Obama Seeks "Cure For Cancer In Our Time"

From REUTERS:

"In his speech to a joint session of Congress on Tuesday, Obama referred to his economic recovery plan and said, "It will launch a new effort to conquer a disease that has touched the life of nearly every American, including me, by seeking a cure for cancer in our time." Both his mother and grandmother died of cancer.

The economic stimulus measure signed by Obama on Feb. 17 included a huge, two-year infusion of about $10 billion for the National Institutes of Health, which funds research, of which about $1.26 billion is expected to go for cancer research."

Harper at America's Mercy

Today was the big day of Obama's visit to Canada. And we discovered just how vulnerable Harper is to the whim of the White House.

During the press conference today, Harper explained his heel-dragging on environmental policy: "Canada has had great difficulty developing an effective regulatory regime alone in the context of an integrated continental economy. It's very hard to have a tough regulatory system here when we are competing with an unregulated economy south of the border."

That was honest and revealing. It shows that Harper was at least unable and probably unwilling to use the levers at his disposal to advance environmental policy. Canada is America's largest oil supplier. Most think it's Venezuela, or Saudi Arabia. In fact, Canada supplies about 1 million barrels of oil per day more than each of Mexico, Venezuela and Saudi Arabia. We are its most visible and respectable ally in Afghanistan, the Right War. We are the top uranium and potash producer in the world, and in the top three for natural gas, nickel, zinc, and asbestos. All of this gives us incredible leverage when negotiating with the world's most voracious economy (maybe being edged out by China now).

We can find other markets. Naturally, we preferred our likeminded and deep-pocketed neighbours. It is in the US's interest to find suppliers that are politically and economically stable. Preferably lickspittle sycophants who parrot your policy du jour.

So now Harper is going to get tough on the environment because he has finally found some coattails attached to someone headed in that direction. Well good for him. But pardon me if I don't find Harper's Change something I can Believe in.

The Illusion of Progress in Cancer

Two investigators from the MD Anderson Cancer Centre in Houston, an internationally renowned research institution, recently published a startling dressing-down of the Medical-Pharmaceutical Complex for creating the illusion of progress in the treatment of cancer. Their writing is direct, harshly critical, and blisteringly accurate, and as such I can not improve on it so present a few lengthy passages below. Their commentary was published in the January 20, 2009 issue of the Journal of Clinical Oncology.

Their main thesis: the initial impressive double-digit survival gains of past decades can no longer be achieved. Instead we are left to produce 'advances' with diminishing returns, at staggering expense, and of dubious benefit. We may even be discarding solutions of true benefit because our research systems are too blunt or cumbersome to detect an advantage in small groups of patients.

Low thresholds for judging effectiveness "benefit many stakeholders. Investigator careers are built on "positive" studies, statisticians become indispensable when advances are so small that only they can detect them, National Cancer Institute programs demonstrate that they help identify "active" new drugs, the US Food and Drug Administration demonstrates that it fosters safe access to "useful" new therapies, companies can market new agents, and providers can bill for new therapeutic options delivered. Drug sales yield advertising dollars to fuel publications and campaign dollars to fuel elections. Insurers simply pass on the higher costs by raising premiums. Almost everyone benefits. Unfortunately, the gain for patients is often exceptionally modest and at exorbitant cost."

"Large armies of dedicated people are fighting very hard in this war on cancer, but maladjusted research goals, governance, economics, politics, legalities, accepted clinical research practices, and dogma unintentionally impede progress."

"a drug that leads to dramatic responses, but only in 5% to 10% of patients, might be predicted to fail in randomized trials involving unselected patients." [...] "It is time to stop investigating efficacy of drugs against tumors defined solely by histopathologic type and to instead investigate efficacy against tumors defined by a combination of histopathology and molecular and genetic profiles." [Note: This has been done to some degree, e.g. for her2/neu-positive breast cancer and trastuzumab/Herceptin, for c-kit-positive gastrointestinal stromal tumours and imatinib/Gleevec, and others]

"Like amassed troops targeting only a nearby trench, large randomized trials aiming to increase survival by a few weeks are a huge expense likely to achieve only modest gains, because modest gains are precisely what they are aiming for. We instead need a plethora of highly mobile smaller trials each with the goal of achieving much more ambitious outcomes."

