Clifton Leaf

This is a very comprehensive book about the War on Cancer. The author's thesis is that the war will never be won unless there are changes in the way we approach it, the way we fund it, and the avenues researchers explore. I highly recommend the book. I'm not really going to review the book, but I am going to set forth some (actually a lot) of bullet points of facts and opinions from the book that I found important and helpful and want to remember:

--There is a disconnect between the rhetoric and the reality of the progress that's been made. The current "cancer culture" has as its goal finding the tiniest improvements in treatment, rather than genuine breakthroughs. There is isolated (and redundant) problem solving going on, instead of cooperation. The system rewards academic achievement and publication above all else. "For the past several decades, reports of shining advances in cancer biology and treatment have streamed into newspapers, magazines, and television sets the world over. But during that time, there has been only minor change in the prospects for most people with active disease: survival numbers have barely improved; new cases keep mounting; death counts continue to rise."

--Between 2000 and 2012 the count for pediatric cancers is up 40%, while the population has only increased 3 %. There is little research going on to find out why.

--STASTICS: I know that it's been said that statistics can be used to support almost anything, but these are Leaf's:

--Over the last 40 years, rate of death for causes other than cancer are down 24%; rate of death from cancer is up 14%
--Statistics using the "age-adjusted" standard population, which is the method by which cancer statistics are usually computed, is being misused
in comparing populations at different times rather than merely comparing populations at the same time.
--"Yes, cancer deaths have been falling...(sic)but only if the United States is a living wax museum where each inhabitant's age is fixed for eternity"
--The often used "5 year survival rate" doesn't show how many are free of the disease at that time or how many are likely to relapse.
--While there are a greater share of patients living at 5 years compared to the 1970's, only a small portion of this is due to improved treatment.
The deadliest malignancies (lung, pancreas, liver, or esophagus) are nearly as deadly as they were in the 1970's. Changes in survival rate are
due to earlier discovery.

--Leaf posits that one of the major problems is our blind focus on trying to cure cancer rather than trying to prevent it.

--PATH TO FDA APPROVAL: 1. Show drug is safe; 2. Prove it does something useful (there is a low bar for this--75% of new cancer drugs are approved
for reasons other than that it helped people live longer). Over the period studied there were 71 drug approvals by the FDA, but only 45 new drugs (the rest were new uses for old drugs), and of these there were only 12 drugs that were shown to extend life, and those by a very minimal amount.

--THE PHILADELPHIA CHROMOSOME and GLEEVEC
--While recognizing that this is one of the few actual break-through drugs, and is said to represent a paradigm shift in cancer drug development
Leaf states that this "has taken the global cancer-fighting enterprise down a perilous path--a path that can never lead to victory in the
war on cancer."
--CML (the cancer associated with the "Philadelphia Chromosome" and treated with Gleevec) is relatively homogeneous and stable in its early
stages. The drug used to treat it is a kinase inhibitor, and in the early stage there is only a single kinase protein involved. Most other cancers
(including leukemias evolving from lymphocytes), have a much larger number of distinct chromosomal patterns, and similar targeted therapies
will probably not bee as effective.
--The danger of Gleevec is that it has oversimplified cancer, treating it as a "lone, driving genetic aberration," which is not the case with most
cancers. In fact, Gleevec doesn't work well for later stages of CML, when it has become more heterogeneous.

--We need to recognize that cancer is not one thing--it is a process. There is no precise moment of conception, no universally accepted beginning, although there are recognizable stages of evolution on the route to clinically apparent disease. The diagnosis of cancer is simply the late recognition of a progressive disease, long in development. For other major illnesses (heart disease and stroke), there is early detection, and vigorous preemption strategies.

--Leaf posits that research should to work toward: 1. identify precancerous lesions; 2. discover how to stop or reverse progression; and 3. Get over the fear of doing this (become less risk averse).

