Last Friday, Mark Crislip posted an excellent deconstruction of a very disappointing article that appeared in the most recent issue of Skeptical Inquirer, the flagship publication of the Committee for Skeptical Inquiry (CSI). I say “disappointing,” because I was disappointed to see SI (Skeptical Inquirer, not Sports Illustrated) publish such a biased, poorly thought out article, apparently for the sake of controversy. I’m a subscriber myself, and in general enjoy reading the magazine, although of late I must admit that I don’t always read each issue cover to cover the way I used to do. Between work, grant writing, blogging, and other activities, my outside reading, even of publications I like, has declined. Perhaps SI will soon find itself off my reading list. Be that as it may, I couldn’t miss the article that so irritated Mark, because it irritated me as well. There it was, emblazoned prominently on the cover of the March/April 2011 issue: Seven Deadly Medical Hypotheses. I flipped through the issue to the article to find out that this little gem was written by someone named Reynold Spector, MD. A tinge of familiarity going through my brain, I tried to think where I had heard that name before.

And then I remembered.

Dr. Spector, it turns out, first got on my nerves about a year ago, when he wrote an article for the January/February 2010 issue of SI entitled The War on Cancer A Progress Report for Skeptics. I remember at that time being irritated by the article and wanting to pen a discussion of the points raised but don’t recall why I never actually did. It was probably a combination of the fact that SI doesn’t publish its articles online until some months have passed after the paper version has been released and perhaps my laziness about having to manually transcribe with my own fingers any passages of text that I might want to cite. By the time the article was available online, I forgot about it and never came back to it–until now. I should therefore, right here, right now, publicly thank Mark (and, of course, Dr. Spector) for providing me the opportunity to revisit that article in the context of piling on, so to speak, Dr. Spector’s most recent article. After all, Deadly Hypothesis Seven (as Dr. Spector so cheesily put it) is:

From a cancer patient population and public health perspective, cancer chemotherapy (chemo) has been a major medical advance.

Dr. Spector then takes this opportunity to cite copiously from his 2010 article, sprinkling “(Spector, 2010)” throughout the text like powdered sugar on a cupcake. There’s the opening I needed to justify revisiting an article that’s more than a year old! And what fantastic timing, too, hot on the heals of my post from a couple of weeks ago entitled Why haven’t we cured cancer yet?

Back to the future, before visiting the past

Before I leap back more than a year, first let me just point out that I agree with Mark 100% when he castigated Dr. Spector for his opening volley. Although thought had never occurred to me at the time, in retrospect I even agree with Crislip’s likening Dr. Spector’s tirade to a Mike Adams screed, at least in dogmatic certainty and tone. Sadly, for entertainment value at least, Dr. Spector lacks the looney hyperbole of Mike Adams. Also, unlike Adams, Dr. Spector is a real scientist, but damn if, references omitted, this first sentence couldn’t have come right out of a Mike Adams special:

A chronic scandal plagues the medical and nutritional literature (Spector and Vessell, 2006; Spector, 2009): much of what is published is erroneous, pseudoscientific, or worse.

Like Mark, I’m a John Ioannidis convert, and I accept that there is a lot of medical literature that is erroneous. (Just search for Dr. Ioannidis’ last name on this blog, and you’ll find copious posts praising him and discussing his work.) In fact, as I’ve pointed out, most medical researchers instinctively know that most new scientific findings will not hold up to scrutiny, which is why we rarely accept the results of a single study, except in unusual circumstances, as being enough to change practice. I also have pointed out many times that this is not necessarily a bad thing. Replication is key to verification of scientific findings, and more often than not provocative scientific findings are not replicated. Does that mean they shouldn’t be published?

