Losing the War on Cancer

After a half-century of heavily funded research, progress against cancer still lags behind other leading causes of death. Why?

President Nixon signed the National Cancer Act in 1971, launching the ‘war on cancer.’ (AP Photo)

Here is my deep dive on an important question in medical research. This article was originally published in Tablet magazine and is reprinted here with permission.

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In 1924, biochemist Otto Warburg observed that cancer cells “feed” differently than normal cells, preferring an unusual energy-generating mechanism where glucose is fermented to lactate. This sugar-driven process of cancer formation is linked to insulin resistance, inflammation, and the formation of new blood vessels that fuel rapid tumor growth. Known for his ascetic lifestyle and his holistic view of biology, Warburg believed that diet profoundly influenced health, and so he avoided alcohol, tobacco, and meat. Even after he won the Nobel Prize for a different discovery, Warburg continued to live a frugal life of solitary laboratory research, despite family wealth and Nobel earnings.

For almost a century, his pioneering discovery of the “Warburg effect” in cancer metabolism has been mostly ignored. Had we grasped its implications, the resultant advice to lower the risk of various cancers would probably have boiled down to: “Don’t eat sugar.” But that public health message was never promoted.

Then in the 1940s, pediatric pathologist Sidney Farber, for whom the Dana-Farber Cancer Institute is named, pioneered the first use of chemotherapy to treat cancer, specifically, childhood leukemia. Dr. Farber collaborated with philanthropist and savvy lobbyist Mary Lasker, of the American Cancer Society, to mobilize public and political support for cancer research. His focus on treatments for childhood cancer put a human face on this tragic disease and helped set the stage for the nation to go all-in on battling cancer a few decades later. Hopes were high that this scourge could eventually be overcome.

President Nixon officially launched the “war on cancer” 54 years ago. It was 1971 and jungle conflict had dissevered the nation. Nixon needed a unifying cause and America needed a cure. So he declared a cancer “moonshot.” Multiply funding tenfold. At last understand the disease’s biology. Target treatments properly. Vanquish an enemy worse than communism—even more powerful, even more pitiless.

A great hope, but what would be the reality?

The reality would be scant successes, billions wasted, dreams dashed. The reality would be meaningful victories in very few battles—most notably in public education to snuff out smoking—instead of a successful campaign to win the whole war.

Financing the War

We don’t really know how much money the war on cancer has cost. One study in the Lancet found that in the year 2020, the U.S. invested $14 billion on cancer research, which amounted to 57% of the total funding globally. Almost 80% of these research grants ($11.1 billion) came from the taxpayer-funded National Institutes of Health (NIH). This total number is surely a low estimate, however, as it does not include the considerable money spent by pharmaceutical companies on research and development of new cancer therapeutics—numbers which are even harder to come by.

Resource allocation for various types of cancer is a real problem. Funding is not allocated proportionately with disease burden. Thyroid cancer is underfunded, while brain and breast cancers receive relatively high funding. Plus, even though we still rely heavily on them for cures, surgery and radiation receive, respectively, only 1.4% and 2.8% of the research funding pie. Instead, a disproportionate amount of public and private funding goes to immunotherapies which, despite their hype and sheen, typically provide only modest benefits for a small subset of patients. Nor do we invest much in prevention and early detection, the key to cancer control globally. Instead of Warburg’s preventive measures, we’ve favored Farber’s interventions to treat, with 70% of NIH’s funding going to the latter.

There are two kinds of medical research: foundational scientific research and then applied research. The first aims to understand the causes and progression of a disease—vital work, but not always having an immediate payout in terms of treatment. The second builds on the first to find clinical methods to cure or ameliorate that disease. We need both.

Investment-wise, it pays to think long term. Yet here’s the challenge: Usually, medical breakthroughs first require getting to grips with a disease’s underlying biological mechanisms. The intricate and complex reasons why particular cancers arise and what sustains them, can provide clues regarding potential targets for treatment. When exploring foundational questions, we need to keep multiple hypotheses in play. What is the role of genetic versus environmental factors, and how do they interact? Does cancer represent a failure of the immune system to kill and clear cells that go haywire before they proliferate? Or is cancer driven primarily by metabolic dysfunction? Or some combination of both—entirely plausible since, as Warburg’s research suggested, metabolic dysregulation contributes to inflammation? Or is there some other explanation entirely?

