabolism, depending on a cell’s needs at the time.
Even with a blood supply in place and its DNA-generating problem solved, a budding cancer cell must face the ultimate problem: if it and its progeny are to survive, it must be immortal. As cells divide, they gradually shorten the ends of the chromosomes, called telomeres. And when the protective ends are gone, the DNA becomes sticky, and the ends of one chromosome can stick randomly to a different chromosome. When cells with stuck chromosomes try to divide, they get pulled in the wrong direction, resulting in an imbalance of chromosomes, chaotic cell division, and, most often, cell death. This is another mechanism the body uses to prevent dangerous unlimited growth. We just run out of telomeres. But the cancer cell reaches, once more, into the embryo’s bag of tricks.
Embryonic cells possess an enzyme, called telomerase, which constantly replenishes the ends of chromosomes so they never get sticky. Otherwise, it would wear out its telomeres even before an infant was fully formed, and growth would stop. Adult cells have no measurable telomerase, because once a foetus is formed, it doesn’t need that kind of rapid growth anymore. Cancer cells reactivate telomerase.
The new studies hold extraordinary promise, but they are virtually impossible to achieve under the government’s current regulations
So now the cancer cell has its growth switch locked in the ‘on’ position, unchecked by suppressors. It is ignoring the cell-death mechanism, it is evading the immune system, and it has created its own blood supply and its own way of obtaining nutrients. Plus, it’s immortal.
But there’s more: the cancer must spread. Cancer patients, with few exceptions, die because cancer cells metastasise, or develop ‘secondaries’ – deposits of cancer cells in vital organs elsewhere in the body. A breast cancer patient never dies because of the tumour in the breast. She dies when it metastasises, or spreads, to bone and liver or brain. The patient dies from the expanding brain tumours or liver failure. A colon cancer patient rarely dies because of the tumour in his colon. He dies because the cancer cells have populated the liver and cause it to fail.
The budding cancer cell reactivates this ability to travel, which is another characteristic critical to the developing embryo. Embryos use this mechanism to move new cells around to form each of our different organs. The scientific term for this programme is the ‘epithelial to mesenchymal transition’ (EMT). Recognition of the importance of the EMT in cancer is another of Weinberg’s major contributions.
The most common cancers derive from epithelial tissue in various organs. That tissue is normally immobile. Mesenchymal cells, on the other hand, can move and cross membrane barriers. When EMT happens, an immobile epithelial cancer cell becomes a mobile, invasive mesenchymal cell. The cancer cell probably does this in its quest to reach favourable areas to grow or to reach out to an area with more robust blood vessels than it can make with its own mechanism. This mobility of cancer cells is the reason surgery or radiotherapy works only in a small fraction of cancer patients. It’s the reason why removing a primary tumour after cells have metastasised doesn’t work. That’s why some form of systemic therapy is necessary for almost all cancers.
So instead of 100 different cancers, each with its own pattern of growth, we have these eight hallmarks typical of all cancers. The importance of each of them varies with the type of cancer. For example, leukemias and lymphomas derive from cells that are normally mobile, so for them activating the EMT programme is less important, because they normally travel in the bloodstream. But with few exceptions, for a cancer to kill its host, it needs all hallmarks.
Weinberg’s hallmarks paper introduces the prospect of another paradigm shift. Just as we learned that a combination of drugs was needed to cure lymphomas, leukemias, and breast and colorectal cancers, we now know that to be most successful in dealing with the hallmarks of cancer, we need to attack more than one.
Attacking multiple hallmarks at the same time requires that we do complex clinical trials of a new kind. We can randomly combine a variety of drugs to try to attack multiple hallmarks simultaneously, but the analysis of such studies would be a statistical nightmare. The new studies need to be planned using the wiring diagram of the cancer cell in question as the blueprint. And they must be conducted in a radically different way from conventional studies.
These studies hold extraordinary promise, but they are virtually impossible to achieve under the government’s current regulations. Normally, when we test a new treatment, we establish a protocol and hold that constant during the trial to isolate the effect of the treatment. But in these new multi-hallmark trials, we will need to monitor the effects and adjust the approach on the fly – during the trial – to fully use all the information at our disposal. Current regulations make it difficult to get that kind of study approved.
Recently, at a dinner for the FDA Commissioner, I sat next to an outstanding clinical investigator who works with the exciting new drugs recently available for advanced melanoma. For the first time in my long career, we are seeing remissions that are likely cures of this ferocious disease. I asked my dinner companion how he was affected by all the regulations that have been piled on the FDA and the NCI. He said: ‘Vince, if they would leave me alone, I could cure so many more patients.’
The truth is, the war on cancer has been one of the most successful government programmes ever. But we have outgrown the original act, and we need a new one, with a new organisation, to finish the job.
