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A New Perspective on the War against Cancer

 Myths and misconceptions about cancer abound. Oncologists are frequently criticized for torturing patients by burning, cutting and poisoning without making any real progress in the war against cancer. Siddhartha Mukherjee, an oncologist and cancer researcher, tries to set the record straight with his new book The Emperor of All Maladies: A Biography of Cancer.  

It is a unique combination of insightful history, cutting edge science reporting, and vivid stories about the individuals involved: the scientists, the activists, the doctors, and the patients. It is also the story of science itself: how the scientific method works and how it developed, how we learned to randomize, do controlled trials, get informed consent, use statistics appropriately, and how science can go wrong. It is so beautifully written and so informative that when I finished it I went back to page 1 and read the whole thing again to make sure I hadn’t missed anything. I enjoyed it just as much the second time.

 Mukherjee says

It will be a story of inventiveness, resilience, and perseverance against what one writer called the most “relentless and insidious enemy” among human diseases. But it will also be a story of hubris, arrogance, paternalism, misperception, false hope, and hype, all leveraged against an illness that was just three decades ago widely touted as being “curable” within a few years.

 In the early 1950s, a woman tried to place an ad for a breast cancer support group in the NY Times. She was told

I’m sorry, Ms. Rosenow, but the Times cannot publish the word breast or the word cancer  in its pages… Perhaps you could say there will be a meeting about diseases of the chest wall.

 The Pink Ribbon campaign has made public discourse about breast cancer not only acceptable, but popular. Before Pink Ribbons we had the Jimmy Fund, the March of Dimes, Mary and Albert Lasker, the American Cancer Society, and other efforts to fight cancer in general. Mukherjee describes the history of these efforts. There was a public outcry for a Manhattan Project to abolish cancer. Money was channeled into cancer research, but not enough and often not directed to where it would do the most good. Progress has been made, but it has been slow; and the idea of completely abolishing cancer with a massive Manhattan Project-like effort is unrealistic.

 Mukherjee’s book reads like a detective story with an exciting plot. In the effort to understand cancer, early clues led to both horrible failures and serendipitous successes. Early physicians attributed cancer to an excess of black bile. They didn’t have microscopes and didn’t know what a cell was, so they couldn’t recognize that cancer is uncontrollable pathological cell division. Later, they thought the white cell excess of leukemia was pus from an infection and were puzzled when they couldn’t find the focus of infection. Halsted’s famous radical mastectomy turned out to be a terrible, disfiguring, mutilating mistake: if the cancer had not spread, a simple lumpectomy would have been plenty; if microscopic foci of cancer were already present in other parts of the body, even the most extensive surgery had no chance of eradicating it. One early chemotherapy researcher made an outstanding breakthrough that permanently cured choriocarcinoma, but it resulted in his being fired!

 Little by little, our understanding grew. Cancer is not one disease but a whole collection of different diseases characterized by uncontrolled growth of cells. We have learned that it usually takes a whole series of mutations to cause cancer. We have learned about proto-oncogenes and oncogenes, some of which are present in our own chromosomes, but which can also (rarely) be introduced to our genome by a retrovirus. Cancer often results not from direct effects of a mutated gene itself, but by its activation or repression of a series of other genes that govern normal cell activities. We have learned about mutations of the cancer cell itself, about cancer stem cells, and about how cancer can change to evade once-effective therapy and achieve a relapse. The more we learn, the more complicated it gets. The simplistic idea of  “a cure for cancer” begins to look ridiculous.

 In 1900 the top four causes of death were TB, pneumonia, diarrhea and gastroenteritis; cancer was number seven. By 1940 the top cause of death was heart disease and cancer was second. Part of the reason was that between 1900 and 1940 the proportion of people older than 60 nearly doubled. Cancer is an age-related disease. People were living long enough to get cancer, plus diagnoses were being made earlier in the course of disease, and causes of death were being more reliably identified.

 Between 1970 and 1994, overall age-adjusted cancer mortality increased slightly. But by the measure of “years of life saved” there was definite improvement. The overall death rate statistics were misleading. Mortality had decreased in those under 55, but had increased in those over 55 by almost exactly the same amount. Death rates from several cancers (colon, breast, Hodgkins’s disease, testicular cancer) had plummeted. The lung cancer death rate for men had peaked and was dropping, but the rate for older women had increased by 400 percent as the effects of smoking caught up to them.

