Bloviations and pontifications on the state of cancer research, part 2 (of 2)

In rapid succession after the last pontificating and bloviating article claiming that there will never be a cure for cancer because it would be too financially disastrous to the medical economy, I’ve been made aware of another pontificating and bloviating article decrying the state of cancer research today, entitled Curing Cancer: Running on Vapor, Remedy: More Brainpower, Less Hype, by George L. Gabor Miklos, Ph.D. and Phillip J. Baird, M.D., Ph.D. On first glance, it looks like a bold proposal for a necessary change of direction in our cancer research effort. Sadly, it doesn’t deliver on its grandiose title. In fact, it doesn’t even come close to delivering. After having seen this article late last week, I hadn’t quite decided whether or not to take this article on when old “friend” and prominent HIV/AIDS denialist blogger Dean Esmay just had to go and make a comment like this:

By the way, I’m sure that a certain cancer surgeon/researcher blogger who often attacks me in a completely malicious and unprovoked manner on his own blog–who shall remain nameless, because I’m tired of “blogwars”–will be linking this with yet another of his patented gaseous rants to condemn me and anything I link or say on this subject, as per usual. Too bad. He’s an MD/low-level bureaucrat and proof positive that you can have a moderately high IQ and make it through med school based on your ability to “know your stuff” (i.e. memorize and regurgitate and axiomatically defend the current wisdom of the day) and not know a critical thinking skill if it runs up and bites you on the ass. Plus, of course, he completely lacks objectivity in this area because his income is largely derived from the status quo. By noting this unassailably correct fact, he and other bureaucrats like him will no doubt whine that it is an “attack” that I say so–as if it wasn’t Ethics 101 to note when you or anyone else has a clear conflict of interest and may lack objectivity as a result. Whatever.

Can’t you just feel the love?

Far be it from me to deny Dean’s plaintive cry for that Respectful Insolence™ that he apparently knows and craves so, but in reality I reserve it more for the article than for him. Little did he realize that, if I wrote anything at all about this article, I had been planning only on mentioning the other two places where I had seen it mentioned or linked to (You Bet Your Life and Grouppe Kurosawa, neither of which are exactly bastions of good scientific information), but how can I resist an invitation like Dean’s? I particularly love the rather obvious way he’s preemptively inoculated himself against any commentary or criticisms from me about the article that he doesn’t like, much as he dismissed my critique of Peter Duesberg’s Scientific American paper about chromosomal chaos and cancer, basically because he doesn’t like me and considers me a minion of the evil cancer research establishment, something I find particularly amusing given his unjustifiably inflated opinion of his own knowledge about AIDS and cancer. So, one may ask, why bother?

Because the reaction to this article by Dean and others is instructive and the article itself is being trumpeted as if it were an utterly devastating critique of how we do cancer research coupled with a clarion call to a brilliant new and better way, when in reality it’s considerably less than that, little more than an example of how to write something that starts with some truth to it but then completely fails by proposing an utterly banal solution to the problem at the end, that’s why. The article starts with an indictment of the entire cancer research establishment, calling it intellectually bankrupt:

It’s easy to tell when an area has run out of ideas. The hype becomes extreme, and technology substitutes for brainpower. The cancer research area has reached this sorry state. The tiniest increase in the survival time of drug-treated cancer patients or median time to progression is touted as a cure, and wildly unrealistic claims about personalized cancer medicine emanate from the highest governmental and academic sources. In contrast, Andy Grove, the former Chairman and CEO of Intel, who has tried to shake this dysfunctional cancer mindset. “In cancer, everybody plays his individual part to perfection, everybody does what’s right by his own life, and the total just doesn’t work.”

How have we reached this low point where a generation of young scientists, biotechnologists, and the massive resources of big pharma are basically running on vapor? The answers are not hard to find. First, understanding some basic clinical facts is a good place to start. Second, clinically irrelevant research avenues need to be jettisoned–pronto. Resources and intellectual horsepower need to flow into areas that have clinical impact.

