1
Trench Warfare
I ONCE ATTENDED a hospital meeting where the director of a new program presented its past year’s accomplishments. Over a million dollars had been raised from the community for this new program, and hopes were high. I wasn’t among those in the room impressed with the results being touted, but I kept quiet—because it wasn’t really my business and because my mother taught me that if you don’t have anything nice to say, you shouldn’t say anything at all. Yet that didn’t stop me from thinking that this program had wasted precious time and resources.
All around me, other participants were expressing their support. Great job! Congratulations! Excellent work! Even though it was obvious to everyone that there was little of value to show for the last year, most of the medical professionals around me played along with the sentiment that everything was great, just great. Nobody, myself included, stood up and yelled, “The emperor has no clothes!”
This problem is not unique to my hospital, but is pervasive in all of public health; it is how any bureaucracy functions. While keeping critical opinions to yourself is generally useful in personal relationships, it’s not useful when it comes to the advancement of science. In order to solve problems, we need to know that they exist. Only then can we understand how current solutions fall short and improve on them. Lives depend on it, after all. But in medical research, opinions that dissent from the specified narrative are not welcome. This problem cuts across entire disciplines, such as the study of obesity, type 2 diabetes, and yes, cancer.
OBESITY
We are witnessing the greatest epidemic of obesity in the history of the world. Look at any statistic about global obesity and you’ll find the news is bleak. In 1985, not a single American state had a prevalence of obesity above 10 percent. In 2016, the Centers for Disease Control and Prevention (CDC) reported that no state had a prevalence of obesity under 20 percent, and only three states had rates below 25 percent.1 Yikes! We can’t simply blame bad genetics, because this change has taken place within the last thirty-one years: a single generation. Clearly, we need interventions, sustainable solutions to help people lose pounds and then maintain a healthy weight.
For decades, we’ve fooled ourselves into believing we have a prescription for obesity: counting calories. The CDC suggests that “To lose weight, you must use up more calories than you take in. Since one pound of body fat contains approximately 3,500 calories, you need to reduce your caloric intake by 500–1000 calories per day to lose about 1–2 pounds per week.” This is fairly standard advice that you can find repeated the world over by doctors and dieticians, and reported in magazines, textbooks, and newspapers. It’s the same dietary advice I learned in medical school. Any physician who suggests that there is a way to lose weight by any other means is largely considered a quack. But the medical community’s obsessive focus on calories has not translated into any success against the obesity epidemic. If we cannot acknowledge that our solutions fall far, far short, we will be powerless to fight the rising tide of obesity.
Few can admit that the advice to “eat less, move more” doesn’t work. Yet the crucial first step toward solving the obesity epidemic is to admit to our shortcomings. Advice to count calories is neither useful nor effective. Instead, as I’ve argued, we must acknowledge that obesity is a hormonal imbalance rather than a caloric one. Let’s embrace the truth and move forward so that we can develop interventions that actually work. Only then do we stand a chance of turning the tide on this public health crisis. As the brilliant economist John Maynard Keynes is quoted as having said, “The difficulty lies not so much in developing new ideas as in escaping from old ones.”
TYPE 2 DIABETES
The horrifying epidemic of type 2 diabetes closely mirrors that of obesity. According to the CDC, about one in ten Americans suffers from type 2 diabetes. Worse, this number has risen steadily over the past few decades, with no salvation in sight (see Figure 1.1).
Figure 1.1
Medications that lower blood glucose, like insulin, are the standard treatment for type 2 diabetes. Over time, patients usually require higher and higher doses of these medications. If you’re taking more insulin, then it’s pretty obvious that your type 2 diabetes has become more severe. Yet we in the medical community (researchers, doctors) simply maintain the position that type 2 diabetes is a chronic and progressive disease, and that’s just the way things are.
None of this is true. When a patient loses weight, their type 2 diabetes almost always improves. We don’t need to prescribe more medication to diabetics; we need to fix their diets. But we have been unwilling to admit that our treatment approach is flawed. That would mean deviating from the agreed-upon narrative that our researchers and doctors are making brave progress against a terrible disease. Admit a problem? No way. The result? A continuing epidemic. Again, as with obesity, if we cannot acknowledge that the prevailing treatment protocol falls far, far short of acceptable, then we will continue to be powerless to help those suffering.