"The current regulatory burden in the conduct of clinical trials is to the war on cancer what World War I mud was to trench warfare. The thigh-deep, sticky Flanders mud jammed rifles, entrapped vehicles, weighed down massively caked clothing, pulled like glue at legs and boots, and swallowed and drowned those who stumbled and fell. This regulatory burden is onerous, misguided, and expensive, with little value added. For example, one author's (D.J.S.) department receives around 600 external serious adverse event (SAE) reports per month for agents that it is studying clinically. A single event may generate a dozen or more SAE reports (one for the original event, one for each follow-up, and a separate copy of each of these for each protocol using the agent). In addition to the SAE reports being highly repetitive, the overwhelming majority report events that are more likely related to tumor progression or comorbidity, are well-known toxicities of the agent, or are irrelevant for other reasons. Despite this, purportedly to raise the safety bar, each copy of each form received required a separate document be prep ared, submitted, reviewed, corrected (to properly conform to the shifting regulatory interpretation du jour) and resubmitted to the institutional review board (IRB). This does not improve patient safety but does magnify research costs and investigator frustration. Similarly, Humphreys et al documented that 16.8% of the total costs of an eight-site observational trial were devoted to IRB interactions, desp ite no visible effect on human subject protection, and the essential procedures of their study never changed substantially despite exchanges of more than 15,000 pages of material."

I recently submitted a clinical trial application for review by my IRB. They reviewed the consent document, a document meant to assist a patient in understanding a trial before making a decision to participate. The trial tests high doses of radiation therapy together with chemotherapy and a new targeted agent in this setting. The patients enrolled to the study have stage III lung cancer, a disease with a five-year survival of about 15%.

The treatments are potentially life-threatening in a variety of ways that I enunciated ad nauseum in the consent document I submitted. Nevertheless, the IRB objected to the omission of a statement that patients may find items on a questionnaire about their quality of life "upsetting." When someone's treatment or disease has a substantial risk of killing them, a likelihood of making them seriously ill, and a certainty of making them feel like hell for about four months, the possible eyebrow-raising discomfiture provoked by a questionnaire item is not a make-or-break feature of the trial.

The document runs 13 pages and contains redundant assurances about protection of privacy, superfluous statements about expenses such as specifying that parking costs will not be covered, and the like. It is a Frankensteinian concatenation of every paternal impulse ponderous regulatory institutions can muster, ostensibly for patient protection, more likely to limit liability.

I applaud the courage of Stewart and Kurzrock for making a case that is long overdue. Their piece is an electrifying manifesto, and should be required reading for every researcher and regulator. I have no doubt that they are incredibly frustrated and inhibited by the regulatory and granting environment they find themselves in. Who knows what great advances we have overlooked, what novel ideas have been turned away, how many eager researchers have been stonewalled by a process that is "perfectly designed to get exactly the results it gets."

Medicare: CT Colonography Not Ready For Primetime

On February 11, Medicare released a preliminary statement on coverage for CT colonography in colorectal cancer screening. The verdict: CT Colonography should not be covered by Medicare. CT Colonography or 'virtual colonoscopy' is a technique to detect cancerous and pre-cancerous lesions of the colon that uses a 3D reconstruction of the colon to create a virtual flythrough and guide further, more invasive, investigations.

The Decision Memo is preliminary, and Medicare canvassed for comments:

"We are requesting public comments on this proposed determination pursuant to Section 1862(l) of the Social Security Act. After considering the public comments, we will make a final determination and issue a final decision memorandum. As with all national coverage analyses, the public may submit comments or additional evidence that cause us to reassess our evidentiary review and arrive at different conclusions. If that should occur during finalization of this decision memorandum and we determine that CT colonography is clinically effective, then we would need to determine, using current or additional cost information, if CT colonography is cost effective. We are asking for public comment on the cost effectiveness of screening CT colonography for the Medicare population if we were to alter our clinical decision."

It's not clear to me if that means Medicare has already determined that CTC is clinically effective but are awaiting evidence of cost-effectiveness or what.

A discussion of the test's accuracy can be found at the New England Journal of Medicine, where a recent report was published on the ACRIN study 6664, "Computed Tomographic Colonography in Screening Healthy Participants for Colorectal Cancer." The study found that CTC could detect 90%of abnormalities greater than 10 mm (about 3/8") in size compared to a gold standard of colonoscopy.

Dr Robert Fletcher commented on the study findings in the NEJM citing several reasons why he was underwhelmed. He notes that 17% of the subjects were thought to have polyps larger than 10 mm, but only 1 in 4 actually did on confirmation colonoscopy. In 16% of subjects, there were incidental findings outside the colon, and these usually don't amount to anything substantial (aside from life-threatening abdominal aortic aneurysms). On this point he cites his previous editorial in support! He also mentions the inconvenience and discomfort of scheduling a colonoscopy to evaluate abnormal colonic findings on CTC, though more than 80% of patients are spared such an examination by undergoing CT first. He warns of the threat posed by radiation risk, though he concedes that the dose from one such scan "may be acceptable" and the "radiation risk is uncertain." It is perhaps worth noting that Dr Fletcher disclosed his past role as a consultant to Exact Sciences, a company exploring competing technology for colorectal cancer screening, stool-based DNA screening.