As for pseudoscience, I’m half tempted to agree with Dr. Spector, but just not in the way he thinks. Unfortunately, over the last 20 years or so, there has been an increasing amount of pseudoscience in the medical literature in the form of “complementary and alternative medicine” (CAM) studies of highly improbable remedies or even virtually impossible ones (i.e., homeopathy). However, that does not appear to be what Dr. Spector is talking about, which is why I looked up his references. The second reference is to an SI article from 2009 entitled Science and Pseudoscience in Adult Nutrition Research and Practice. There, and only there, did I find out just what it is that Dr. Spector apparently means by “pseudoscience”:

By pseudoscience, I mean the use of inappropriate methods that frequently yield wrong or misleading answers for the type of question asked. In nutrition research, such methods also often misuse statistical evaluations.

Ah, now I get it! Dr. Spector doesn’t really know the difference between inadequately rigorous science and pseudoscience! Now, don’t get me wrong. I know that it’s not always easy to distinguish science from pseudoscience, especially at the fringes, but in general bad science has to go a lot further than Dr. Spector thinks to merit the the term “pseudoscience.” It is clear (to me, at least) from his articles that Dr. Spector throws around the term “pseudoscience” around rather more loosely than he should, using it as a pejorative for any clinical science less rigorous than a randomized, double-blind, placebo-controlled trial that meets FDA standards for approval of a drug (his pharma background coming to the fore, no doubt). Pseudoscience, Dr. Spector. You keep using that word. I do not think it means what you think it means. Indeed, I almost get the impression from his articles that Dr. Spector views any study that doesn’t reach FDA-level standards for drug approval to be pseudoscience. He also piles on nutritional science (that is, after all, his area of specialty), and there is no doubt that here is a lot of pseudoscience there; however the vast majority of it is not in the scientific literature. Rather, it’s snake oil salesmen selling diets and supplements based on less rigorous science, the willful twisting and misinterpretation of acceptable science, and making up claims out of whole cloth.

Here’s the deal. Medical science, when it works well, tends to progress from basic science, to small pilot studies, to larger randomized studies, and then–only then–to those big, rigorous, insanely expensive randomized, double-blind, placebo-controlled trials. Dr. Spector mentions hierarchies of evidence, but he seems to fall into a false dichotomy, namely that if it’s not Level I evidence, it’s crap. The problem is, as Mark pointed out, in medicine we often don’t have Level I evidence for many questions. Indeed, for some questions, we will never have Level I evidence. Clinical medicine involves making decisions in the midst of uncertainty, sometimes extreme uncertainty. One example is hormone replacement therapy for menopause before the results of the Women’s Health Initiative study were reported. Indeed, Dr. Spector makes much hay out of the widespread use of hormone replacement therapy (HRT) back in the 1980s and 1990s, as an example of what happens when we don’t adhere to proper clinical trial design, labeling Deadly Hypothesis Two as:

The hypothesis was that if women replace these hormones postmenopausally with HRT, they will remain “youthful” and not suffer from heart disease, dementia, vaginal dryness, hot flashes, and fractured bones.

Dr. Spector then proceeds to paint a picture of reckless physicians proceeding on crappy studies to pump women full of hormones. Actually, it was more than a bit more complicated on than that. That was the time when I was in my medical training, and I remember the discussions we had regarding the strength (or lack thereof) of the epidemiological data and the lack of good RCTs looking at HRT. I also remember that nothing works as well to relieve menopausal symptoms as HRT, an observation we have been reminded of again since 2003, which is the year when the first big study came out implicating HRT in increasing the risk of breast cancer (more later). It’s also hard not to point out that, these days, it’s not physicians promoting HRT. Rather, it’s women like Suzanne Somers promoting “bioidentical hormones” and telling postmenopausal women that they should strive for the estrogen levels that they had when they were 25. Be that as it may, I found a rather fascinating editorial in the New England Journal of Medicine from more than 20 years ago that discussed the state of the evidence back then with regard to estrogen and breast cancer:

Evidence that estrogen increases the risk of breast cancer has been surprisingly difficult to obtain. Clinical and epidemiologic studies and studies in animals strongly suggest that endogenous estrogen plays a part in causing breast cancer. If so, exogenous estrogen should be a potent promoter of breast cancer. Although more than 20 case–control and prospective studies of the relation of breast cancer and noncontraceptive estrogen use have failed to demonstrate the expected association, relatively few women in these studies used estrogen for extended periods. Studies of the use of diethylstilbestrol and oral contraceptives suggest that a long exposure or latency may be necessary to show any association between hormone use and breast cancer. In the Swedish study, only six years of follow-up was needed to demonstrate an increased risk of breast cancer with the postmenopausal use of estradiol. It should be noted, however, that half the women in the subgroup that provided detailed data on the duration of hormone use had taken estrogen for many years before their base-line prescription status was defined. The duration of estrogen exposure in these women before the diagnosis of breast cancer was probably seriously underestimated; a short latency cannot be attributed to estradiol on the basis of these data. Other recent studies of the use of noncontraceptive estrogen suggest a slightly increased risk of breast cancer after 15 to 20 years’ use.

One notes that, even now, the evidence is conflicting regarding HRT and breast cancer, with the preponderance of evidence suggesting that mixed HRT (estrogen and progestin) significantly increases the risk of breast cancer, while estrogen-alone HRT very well might not increase the risk of breast cancer at all or (more likely) only very little. Indeed, I was just at a conference all day Saturday where data demonstrating this very point were discussed by one of the speakers. None of this stops Dr. Spector from categorically labeling estrogen as a “carcinogen that causes breast cancers that kill women.” Maybe. Maybe not. It’s actually not that clear. The problem, of course, is that, consistent with the first primary reports of WHI results, the preponderance of evidence finding health risks due to HRT have indicted the combined progestin/estrogen combinations as unsafe. Even at this late time, we do not truly know whether estrogen-alone HRT carries significant risks (there are even some studies, a subgroup of the WHI included, that hint at a slightly protective effect of estrogen against breast cancer), but we do have a pretty good idea that estrogen-alone HRT is almost certainly safer than estrogen-progestin HRT, at least with respect to breast cancer. Unfortunately, there is good evidence that estrogen-only HRT increases the risk of uterine cancer. Either way, Dr. Spector’s dogmatic and unnuanced discussion of the issue suggests an axe to grind more than an interest in providing an accurate picture. Indeed, he even goes so far as to slip this sentence in there: “In legal challenges the U.S. Supreme Court has upheld the notion that HRT causes breast cancer.”

What? Who cares what the Supreme Court says about medical causation? That’s a legal standard, not a scientific standard! There’s no reason to throw such a sentence into a serious medical article.

The rest of the “Seven Deadly Medical Hypotheses” remain just as questionable, particularly the way Dr. Spector castigates the idea that screening populations for breast and prostate cancer saves lives. In all fairness, Dr. Spector’s skepticism towards screening is actually the least unreasonable part of his most recent article, given recent evidence. He even concludes that mammography has a small benefit. Therein lies a contradiction. If mammography, for instance, is beneficial, even if only slightly, then how can it be part of a “deadly medical hypothesis”? Calling screening a “deadly” medical hypothesis is, as is the case with much of this article, way over the top. A “disappointing” medical hypothesis would be a far better description. In any case, for a far more nuanced discussion of cancer screening, I will blow my own horn and suggest that you go to read these posts:

Posts by yours truly:

1. The early detection of cancer and improved survival: More complicated than most people think
2. Early detection of cancer, part 2: Breast cancer and MRI
3. Do over one in five breast cancers detected by mammography alone really spontaneously regress?
4. Are one in three breast cancers really overdiagnosed and overtreated?
5. The cancer screening kerfuffle erupts again: “Rethinking” screening for breast and prostate cancer
6. The USPSTF recommendations for breast cancer screening: Not the final word
7. The mammography wars heat up again
8. Molecular breast imaging (MBI): A promising technology oversold in a TED Talk?