CANCER
This brings us, finally, to cancer. Certainly, we must be making great progress against cancer, right? Almost every day, we hear reports of some cancer breakthrough or medical miracle discovered by our pioneering scientists. Unfortunately, a sober look at the available data indicates that progress in cancer research has lagged behind that of almost every other field of medicine.
In the early twentieth century, cancer didn’t attract much attention. The biggest threats to public health were infectious diseases like pneumonia, gastrointestinal infections, and tuberculosis. But public sanitation improved, and in 1928, British researcher Alexander Fleming made the world-changing discovery of penicillin. Americans’ life expectancy began to climb, and the focus shifted to chronic diseases such as heart disease and cancer.
In the 1940s, the American Society for the Control of Cancer (the ASCC, which would later become the American Cancer Society) stressed the importance of early detection and aggressive treatment. The ASCC championed the routine use of the Pap smear, a gynecological screening test for cervical cancer. The results were a stunning success: with much earlier detection, death rates from cervical cancer dropped dramatically. This was an auspicious start, but death rates from other types of cancer continued to increase.
Deciding that enough was enough, then president of the United States Richard Nixon declared war on cancer in his 1971 State of the Union address, proposing “an intensive campaign to find a cure for cancer.” He signed the National Cancer Act into law and injected nearly $1.6 billion into cancer research. Optimism was running high. America had ushered in the atomic age with the Manhattan Project. The country had just put a man on the moon with the Apollo program. Cancer? Surely that could be conquered, too. Some scientists enthusiastically predicted that cancer would be cured in time to celebrate America’s bicentennial in 1976.
The bicentennial came and went, but the cure for cancer was nowhere closer to becoming a reality. By 1981, the tenth anniversary of the “war on cancer,” the New York Times questioned whether this highly publicized, decade-long war had “brought real progress against this dreaded disease, or . . . been an extravagant $7.5 billion misfire?”2 Cancer deaths continued their ruthless climb; the past decade’s efforts hadn’t even slowed its ascent. The war on cancer, so far, had been a complete rout.
This was not news to insiders like the National Cancer Institute’s (NCI) Dr. John Bailar III, who also served as a consultant to the New England Journal of Medicine and a lecturer at Harvard’s School of Public Health. In 1986, Dr. Bailar questioned the effectiveness of the entire cancer research program in an editorial in the New England Journal of Medicine.3 In the article, Dr. Bailar noted that from 1962 to 1982, the number of Americans who died of cancer increased by 56 percent (see Figure 1.2). Adjusting for population growth, this still represented a 25 percent increase in the rate of death from cancer, at a time when death rates from virtually every other disease were dropping quickly; crude death rates from causes other than cancer had decreased by 24 percent. Dr. Bailar noted that the data “provide no evidence that some 35 years of intense and growing efforts to improve the treatment of cancer have had much overall effect on the most fundamental measure of clinical outcome—death. Indeed, with respect to cancer as a whole, we have slowly lost ground.” He wondered aloud, “Why is cancer the only major cause of death for which age-adjusted mortality rates are still increasing?”
As an insider on the cancer wars published in the most prominent medical journal in the world, Dr. Bailar had effectively yelled, “The emperor has no clothes!” He recognized the need to energize new thinking in the stultifying morass of cancer research, which had been mummifying in reiterations of the same cancer paradigms that had failed so utterly. In recognizing the failures of the medical community, Dr. Bailar bravely took the first step to making progress in the war on cancer.
Figure 1.2: Cancer deaths, 1900–2000.
Unfortunately, the rest of the cancer establishment was not yet ready to admit to a problem. Dr. Bailar’s article received heavy criticism; it was called “erroneous” at best and “reprehensible” at worst. In the polite world of academia, this language was tantamount to the highest profanity.4 Dr. Bailar became almost universally reviled within the community he had once led. His motives and intelligence were routinely questioned.
