Book Review: The Emperor of All Maladies
The Emperor of All Maladies: A Biography of Cancer
by Siddhartha Mukherjee
In The Emperor of All Maladies, oncologist Siddhartha Mukherjee has written what surely will be the definitive popular history of cancer medicine. The author credits Richard Rhodes’ monumental account of the Manhattan Project, The Making of the Atomic Bomb [read my review], for inspiring the writing of this book. In subject matter, though, this book is more along the lines of Horace Judson’s The Eighth Day of Creation. Indeed, the history of cancer is also the history of medicine. As other human diseases were conquered by vaccination (18th century), antisepsis (19th century), and modern pharmaceuticals (20th century), cancer remained resistant to the primitive onslaughts of early medicine. The ancients knew just enough about cancer to pronounce it incurable, and only recently have we discovered enough about cancer biology to mount a direct attack against it.
The book is subtitled “A Biography of Cancer,” reflecting its largely chronological organization as well as the author’s desire to write a “biography” of a living being, rather than a “history” of a disease. But I found the clever conceit of anthropomorphism to be more of a distraction than a useful tool, for it does not really add much to an already fascinating story. Indeed, Mukherjee largely abandons it after the first hundred pages or so, returning to it only briefly and sporadically until the final chapter. Perhaps it was a device that helped warm him up and get into the groove of writing.
Perhaps, too, it reflects on the author’s literary leanings, for the book is peppered with references to writers from Sontag to Solzhenitsyn. Apparently, Dr. Mukherjee was forced to memorize a lot of poetry while attending a Catholic high school in his native India. Let it not be said that poetry is useless to a physician, for the lingering effects of his literary training show up in this book’s eminent readability and some rather inspired word choices. For example, in describing his own emotions when a patient dies, he writes of the “astonishing, punctuated clarity of a gunshot in winter.” (p. 305) That phrase is so crisp that you can feel it leap off the page.
Dr. Mukherjee draws not only on the usual historian’s repertoire of personal interviews, archival papers, and other works. As a practicing oncologist, he also cites the original papers in the medical literature that announced notable breakthroughs. Endnotes comprise 69 of the book’s 571 pages, and I do believe he read every single one of those books cover to cover! With his training in oncology and gift for explaining complex medical topics, the author helps the reader to appreciate the significance of each advance: both the excitement of discovery and the numerous disappointments that often followed.
Intriguingly, Mukherjee also uses cancer as a springboard to explore related topics: hematology, anatomy, genetics, molecular biology, genetic engineering, the AIDS crisis, even the dye industry. You see, the dye industry grew alongside textile mills in the first wave of industrialization, and it was thus critical in the formation of the chemicals industry. Success in textiles built up Imperial Germany into a world power, and success in dyes also led Germany to develop chemical weapons as it tried to force a decision on the Western Front of World War I. Mustard gas turned out to have a longer-term effect on its victims, killing white blood cells and thus depleting the bone marrow. Experiments with nitrogen mustard during the Second World War then anticipated Sidney Farber’s later pioneering work in chemotherapy.
After all, Dr. Mukherjee is a man who attended Stanford for undergrad, then Oxford as a Rhodes Scholar, followed by Harvard Medical School and an oncology fellowship at Mass General, and is now married to a MacArthur Award winner. [How Cancer Acquired its Own Biographer, The New York Times, November 8, 2010.] He does not stop his in-depth research of a topic until he feels he has fully understood the content, the context, and the history. Rarely have I ever encountered a book that so telepathically anticipated the interested reader’s questions. And the author does not shove them into footnotes, either. Rather, he explores the most relevant connections in the body of the text, for if they are worth explaining at all, then they are surely worth explaining well. This is a man who celebrates his daughter’s birth by running off to the lab with the umbilical cord, harvesting stem cells in anticipation of future therapeutic usage. Meanwhile, he’s pointing out to the reader that the newborns are housed right next to the cancer ward in the hospital, for the newborns were most nearly aseptic and thus posed the lowest risk of infection to the immunosuppressed cancer patients.
He’s not content just to introduce notable personages with brief biographical sketches, but also seeks to understand their career path and personal circumstances. Sidney Farber, for example, went to the University of Buffalo for undergrad, then went to medical school in Germany at Heidelberg and Freiburg before returning home as a second-year medical student at Harvard Medical School. Now, that’s strange. Why the detour in Germany on the way to Harvard? Because, Mukherjee explains, the prestigious mainline American medical schools of the day had strict Jewish quotas.