If the NIH sidelines metabolism in favor of immunotherapies, as it has done in recent decades, despite evidence for both theories, this signals to researchers and regulators that the latter is considered “gold standard” science while the former is marginal, if not fringe. But as anyone familiar with the history of science knows, prevailing theories favored by the scientific establishment are often proved wrong, and frequently hard to dislodge even when they are wrong.

Teasing out answers to these basic questions is painstaking work, with plenty of dead ends, a high failure rate, and lag-times of up to 17 years. Which is why the NIH tends to focus on it, leaving the development of immediately applicable, patentable treatments to pharmaceutical companies. But with cancer proving such an elusive enemy, is it time to question the strategy of relying on public funds to move the ball down the field, leaving the industry to run the plays that put the ball in the end zone?

The Copycat Industry

A major breakthrough in cancer treatment should prove enormously profitable, and Big Pharma can afford the best scientists. Why, then, do pharmaceutical companies tend to focus on lower risk, short-term investment returns through “copycat” drugs? Why would companies seek only marginal gains in cancer treatment, when they could focus their R & D on a game changer? Why shy away from a strategy that aims to throw a 50-yard touchdown pass? The answer lies in the dynamics of publicly owned pharmaceutical firms.

Like any company, pharmaceuticals are legally required to focus on maximizing shareholder value. Which means, as far as cancer is concerned, developing products with the greatest profit potential and the least risk. Inventing an approved drug that is truly different from those already on the market requires enormous investments, estimated between $1.2 billion and $1.8 billion.But if there is already a treatment the FDA has approved for one cancer, there are strong incentives for companies simply to get the FDA to grant “supplemental approvals”—i.e., licenses to use the same drug to treat different cancers. And even if this will bring only marginal clinical benefits. (Enroll enough patients in a clinical trial, even if those patients only survive a few more months, the aggregate achievement might be statistically significant even if it is not clinically significant.) Of course, faced with imminent death, a patient will gladly accept two more months of life. But writ large, the sector/market is eschewing the possibility of more transformative treatments for everyone else. Again, we’re aiming at 1-yard gains, not 50-yard touchdowns.

Only 42% of newly approved therapies can be considered “clinically meaningful improvements” according to modest criteria set by practicing oncologists. The rest offer perhaps a few more months of life. Novel immunotherapies, for example, may only be applicable to only 2% or 3% of patients with a particular type of cancer, perhaps a few thousand patients in the U.S. But if a company develops a successful drug for one of those targets, other companies often develop similar copycat compounds to compete in the market. Compared to existing drugs, these products are tweaked just enough to secure a separate patent, but remain functionally the same in terms of their mechanism of action. These therapies nevertheless frequently cost $15,000 or more per month. While this approach may be profitable, it is not an effective overall anticancer strategy.

Pharmaceutical companies take safe bets in other ways too. All too often their R & D strategies are geared toward market competition, not the best treatments. Consider, for example, the billions of dollars spent on one potential therapeutic strategy, which involved attempts to starve tumors by choking off their blood supply with molecules that target blood vessels. In recent years, more than 50 tyrosine kinase inhibitors which operate on this principle entered clinical trials—most of these before a single one had been approved or even demonstrated proof of concept. Billions of dollars later, only five of these drugs have received approval, and they show extremely modest results in overall survival. The four agents approved for renal cell carcinoma were clearly redundant.

Billions of dollars were also wasted disproving the mitosis hypothesis. (Many researchers mistakenly thought that microtubule-targeting drugs like Taxol might inhibit the process of cell division known as mitosis.) Twenty-five drugs targeting mitosis entered clinical trials before any of them were proved to work. Companies spent billions testing these drugs on 2,000 different cancers, with results showing only a 1% response rate. A properly coordinated war on cancer, with adequate data-sharing across the private sector, could have disproved the hypothesis for a lot less money, time, and effort.

The copycat approach to drug development has become the industry rule rather than the exception. One analysis of drugs in the pharmaceutical company pipeline found that three-quarters of them had overlapping mechanisms of action—that is, they were not substantially different from competitor products. There is not necessarily a single nefarious villain to point to here—no rapacious executive or unimaginative board member who intentionally places profits over patients. No doubt, most company executives, employees, and scientists sincerely want to make real progress in cancer and the other diseases they target. But structural incentives tend to discourage ambitious efforts aimed at meaningful advances achieved by truly groundbreaking therapeutics.

