How to cure cancer? A review of "The Truth in Small Doses" by Clifton Leaf

No single word divides cancer researchers, patients, physicians and drug developers more than "cure". The vision of those who dream of cures and demand them of the R&D community has unassailable moral purity: we should focus our cancer research efforts on saving lives; everything else is window-dressing and distractions.

On the other side of the debate are those humbled by cancer's complexity and our relative lack of understanding of its development: veterans of numerous "hype and bust" cycles around promising mechanisms, targets and drug classes who continue to seek cures, but also appreciate first-hand that even "modest" improvements in quality of life and overall survival can yield profound benefits for individual cancer patients and their families.

Journalist and cancer survivor Clifton Leaf is in the first camp. Writing in Fortunein 2004, he presenteda well-reasoned, thoughtful, scathing critique of the "War on Cancer", lambasting both the huge sums invested with limited results and the Potemkin village of rhetoric suggesting we had made great progress. In almost 10,000 words, he indicted a dizzying array of culprits, including scientists, for focusing on the "wrong" questions in cancer biology; NCI, for creating and propagating a culture that discourages innovation and collaboration; and the FDA, for requiring overly conservative clinical trial designs that are not suitable for cancer therapies. He ended on a hopeful note, though, by citing Judah Folkman, pioneer of anti-angiogenesis therapy in oncology (epitomized by Avastin), as an example of someone who bucked conventional thinking to open up new possibilities for curing cancer, despite the establishment's seemingly insurmountable barriers:

Who knows? A new paradigm in treatment may emerge from Folkman's 40-year-old idea. Yet to make this simple and seemingly obvious shift, the entire cancer culture must change--from the rules governing drug approval to tort law and intellectual property rights. Science now has the knowledge and the tools; we need to act.

Almost ten years later, Leaf expands on the same theme in The Truth in Small Doses: Why We're Losing the War on Cancer - and How to Win It (Simon & Schuster). Reading the original article and the new book side-by-side, the most striking realization - and, in fact, the most powerful argument in Leaf's favor - is how little has changed in the last decade. For example, Leaf argued in his 2004 article that we can only have a sizable impact on cancer deaths by reducing the incidence - in other words, by detecting and treating pre-cancerous lesions before they become full-fledged cancers, as has been done successfully for cervical cancer and colon cancer (with Pap smears and colonoscopies, respectively) - and that we already have the knowledge to do so. In the book, he makes essentially the same argument, concluding the chapter with palpable incredulity at the lack of progress in the intervening period:

The answer, as many in the cancer research community knew in the early 1970s, at the start of the modern American cancer war, is preemption. This is the only way to tackle both ends of the growing cancer burden: the soaring number of new cases and the unending parade of deaths. We have to pursue this strategy, even if current models make the prospect seem untenable.  [Emphasis his]

This apparent redundancy doesn't diminish the fact that the new book is worth reading. Although there are few new arguments that weren't at least alluded to in the original article, the longer format has given Leaf room to explore the wide range of issues in more detail, and several chapters merit reading as stand-alone pieces. In particular, he thoughtfully and logically describes the emergence of "targeted therapies" in cancer, like Novartis's Gleevec, and presents a well-reasoned argument why these agents are unlikely to yield "cures" in most solid tumors. Regardless of one's scientific perspective on this question, Leaf's analysis is clear and accessible to scientists and non-scientists alike, and should probably be read and debated by senior executives at all oncology-focused drug companies.

But at its core, Leaf's book poses the same two fundamental questions as his Fortune article did a decade ago - a scientific one and a political one. Scientifically, Leaf believes that oncology is ready for an "engineering" approach focused on bringing the right leadership, expertise, processes and coordination to bear on the single-minded goal of curing cancer. He looks back reverently at successes in understanding, diagnosing and treating cancers like ALL, Burkitt's lymphoma and cervical cancer, but instead of using these stories as a hagiography, like Siddhartha Mukherjee did in The Emperor of All Maladies, Leaf presents them as an implicit challenge: We did it before, why can't we do it again? Success, Leaf believes, merely requires replicating what worked in those examples across all of oncology.