Likewise, Yella Subbarao, who supplied Farber with anti-folates, found work at a pharmaceutical company after being denied tenure at Harvard, despite his groundbreaking work on purifying ATP and creanine. Indeed, Subbarao arrived in the United States penniless, and had to work for a time as a night porter at Brigham and Women’s Hospital before obtaining more suitable employment in the biochemistry laboratories. It was a time when such rags-to-riches stories were commonplace. Dr. George Papanicolaou also arrived in American penniless, and worked as a (very unsuccessful) carpet salesman before landing a research position studying the menstrual cycle of guinea pigs. Since these pigs do not bleed during their menstrual cycle, Papanicolaou worked out how to time their cycle by scraping off cervical tissue and smearing it on a slide — resulting in the Pap smear.
But the history of cancer medicine is also inseparable from money. Sidney Farber was instrumental in launching not just modern chemotherapy, but also the Jimmy Fund, one of the earliest media-driven fundraising campaigns against a specific disease. In this way, Farber was able to move beyond the disapproval directed at him by other doctors, who thought that his heroic efforts were jeopardizing the well-being of patients best served by palliative medicine for an incurable disease. The Jimmy Fund built him a bright and cheerful new building in which to pursue his chemotherapies, borrowing from show business glamour with big paintings of Disney cartoons on the walls. But the reality behind the cheerful façade was that the vast majority of these children would gain only a few months of miraculous remission — miraculous in comparison to the rapid and certain death that they faced previously — before a resistant form of the cancer would return. As it turns out, the eponymous Jimmy would be cured and would live to the year 2001, but very few of his fellow patients would.
But even the millions of dollars provided by the Jimmy Fund proved too small for the daunting task ahead. Farber was soon working closely with Mary Lasker to lobby for government funding. That funding would arrive, and it would multiply in spades once Nixon launched the famous War on Cancer. Mukherjee traces the origins of the War on Cancer to the success of the Apollo Project, combined with peacenik-era exhortations to turn our efforts towards the study of “inner space,” along with a growing awareness of cancer’s prevalence. A disease that once could not be spoken of in polite society became a major plot point in the 1969 hit film Love Story.
Farber’s assault on leukemia was only the beginning. In the 1950s, Frei and Freireich attacked cancer relapses with combination chemotherapy at the National Cancer Institute, drawing inspiration from the combination therapy used to prevent pathogens from developing antibiotic resistance. Meanwhile, Min Chiu Li would antagonize institutional review boards by continuing to treat patients until they reached an hcg level of 0, subjecting them to the toxic effects of vicious chemotherapy drugs long after they appeared visibly better. He would lose his job for that belief, but he would also turn out to be right. Any remote trace of cancer, as detected by indicators such as hcg level, would be sufficient to result in a relapse some months later. What’s worse, that relapse would be resistant to the last round of drugs.
Soon after, Stanford radiologist Henry Kaplan would resurrect radiation therapy for localized early-stage cancers, using chemotherapy as an adjuvant to kill off any stray cells that had migrated to other parts of the body. That led to a regimen for acute lymphoblastic leukemia that Mukherjee and other cancer fellows referred to as “total hell”: combination chemotherapy, combinations of combinations, spinal injections to attack cancer through the blood-brain barrier, and X-rays, altogether up to two years of therapy.
The standard regimen for cancer treatment had thus been systematized: radiation and chemotherapy. This grueling regimen would set the pattern for cancer treatment for decades, becoming enshrined in countless works of fiction, and serving as an iconic reminder of the trials faced by cancer patients. It would not be until the first years of the 21st century that alternatives would truly start to take over.
The Age of Randomized Trials
An earlier generation of surgeons had been convinced of their ability to exorcise cancer by its roots, using disfiguring radical surgery. As feminism and the patient rights movement began to challenge the established authority of medicine, patients began to refuse radical surgery. But the radical surgeons stuck to their guns. It was not until 1981 that randomized radical surgery was conclusively shown to be no better than local surgery. The randomized trial barely attained the required statistical power, for as the author points out, it was difficult to convince a patient to volunteer for a study in which she would randomly be assigned to either lose or keep one of her breasts. In 1975, it was shown that local surgery, plus adjuvant chemotherapy, was effective against some early-stage cancers. That trial also barely got off the ground. The surgeons in the United States had such tight control over the treatment of breast cancer that its proponent ended up launching the trial in collaboration with a maverick surgeon in Italy.