That’s all well and good, but my skeptical antennae start twitching whenever I hear such a sweeping indictment of, in essence, an entire field of study. Even so, you never know. They might have good ideas for how to improve the state of cancer research and care; so I thought I’d read on, hoping that I, mere cog in the vast cancer research machine that I am, would be able to glean just a bit of the enlightenment that I apparently need from the wisdom of Miklos and Baird about which research avenues are “clinically irrelevant” and which areas we should be pouring money and “intellectual horsepower” into. After all, when someone has the chutzpah to start out an article with such a blistering attack on a field as large and diverse as that of cancer research and the implication that there is a better way, is it so unreasonable of me to expect that the article will actually try to educate us about what that supposedly better way is? I think not, but that’s just me. Reading this article, I waited with bated breath for the apparently promised fantastic answer that would take cancer research off of the horribly wrong track upon which Miklos and Baird apparently think it is on. What I got was a critique that, in essence, points out that we still don’t do so well against metastatic solid cancers, calls cancer research intellectually bankrupt, and argues that it’s a waste of time to be studying cancer genomics. Really, that’s about all there is to the critique. Worse, the answer that I so craved as to what this amazing better way to attack cancer is never came.

In the article, we are solemnly told that, for all the effort in the “war on cancer” started during the Nixon administration, we aren’t doing well. Well, yes and no. In some areas we are doing pretty well; in others not so well. (After all, cancer is not just one disease; so it would be rather surprising if we were doing well or poorly in all areas.) For example, expected survival for childhood tumors is now in general in the 70-90% ranges; back in 1971, most of these same tumors (leukemias, lymphomas, Wilm’s tumor, sarcomas, etc.) were virtual death sentences. Indeed, just since 1985, considerable progress has been made, as this German study shows. The more pessimistic SEERS Database (Figure XXVIII-1) shows that, from 1975 to 2004, overall mortality from cancer has declined by nearly half, even as incidence has increased. Certainly, there is more work to be done, but there is little doubt that our management of childhood cancer has improved markedly.

But, I’m sure Miklos and Baird would retort, childhood cancer makes up only around 1% of all cancer; so let’s look at the adult cancers. Here, they are correct that the picture has not improved as much as we would like, although they clearly overemphasize the negative and dismiss advances that have been made. It’s pointed out, for example, that the latest regimens for metastatic colorectal cancer (namely, the addition of Avastin) only increased median survivals by 4.7 months (although they neglect to mention that, if you add up improvements from other innovations, median survivals for metastatic colorectal cancer to the liver have increased from around 12 months to 20 months over the last decade, with the FOLFOX regimen having improved survival from 12 to around 15 months, and the addition of Avastin having added the additional months). They also mention that the highly touted Herceptin improves survival in metastatic breast cancer from 4.4 to 8.4 months and that it only benefits about a third of patients, also true. If I wanted to look at the glass as half-full, I could point out that these represent nearly doublings of median survival times for patients with metastatic cancer, but that would not change the fact that these diseases still remain incurable when metastatic and that we are looking, by and large, at improvements measured in months. Even so, I don’t think it is unreasonable to point out that, relatively speaking, these represent pretty significant improvements in survival, even if we do have along way to go. What do Miklos and Baird expect? Instant cures? They also totally neglect improvements in cancer care that may not have increased the overall survival of cancer patients but have greatly increased their quality of life. For example, in the 1970’s nearly every woman with breast cancer got either the highly disfiguring radical mastectomy or the somewhat less disfiguring modified radical mastectomy, both of which involved the removal of all the lymph nodes under the arm, with the attendant and all-too-common complication of lymphedema. Now, over 70% of women get a breast-sparing procedure, like a lumpectomy, along with a sentinel lymph node biopsy. Only a minority get mastectomies or lymph node dissections these days, and many of those who do have reconstruction done. The same sorts of improvements are true of colon cancer and a variety of other cancers. Yet Miklos and Baird totally neglect these advances.