Vincent DeVita Jr., then the director of the NCI, called Dr. Bailar’s editorial irresponsible and misleading while implying that Dr. Bailar himself had “departed with reality.”5 The president of the American Society of Clinical Oncology called Dr. Bailar “the great naysayer of our time.” Ad hominem attacks were plentiful, but there was simply no denying the statistics. Cancer was getting worse, but nobody wanted to acknowledge it. The research community responded to the message by killing the messenger. Everything is awesome, they said, even as the bodies piled up.
Little had changed eleven years later, when Dr. Bailar published a follow-up paper titled “Cancer Undefeated.”6 The death rate from cancer had increased by another 2.7 percent from 1982 to 1994. The war on cancer had resulted in not just a rout, but a massacre. Still, the cancer world could not admit there was a problem. Yes, there were some notable successes. Cancer death rates for children had dropped by about 50 percent since the 1970s. But cancer is the quintessential disease of aging, so this was a major victory in a minor skirmish. Of the 529,904 deaths due to cancer in 1993, only 1,699 (3 percent) were in children. Cancer was delivering punishing uppercuts to our face, and we had managed only to tousle its fancy hairdo.
The war on cancer was reinvigorated by the continuing revelations from the study of genetics that took place throughout the 1980s and ’90s. Aha, we thought, cancer is a genetic disease. A new front opened in the war on cancer, focusing our efforts on finding cancer’s genetic weaknesses. A massive, multimillion-dollar international collaboration oversaw the 2003 completion of the Human Genome Project. The research community felt certain that this genetic map offered a winning battle plan against cancer. We now had a complete diagram of the entire human genome, but surprisingly, this did little to move us closer to beating cancer. In 2005, an even more ambitious program, the Cancer Genome Atlas (TCGA), was launched. Hundreds upon hundreds of human genomes were mapped in an attempt to uncover cancer’s weakness. This massive research effort, too, came and went while cancer continued its progress undisturbed, calm as bathwater.
We brought our human ingenuity, massive research budgets, and fund-raising efforts to create new weapons to penetrate cancer’s imperturbable shell. We believed that the war on cancer would be a high-tech battle of smart weapons. Instead, it more closely resembled the trench warfare of World War I. The front lines never moved, the war dragged on without noticeable progress, and the bodies piled up.
The stalemate in cancer stands in stark contrast to the dizzying progress in other areas of medicine. From 1969 to 2014, total deaths in the United States from heart disease dropped approximately 17 percent despite the increasing population. But cancer? During that same time period, deaths from cancer rose a chilling 84 percent (see Figure 1.3).
Figure 1.3
In 2009, the New York Times ran a headline that reflected this reality: “Advances Elusive in the Drive to Cure Cancer,”7 noting that the adjusted death rate for cancer had dropped only 5 percent from 1950 to 2005, compared to heart disease deaths, which had dropped 64 percent, and to flu and pneumonia, which had dropped by 58 percent. Once again, an American president, this time Barack Obama, promised to “launch a new effort to conquer a disease that has touched the life of nearly every American, including me, by seeking a cure for cancer in our time.”8 Nobel Prize laureate James Watson, the co-discoverer of DNA’s double helix, ruefully noted in a 2009 opinion piece published in the New York Times that cancer killed 560,000 Americans in 2006, 200,000 more than in 1970, the year before the “war” began.9
The war on cancer has not stagnated for lack of funding. The 2019 budget for the National Cancer Institute was $5.74 billion, all derived from taxpayer dollars.10 Nonprofit organizations have proliferated like mushrooms after a rainstorm. By one count, there are more nonprofits dedicated to cancer than those for heart disease, AIDS, Alzheimer’s disease, and stroke combined. The American Cancer Society generates over $800 million per year in donations to fund “the cause.”
Perhaps at this point you’re thinking, But what about all the cancer breakthroughs we keep hearing about in the news? All that funding must be saving lives? It’s true that advances in treatment have been made, and these treatments have certainly made a difference. However, they’re not saving as many lives as you might think.
Cancer drugs are approved by the Food and Drug Administration (FDA) if they show efficacy with minimal toxicity. But efficacy can be defined in many different ways—not all of which include saving lives. Unfortunately, from 1990 to 2002,11 fully 68 percent of the FDA approvals were for cancer drugs that did not necessarily show an improvement in life expectancy. If these drugs didn’t improve survival, what did they do? The most common reason for approval is called the “partial tumor response rate,” which means the drugs were shown to shrink the primary tumor in volume by over 50 percent. That sounds pretty good, except when you consider that this measurement is almost completely irrelevant to survival.