Radiation, local surgery, chemotherapy. It worked — up to a point. Outcomes improved for some cancers that were curable. Others remained incurable. The side effects of the drugs got nastier; Cisplatin made patients vomit uncontrollably. The combinations got nastier. The regimens became more and more audacious. Marrow transfusions made it possible to take patients closer to the edge of death, hopefully wiping out previously recalcitrant cancers using doses ten times higher than ones that would once have killed patients. Symbolizing the panic felt by a field that had run out of new ideas and was attempting to beat cancer by brute-force, “Tom Frei — cautious, levelheaded Frei” became one of the foremost proponents of transfusion therapy.
But the sheer number of procedures involved also generated extreme costs. Insurance companies refused to pay for it, and this in turn ran right into the patient rights movement and the growing healthcare cost crisis that afflicts us today. Patient lawsuits against insurance companies resulted in eye-popping multimillion-dollar damages, while patient advocates convinced state legislatures to mandate coverage for transfusion. The rhetoric of patient activism also heaped scorn on the traditional double-blind trials for assessing effectiveness. How can you calmly sit there condemning people to death by the flip of a coin? Megadose transplant therapy for all!
Oh, yes, the evil insurance companies paid up, and so did all the subscribers to the insurance plans. Billions of dollars were spent on transplant procedures, while patients refused to take part in randomized trials. Those studies barely achieved their patient recruitment goals, but the results all seemed to be equivocal or negative. All, that is, except for one: Doctor Werner Bezwoda of South Africa seemed to be working wonders with transplant therapy. Then in 1999, he was found to have falsified his records, treating primarily poor black women without even obtaining their consent for treatment. From 1999 to 2003, the STAMP study sought to settle the question, and finally demonstrated conclusively that megadose therapy was no more effective than standard therapies — despite being vastly more costly and far more hazardous to the patient.
Into the Modern Era
Many scientists had initially opposed the War on Cancer, protesting that we could not attack a disease that we barely even understood. Indeed, Mukherjee sees the failure of megadose transplant therapy as a signal that the War on Cancer was “lost” in both senses of the word. We had lost because cancer appeared to have won, but we were also lost because we did not have a map of cancer biology.
But statistics proved to be vital for improving our understanding of cancer. Statistics discredited radical surgery and megadose transplant therapy as treatments for cancer. Statistics also showed that the mammogram was helpful for early screening and improves outcomes. The initial 1963-1971 HIP trial turned out to have a bias that put more high-risk women into the control group. The later Canadian National Breast Screening Study was biased the other way, as it was randomized by alternating lines on a ledger, but it was not double-blind and could thus be manipulated by the healthcare practitioner. It is now suspected that nurses were compassionately steering high-risk women towards the mammogram group, possibly saving the lives of those women but also ruining the study. It was not until 2002 that a gigantic study following 247,000 Swedish women over 26 years finally demonstrated the equivocal benefits of mammography: useful for women over 50, but negligible for women under 50.
Statistics also helped to reveal the link between cigarette smoking and lung cancer. Cigarette smoking had once been so common among the general populace that its effect on cancer was statistically indistinguishable from that of “nylon stockings.” After all, if all women who smoked also wore nylon stockings, then there’s no way to tell which was causing cancer. Experienced surgeons had gotten so used to seeing lungs blackened by cigarette smoke that they thought nothing of it. After all, aren’t lungs naturally black? Well, in a world where almost everyone smoked, lungs were indeed black! It was the Young Turks of surgery who saw what was in plain view in front of them, for they had not yet had time to grow inured to the sight.
Slowly, the link between smoking and cancer was teased out, through autopsies, through tar-painting experiments, through association studies. In its investigations, the Surgeon General’s cancer advisory committee pioneered the use of the meta-analysis, which has now become standard practice in medicine. Since mice could not be shown to develop cancer by inhaling cigarette smoke, new standards for epidemiology had to be adopted. In yet another of those coincidences that so often occur in real life, the tobacco companies enlisted Clarence Little, who had been pushed out by Mary Lasker as president of what later became the American Cancer Society, to create doubt about the harmful effects of smoking. Mukherjee’s account of this process is as clear as any I’ve ever read — and it also taught me a number of things that a lifetime of exposure to the media did not.