Posts by Harriet Hall:

1. Screening Tests – Cumulative Incidence of False Positives
2. Overdiagnosis

By Val Jones:

• The Mammogram Post-Mortem

Read them now, or read them later. They are far more informative and nuanced than anything Dr. Spector has written on these topics for SI. For example, you won’t find the word “deadly” in there anywhere. In the meantime, let’s move on to the article that irritated me so over a year ago. Oddly enough, it was a bit more balanced and less dogmatic than the current article.

“We’re losing the war on cancer”?

The beginning of The War on Cancer A Progress Report for Skeptics, while not as over-the-top as the beginning of Seven Deadly Medical Hypotheses, is still pretty negative:

In 1971, President Nixon and Congress declared war on cancer. Since then, the federal government has spent well over $105 billion on the effort (Kolata 2009b). What have we gained from that huge investment? David Nathan, a well-known professor and administrator, maintains in his book The Cancer Treatment Revolution (2007) that we have made substantial progress. However, he greatly overestimates the potential of the newer so-called “smart drugs.” Re searchers Psyrri and De Vita (2008) also claim important progress. However, they cherry-pick the cancers with which there has been some progress and do not discuss the failures. Moreover, they only discuss the last decade rather than a more balanced view of 1950 or 1975 to the present.

On the other hand, Gina Kolata pointed out in The New York Times that the cancer death rate, adjusted for the size and age of the population, has decreased by only 5 percent since 1950 (Kolata 2009a). She argues that there has been very little overall progress in the war on cancer.

I find it rather amusing how Dr. Spector accuses investigators like Dr. Vincent DeVita (who is a coauthor of one of the widely used textbooks of oncology there is, a copy of which sits on my shelf in my office) of “cherry picking” cancers for for which progress has been made and focusing primarily on the last decade while at the same time stating that he is going to focus on adult solid cancers, where less progress has been made. One might argue that this is a correct way to do it, and far be it from me to claim that the war on cancer has been an overwhelming success. As I pointed out a couple of weeks ago, however, there is a reason (many reasons, actually) why progress has been so elusive. There is also at least one other reason. However, it’s quite obvious in both articles that Dr. Spector has himself concentrated on data that he can use to make the situation look as dismal as possible; i.e., to support his apparently preconceived conclusions that the war on cancer has been a miserable failure and that chemotherapy doesn’t work (that is, except when it does work very well). Indeed, in his most recent article, Dr. Spector uses terminology that is even more negative about chemotherapy than in his previous article. For example in the current article, Dr. Spector writes:

The hypothesis behind current chemotherapy is deeply flawed. How can we expect these drugs, most of which are nonspecific cellular poisons, to kill only wiley cancer cells and not normal cells? In fact, cacner chemotherapy routinely kills bone marro and the cell lining of the gastrointestinal tract, with very distressing (indeed sometimes fatal) side effects.

It rather shocks me that a pharmacologist like Dr. Spector would write something like this without mentioning that the reason chemotherapy can work in some tumors is because it is more toxic to the cancer cell than it is to (most of) the surrounding normal tissue. The same thing is true of radiation. This is not a trivial point. Dr. Spector makes it sound as though chemotherapy poisons everything equally and that it’s a miracle that it ever works at all. He then writes:

However, it cannot be denied that there are a few populations for which chemotherapy is marvelously effective, as noted above, and must be used.

No kidding! For example, many leukemias and lymphomas, testicular cancer, and anal cancer (which is treated primarily with the Nigro protocol, which consists of chemotherapy and radiation), among others!