If, as Leaf suggests, the barriers are inherently structural - for example: permit and encourage rapid, innovative clinical trials; openly share information and reagents; focus resources on early detection and treatment - then Leaf may be correct that we can win the war across all of oncology, at least theoretically.  But is that the state of cancer research? Yes and no. Certainly, there are examples where the scientific barriers to advancing cancer care have been removed, and only practical ones remain. Given the rich array of anti-cancer drugs we have or are developing across multiple mechanisms, including chemotherapeutics, targeted therapies and immunotherapies, we should be able to deploy efficient approaches to test combinations in the clinic that use novel trial designs (like adaptive trials, for example) and surmount financial and legal barriers between companies. Similarly, for tumors in which population-based detection and treatment of pre-cancers yields demonstrated benefits, such as in the colon and cervix, we can and must work to ensure there is universal access to screening and therapy, in both the developed and developing world.

But in other areas, the story is more complex, and perhaps not purely an engineering problem after all. When the "War on Cancer" was declared and funded in 1971, we knew profoundly little about the biology of cancer and how to treat it - and notwithstanding the mixed record on clinical progress, it's clear that sustained investment in basic science and biotechnology research have yielded key insights. Leaf's critique of the philosophy behind developing targeted therapies for solid tumors, for example, is only possible on the backs of the countless researchers and clinicians who invested much of the past half-century in developing and studying these agents, their utility and their limitations, though little of that work was predictable or even possible in 1971.

More importantly, however, the story of research in cancer (and, in fact, in all of medicine) is one of sustained trial and error, not of moonshot-style efforts. It is critical to balance efficiency and focus (when many of the fundamental scientific problems have been addressed, leaving only technical ones remaining) with broad, messy, inefficient scientific inquiry (when they have not), and to recognize that we can often only evaluate a hypothesis's impact in the clinic after many years of sustained effort and investment. In his 2004 article, Leaf lionized Folkman as a pioneer, and noted that "[a]fter decades of resistance, the cancer culture has finally come around to Folkman's thinking--as the reception greeting Avastin makes clear." A decade later, in contrast, Leaf notes that Avastin's manufacturer, Genentech (now part of Roche), ran over 1,000 clinical trials of the agent across multiple tumors and setting, and excoriates the company in his book for "doubling, tripling and quadrupling down on a barely effective cancer drug". But it's not clear what alternate R&D approach he would have proposed if he were in charge at the time, with data emerging in real-time and persistent hope in generating meaningful clinical benefit. As everyone on the front lines of cancer R&D knows, there's no easy answer to that dilemma, except in retrospect.

And this brings us to the second question Leaf's book poses: How do you transform a complex, multi-faceted system like cancer R&D? Leaf's conceptual "roadmap" for success comprises a single, short chapter within a book of 300 pages - a short shrift that Leaf unapologetically defends in his introduction:

There may seem to be something cowardly in spending so much time dissecting a broken system without also offering a litany of concrete "fixes". ... [But] the route to victory in the cancer war is not as complex as it might seem. ... What is needed is ... a fierce public commitment to undo the incentives, rules, and daily practices that don't work.

Leaf's rhetoric is reminiscent of that used by advocates of large-scale US healthcare reform, and like in that debate, it faces two challenges. First, the transformative structural changes Leaf proposes often rest on profound philosophical questions on which smart and reasonable people can and do disagree. (For example: what is the right balance between individualism and cooperation in driving scientific innovation?) Second, and perhaps even more importantly, even supporters of some of all aspects of his high-level, seven-point plan will likely find themselves voicing pedestrian, "Yes, but..." excuses: it's too hard to change these things; there are too many entrenched stakeholders; it's too expensive to change so many things all at once; we need to compromise on near-term, incremental fixes.

The hope and opportunity, though, are that others will be inspired by Leaf's book to write the follow-up - or rather, the follow-ups, for each of his proposed solutions deserves its own discussion of near-term solutions that can be implemented in the current environment, demonstrate the potential value of "doing things differently" and serve as models for wider-scale change. We're already seeing some examples in this regard - "open innovation" collaborations in biomedical research, wider use of more efficient clinical trial designs, and  more permissive regulatory guidelines for "breakthrough" advances, just to name a few. Change in cancer research may not be coming fast enough or in a coordinated enough fashion for Leaf, but there are glimmers of hope that the tide is shifting toward more widespread improvements.

There's clearly more to be done, however, and Leaf's book serves as a powerful call-to-action that our current system is too structurally flawed to provide the transformation in cancer care we all seek. Leaf has forcefully articulated the "why" and the "what" for winning the war on cancer; now it's time to focus on the "how".