Medicine also managed to dust off the old finding that pathogens could cause cancer. Hepatitis B and H. pylori were both discovered serendipitously and shown to result in forms of cancer. The Rous sarcoma virus, first shown to cause cancer in chickens in 1910, had only four genes and proved amenable to early recombinant DNA technology, resulting in the discovery of the src gene. As genetic techniques continued to improve, researchers then discovered ras and p53 and the multitude of oncogenes and tumor suppressors that we know of today. By 2000, Robert Weinberg would be able to distill the molecular biology into the Hallmarks of Cancer.
The last two hundred pages of the book are most similar in spirit to Horace Judson’s book on the formation of modern molecular biology, The Eighth Day of Creation. To arrive at the hallmarks of cancer, Mukherjee has to start with Mendel and Morgan and trace much of the history of modern cell biology.
Genentech was founded in the 1970s to exploit the potential of recombinant DNA. So it is perhaps fitting that Genentech was also involved in the development of Herceptin, the first blockbuster biologic targeted at cancer. But it did not accomplish this task willingly. The drug was created in the 1980s, after a slew of cancer drugs from several other pharmaceutical companies had failed in clinical trials. Even though it had the backing of VP of Research David Botstein, along with future CEO Art Levinson, Herceptin received only minimal funding at Genentech and was pursued largely as a skunk works project. Herceptin also ran into the patient rights advocates, but this story finally has the happy ending that had eluded us for so long. Herceptin boosts survival significantly — and without the toxic effects of chemotherapy.
But it was Gleevec that would prove to be the most extraordinary of the new drugs. Mukherjee clearly remembers every detail of his first encounter with a patient taking Gleevec. It was an epochal event, dividing oncology into a pre-Gleevec era and a post-Gleevec era. But Gleevec also ran into skepticism within the pharmaceutical company that developed it: Ciba-Geigy, then in the process of merging into Novartis. That pharmaceutical giant wasn’t thrilled about spending $200 million to run clinical trials on a drug for chronic myelogenous leukemia, which only afflicted a few thousand patients a year. It was Brian Druker at Oregon Health and Science University who pushed for the trials.
(Here, Mukherjee uncharacteristically misses a neat tidbit about the lives of scientists, for Druker met his wife when she interviewed him for People magazine. After discovering that he did nothing but work all day and night, she commented that he had no balance in his life and apparently decided to correct this problem. [Researcher Behind the Drug Gleevec, The New York Times, November 2, 2009.]
When it is noted that mean survival of CML patients with Gleevec is now 30 years, it becomes quite clear why the drug marks such a watershed in cancer treatment. In a field where a few months of extra survival was considered a success, 30 years is a miracle. But patients must continue to take Gleevec for the rest of their lives. Indeed, as Mukherjee points out, CML was a rare disease not just because it only afflicted a few thousand people each year, but because almost all of them died in short order. But now that Gleevec is keeping patients alive for essentially their full natural lifespans, the number of CML patients has now increased. In this way, Novartis is now making extreme amounts of money on a drug that it once considered to be commercially unviable.
Recent advances in targeted cancer therapies allow Mukherjee to end his book on an optimistic note. Perhaps too optimistic, for Gleevec and the other targeted therapies are not cures, but treatments that must be continued for the rest of the patient’s life. Compared to the high death rates faced previously, they are miraculous. But they also raise troubling economic questions.
The developed world is already facing a health care cost spiral. What are the implications of a future in which we can keep cancer patients alive indefinitely, but at an annual cost approaching twice the per-capita annual GDP? Mukherjee tackles the brave new world of biologically-targeted genetics-inspired cancer therapies largely from an oncologist’s perspective. He does not deal with the economic questions, and does not even comment on the price of Gleevec. Dr. Mukherjee’s life is already a constant battle against cancer on behalf of his patients. It does not even occur to him that it might be a scary situation for the rest of us to have our lives consumed by cancer as well.
