The Emperor of All Maladies

I finished yesterday Siddhartha Mukherjee's The Emperor of All Maladies. With the exception of one shocking lapse, it's a very good history of cancer therapy and I strongly recommend it for anyone interested in cancer.

Mukherjee is an oncologist and interleaves his historical view of cancer with the experiences of selected patients he tended. This humanizes the subject and brings useful context. On the historical side, he reaches all the way back to the first written description of cancer, from Pharonic Egypt (which was also the first expression of futility at treating cancer). A major thread running through the early part of the book is the career of Sidney Farber, who pioneered chemotherapy, and Mary Lasker, who reshaped the role of the U.S. government in cancer research despite having never held elective office.

The book is written for a lay audience and I think he does a good job. There are some key lessons which need to be heard widely. Mukherjee describes many of the twists and turns, the clever leaps of logic and the leaps that failed. For example, Farber's key insight was that leukemia was characterized by improperly functioning bone marrow, a trait shared with several nutritional deficiencies which had just been solved. So he tried treating childhood leukemias (deemed utterly untreatable by oncologists of the time) with B-vitamins, to disastrous results. But, then the second leap occurred -- Farber tried B-vitamin antagonists, and soon found success.

Mukherjee also captures many of the missed opportunities and the non-scientific barriers to progress. Farber was shunned by many colleagues because he was not an oncologist, but a pathologist. The initial misstep led to utter non-cooperation from the oncologists, leaving Farber's doctors to sharpen their own needles and dump their patient's bedpans. His supply of anti-folates came from an immigrant doctor who had left for chemistry and industry after his foreign credentials proved useless. Much more recently, there is the story of how Weinberg's group discovered Her-2 but didn't contemplate pursuing therapy against it. Far worse is how the lawyers at the institute Farber founded nearly iced Gleevec, and even after that issue was dealt with (when Gleevec's proponent Brian Druker moved to another institution) the management of Novartis nearly killed it. Similarly, Genentech all but dropped Herceptin; again it was an outside oncologist who drove the project to success.

The book also gives a good overview of how many things needed to be invented along the way and issues which arise. Simple epidemiology noted the high incidence of scrotal cancer in boy chimney sweeps; the intersection of a rare cancer and rare occupation made the relationship unquestionable. But later, researchers were faced with the challenge of proving a common cancer (lung) was linked to a common environmental factor (smoking) and this required new methods such as the case-control study. In the chemotherapeutic arena, the book covers many iterations of trial design and testing strategy and also brushes a bit on the changing ethical landscape.

If you've read my previous book reviews, a typical exercise for me is to ask what else could have gone in. Now, this is admittedly sometimes unfair to the author and one prior reviewee has politely chided me that some of what I missed ended up on the editor's floor. Plus, books that want to be read and not doorstops need to respect certain length limits. But, when I am writing I find it a useful exercise; only when we consider the whole range of possibilities can we be confident that the correct balance has been reached.

Perhaps the most surprising area barely touched on is angiogenesis and anti-angiogenic therapy. Some of this may have to do with timing; most of the book concerns events before about 2004, though with an impressive quick coverage of some of the learnings from cancer genomes. So many of the travails of Avastin would be after that rough divide. Still, this is a hot topic and perhaps that is why I miss it from the book. This book deserves to be widely read and probably will be (it is certainly the de facto Book-of-the-Month at work) and will therefore form the foundation for many public conversations about cancer

Another topic essentially absent from the book are various types of immunotherapy. Again, this is an area having some resurgence (with the approval of the prostate cancer vaccine Provenge), but it isn't clear how important it will be long term. I think there was a passing mention of Coley's toxins, but saw none of the late 70's excitement around interferons (which, alas, became only a niche player in oncology) or the 80's focus on interleukins.

Finally, though there is some coverage of the world of molecular analysis of cancers (such as cancer genomics), the field of microarray classification of cancer and guiding therapy isn't explored. This is a pretty complex topic with a lot of shifting (and, as noted in the recent George Poste Nature opinion piece, far more smoke than light) so it's a bit understandable it was left out.

Overall though, I can't think of anything that is clearly missing. But now my quibble and serious complaint. Certainly the book not only filled in a lot of areas I just hadn't been exposed to, but even had me running for articles very close to where I see my core training.

The quibble is a bit of a pet peeve. The book, like many (and myself), roughly divides cancer chemotherapeutics into two bins (with room for a small "unclassified" bin as well). Cytotoxics are broad-spectrum cell killers and constitute the bulk of cancer therapy agents.

Targeted therapies are the sticking point. For me, it is important to reserve this category for agents that have two critical properties: we know what the drug acts on in cells and we know something about the relevance of that mechanism to a tumor. Mukherjee gives a number of interesting stories about targeted therapies. For example, anti-estrogen therapy for breast cancer can trace back to a doctor hearing from Scottish shepherds that removing a ewe's ovaries would cause their udders to shrink. Another fascinating story relayed in the book shows how these categories can be tricky. By undescribed means (probably random screening), it had been found that cis-retinoic acid could be used to treat the aggressive leukemia APL, though with highly variable results. An inspired leap of logic led to the decision to test all-trans retinoic acid (ATRA) in APL, with stunningly successful results. Only later was it discovered that most APL cases are driven by a fusion protein derived from a retinoic acid receptor. So ATRA started as "other" and only later fits my definition of targeted therapy.

So what's my beef? It's when Mukherjee describes Velcade, thalidomide and Revlimid in multiple myeloma as targeted therapies. He's hardly alone; this is a common description. But in my taxonomy, Velcade is a cytotoxic. We know where it acts in the cell but not why that is important in cancer and not how to select which patients to use it in. Thalidomide and Revlimid probably should go into the "other" bucket; we're not sure of the mechanism but they aren't generically cytotoxic. Even one of the drugs I currently work on (an HSP90 inhibitor) I would generally call a cytotoxic; it's not a perjorative in my book. On the other hand, in one subset of lung cancer there is a strong hypothesis as to how such HSP90 inhibition works at a molecular level. So as with many biological classifications, they're a bit smudgy -- but I still think they are useful and worth being precise about.

Finally, the big complaint. One of the longer stories in the book concerns the apogee of intensive chemotherapy, in which breast cancer patients were given doses high enough to utterly destroy their bone marrow, followed by bone marrow transplants. This was an important and controversial approach to therapy, with patients begging to get into trials and fighting legal battles to have their insurance companies pay for these unproven treatments. Indeed, Masschusetts was one state which enacted legislation to mandate coverage of this particular treatment. However, when the clinical trial results rolled in, all but one large study showed no benefit. The outlier study showed a huge benefit. However, on closer inspection the outlier turned out to a fraud of truly monstrous proportions. In discussing that denouement, Mukerjee points out that a male patient "obviously" couldn't have been a legitimate member of the trials. Breast cancer in men is rare, but rare is not impossible and it is particularly critical for oncologists to not have that blind spot. Indeed, this is particularly important in families with a history of breast cancer; the risk of male breast cancer is much higher in BRCA1/2 familes.

That one blemish aside, though, I can strongly recommend this book. As I've noted before, if many read it then there will be a much stronger general basis for discussing cancer and the public policy around it.