 Between 1990 and 2005, the cancer-specific death rate dropped by 15%, the breast cancer mortality by 24% (due about half to mammography and half to chemotherapy). Some cancers, especially childhood cancers, have become curable, while the death rates for others like pancreatic cancer have remained unchanged.

 We have learned that there are 6 essential alterations in cell physiology that collectively characterize malignant growth.

            1. Self –sufficiency in growth signals (accelerator pedals stuck “on”).

            2. Insensitivity to growth-inhibitory signals (brake pedals inactivated).

            3. Evasion of programmed cell death (apoptosis)

            4. Limitless replicative potential

            5. Sustained angiogenesis

            6. Tissue invasion and metastasis.

Many of the genes and pathways that enable these behaviors have now been identified. Cancer genomes are being mapped the same way the human genome was. Now a new kind of cancer medicine is possible, based on specific attributes of cancer cells. Once we know what the mutant genes are, we can start to investigate what the mutant genes do, and then we can search for targeted therapies.  

 Gleevec is the first of a new kind of cancer drugs; instead of nonspecifically killing all rapidly dividing cells, it targets a specific enzyme that is overactive in a specific type of cancer. Before 2000, we told patients with CML (chronic myelogenous leukemia)

…that they had a very bad disease, that their course was fatal, their prognosis was poor with a median survival of maybe 3 to 6 years, frontline therapy was allogeneic transplant… and there was no second-line treatment…

 Today we can tell them that

 …the disease is an indolent leukemia with an excellent prognosis, that they will usually live their functional life span provided they take an oral medicine, Gleevec, for the rest of their lives.   

Ironically, Gleevec is turning a once-rare disease into a fairly common one, because patients are surviving. The incidence has not changed, but the prevalence has.

James Watson, testifying before Congress, said

We shall soon know all the genetic changes that underlie the major cancers that plague us. We already know most, if not all, of the major pathways through which cancer-inducing signals move through cells. Some 20 signal-blocking drugs are now in clinical testing after first being shown to block cancer in mice. A few, such as Herceptin and Tarceva, have FDA approval and are in widespread use. 

The biology of cancer is deeply embedded in our genes. Oncogenes involve mutations in genes that are essential to normal cell growth and repair mechanisms. The processes of cancer are the same processes that govern aging, regeneration, healing, and reproduction. Cancer cells grow faster and adapt better; they exploit the very features that make us successful as a species or an organism. They could be considered more perfect versions of ourselves. To quote Pogo: 

We have met the enemy and he is us.

It may be unrealistic to hope that we can abolish this emperor of all maladies. Carcinogens in the environment cause some mutations; other mutations arise from random copying errors when cells divide; the latter might not be preventable. Instead of curing cancer, we may only be able to control cancer and postpone deaths to an advanced age. Cancer may become a chronic disease that requires many of us to take regular medication. We may have to redefine what constitutes victory in the war against cancer.

Posted in: Book & movie reviews, Cancer, History

Leave a Comment (26) ↓

26 thoughts on “A New Perspective on the War against Cancer

  1. This book review is itself so beautifully written and so informative that when I finished it I went back to the beginning and read the whole thing again to make sure I hadn’t missed anything. I enjoyed it just as much the second time.

  2. The Blind Watchmaker says:

    Thank you, Dr. Hall. I will be sharing this with my patients.

  3. Paul says:

    I’m halfway through the book now. It really is fantastic. Great review!

  4. passionlessDrone says:

    Hello friends –

    Here is a link to the author on Fresh Air a few weeks ago for a long segment. A good listen.

    http://www.npr.org/2010/11/17/131382460/an-oncologist-writes-a-biography-of-cancer

    - pD

  5. WilliamLawrenceUtridge says:

    Anyone else think the whole “take this for the rest of your life” thing will cause significant freak-out from the “Big Pharma is EVUL” crowd? I do.

    The review really sells the book Dr. Hall, I’ve reserved it from the library and may even purchase it! Sounds exciting!!