Dr. Spector correctly points out that smoking tobacco products is a major cause of lung cancer, which causes most cancer deaths these days in both men and women. He even shows several very nice graphs that demonstrate that lung cancer death rates began to skyrocket about twenty years after cigarette consumption began to skyrocket (Figure 3) and that lung cancer death rates have been declining (in men at least; they appear to be peaking in women, Figures 4 and 5), approximately 25 years after cigarette consumption began to decline. All of these results are very much in accord with what we know about cigarette smoke as a carcinogen. One thing is clear: If we could eliminate cigarette smoking completely, approximately 20 years later, declines in lung cancer deaths would drive major declines in overall cancer deaths. There’s little doubt of that. However, such an observation is very much a “Well, duh!” conclusion. It’s not as though public health authorities in the U.S are unaware of such statistics or that dramatic gains or haven’t been working to try to discourage smoking. Changing behavior is very, very hard. In fact, I would argue that decreasing cancer mortality by 5% since 1950 is actually pretty darned good, given that lung cancer mortality tripled among men between 1950 and 1990 and more than doubled among women from 1970 to 2000. If you don’t believe me, take a look at these graphs from the SEER Database of cancer death rates from the various major forms of cancer, in particular Figure 4 and Figure 5. Then there is this graph in Figure 2:

This demonstrates that, although cancer incidence rates are leveling off, cancer death rates are decreasing. Sure, it’s not as good as we need to do, but notice that the curves are separating. Indeed, if you look at Figure 7, you’ll see an estimate of how high cancer mortality would be if cancer mortality rates had remained the same over the last 20 years:

The American Cancer Society attributes the decreases in cancer mortality to this:

The decrease in lung cancer death rates among men is due to a reduction in tobacco use over the past 50 years, whereas the decrease in death rates for female breast, colorectal, and prostate cancer largely reflects improvements in early detection and/or treatment. Between 1990–1991 and 2006, death rates increased for liver cancer in both men and women, esophageal cancer and melanoma in men, and lung and pancreatic cancer in women. Figure 7 shows the total number of cancer deaths avoided since death rates began to decrease in 1991 in men and in 1992 in women. Approximately 767,000 cancer deaths (561,400 in men and 205,700 in women) were averted between 1991–1992 and 2006.

Death rates from all cancer are a rather crude measure of how the war on cancer is going, anyway, being an aggregate number that is only likely to be affected very late as a result of improvements in cancer therapy. Our population is aging, which means that more people are living long enough to develop cancer, particularly given that we’ve made such dramatic progress in decreasing death rates from cardiovascular disease. People who live longer because they don’t die of cardiovascular disease have to die of something, and cancer, being number two (although not for long), is the next most likely cause. In any case, let me provide an example of what I find wrong with Dr. Spector’s thesis. In his “war on cancer” article a year ago, Dr. Spector wrote:

The FDA has approved bevacizumab for the cancers listed in table 5 (Physicians Desk Reference [PDR] 2009; Health Agencies Update 2009). Since the median survival of colorectal cancer is eighteen months, bevacizumab therapy would cost about $144,000 (in such a patient) for four months prolongation of survival (Keim 2008). In the other cancers in table 4, there is no prolongation of survival. Moreover, bevacizumab can have terrible side effects, including gastrointestinal perforations, serious bleeding, severe hypertension, clot formation, and delayed wound healing (PDR 2009). By the criteria in table 4, bevacizumab is at best a marginal drug. It only slightly prolongs life, demonstrable only in colorectal cancer, has serious side effects, and is very expensive.

Here’s a more provocative and somewhat more optimistic assessment of the progress we’ve made in treating metastatic colorectal cancer in graph form (click to make bigger):