Firms are pushed in less-than-productive directions by the internal dynamics of publicly traded companies. The wolves of Wall Street often act more like sheep. Stock price depends on investors’ trading behavior, not merely the company’s profitability. Investors naturally want higher returns, but they also strongly favor lower risks. A company’s decision to invest in a radically new breakthrough treatment may promise considerable rewards in terms of long-term earnings, but at the cost of significant short-term risks. Even if the basic science is promising, investors are easily spooked into selling shares when such ambitious ventures are announced, with the result that stock prices drop and shareholder value diminishes.

Like politicians aiming only at the next election cycle, companies concerned about quarterly earnings and stock prices are thus disincentivized to invest in longer-term, riskier ventures—precisely the kinds of research and development efforts that sometimes yield substantial overall gains for medicine. In short, nobody calling the plays in industry is attempting to throw a Hail Mary pass.

Disincentive Structures

Added to this market failure is a regulatory one. Rules around reimbursement of insurers distort supply and demand.

Due to legal mandates, Medicare—the largest purchaser of insurance, of course—is legally required to reimburse for any chemotherapeutic drug, regardless of its relative benefit over other drugs, so long as it is given for a “medically approved indication” (commonly interpreted as FDA approval). Until very recently, the government had little ability to negotiate drug prices. For drugs covered under Part B, Medicare will pay 106% of the average sales price. Many states impose similar rules on private insurance companies. Thus, Medicare tends to set the standards for all medical billing and reimbursements.

This, in part, guarantees profits for approved drugs, regardless of their degree of clinical benefit. So long as the pharmaceutical company successfully markets these products to physicians, and oncologists choose to include them in chemo regimens, the drugs are guaranteed to make money, even when their clinical benefits are marginal. If a new, expensive drug still appears to be the best that can be done under bad circumstances, an oncologist will naturally be inclined to prescribe it, even if it only extends the patient’s life by a month or two.

With these market and regulatory dynamics at work, like the trench warfare battle lines in World War I, taxpayers and industry expend massive resources only to move the battle front in the war on cancer a few meager yards.

Sometimes we face the opposite problem. Rather than expensive but largely ineffective cancer drugs flooding an already crowded market, effective but cheap treatments end up in beguilingly short supply. After the 20-year patent expires and a drug becomes available in generic form, the price usually drops significantly due to market competition from several suppliers. At first this is good, lowering the cost of treatments. But at a certain point these lower-priced drugs don’t make enough money, even though they have proven efficacy and might work just as well, or even better, than more expensive patented options. In these circumstances, a company may stop producing a generic drug altogether, creating sudden supply shortages and pushing doctors toward costlier, though not necessarily more clinically efficacious, alternatives. Imagine being a front-line soldier and fighting a war where cheaper yet more effective weapons were not being produced and shipped to the front, and you’ll know how clinical oncologists sometimes feel.

In one survey, four out of five oncologists reported that they were unable to prescribe a preferred chemotherapy regimen in the last six months due to supply shortages. Three-quarters of these reported having to settle for an alternative (and often costlier) regimen they believed was less effective. This is how optimal treatments, which should theoretically be available, are not finding their way to the bedside. Devising policies that incentivize solutions for this fixable problem seems like low-hanging fruit.

Sometimes the problem doesn’t have anything to do with economics; it’s basic psychology that’s at issue. In the life-and-death context of cancer, access to new therapies becomes a fraught issue for patients. Facing the ordeal of failed treatments, many patients become understandably desperate and strongly inclined to try experimental options in the hopes of landing on something—anything—better than the dismal status quo. Patients facing death are not disposed to limit costs or forgo drugs that promise even marginal potential benefits (especially when those costs are not coming out of their own pockets). And if policymakers complain about the $15,000-per-month price tag for a new cancer drug that only extends life by a month or two, they risk appearing heartless—for “what is a human life worth,” after all? Any proposal that might limit a dying patient’s options becomes a political hot potato.