  6. TsuDhoNimh says:

    One early chemotherapy researcher made an outstanding breakthrough that permanently cured choriocarcinoma, but it resulted in his being fired!

    say WHAT?

  7. Jacob Vohs says:

    As one of those who will be taking a daily medication for the rest his life because of cancer, I’d like to say how good it is to see a book of this type in print. I’m likely to have a normal life expectancy because my cancer was detected early and as a result of the progress of medical science. Finding my cancer early also significantly reduced the likelihood the cancer would de-differentiate into something nasty and untreatable. Early detection, surgery and radiation treatment in my case was pretty much a cure. That my circumstance added to the number of cancers in the current statistics, that in decades past would not have been detected or treated, is something I can live with just fine. I think I’ll be ordering this book soon and I’m quite pleased to see it’s a reasonably priced paperback. Great review Harriet!

  8. pmoran says:

    Halsted’s famous radical mastectomy turned out to be a terrible, disfiguring, mutilating mistake —

    In my view an unfortunate overstatement that will be misused in certain quarters.

    That operation did produce lower loco-regional recurrence rates than any other contemporary approach, probably lower even than would be possible with the present standard, lumpectomy combined with radiotherapy, in equivalent cases .

    In the best hands local recurrence was of the order of 3-5% with what were usually more advanced cancers than are seen today. I don’t think lumpectomy and radiotherapy can match that; we only know that overall 5-10 year survivals seems the same within a wide range of ways of treating the local disease.

    Considering the appalling consequences of uncontrolled chest wall disease the radical mastectomy a reasonable approach for the times. Even today a sine qua non of treatment of breast cancer should be to ensure control of the local disease.

    1. Harriet Hall says:

      Halsted’s radical mastectomy was the standard of care for a long time, but it was based on a misconception about how cancer spreads, and on the hypothesis that if you just extended the surgical margins far enough, you could prevent metastasis as well as recurrence. It undoubtedly saved lives, but was not as effective as Halsted originally thought, and when the evidence started to turn against it, Halsted and his disciples failed to recognize the facts for a long time. I had to take the book back to the library, so I can’t look up the specific details cited by Mukherjee. One problem was that Halsted’s followers logically extended the basic concept to justify ever-more-mutilating operations – in some cases removing ribs and clavicles, pretty much collapsing the chest wall.

  9. pmoran says:

    There’s still too much hindsight and breast-beating for my taste, Harriet.

    When surgery was the dominant mode of treatment it was logical to determine if more radical surgery could improve results, especially if results could be improved by eliminating the internal mammary and supraclavicular lymph nodes as a possible persistent focus for cancer metastases. That was the objective of the “extended” radical mastectomy.

    There certainly was a “misconception as to how cancer spreads” but that only changed in relation to breast cancer with later experience, when relatively new methods of prospective clinical study were applied to various forms of treatment.

    Was it slow for surgical thinking to change? Compared to what? It awaited the performance and publication of five and ten-year comparative studies such as that showing that Urban’s “extended” radical mastecomy gave no better results than the standard radical mastectomy, but significantly greater morbidity.

    Meanwhile similar studies from across the Atlantic were showing that simple mastectomy and radiotherapy gave roughly the same results as more radical surgery.

    Many such studies forced such a change in thinking that a mere 2-3 decades later, with considerable bravery, and helped by certain advantages in the kind of breast cancer normally presenting to surgeons, someone was able to test out whether simple lumpectomy could be adequate local treatment, if combined with radiotherapy and some kind of attention to the axillary lymph nodes and this was quickly embraced.

    Some day someone will be scoffing at this primitive approach.

    *(some cancers do metastasise late, or not at all)

    1. Harriet Hall says:

      Mukherjee provides a detailed story of the successive comparative studies and how thinking changed step by step. He tells how difficult it once was to even persuade surgeons to cooperate with a test of lesser surgery because of their strong belief in radical mastectomy. Mukherjee thinks surgical thinking was slow to change. You can read his account and see if you think he has a valid point. Mukherjee is an oncologist and researcher; as a surgeon with clinical experience, you may interpret the history differently.

  10. jre says:

    Some day someone will be scoffing at this primitive approach.

    Mukherjee thinks surgical thinking was slow to change.