If you wish to influence Medicare's decision, you can submit your comments here, I believe. They do take public commentary seriously. In fact, they provide a detailed review of public comments in their Decision Memo. The comments included feedback in support of CTC from the American Cancer Society, American College of Radiology, American Gastroenterological Association, and--perhaps less impressively--from the Medical Device Manufacturers Association and Medical Imaging Technology Alliance. Thirty-four lay public also commented, and the content of their comments are noted in the memo.

To be honest, I'm impressed with the transparency, frankness, comprehensiveness, and quality of the Decision Memo, and agree that the evidence for supporting CTC in the Medicare population, with an average age of 75 years, is weak. Probably worthwhile applying this technology to younger subjects, however. This decision should not be taken to suggest otherwise.

Obama's Trillion-Dollar Pork Project

During the campaign, McCain accused Senator Obama of seeking $932m in pork barrel projects for his state, Ilinois. Now President Obama has petitioned Americans and Capitol Hill to rescue the country with a trillion-dollar bailout scheme several orders of magnitude bigger--enough for a thousand Illinois-- surrendering control of the expenditures to Congress in exchange for safe passage, at least according to the Economist:

Dear Reader,

This week could have marked a turning-point in the an ever-deepening global slump, as Barack Obama produced the two main parts of his rescue plan: a $789 billion stimulus plan and his outline for a (probably even more expensive) bank bail-out. This double offensive could have broken the spiral of uncertainty and gloom that is gripping investors, producers and consumers across the globe. Alas, that opportunity was squandered. Mr Obama ceded control of the stimulus to the fractious congressional Democrats, so the fiscal boost is less efficient than it should have been. The financial-rescue blueprint, touted as a bold departure from the incrementalism and uncertainty that had plagued the Bush administration's Wall Street fixes, is depressingly more of the same: timid, incomplete and short on detail.


John Micklethwait
Editor in Chief

Energy Density and the Carbon Economy

I read an interesting article in the Bulletin of Atomic Scientists regarding one of the fundamental limitations of pursuing energy storage alternatives to hydrocarbons: hydrocarbons are incredibly energy dense.

Evaluating various energy storage media in terms of megajoules per kilogram, author Kurt Zenz House describes the attraction of hydrocarbons for energy storage: they store large amounts of energy in a material that is stable at room temperature and easy to transport, store, and convert. One kilogram of crude oil contains 50 megajoules per kilogram. Natural gas and coal are in this ballpark at around 55 and 20-35 MJ/kg respectively.

Batteries pack virtually no energy wallop by comparison. Lead-acid batteries store about 0.1 MJ/kg, about the same amount of energy stored in half a teaspoon of crude (2 ml). Lithium-ion batteries can store about o.5 MJ/kg, with a theoretical limit of 2 MJ/kg that has been elusive to achieve.


Capacitors and superconductors have still yet to exceed a density of 1 MJ/kg and the theoretical limits of these strategies are shy of 10% of hydrocarbon's phenomenal capacity. House describes other fanciful strategies including toroid carbon nanotubes, zinc-air batteries, elemental aluminum, without suggesting any real hope these strategies could reach their theoretical limits or feasibly be implemented.

Hydrogen combustion releases triple the energy per kilogram as crude oil. The only problem: hydrogen is a gas at standard temperature and pressure, and pressurizing hydrogen to 700 bars yields only 6 MJ/l compared to 34 MJ/l for gasoline at 1 bar. Pressurizing hydrogen requires the baggage of a heavy cylinder for vehicle transport, and heavy pipelines for line transport.

House concludes that hydrocarbons will be with us for a long time until these limitations can be superseded. House's comments mislead in several ways.

While batteries have low energy density, they require very little overhead for the conversion of their potential energy to kinetic energy. Small motors driving wheels are far lighter than heavy engines, transmissions, and exhausts required in combustion systems. When the bulk of the energy released in the internal combustion engine is dissipated as heat or consumed in moving the weight of the vehicle itself rather than the occupants, we see that hydrocarbons have limitations, too.


Moreover, biodiesel offers a way to fix carbon dioxide from the atmosphere and reintroduce it into the hydrocarbon/combustion energy infrastructure. You can regard biodiesel fuel generation as a form of solar power, fixing solar energy, CO2 and water into organic compounds that can be burned. For biodiesel, hydrocarbons remain the energy storage medium, but fossil fuels aren't used.

The biggest problem with biodiesel is that current paradigms require freshwater and arable land, commodities that will become increasingly scarce before fossil fuels do. New paradigms of biodiesel employ saltwater based algae, no land or freshwater required.

Algae: some food for thought. Before Soylent Green was people, it was algae. Is there nothing Charlton Heston can't teach us?

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