Given these problems, would we fare better if more clinical research was done by academic institutions rather than pharmaceutical companies? There are pros and cons to both approaches. Starting in the 1990s, clinical research for cancer shifted strongly in the direction of pharmaceutical companies, who typically have more resources and the ability to move nimbly and pivot quickly compared to academic research centers. As compared to industry studies, clinical research in academia moves slowly, with less available funding and more bureaucratic hurdles. However, in contrast to industry standards, academic research findings are typically published and therefore accessible to other researchers, facilitating efforts at rational coordination and collaboration across institutions, and reducing wasteful redundancy.

The overall consequences described here of the shift from academia to industry for applied clinical research have doubtless been unintended, though they are no less concerning, even if there is no “greed is good” corporate or Wall Street oligarch toward whom we can point an accusing finger. The regulatory and market dynamics for cancer drugs differ profoundly from other consumer products like cars or smartphones. Even though it would be extremely profitable if they could achieve it, paradoxically, the current pharmaceutical company ecosystem is not likely to produce breakthrough products that significantly advance the overall treatment of cancer.

Cancer research is not the only division within the war on cancer where money is often wasted or misallocated. Cancer treatment centers are often guilty of the same, in ways that mislead patients and promote false hopes. The 1,200 cancer centers around the country, all competing for the same patients, have massively escalated their spending on marketing—more than tripling their marketing budgets (from $54 million to $173 million) between 2005 and 2014, according to the most recent industry study. A yearlong investigation by Truth in Advertising showed 43 of 48 cancer centers studied “were deceptively promoting atypical patient experiences through the use of powerful testimonials.”

If a particular cancer has a 5% five-year survival rate, once you treat enough people you can always find a patient in that fortunate minority, whose rare outlier story then becomes part of your marketing campaign. Such marketing strategies take advantage of vulnerable patients who could get similar treatment elsewhere—often closer to home and at lower cost. But few watchdogs hold these institutions to account when they overpromise and underdeliver. After all, prestigious cancer centers are staffed by accomplished doctors and nurses just trying their best to treat a deadly illness—a hard group to publicly criticize.

Assessing Our Progress

More than 50 years later, the news regarding the war on cancer’s overall progress is sobering.

The most significant victory in this war has not been a breakthrough cancer treatment, but a public education effort aimed squarely at prevention. In 1964, the U.S. Surgeon General Luther Terry issued the landmark report linking smoking to lung cancer. (In an ironic twist, like many physicians of his day, Dr. Terry was himself a smoker but quit prior to his work on the report.) As every American knows, the report concluded that cigarette smoking is a major cause of lung cancer and other diseases. This turning point in public health reshaped attitudes toward tobacco use and paved the way for modern antismoking campaigns. Its findings led to immediate policy changes, including mandatory warning labels on cigarette packs and restrictions on tobacco advertising.

With anticipated pressure from tobacco companies, the 10 scientists working on the report had labored in complete secrecy and under tight security, with meetings held in a locked room at the National Library of Medicine. The final report was so sensitive that it was hand-delivered to President Johnson. In an unusual twist, Terry received support from some tobacco industry scientists who privately acknowledged the health risks of smoking and surreptitiously provided data to the committee. Publicly, however, the tobacco industry continued to dispute the report’s findings for decades. Nevertheless, the report catalyzed a decline in smoking rates in the U.S., from 42% of adults in 1965 to under 20% by the 2000s.

In the wake of the public health victory against (smoking-related) lung cancer, precious few subsequent battles in the war have been decisively won. The next most notable victory has been against childhood leukemia. Building upon Sidney Farber’s pioneering work, newer chemotherapies have led to significant advances in treating this cancer of white blood cells. Another blood cancer, chronic myeloid leukemia (CML), which primarily afflicts adults, has similarly seen major advances in survivability. Drugs like imatinib now cure most CML patients, compared to earlier treatments like interferon, which extended life only minimally. Also in the victory ledger, testicular cancer now has a 90% cure rate with cisplatin, surely a significant gain. We’ve also seen significant progress in treating melanoma.

Besides these select victories, and smoking cessation’s beneficial effects on the incidence of lung cancer, there’s surprisingly little to report in terms of good news. Even when we include these advancements in treating some cancers, overall cancer mortality rates declined by only 5% in the more than half-century from 1950 to 2005. While cancer death rates have shown additional improvement during the most recent two decades, this is attributable largely to declines in both incidence and death rates for lung cancer and several other smoking-related cancers. In short, after we won the public opinion battle against cigarette smoking, the rest of the war on cancer is not going so well.