    Stop! You’re both right!

    But seriously, folks — isn’t the fact that we expect the techniques of the present to be seen by our successors as barbarous, given enough time, exactly what sets empirical medicine apart from woo? If Halsted and his followers were resistant to challenge, that’s unfortunate, but at least there was no doubt that they could be challenged, and the methods and grounds for fair challenge were accepted by all.

    Contrast that with the bulletproof confidence evinced by some of beatis’ commenters. I’ve lost track of how many mutually incompatible theories of oncogenesis I’ve come across over there, but I have learned two things:
    1) Each theory is perfect and unchangeable.
    2) All agree that scientific medicine is both evil and wrong.

    In the end, the only thing that opens the door to progress is to admit the possibility that you may suck, but resolve to suck less with every passing day.

    Oh, and Dr. Hall — a lovely review, delightful to read. Thanks!

  11. pmoran says:

    OK, I’ll shut up. Mukherjee may have observed a parochial attachment to radical mastectomy which I don’t believe applied in England or Australia.

    A parenthensis of mine didn’t come through. I altered a “misconception as to how cancer spreads” to “misconception as to how (some kinds of cancer can) spread”. Sometimes cancer is a generalised disease and sometimes not.

  12. David Gorski says:

    When surgery was the dominant mode of treatment it was logical to determine if more radical surgery could improve results, especially if results could be improved by eliminating the internal mammary and supraclavicular lymph nodes as a possible persistent focus for cancer metastases. That was the objective of the “extended” radical mastectomy.

    Indeed. People are fast to forget that adjuvant therapy is a relatively recent innovation, at least compared to surgery. When Halsted was doing radical mastectomies, for instance, it was not unreasonable to assume that a complete en bloc resection of the breast, with associated lymph nodes and attached muscle, would result in a greater chance of cure. And, in fact, it appeared to. Halsted’s results were far better than those of other surgeons of the time.

    It’s very easy to forget that our current success in breast surgery depends upon excellent adjuvant therapy, including radiation therapy and chemotherapy.

  13. mcliedtk says:

    Thanks for a great review; I’ll have to add it to my list.

    Somehow this recent xkcd seems fitting.

    http://xkcd.com/836/

  14. Roadstergal says:

    I blew through this book in a couple of days, and bought a copy for my manager for her Holidaychristkwanzmakkuh gift. It’s just magnificently written. As a medical researcher, I love books that capure the process and the humanity as well as just the facts (ma’am).

    For the e-readin’ types, it’s available on Kindle (free app for Droid).

  15. Thanks for the wonderful review – I’m looking forward to reading the book.

    My father was a doctor (GP) and he once pondered a philosophical question: if we were to ‘cure’ cancer – what will people die of? There has never been a shortage of people in our history, so what are the implications of not dying from most disease? Will we all sit around, waiting to die of old age at age 130? Is that living?

    Makes you wonder.

  16. Artour says:

    Decades of medical research suggest that cancer still have only one primary cause: cell hypoxia, while several studies found that terminal cancer patients routinely exhibit 30-40 breaths per minute. Surely, such breathign rates (either hyperventilation or shallow costal breathing) do not do any good for oxygen transport. In fact, hyperventilation reduces tissue oxygenation in a dose-dependent manner.
    All these medical studies are linked to this web page:
    http://www.normalbreathing.com/diseases-cancer.php

    Now the question is: If heavy breathing is the cause of cell hypoxia for cancer (or the cause of cancer), what would happen if we remove this cause? The answer is in the Ukrainian controlled clinical trial, where 60 women with metastaized breast cancer tried hard to slow down their deep and fast breathing. The 3-year mortality in this group was reduced … 5 times and the only 3 women who died had diabetes and heart disease, as additional pathalogies. These women could not restore normal breathing parameters (expired CO2 was measured):
    http://www.normalbreathing.com/nb-word/A-Paschenko-ENG.pdf

    Hence, we can suggest that the cause of cancer is under the nose.

  17. Harriet Hall says:

    Artour,

    Cancer has many causes, but hypoxia is not one of them, much less the one primary cause. Tissue hypoxia can be a result of cancer. The website you cite is not a reliable source of information.