At the least, a new act should call for the creation of a new position, a cancer tsar, with budget authority over all government components of the cancer programme. The original cancer act called the war on cancer the National Cancer Program. I was appointed director of the National Cancer Program in addition to being director of the NCI. The framers did this because they envisioned the programme expanding beyond the confines of the NCI. And they were correct. Not only is there today a very significant component in private industry, but hundreds of millions of dollars of support for cancer research now exists in the US Defense Department, the US Centers for Disease Control, and other agencies.
There is no coordination among the different entities. One hand doesn’t know what the other is doing. A tsar would finally allow the cancer programme to set and manage its own priorities. The NCI’s Cancer Centers Program should be able to operate the way it was originally designed to. There were only three cancer centres when the act was passed, so the framers had to look into the future. Here is what they envisioned: an expanded network of cancer centres that would have sufficient geographic distribution so that every cancer patient could reach a cancer centre if he or she needed special care.
And a comprehensive centre would be just that – an institution that is research-oriented but that could bring the full panoply of research to the bedside. A freestanding, independent entity.
Instead, the centres are tightly overregulated by both the NCI and the FDA. Combination anti-hallmark therapy? Forget it. It’s virtually impossible under the constraints we face today. The FDA and the NCI should delegate all authority for early clinical trials (phases I and II) to cancer centres. Modern approaches to developing clinical trials require flexibility and the ability to adjust protocols on the run. Each centre deserves the right to have the equivalent of its own Society of Jabbering Idiots. Most important is the fact that far more expertise exists at cancer centres than at the NCI and the FDA combined. Today we have the tail wagging the dog. And as a result, we are depriving cancer patients of what they – and their families – want most. A chance. We are losing too many people who should not be lost.
forward movement requires that some people relinquish their positions of power, and power players can be entrenched
Finally, the method of funding centres needs to be reexamined. The current mechanism is archaic. It was set up 40 years ago and hasn’t changed since. Cancer centre directors should have real authority over all NCI-funded programmes at their institutions to allow them to build truly functional research programmes.
We are so close to ending the death threat of cancer. We have the science. We just need to put the final pieces in place. But forward movement requires that some people relinquish their positions of power, and power players can be entrenched.
In 1998, I met with John Seffrin, then CEO of the American Cancer Society, and Harmon Eyre, the group’s chief medical officer at the time, to discuss the creation of a new organisation to save the war on cancer. The plan was to ask the former president George H W Bush, who had lost a daughter to cancer, to serve as chair of a new organisation called the National Dialogue on Cancer, whose purpose would be to get all the major advocacy groups to speak with one voice to reactivate the cancer act. He agreed and, to make it a bipartisan effort, asked Senator Dianne Feinstein to act as co-chair.
After an initial planning session, a meeting of about 100 people representing every group with an interest in cancer was held in 1999 in Washington, DC. Deliberations were dominated by the advocacy groups, and most of the debate focused on protecting the interests of existing organisations. In the end, the committee recommended a new, expanded organisational structure to coordinate the country’s efforts in the war on cancer, although the resistance to this, especially from the NCI, which would have lost its primacy in the new organisation, was fierce.
The completed proposal was presented to George W Bush, in the week of 10 September 2001. Then terrorists flew planes into the World Trade Center and the Pentagon, and the president and the rest of the country got distracted by another war. Later, a committee of the Senate, chaired by Senator Ted Kennedy, reexamined the passage of a new cancer act. Again, advocacy groups protecting their own interests dominated the process. The last draft that I saw looked like a laundry list of tired old programmes.
Despite this, the war on cancer forges ahead – albeit in more cumbersome fashion than it should. And I still get emails and phone calls from patients who have found my name on the internet or in an academic paper, asking for help. Often I can, but just as often I am frustrated by obstacles that I know should not be there.
In the midst of these calls for help, I receive emails, letters and phone calls from the people who took part in my earliest research. At first, these letters were about their survival and then, often, their marriages and the births of their children and, years later, their grandchildren. Though I have kept all their letters, I have not seen most of my former patients since they came to the NCI as teenagers and young adults.
Whenever I receive a new letter or email, two things cross my mind. The first is that in any war there are heroes, people who risked everything for the cause. There are a handful of doctors in this category, who risked everything to save people. They endured and finally received the acclaim that was always their due. But it is the patients who were the real heroes of the early war on cancer. They often thank me, but really we should all be thanking them.
The second thing I think is something I rarely put into words. How can I tell these people, who reach out to share their lives, that while I remember them clearly and cherish their missives, they are not the ones I think about the most? No. It is the ones we lost whose memory I carry with me most vividly.
Adapted from ‘The Death of Cancer’ by Vincent T. DeVita Jr., M.D. and Elizabeth DeVita-Raeburn, to be published in November 2015 by Sarah Crichton Books / Farrar, Straus and Giroux, LLC. Copyright © 2015 by Vincent T. DeVita Jr., M.D. and Elizabeth DeVita-Raeburn. All rights reserved.
