The tail is wagging the dog

Vincent DeVita and Elizabeth DeVita-Raeburn write at Aeon,

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 Rather, obstacles take the form of not using the tools we already have to cure more; a reluctance to drop outdated beliefs; bureaucratic battles among physicians and medical groups; and outdated regulation by the US Food and Drug Administration (FDA) whose policies hinder the innovations wrought by cancer drug‑development in recent years.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.

...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.

...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.

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.

...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.

...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.

...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.

...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.’

...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.

...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.

...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.

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