  18. Artour says:

    If hypoxia is not even one of the causes, why do they publish these articles with such “strange” titles? (I can provide about 30 other quotes of the same nature.)

    Brizel DM, Scully SP, Harrelson JM, Layfield LJ, Bean JM, Prosnitz LR, Dewhirst MW, Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma, Cancer Research 1996, 56: p. 941-943.

    Ryan H, Lo J, Johnson RS, The hypoxia inducible factor-1 gene is required for embryogenesis and solid tumor formation, EMBO Journal 1998, 17: p. 3005-3015.

    Evans SM & Koch CJ, Prognostic significance of tumor oxygenation in humans, Cancer Letters 2003 May 30; 195(1): p. 1-16.

    Harris AL, Hypoxia: a key regulatory factor in tumor growth, National Review in Cancer 2002 January; 2(1): p. 38-47.

    1. Harriet Hall says:

      Artour: These titles and the abstracts do not indicate that hypoxia causes cancer. They relate to the behavior of already existing tumors. If hypoxia caused cancer, couldn’t you produce cancers by exposing animals to hypoxic conditions? I don’t know of any such studies, do you? Also, wouldn’t one expect epidemiologic studies to show a correlation between tumors and people living at high altitudes?

  19. Artour says:

    The medical studies that I quoted above investigated cell hypoxia (or tissue hypoxia) or oxygen availability in cells. Altitude, except extreme altitude, does not lead to cell hypoxia. Most people with cancer do not live at high altitude either.

    There is a more simple method to create cell hypoxia: hyperventilation or breathing more than the tiny medical norm (6 L/min and 10-12 breaths/min).

    Chronic hyperventilaiton is a common finding for the sick, cancer included. Here is a medical research table – 36 articles with minute ventilation numbers:
    http://www.normalbreathing.com/i-hyperventilation-syndrome.php

    Hyperventilation is even normal for modern ordinary people, as another Table shows. It causes, if there are no problems with lungs, hypocapnic vasoconstriction (reduced perfusion) and suppressed Bohr effect (increased affinity of oxygen to red blood cells). Hence, reduced oxygen tansport to body cells in a dose-dependent manner.

  20. Harriet Hall says:

    I think you are mistaken, and I think you are relying on misrepresentations and misinterpretations from a website that is promoting the pseudoscientific concept of breath control as a preventive or a treatment for many diseases.

    The partial pressure of oxygen decreases continuously with altitude, which leads to decreased oxygen levels in the blood and in the tissues. The effect occurs progressively at higher altitudes and is not just restricted to high altitudes. People living at high altitudes have developed at least 3 different ways of coping with reduced oxygen levels. In Tibet, they adapted by increasing air flows (hyperventilating). This contradicts your hypothesis because their hyperventilation did not create cell hypoxia, it returned cell oxygen levels to normal.

    There is simply no evidence that hypoxia causes cancer. There is evidence that cancer can cause localized hypoxia in affected tissues.

  21. Jan Willem Nienhuys says:

    One nit about the book: on page 360 and 362 of my copy there is a reference to The Hunting of the Snark by Lewis Carroll:

    http://ebooks.adelaide.edu.au/c/carroll/lewis/snark/

    However the Snark isn’t invisible at all. (“you may serve it with greens, and it’s handy for striking a light.”) In the end it isn’t one of the hunters. When one of the hunters finally found it he immediately disappeared: “For the Snark was a Boojum, you see.”

    Regarding the efficacy of Halsted’s procedure, Mukherjee quotes Fisher’s result
    http://www.ncbi.nlm.nih.gov/pubmed/7284980

    as follows: patients were randomized into three groups: radical mastectomy, simple mastectomy, surgery followed by radiation.

    Results: The rates of breast cancer recurrence, relapse, death and distant cancer metastasis were statistically identical among all three groups. The group treted with radical mastectomy had paid heavily in morbidity, but accrued no benefits in survival, recurrence, or mortality.

    The trial comprised 1765 patients in 34 centers. My comment: with these numbers a 4% advantage of radical mastectomy (e.g. 64% cured rather than 60% cured) cannot be statistically significant, more precisely: a real advantage of 4% would only have about a 50% chance of yielding a (barely) one-tailed significant result.

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