--HISTORY OF WAR ON CANCER--the 1971 legislation proclaiming the war on cancer did not follow the recommendation of the panel of experts who studied the issue and recommended the creation of a NASA-like National Cancer Authority. Instead the legislation left control of cancer research with the NIH, leaving things as they were, the only change being there was more money. (This failure to accept the panel's recommendations was partly political--conservatives were strongly opposed to Ted Kennedy and didn't want to accept his proposed bill).

--PROBLEMS WITH NIH GRANTS--the decision-making is arduous, bureaucratic and tradition-bound. There is no "vision." As a result, "doing science" today is much more difficult than it used to be:

--Biomedical researchers have less than half the chance of getting a grant than they had in 1972. Now they must devote a much greater share
of their time writing grant application than doing science. For younger scientists it is hard to get on tenure-track without major grants, and
many spend years as poorly paid post-docs. Universities expect or require faculty members to provide half of all their salary from research
grants. (When my daughter was considering whether to go back to school for her Ph.D, the post-doc in the lab where she worked strongly
advised her not to for this very reason).
--The number of universities and research institutions that are getting grants are getting fewer. The largest grant receivers are the same, year
after year. (These include the University of Wa., but not Stanford; Johns Hopkins consistently comes in first place).
--Grants for new research is becoming proportionately less. The overwhelming share goes to support existing research efforts.
--30% of the amounts doled out by the NIH goes to reimburse universities for indirect or "facilities and administrative" costs. Each
university negotiates its own rate of reimbursement. At Johns Hopkins for every $100,00 awarded to a grant applicant to pursue a specific
project, an additional $64,000 goes to the university for its common expenses.
--During 2003-2005 US taxpayers spent $12.5 billion to pay overhead at NIH funded institutions.
--There is a "herd mentality" in the types of projects that are funded. To apply, the scientist needs to have a discrete, specified and
circumscribed project; they need to have already published studies in that area, with at least one in a top-tier journal--and they need to have
been "first author" on some of the papers.
--Stanford professor: "It's not that the grants that are funded are bad or low-quality ideas. They are not doubt decent and very good ideas.
But it's extremely unlikely that they will be innovative and really change the paradigm. It's more of the same kind of low-risk research."
This same professor states that any seriously innovative idea has absolutely no chance of being funded. Another Stanford scientist says,
"If the work that you propose to do isn't virtually certain of success, then it won't be funded." This same professor, who has made
important discoveries in genetics, feels that if he was beginning his research now instead of in the 70's, he would have little chance
of being funded.

---PUBLICATION: It's harder to get early "fuzzy" discoveries published today. For example, for the chromosomal anomaly discovered by Nowell and
Hungerford (the Philadelphia Chromosome), they had no theory about why, no idea of the mechanism of action, its sample size was small,
there were no controls, it was happenstance, not hypothesis driven, there were fuzzy research goals, and it was only an unexplained
coincidence. Yet it was published, and that 238 word paper is today one of the most widely cited papers in cancer research. Nowell states
that had the same experimental report been submitted for publication today, it likely would not have met the threshold for publication in
any serious academic journal.

--Leaf believes that good science needs to follow hunches and instinct as often as a plan. It needs to swerve from chance observation to a question and more questions, not a hypothesis. His suggestions: 1. Let scientists follow their questions where they might lead--learn as they go instead of formulating discrete hypotheses; 2. There must be genuine collaboration--no ownership of theories or ideas; 3. Forget the myth that great cancer science needs to be expensive; 4. Need to act, not wait endlessly for more studies when lives are at stake.

--DRUG DEVELOPMENT--a new drug takes an average of 6 years of testing before submission to the FDA. Pre-testing time is 4 years. Time for
FDA approval is 1.3 years.
--Companies are driven to produce drugs that require little risk-taking, but offer potential for high revenues--"me-too" drugs.
--Drug discoveries today, particularly in oncology, are rarely about bringing novel compounds to market, but about increasing the number
maladies for which an already approved drug can be prescribed.
--Avastin, approved in 2004, statistically extends life 4.6 months. It costs $90,000 per year, and has serious side effects. It produced
revenue of $6.3 billion in 2010.… (mehr)