During this same period, the incidence of cancers associated with obesity and insulin resistance has been rising—including breast, uterus, colorectal, pancreas, kidney, and liver cancers. At least 13 types of cancer representing 40% of the total cases in the U.S. have been linked to obesity, hyperglycemia, and inflammation—in other words, metabolic dysregulation driven by dietary and environmental factors. The hundred-year-old ghost of Otto Warburg, whom we met in the opening paragraph, continues to haunt us. The public health success story in reducing smoking has not translated to widely adopted lifestyle modifications for other modifiable cancer risk factors. And for most other cancers, the promised miracle cures have not materialized.

By comparison, during that same half century the number of deaths adjusted for age and the size of the population plummeted for other leading killers like heart disease, stroke, influenza, and pneumonia. By contrast, cancer remains the second leading cause of death in the United States. Data from the CDC suggest that, with improvements in cardiovascular disease and the treatment of aging-related ailments, cancer may soon become the No. 1 cause of death for Americans. The cost of cancer therapies has also risen sharply, with many new treatments costing upward of $10,000 to $15,000 per month. As already mentioned, many of these novel and costly therapies yield, at best, only marginal benefits.

Perhaps there are alternative explanations for this apparent failure? Some have proposed the “competing cause-of-death” hypothesis: In days past you might die of a heart attack, but with medical advances in that domain, people now live long enough to later die of cancer. This would make cancer rates appear higher, even if we enjoyed simultaneous advances in cancer treatment. Unfortunately, however, this hypothesis is not borne out by age-adjusted statistics, which calculate death rates within discrete age groups.

Another potential rejoinder is that, with increased screening, we diagnose more cancers by catching those that would otherwise have been missed. Thus, it might appear that cancer rates are rising, but this is merely due to better detection, which should lead to earlier interventions and thus better overall outcomes. But this hypothesis likewise does not hold up under scrutiny. While cancer is diagnosed more frequently today, this does not account for the increased death rates from cancer. Improved screening means there are more “cancer survivors” counted in the general population. But if treatments do not improve for lethal cancers, the age-adjusted death rate remains more or less constant, as we have seen for most cancers. Thus, more survivors do not necessarily correlate with fewer deaths.

Let’s examine a few of the key battles. While advocates of universal HPV vaccination promised to virtually eliminate the most common types of cervical cancer, actual gains since the introduction of the vaccine in 2006 have been modest at best. From 2006 to 2023, age-adjusted mortality in the U.S. for this cancer only declined from 2.4 to 2.2 per 100,000. Meanwhile, in some regions globally, rates of cervical cancer have risen during this same period due to poor screening and changes in sexual behavior.

Surgical treatments for breast cancer have shifted from more-invasive mastectomies to less-invasive lumpectomies—a modest victory—though overall rates of breast cancer have been rising, and death rates remain steady. Naturally, cancer researchers and physicians are not responsible for the increased risk factors, from obesity to delayed pregnancy among women, which contribute to this rise. Giving birth to multiple children is among the strongest protective factors against breast cancer, though it’s hard to imagine a public health campaign today aimed at that goal. We remain dismayingly far from claiming victory, or even much by way of advancing the front lines, against the most common cancer that afflicts women (breast cancer accounts for 31% of cancer diagnoses in females).

In a battle where we have lost ground, more young people are developing colorectal cancer. Over the past decade, colorectal cancer cases rose 2.4% annually in those under 50. Over the last quarter century, the proportion of cases in those under 55 doubled from 11% to 20%, with death rates among the young rising 1% per year for the last couple of decades. Colorectal cancer has thus become the leading cause of cancer death in men under 50, and the second leading cause in women under 50 (after breast cancer), up from the fourth leading cause two decades ago.

Again, this scourge—along with a dozen other cancers—is linked to dietary, environmental, and metabolic factors, which the cancer establishment has tended to overlook. Changes to our food supply and diet, with judicious help from pharmacological agents like metformin and GLP-1 agonists, could very well put a bigger dent in cancer deaths than dozens of pricey immunotherapies. We need the equivalent of the antismoking campaign—don’t eat sugar and processed foods—for the rising rates of metabolic cancers.