In fairness, I will point out that not all of their criticisms are overblown or without merit. I’ll even point out that I share some, but not all, of the reservations regarding the Cancer Genome Anatomy Project (CGAP), upon which Miklos and Baird heap their scorn, all but calling it a $12 billion boondoggle. Even seeing Dr. Francis Collins defend it at the recent AACR Meeting didn’t quite assuage my doubts. Miklos and Baird also point out appropriately that tumors are very heterogeneous, as if they actually thought that this were something that researchers working on the CAGP weren’t aware of. They also seem not to recognize the controversy over whether the genetic changes needed for metastasis, the primary killer, have already occurred by the time the tumor starts to metastasize and do not necessarily arise as a consequence of the primary malignant transformation, a concept that may be true but is by no means settled scientifically speaking.

The worst thing about this article, however, comes near the end, when, after lambasting the current cancer research establishment, raking the system over the coals for supposedly being intellectually bankrupt, desperate, and in a “decadent phase where scientists no longer think anymore and cannot see what the problems are,” when it should be time for Miklos and Baird to put up or shut up.

They should have shut up while they were still making a modicum of sense:

The clinical issue is straightforward. If a solid tumor is detected before any of its cells have disseminated and the tumor is resected, then the patient is cured. Hence, the key is early detection. Instead of misguided megasequencing projects and bioinformatic deconvolutions that are manifestly tangential to the main issues of dissemination and metastasis, it would seem more prudent to invest in the development of diagnostic technologies for detecting cancer growths, as well as the properties of cells that are destined to metastasize.

[…]

We believe that scarce resources can be used most prudently in areas of clinical reality, not in research areas that are clinically irrelevant and represent the misguided dreams of a few. Is the future of cancer medicine one in which doctors become financial advisors, telling their patients whether they can or cannot afford expensive treatments of dubious survival value? Surely not. The future is far brighter. The solution is to get back to using old fashioned human brainpower to develop noninvasive screening technologies for detecting the earliest possible cancerous growths.

I was left scratching my head. That’s it? Better early detection of cancer is the main answer? That’s “thinking outside the box”? After all that castigation of present-day cancer researchers as being unimaginative and decadent, that‘s Miklos’ and Baird’s big idea, the one that’s so much better than what the cancer establishment is already doing now? I was flabbergasted. Although there’s little doubt that early detection has improved survival for common cancers, the benefits are not nearly as radical (or even as easy to demonstrate in epidemiological and clinical studies) as Miklos and Baird naively seem to think. Also, certainly for some cancers (pancreas or ovarian cancer comes to mind), early detection can’t but help, given that these tumors are very often found at an advanced stage. However, for the common cancers for which we do screen (breast, prostate, or colon), we seem to be already coming close to the point of diminishing returns as far as improvements in survival attributable to better early detection. Here’s why. As I’ve discussed extensively before, more sensitive and detailed screening is not necessarily better because it will detect ever more disease without necessarily having any effect on the desired outcome: Survival. (The Cliff Notes version is here.)

It’s clear to me that neither Miklos nor Baird are clinicians who deal with treating cancer patients, and, in fact, they ought to read up on lead time bias, length bias, and the Will Rogers effect before making such blanket statements if they want to avoid looking so naive and foolish in the future. Also, if they were clinicians, they might realize just how difficult it is to implement new screening tests and that, contrary to their simplistic concept that earlier, better screening will necessarily improve survival, in some cases it very well may end up causing more harm than good, depending on the cancer and the specific screening test. Given that, I found it particularly ironic that on their company’s own website, Secure Genetics, they cite the very same information that I cited in the posts linked to above regarding the problems involved in detecting cancer early, and use it to condemn the current paradigm:

Judah Folkman MD, of the Department of Surgery, Childrens Hospital and the Harvard Medical School, (2004, Nature 427, 787), has highlighted the well known fact that most people carry dormant tumors that never progress to the metastatic condition. Thus almost all autopsied individuals between 50 and 70 have in situ carcinomas of the thyroid gland, but only 1 in 1000 of the individuals in this age group are diagnosed with thyroid cancer in this age group.