Cancer is deadly because of its propensity to spread, or metastasize. Cancer is deadly because it moves, not because it is big. Cancers that don’t metastasize are called “benign” because they very rarely cause significant disease. Cancers that do metastasize are called “malignant” because of their tendency to kill.
For example, the very common lipoma, affecting approximately 2 percent of fifty-year-olds, is a benign cancer of fat cells. It may grow to weigh up to fifty pounds. Yet despite this enormous bulk, this benign cancer is still not life-threatening. A malignant melanoma (a type of skin cancer), however, may weigh only 0.1 pound and be thousands of times deadlier because of its predisposition to spread. Once unchained, many cancers become unstoppable.
For this reason, local cancer treatments such as surgery or radiation are of limited efficacy once a cancer has metastasized. Surgeons go to great lengths in the quest to “get it all.” They will cut huge swaths of normal tissue out of cancer patients to remove even the faintest rumor of a whiff of cancer cells. Surgery for cancer is performed to prevent metastasis, not because the cancer is too big. A cancer medication’s ability to shrink a tumor is immaterial to overall patient survival. A drug that destroys half the tumor is no better than surgery to remove half the cancer—in other words, almost completely useless. Getting half the cancer is no better than getting none of it.
Yet the majority of new cancer drugs were approved based solely upon this questionable marker of “efficacy.” From 1990 to 2002, 71 new drug approvals were granted for 45 new drugs. Of those, only 12 medications were proven to save lives, and most extended life by only a few weeks or months. In that same time, the phrase “cancer breakthrough” appeared in 691 published articles. The strange math goes like this: 691 breakthroughs = 71 cancer drug approvals = 45 new drugs = 12 drugs that barely extended patients’ lives.
All these shiny new weapons in the war on cancer amounted to a jeweled handle on a broken sword. By the mid-2000s, hope for the war on cancer was fading quickly. Then a strange thing happened. We started winning.
A NEW DAWN
Amid all the doom and gloom, hopeful signs emerged. Cancer deaths, adjusted for age and population growth, peaked in the early 1990s and have now been steadily declining. What changed? Some of the credit must be given to the smoking-cessation efforts that have been consistently championed by public health officials since the 1960s. But our paradigm of understanding cancer has been slowly undergoing a revolution, and this has contributed to new treatments, which drive our recent and, hopefully, continuing progress.
The most pressing question in cancer research is the most elusive: what is cancer? In this decades-long war, we simply didn’t know our ancient enemy. The Manhattan Project had a clear goal: split the atom. World War II had a clear foe: Adolf Hitler. The Apollo project had a concrete task: put a man on the moon and bring him back, with a little luck, alive. But what was cancer? It was a nebulous adversary, with hundreds of different variations to discern. Wars on murky ideas, like the wars on poverty, drugs, and terrorism, generally end in frustration.
Approaching a problem from the wrong angle gives you no chance of solving it. If you’re not facing the right direction, it doesn’t matter how fast you run; you’ll never reach your destination. This book is an exploration of the story of cancer. It is not meant to offer a cure for cancer. That, for now, is still largely impossible. Instead, my goal here is to chronicle the surprising journey in our understanding of the greatest mystery of human disease. It is perhaps the strangest and most interesting story in science. What is cancer? How did it develop?
Over the last one hundred years, our understanding of cancer has undergone three major paradigm shifts. First, we considered cancer a disease of excessive growth. That’s certainly true, but this did not explain why cancer was growing. Next, we considered cancer a disease of accumulated genetic mutations that caused excessive growth. Also, certainly true, but this did not explain why these genetic mutations were accumulating. Most recently, a completely new understanding of cancer has emerged.
Cancer is, improbably, a disease unlike any other we’ve ever faced. It is not an infection. It is not an autoimmune disease. It is not a vascular disease. It is not a disease of toxins. Cancer is originally derived from our own cells but develops into an alien species. From this paradigm of understanding, new drugs have been developed that threaten, for the first time, to end this war in the trenches.