Meanwhile, other types from pancreatic cancer to glioblastoma (a highly invasive brain cancer) remain virtually incurable using our current approaches. Overhyped “breakthroughs” for the deadliest cancers, periodically announced by scientists and research centers hungry for more funding, have fueled increased public skepticism by repeatedly raising false hopes that fail to deliver.

In summary, a sober assessment of overall progress in the war on cancer can only conclude that the war effort has sunk massive expenditures for only very modest results.

Renewing the War Efforts

Undeterred by this slow progress, champions of the war on cancer have periodically reappeared on the political scene to renew the war effort and stir up public support. Andrew von Eschenbach had a passion for science but struggled academically—his college dean bluntly told him his grades would never get him into medical school. A stern intervention from his father and a Jesuit priest who enrolled him in summer school turned things around, propelling him to Georgetown University School of Medicine, a stellar career in oncology, and eventually, a 2021 Pontifical Hero Award from the Vatican for blending science, faith, and public service.

In what might be interpreted as an enormous act of faith in science, in 2003, von Eschenbach, by then director of the National Cancer Institute, the oncology division of the National Institutes of Health, set an ambitious goal to eliminate cancer-related suffering and death by 2015—a target also supported by the American Association for Cancer Research. Dr. von Eschenbach drew inspiration from successes like testicular cancer treatments, which he believed could be replicated using genomics to discover why a small percentage of patients respond to drugs while others do not. Like many in cancer research whose personal grief drives their professional ambitions, he founded MD Anderson’s Prostate Cancer Research Program in 1996 partly because his own father battled the disease.

By von Eschenbach’s target date of 2015, overall cancer death rates had declined about 20% compared to 1991. But as noted above, most of these gains were due to declines in smoking, not primarily to NCI-funded research on cancer treatment. While the battle front has moved modestly in recent decades, we are obviously very far from declaring victory in this war.

With its $7.2 billion budget this year, the NCI remains the largest funder of cancer research in the world by a long shot. The latest report of the NCI is brimming with information on prevention, early detection, diagnosis, treatment, life after diagnoses, and end-of-life care plans. But there is nothing in the report to indicate what we really need to know: whether any of the treatments have actually worked. Similarly, the blitz of statistics about screening obfuscates the real metric we need: death rates. While these reports are chock full of statistics, they lose the forest for the trees. One could read all the NCI reports from the last 20 years and still not gain a clear understanding of whether we are making progress or moving the major battle lines in the war on cancer.

The NCI’s wildly ambitious goal of eliminating cancer by 2015 was not the only occasion in recent memory for publicly renewing the war on cancer. The 21st Century Cancer ALERT Act, passed in 2009, aimed to overhaul the original 1971 act by funding early detection research, providing screening grants, and increasing clinical trial access. That same year, Obama’s stimulus package allocated $10 billion to the NIH, with $1 billion earmarked specifically for genetic cancer research and targeted therapies. But these laudable efforts have had little overall impact 16 years later.

Undeterred, the war on cancer was once again revivified in 2016 and again renewed in 2022 when President Biden launched a “cancer moonshot 2.0,” which sought to reduce cancer deaths by 50% over the next 25 years. Citing the loss of his son Beau to brain cancer, Biden’s plan included a “cancer cabinet” with representation from over 20 federal agencies, billions more in funding, and a focus on public-private partnerships in cancer research.

These periodic public renewals of the war effort are entirely understandable. One would be hard-pressed to find a single politician who does not want to cure cancer. As most Americans have lost loved ones to this terrible affliction, few voters would object to increased funding for cancer research. As was true in Nixon’s day when the war on cancer commenced, in our divisive and polarized political climate, support for cancer research seems like a rare issue everyone can agree on.

In medicine, an appropriate treatment plan always follows an accurate diagnosis. To move us closer to victory in the war on cancer, we must accurately and honestly assess our losses and casualties, admit our stalled progress relative to other diseases, and examine the complicated reasons for our failure to advance the front lines very far despite massive expenditures and many noble efforts. Without this sober assessment of the war’s half-century record of (mostly) disappointing results, it’s not clear that an updated 2.0 version of the war on cancer will fare any better than the original. Surprisingly, there is little published evidence that this critical self-assessment by the established cancer enterprise has yet happened.