Untreated metastatic colorectal cancer has about a four to six month median survival. Our old chemotherapy regimens increased the medical survival in metastatic colorectal cancer to around 12 months. Newer regimens boosted that to around 16 or 17 months. Adding bevacizumab then increased the survival to around 21 months. All of this has occurred since the mid-1990s. Is it enough? Of course not! But as a clinician I would argue that quadrupling the life expectance of someone with metastatic colorectal cancer is nothing to sneeze at. Indeed, I even have personal experience with this. The father of a good friend died last summer of metastatic colorectal cancer after having lasted over six years. A combination of surgeries, chemotherapy, and other treatments kept him going. He played golf until a week before his health declined precipitously and unexpectedly, and he died. Yes, he was certainly an outlier, but if the median survival of a group of cancer patients is pushed longer and longer, there will be more and more outliers like my friend’s father. True, we would much prefer a cure (or at least a reasonable chance of a cure), but ask the cancer patient what that extra year or several months means to him or her. Also true, as a society, we have to decide how much we are willing to pay for that additional survival, but that is a societal question more than anyone else. It’s also rather disappointing that Dr. Spector would describe bevacizumab as a “nonspecific toxin” that interferes with blood vessel growth throughout the body. That’s not quite true. Bevacizumab does interfere with angiogenesis, but it tends to be much more specific for tumor blood vessels and other abnormal blood vessels than for normal blood vessels. Indeed, the most recent concepts regarding bevacizumab is that it actually “normalizes” tumor blood vessels, allowing chemotherapy to get to the tumor better. This observation explains a paradoxical observation that I made in the 1990s that radiation and antiangiogenic therapy with anti-VEGF antibody produced greater than additive anti-tumor effects.

Be that as it may, suppose I’ll be accused of “cherry picking” this example, but I don’t care that much. I choose it because I want to point out that the situation is not always as grim as Dr. Spector claims and that we have made enormous progress in treating some cancers over the last 40 years. I would also point out that the $105 billion we have spent on the war on cancer since 1970 breaks down to only around $2.6 billion a year. In recent years, the yearly budget for the National Cancer Institute has hovered in the $4.7 to $5.2 billion range. This may sound like a lot of money, but in reality it is only 0.1% of the $3.8 trillion federal budget this year. Let’s just put it this way, the entire yearly budget for the NCI would fund the war in Afghanistan for approximately 16 or 17 days. That is not a lot of money in the grand scheme of things; certainly it isn’t enough money to pay for a real “war” on cancer.

Where do we go from here?

Let me just begin my conclusion by conceding that Dr. Spector does make a few good points, albeit in insufficient detail in some cases. For example, his discussion of lead time bias is superficial and doesn’t even use the proper term for the concept, and he leaves out the concept of length bias in screening altogether. More irritating, though, is that there’s clearly a relentless effort on his part in both articles to paint as grim a view of the situation as before. Yes, Dr. Spector is correct that, if we could only decrease smoking to nothing we could decrease the death rate from breast cancer dramatically over the next 20-30 years. He’s also correct that decreasing use of HRT will help decrease the death rate from breast cancer, but in reality we’ve already done that. HRT use has declined precipitously after 2002; there isn’t much room to decrease it further. He also recommends vaccines to prevent HPV infection and thereby decrease the risk of cervical cancer, but that is really a pretty small contribution to the overall cancer death rate. Even so, let’s say we do all these things that Dr. Spector suggests because they are good things to do and will have an effect. Ignore for the moment how difficult it is to get people to stop smoking to prevent lung cancer, to stop drinking to prevent head and neck, esophageal, and liver cancers, and to lose weight to decrease the incidence of obesity-related cancers. Let’s say we can do it. What then? We will still have lots of people who will develop cancer and die from it if we don’t come up with better therapies. How do we do that? On that score, Dr. Spector is profoundly self-contradictory. I’ll show you what I mean.

At one point, Dr. Spector opines:

In my view the principal problem is that we just do not understand the causes of most cancers. We don’t even know if the problem is genetic or epigenetic or something totally unknown. In theory, problems 2 through 6 in table 6 are all correctable with political and scientific will and more knowledge. Even though we know cancer of the lung is caused by cigarette smoking, we do not know the mechanism, and (except for surgery) we do not know how to meaningfully intervene (see table 2). The pharmaceutical industry cannot make real progress until we understand the mechanisms and molecular causes of cancer so that industrial, academic, and governmental scientists have rational targets for intervention. We will make no progress if there are five hundred or more genetic abnormalities in a single cancer cell. Where would one begin?

