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History reveals the future in cancer biography
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I ran a fellowship program in hematology and oncology for more than 30 years. Our faculty chipped in and bought books each year for graduating fellows. Early on, these included Wintrobe’s famous text; later, the multi-edited texts from the likes of DeVita, Hoffman, Schafer, Williams, etc. For a while, we provided Jandl’s award-winning, single-authored Blood: Textbook of Hematology. Jandl’s marvelous prose equaled that of Lewis Thomas’ (also award-winning) Lives of a Cell. It is hard to say whether these two latter gifts were appreciated as much as the drier compendia of multiple editors. Nonetheless, if I still had influence on our current fellowship program at the University of Minnesota, I would send our matriculating progeny off to battle cancer with a new, spellbinding literary gem written by a recent Massachusetts General Hospital hem/onc fellow.
I first became aware of Siddhartha Mukherjee during his public radio interview with Terry Gross a few weeks ago. In the interview, he came across as wonderfully articulate and learned without seeming arrogant or pedantic (a problem encountered too often in our profession). I decided his Pulitzer Prize-winning book, The Emperor of All Maladies: A Biography of Cancer, might be worth scanning. Little did I suspect that I would be completely engrossed for 4 straight days (and some nights) enjoying his erudite, lilting prose chronicling cancer matters back to Galen, the Greeks, and even to an Egyptian caregiver 2,500 years ago.
His descriptions of the recent, circuitous trails we have lurched along to arrive at our current era of Herceptin/Gleevec “rational” therapies is the most beguiling part of the book; I believe it to be the most literate history on the subject that I have read. In fact, although the book is written for lay people, I learned much about oncogenes, tumor suppressors, carcinogens and more; stuff I previously professed to know (but didn’t) while teaching students and fellows. Hematologists and oncologists would do well to find time this summer for this treasured volume.
Eras of disease
Mukherjee divides his biography into eras; the modern one starting with Saul Farber’s discovery of the antifolate compound aminopterin, and its slight but significant beneficial effect in some children with acute lymphoblastic leukemia. A cure for all cancers was imagined, and with the actual cure of 12-year-old “Jimmy” — whose real name, we learn from Mukherjee, was Einar Gustafson of New Sweden, Maine — the hype crescendoed into “The War on Cancer.”
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In the late 1950s, an exuberant fundraiser and socialite, Mary Lasker, joined with baseball celebrities such as Ted Williams to found the Jimmy Fund and its Harvard-affiliated hospital under the direction of Farber. As a medical student, I recall Dr. Farber as a quixotic and seemingly arrogant professor (not so, I learned later — well, maybe quixotic). His belief that cancer might be curable by drug therapy was not taken seriously by my other HMS professors, but luckily, Lasker and others stood by his belief.
In the next decade, leukemic volunteers received a cascade of toxic chemotherapy infusions, especially at the NCI, administered by oncologists such as the “Two Emils,” Frei and Freireich. Ever increasing doses of drugs were provided with the supposition that every last cancer cell must be eradicated for cures to be realized. This era was mischievously summarized in the book by a quote from Anna Deavere Smith: Cancer therapy is “like beating a dog with a stick to get rid of his fleas.”
Bad medicine
The underpinning of this erroneous conceptualization actually was provided by a century of equally erroneous surgical dogma in breast cancer. That is, radical mastectomies became more and more “radical” and disfiguring following Halsted’s lead in the 1890s.
It took exactly a century to disprove the more-is-better approach in cancer surgery. Simple mastectomy or lumpectomy with radiation and/or adjuvant chemotherapy or hormonal therapy is no less beneficial and certainly less morbid than radical surgery. This finding finally made clinical oncologists start to pay serious attention to cancer biologists such as Phil Leder, Stan Korsmeyer and others. Their data demonstrated that cancers of different organs are not the same and, in fact, tumors of a single organ (eg, breast) behave differently from one patient (or mouse) to another, metastasizing before detection — even by mammography (or MRI) — in some.
Radical mastectomy is now recognized as a useless and butchering exercise. Likewise, we clinicians, now with good conscience, need no longer blindly pursue other “rescue fantasies,” such as autologous bone marrow transplant salvage for carcinoma patients assaulted with horrendous chemotherapy regimens.
Environmental carcinogens
This era was followed by a period in which cancer prevention finally received much-deserved attention. The conceptualization of environmental carcinogens had long been ignored, despite the publication of Percival Pott in 1775. Pott, an English surgeon, described epidemic scrotal cancers in adolescent chimney sweeps and suggested that constituents of soot might be tumorigenic. One would think that incinerated cellulose-based substances would have elicited major concern about their possible carcinogenic properties, yet another incinerated hydrocarbon was allowed to assault millions around the planet in the last century.
Mukherjee pointedly reminds us of how for decades the tobacco industry escaped indictment through disingenuous obfuscations of data that clearly exposed the most prevalent carcinogen of our time.
The final chapters review the profound cancer molecular biology achievements of the last couple of decades: the role of viral oncogenes in altering cancer cell genomes (Varmus & Bishop); the discovery of such distorted genes in animal and human cancer cells (Weinberg and numerous collaborators); the progression of genetic mistakes leading from precancerous adenomas to carcinomas (Vogelstein and colleagues); and finally, the development of rational therapies based on these molecular insights exemplified by Herceptin (Slamon et al), Avastin (Folkmann and co-workers) Gleevec and analogues (Drucker, Sawyers and others) and many more to come.
Although “we’ve come a long way, baby” (slightly altered from a wicked and sexist tobacco advertisement), Mukherjee reminds us that we are really like Red Queens in Lewis Carroll’s Through the Looking-Glass, running to stand still in our battles with the ever-changing cellular disorders called cancer.