Public Research Troubles

We also need to reckon with a set of serious problems plaguing biomedical research as a whole.

It’s not just industry pursuing “safe bet,” incrementalist approaches; academia is also settling for less. Once again, it’s not that scientists are stupid; the impasse owes to major structural problems besetting higher education.

For decades, NIH funding has been funneled to the largest universities on the coasts. The consequence is an insulated monoculture, one that tends to police in-group thinking as researchers mostly interact with other scientists who already agree with their theories. In this system, insiders protect their turf by dismissing or excluding upstarts with new ideas.

The review process for NIH grants also tends to embed a risk-averse conservatism, as the new director of the NIH, Jay Bhattacharya, has acknowledged. Reviewers will push for a portfolio where the maximum number of grants succeed, often funding only the safe projects most likely to pan out. The current configuration of grant-reviewing by established researchers disincentivizes research that potentially challenges the current consensus—which is what we desperately need. (And even if an intrepid researcher manages to get their innovative study funded, an anachronistic peer-review process, whereby a handful of reviewers with established interests tend to act as gatekeepers, often ensures the research never sees the light of day.)

For years the NIH had a policy that anyone sitting on a study section, the prestigious panels which review grant requests, was required to have an active, large NIH grant themselves. Being on a study section could help an academic researcher obtain their own NIH grants, permitting them, for example, to suggest names for who might review their grant proposals. Thus, only already accomplished scientists, with vested interests in protecting their own research results and perhaps increasing their lab’s funding, were responsible for deciding which young investigators are allowed into the club through the gateway mechanism of NIH funding.

These institutional dynamics may help us understand the decadeslong disinterest at the NIH in the metabolic theory of cancer, even though Warburg’s foundational research goes back a hundred years. A groupthink skew toward the immunological theory led to generations of complex immunotherapies that had very little impact on overall cancer mortality, while overlooking the likely enormous impact of sugars in initiating cancers and fueling tumor growth. Why are we only beginning to rigorously study this issue now, even though the basic research is a century old? Like smoking-cessation campaigns, public health efforts to reduce sugar intake just might have prevented more cancers than anything else the NIH has funded (not to mention reducing a host of other obesity-related diseases like diabetes).

Then there is the replication crisis in science. The hallmark of a reliable scientific study is that another researcher can use the same methods, run the same experiment, and get the same result. The replication crisis refers to the widespread concern that an astonishing number of published research findings cannot be reproduced or verified with a repeat study. This lack of reproducibility undermines the reliability of supposed scientific knowledge. A landmark 2005 paper by the eminent Stanford professor John Ioannidis, provocatively titled, “Why Most Published Research Findings Are False,” drew attention to this elephant standing in the room of science. He argued that systemic flaws in research design, analysis, and publication practices lead to a high rate of false findings in published studies. This rather dismal assessment of the state of contemporary science unfortunately includes cancer research.

Since Ioannidis’ groundbreaking paper, additional work has confirmed that many studies, when repeated by other scientists, do not yield similar findings. Starting in the early 2010s, several papers estimated that 50%-90% of published findings in fields ranging from preclinical research to cancer biology may not be replicable. One survey of scientists in Nature found that more than 70% of researchers have tried and failed to reproduce another scientist’s experiments, and more than half have failed to reproduce their own experiments. A 2015 study estimated that $28 billion in U.S. preclinical research alone is spent on irreproducible studies.

Outright fraud turns out to be more common in published scientific papers than we would like to think, and without efforts at replication, frankly fraudulent results often go uncorrected. To mention just one staggering cautionary tale from the world of Alzheimer’s research: In 2022, a whistleblower revealed that a landmark 2006 paper published in Nature contained manipulated images and deliberately falsified data. This paper, which supported the so-called amyloid hypothesis for the etiology of this disease, helped set the course for Alzheimer’s research over the next decade and a half. This resulted in an estimated $1.6 billion of wasted NIH funding in a failed attempt to build upon a line of inquiry which rested upon an entirely fraudulent foundation.