And:

Moreover, with better mechanistic understanding of cancer, we could make truly “smart” drugs, as has been done in recent years for atherosclerosis (heart attacks), hypertension (strokes), gastrointestinal diseases (ulcers), and AIDS—with truly remarkable results. Let us hope cancer is next.

I can’t argue with that. Indeed, I’m very much about trying to understand the biology of cancer much better, so that we can design treatments that will be much more effective, “truly smart drugs,” as Dr. Spector puts it. That’s the direction, in fact, that I’m trying to move my research effort, with the help of a very good systems biologist. Here’s the problem. In his most recent article, Dr. Spector dismisses as useless and deadly the very techniques that we will require in order to generate the hypotheses that could lead to that better understanding of cancer upon which Dr. Spector’s proposed next generation of “smart drugs” would be based. Yet Dr. Spector poo-poos genome-wide association studies (GWAS), using them as an example of Deadly Hypothesis One. He lambastes the concept of personalized medicine and the genetic studies that will be necessary to achieve it as Deadly Hypothesis Six. He praises the methods used by the FDA, but, as explained by Mark Crislip, the rigor demanded by the FDA is the final step in a long process that begins with basic science, progresses through epidemiology and pilot studies, and then finally concludes with large, phase III randomized trials. Moreover, the final studies leading to FDA approval really are the “safest” part of the process, based on scads of data from all those earlier studies.

In other words, Dr. Spector, while claiming we need new and innovative hypotheses and ways to understand biology is in reality advocating very safe science indeed.

Dr. Spector makes a point that we need a better understanding of cancer, but he clearly has little idea about how to bring that about from a basic science perspective. So boxed into his clinical trial and pharma perspective is he that he castigates the very means of developing new hypotheses to test that we need. While Dr. Spector is correct that GWAS and gene expression profiling studies have been disappointing thus far, one needs to remember that the technology to do these studies has been in existence only a relatively few years and that these studies generate huge masses of data that strain even the best computers to analyze. In other words, we are early into these processes, but, as the cancer genome anatomy project demonstrates, we are learning.

That’s why I conclude that the worst aspect of Dr. Spector’s most recent article and his whole attitude in general is how he labels as Deadly Hypothesis One the concept that either “the investigator does not need a specific hypothesis and/or can use an inadequate method to test the hypothesis.” Yes, failing to use a specific hypothesis is not a good idea later in the process of drug development, but if we are to understand the biology of cancer sufficiently to design the next generation of “smart drugs,” we need new hypotheses, and these come from pilot studies. We sometimes call these studies “fishing expeditions” or, less pejoratively, “hypothesis generating experiments.” Come to think of it, one wonders whether Dr. Spector approved of the Human Genome Project. After all, there was no hypothesis to test there; scientists were simply trying sequence the entire human genome, and they learned a lot. More importantly, the results of the HGP generated many new hypotheses to test, many of which are being tested now, along with a revolution in genomic technology. The problem with Dr. Spector’s point of view is that he strikes me as seeing everything through the lens of pharma and the FDA. Scientific rigor is a good thing before approving drugs and treatments; in fact, it’s absolutely essential. However, the discovery process often begins by looking around and seeing if there’s anything interesting to see. Without that discovery process, all those rigorous trials meeting FDA requirements would never come to fruition because there would be no basic science pipeline to supply the translational research pipeline that eventually results in new drugs. Many–the vast majority, actually–of these hypotheses will never pan out, but they are just as essential to science-based medicine as the studies Dr. Spector loves.

Can we do better in the “war on cancer”? Of course we can–and must. However, it must be remembered that the “war on cancer,” like most wars, is not World War II. There is not, nor will there be, a total victory, an atomic bomb-like magic bullet that destroys all cancer. There will, as with most wars, be equivocal results, wins and losses, and pyrrhic victories. But we won’t get even that far if we embrace scientific nihilism over healthy skepticism.