Only 1% of women in the 40-50 age group are diagnosed with breast cancer, yet in excess of 30% of women in this age group are found to have in situ tumors of the breast at autopsy. In women diagnosed with ductal carcinoma-in-situ of the breast, 80% never become invasive even if left untreated (2000, The Breast Journal, 6, 331). Similarly, prostate cancer is often manifest in many different foci, only one of which may be invasive, (2000, Nature, 404, 921).

[…]

While hundreds of millions of women world-wide have first hand experience of the Pap smear test for the detection of cervical cancer, detection of prostate cancer in tens of millions of men routinely involves the Prostate Serum Antigen (PSA) test. Given the results, radical prostatectomy, external beam radiotherapy, hormone therapy to lower testosterone and competitive androgen receptor antagonists are then used to treat localized prostate cancer…However, it is now clear that the serum PSA test can be misleading in the diagnosis of prostate cancer and it has little to offer as regards the likelihood of metastasis.

Déja vu, dudes. Clearly, there’s a disconnect between Miklos’ and Baird’s indictment of cancer care and clinical reality, just as there is a disconnect between what they cite on their website as one of the major shortcomings of present day cancer care and what they propose as a solution. In fact, their description of PSA testing is an excellent example of the shortcomings of the very approach they espouse!

So how is Miklos’ and Baird’s approach (screening for the “earliest possible” cancer growths) any different than the “desperate” and “decadent” approaches of conventional cancer researchers? Here’s their dirty little secret: When you get right down to it, it isn’t, really, at least not in any meaningful sense. After proposing nothing more than better, less invasive, and more sensitive screening tests to find the “earliest possible” cancer growths and then cut them out, they simply express faith that looking at individual metastatic cancer cells will allow them to determine which of these will fail to progress to metastases and which are dangerous. In reality, although they recognize some of the shortcomings of current cancer research, after all their bloviations and pontifications, they have nothing that is any better to offer. Their article seemed to be building to a thunderous crescendo, but it ended with a peep. If these guys are rebels against the cancer establishment, I’d hate to see a real establishment lackey.

From my perspective, all this sound and fury signifying little published Miklos and Baird actually has less merit than Duesberg’s chromosomal chaos hypothesis of cancer, which as you may recall, I called an “intriguing hypothesis argued poorly” and considered seriously. Worse, this rather bad article has fed conspiracy-mongering of a kind similar to what I described in yesterday’s piece about a claim that there will never be a “cure” for cancer because supposedly we in the cancer research field are too dependent upon the current system and the current way of thinking ever to give up the gravy train, as exemplified on a regular basis by You Bet Your Life and Grouppe Kurosawa. At the risk of being excessively snarky, I can’t help but note that Dean Esmay seems to be a big fan of a variation of the very sort of nonsense that I shredded yesterday (and, yes, whatever defects there are in the present NIH system for awarding research grants, Dean’s and Bialy’s conspiracy-mongering about how we as cancer researchers supposedly have too much invested in the current system ever to find a cure is nonsense). Indeed, that Dean considers the Miklos and Baird article to be such an impressive critique of the cancer establishment also shows just how little he understands. Of course, Dean views me as being part of the brainwashed hordes of big pharma-zombified NCI dark minions who supposedly persecute his hero Peter Duesberg; so anything I say he’ll automatically dismiss, his mind as utterly and irredeemably closed as he seems to think that mine is, the better to keep any thoughts that threaten his self-image as a free-thinking iconoclast or rebel against the establishment safely at bay as he continues to demonstrate how little he knows about how the NIH works.

Describing why may be a topic for another day. Or not, depending upon my mood. After all, I’ve already reached the length of this post at which no doubt Dean would consider it to be a “gaseous rant,” and I wouldn’t want to provoke a blog war.

Right?