The war on cancer intersects with political battles waged for the control of public opinion. This can influence the kinds of hypotheses that can be entertained, and those which the establishment attempts to prohibit. Some scientific questions are hard to ask. For example, the latest neuralgic flashpoint among skeptics of the scientific establishment relates to worries that the novel mRNA COVID shots may be triggering new cancers or causing old cancers to relapse that had long been in remission. Even some insiders are quietly asking this unmentionable question: The director of a leukemia/lymphoma program at a leading cancer hospital reached out to me early in the vaccine rollout expressing precisely this concern, as he was seeing a sudden explosion of new cancers and inexplicable relapses in his patients following the injections. Early published observational studies as well as papers proposing potential mechanisms lend plausibility to this extremely worrisome hypothesis, with other analyses disputing the link.

In any case, more rigorous research is urgently needed. But strong political and social forces mitigate against even asking a question like this one, much less attempting to answer it. Sometimes science is inconvenient, and some people would rather not know the answer if the research findings are not to their liking. Despite its elevated cultural status, science often remains a human, all too human, endeavor.

A Path Forward?

In cancer research, we desperately need more shots on goal. Only transformed systems—state and market institutions that work in a radically different way—will let us take those shots. We’ve got to take the risks necessary to move the ball farther down the field, to mix sporting metaphors—which will mean, paradoxically, living with more failure. Not every play should be a Hail Mary pass; but it’s hard to score a touchdown when the play-calling only ever includes 2-yard runs.

We need to entertain the possibility that we are overlooking or forgetting important hypotheses on foundational questions. So, we clearly can’t neglect researching the basic science. But we also need public funding to get from that research novel clinical treatments, however long they take. We need to incentivize both the state and the market to play the long game rather than cravenly settle for the next short-term, quick-hit, copycat incremental efforts.

In closing I’ll mention just a few ideas among the dozens of policy proposals that one could suggest from this analysis. In the public sector, centrally controlled top-down science should be decentralized and diversified to allow for adequate exploration of competing hypotheses. There are many ways this could be done; but perhaps we explore federal block grants to states to fund scientific research. Instead of one NIH we could have 50 SIHs—state institutes of health—all competing to attract researchers. Since there are notable regional variations in the incidence and mortality rates of different cancers across the U.S., various states could carve out specific niches within the research enterprise by focusing on cancer types that disproportionately impact their citizens. Of course, any discovery in this regard benefits everyone. This decentralization of research funding could open new possibilities for exploring relevant questions that tend to get stifled when a select few people control the purse strings.

In the private sector, we need better data sharing. After a certain duration, pharmaceutical firms should be required to publish their research. Judicious redactions of this published work can protect the companies’ proprietary interests while still informing the broader research enterprise. The war on cancer hinges ultimately on finding a better balance between private interests and the public good.

Pharmaceutical companies will only pursue patentable and profitable treatments. The NIH may therefore be able to rely on them for those clinical trials. But therapeutics like surgical innovations or advances in radiotherapy will require public funding, and may have a bigger payoff than new chemotherapeutics, for reasons already discussed. Likewise, the NIH should vigorously fund potential therapeutics using repurposed off-patent drugs, which no pharmaceutical company will invest in.

As anyone afflicted with cancer who does a Google search can attest, the internet is teeming with claims of cures from repurposed generic drugs and other nonpatentable agents, from ivermectin to various nutraceuticals. Without placebo-controlled trials—which no pharmaceutical company will pay for—these claims remain anecdotal and practically unfalsifiable. While we should be appropriately skeptical of claims of miracle cures, many of these reported cases, including some from treating physicians, seem plausible. For any of these agents with a credible mechanism of action and sufficient anecdotal evidence of efficacy, we should publicly fund clinical trials to find definitive answers. Most of these studies will not pan out, but if we find even a few diamonds in the rough the effort will be worthwhile.

Regardless of whether we do these rigorous studies, in the absence of better mainstream therapeutics, patients will continue to avail themselves of these alternative options. So we would do well to learn with more conclusive evidence whether or not they really work. Rather than merely dismissing anecdotal claims with a wave of the hand, the medical establishment can find clearer answers if we invest the resources in rigorous studies. Who knows, we may just discover a major advance that will turn out to be relatively inexpensive. Some available answers may be hiding in plain sight, only waiting for us to take a rigorous look.

Despite our stalled progress, it goes without saying that we need to keep fighting. Because whatever our differences, this is a war that all of us sincerely want to win. As Winston Churchill wrote to FDR on Feb. 9, 1941, “Give us the tools and we’ll finish the job …”

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