His conclusion is also at odds with much of the recent news coverage of the 40th anniversary of the War on Cancer. In the book’s narrative arc, the development of targeted therapies, along with our improved understanding of cancer biology, serves as a triumphant capstone on decades of frustration. Decades of pushing back the onset of death with chemotherapy, only to see most patients die in the end. Indeed, the chapter is titled “The Fruits of Long Endeavors.” But read between the lines of the optimistic conclusion, and a very different story can be told. It is a story in which 50% of multiple myeloma patients do not live beyond five years. This is far better than the nearly 0% five-year survival rate of 1971, but it is still nowhere close to the proverbial cure for cancer.
Mukherjee points out that many cancers still do not have targeted therapies, and that outcomes are therefore highly heterogeneous depending on what type of cancer is afflicting a patient. He also explains that cancer is inherently the result of our own bodies running amok, and that the current hypothesis that cancer lurks in stem cells makes it inherently difficult to eradicate. If true, the hypotheses would also explain why targeted cancer drugs must be taken for the rest of the patient’s life. New cancer cells would constantly be regenerated from the stem cells, which are by design difficult for chemicals (drugs) to reach.
But a mere 30 pages takes us from the end of the Gleevec story to the end of the book. After squinting at 500 pages of small type font, the reader is no doubt looking forward to the conclusion with as much relief as the author. However, these pages contain some very troubling remarks that deserve more elaboration if the reader is to have the full picture of present practices in cancer treatment. We’ve read throughout the book of remissions followed by relapses. We’ve read throughout the book of the various forms of cancer, each treated very differently. So which is which?
Without a table, it is difficult to keep track of all the information that has been presented in paragraph form. What are the present best outcomes for each form of cancer? What is the cost of treatment? Quality of life? For which cancers do we see tremendous improvements in outcomes, where tremendous is defined as decades of increased life expectancy? And where do we see “merely” significant improvements, in the sense that even a two-month extension of life may be statistically significant? In telling a narrative story, Dr. Mukherjee captures a century of cancer medicine — a century of victories followed by heartbreak — but also leaves the reader with a very scattered picture of the present situation. Chemotherapy drugs are still being developed into the post-Gleevec era of targeted therapy, but you wouldn’t know it from this book.
Also flying by in the rapid wrap-up are some very interesting philosophical points about cancer as a condition rather than as a disease. Maybe the only way to win over cancer is to redefine victory. Maybe everyone is destined to die of cancer someday — because cancer is what kills us after medicine has cured every other disease. In that sense, we need to be asking difficult questions about how best to handle death. There have been articles about cancer support groups that kick out people who are succumbing to cancer, for it disrupts the relentlessly upbeat environment and reminds “survivors” of the probabilities. [Advances Elusive in the Drive to Cure Cancer, The New York Times, April 23, 2009] We, as a society, have a difficult time facing death. Putting a value on human life is treated as a disgusting and immoral action. The revival of palliative care, which Mukherjee does touch on in the middle of the book, faced strenuous objections at the time from people who thought that accepting death meant giving up on life.
Cancer forces us to confront difficult questions. The advent of mass vaccination and antibiotics turned previous scourges of humanity into rare conditions. Gone were the iron lungs, the children with leg braces, the ever-present smallpox scars on survivors’ faces, the quarantine tape over doors and windows of infected households. A futuristic world of health and well-being seemed to be at hand, one in which disease would be an afterthought and no more dangerous than a mechanical breakdown in your automobile. But cancer still proves resistant to that form of trivialization — even with targeted therapies, even with better screening, even with improved knowledge of risk factors.
Dr. Mukherjee has written a remarkable book about a remarkable disease. One may quibble with the philosophical direction that the book takes, but the magnitude of his narrative achievement is undeniable. He has managed to capture the excitement of scientific discovery alongside the clash of medical egos, tracking the progress of human understanding of this most difficult of diseases. At times, the chronological narrative bogs down a bit in the mass of details and clash of competing models. But for the most part, the author produces some of the clearest and most vivid popular scientific writing that I’ve read.
The story of cancer is the story of a disease that has altered our expectations of medicine, frustrated our technological skills, and challenged our brightest minds. Our successes have been hard-won, and our failures have turned out to be paradigm-changing. That is why cancer is, truly, the emperor of all maladies.