Below, a guest-post by HealthBeat reader Frederick L. Moolten, M.D. Professor of Medicine at the University of Pittsburgh Medical Center, he has devoted several decades of his career to cancer research, supported by the NIH and the VA.
We love wars. Ever since our nation was forged in the heat of the American Revolution, we have celebrated victories in some (World War II – the “good war”), lamented the agony of others (the Civil War), and debated the merits of more recent ones, including Iraq and now Afghanistan. Our combativeness extends into the realm of metaphor—hence the War On Drugs, the War On Poverty, and the War On Terror (only part metaphorical). None of these has yet outlasted the War On Cancer, which we have been fighting for more than a century. Why have we not yet won?
The Survival of the Toughest
The question is sometimes posed by way of comparison. We have conquered most bacterial infectious diseases, we long ago converted juvenile diabetes from a fatal illness into a controllable one, and we are beginning to impose our medical will on heart disease, via diet, exercise, medication, and when necessary, surgery. What failure of will or intellect has allowed cancer to escape?
In fact, we have done some winning, as evidenced by some recent slight reductions in cancer rates, but we can’t defeat “cancer”, because we are not fighting an “it” but a “them” – not a single entity but a multitude of related conditions, linked by a common set of biological underpinnings but often disparate in behavior. We can cure many by surgery or radiation, if they are detected before they metastasize beyond our control. Others spread too early to detect in time, and still others are often missed because tools available to catch them are insufficiently utilized—colonoscopy for colon cancer is a salient example. Localized cancers are rarely the problem aside from those in inaccessible areas such as the brain. The lethality of cancer remains a daunting public health problem because of our very limited ability to cure cancers that have spread.
Are We Willfully Losing The War?
Those of us who browse the Internet when we should be spending our time doing something useful will sooner or later encounter claims that a cure for cancer has been discovered, but has been suppressed by the medical establishment or drug companies because the end of cancer would threaten their source of income. A variation on this theme is the claim that a potential breakthrough has been identified, but remains undeveloped because it resides in a common substance that is not patentable. How much credibility do these claims merit? In essence, none. Most alleged cures are frauds, including the historical standbys—laetrile and krebiozen. A smaller proportion includes newer treatment modalities with justifiable rationales that deserve to be explored, but which promise limited benefits. An example is dichloroacetic acid--a subject of media hyperbole in 2007 despite only modest cancer inhibitory effects in laboratory tests that offered little reason to expect it would be curative.
The false claims illustrate the principle that in areas where hope exceeds reality, Internet misinformation tends to outweigh accurate information. At least a few websites, however, are trustworthy sources of cancer information, although none purports to substitute for the advice individuals should seek from their personal physicians. These sources include Oncolink and The National Cancer Institute.
The conspiracy to frustrate our attempts to cure most cancers, once they have spread, is not the work of human malefactors but the workings of nature, which has conspired to confront us with a challenge far more vexing than the bacterial diseases we now treat effectively. The “easy” diseases have already been conquered, more or less – rheumatic fever due to streptococcal infection, vitamin deficiencies, and polio are a few examples—and we are left with the hard ones. Cancer, to invert another metaphor, is the “high hanging fruit.”
The reason resides in the similarity between cancer cells and the normal cells from which they originate through mutations or other alterations in the way our cellular genes are expressed. Unlike bacteria, which possess very non-human attributes we can target, such as cell walls; cancer cells do the same things as normal cells, except a bit too much of some behaviors (multiplication), and a bit too little of others (maturation and death). The line between the normal and the malignant is thin, and treatments that attack cancer cells attack our normal tissues to an extent that often makes it impossible to employ doses sufficient to eradicate all the malignant cells.
The Role of Cancer Research
Anyone who is “shocked, shocked” to learn that drug companies strive for profits has not been reading these blogs. The companies, nevertheless, confront the reality that cancers are not easy to treat, and so their attempts to derive income from this field rely on the limited advances that science has so far achieved. Until recently, these have involved mainly chemotherapeutic agents that kill cells on the basis of their growth tendencies, which cancer cells express in excess. These agents are highly toxic. More recently, other features of cancer have been exploited, including their dependence on the formation of new blood vessels, an area pioneered by the late Judah Folkman. The drug Avastin, now in clinical trials, exemplifies this approach, which in some cases has met with modest although not dramatic success.
Other newer agents include various “biologics” such as antibodies inhibiting receptors for growth signals found in excess on the surface of cancer cells. These are less toxic than the chemotherapeutic drugs, but also more expensive to develop. The most successful to date has been Herceptin, which has significantly improved survival in subsets of patients with breast cancer, particularly in combination with tolerable doses of chemotherapeutic drugs.
The cost/benefit calculation involving agents that are expensive on one hand, and efficacious on the other, but only marginally so, poses difficult ethical and practical dilemmas as exemplified by recent arguments about “death panels” that would allegedly deny treatments to some individuals if the treatments cost too much. The biologic agent cetuximab has been cited as an example. Some analysts have suggested that future research studies be designed with a power adequate only to detect benefits of substantial rather than marginal extent.
Although the expense inherent in developing new treatments may be considerable, drug industry profits, as well as marketing, advertising, and other non-research expenses also contribute to very high costs. I have suggested elsewhere that drug costs, including costs for agents to treat cancer, could be substantially reduced if much of the research currently conducted by the pharmaceutical industry were performed instead by a public resource such as the NIH. As I explained, the scientists who do the actual research are not motivated primarily by profits, and many would be eager to work for NIH dollars rather than those paid by drug companies.
Although cancer cells are elusive targets, a few types differ sufficiently from their normal cellular counterparts to permit ingenious scientists to exploit the differences in dramatically effective ways. The drug Gleevec (imatinib) is an example with Nobel Prize potential for its developers, Brian Druker, Charles Sawyers, and Nicholas Lydon, who focused on an unusual rearrangement of genes found in chronic myelogenous leukemia (CML), a disease that had previously been observed to progress inexorably over time to a fatal outcome. The rearranged genes mediated the overexpression of an enzyme, tyrosine kinase, that drove leukemia cell growth. By inhibiting this enzyme, imatinib has converted CML into what is essentially a chronic disease, controllable by treatment in the majority of cases. Just as insulin does not “cure” diabetes, imatinib
does not appear to cure CML, but rather allows CML patients to live a normal life in the presence of their disease.
Defense vs. Offense
In the world of metaphor, cancer treatment is akin to “going on offense” against cancer, while prevention is the equivalent of “playing defense.” Most sports enthusiasts know that more games are won on defense than offense, and cancer is no exception. The incidence of most cancers is profoundly affected by environmental factors. In some cases, these involve workplace exposures to carcinogens, but more often, they reflect lifestyle choices subject to personal control. The most obvious is smoking, with its toll in deaths from cancer of the lung, head and neck, esophagus, and other sites. Excessive sun exposure greatly elevates the risk of skin cancers – the treatable ones such as basal cell and squamous carcinomas, but also the more deadly forms such as melanoma. (On the other hand, vitamin D, which the body manufactures in response to sunlight, exerts anticancer and other health benefits, and may require supplements in pill form for individuals who reduce their exposure to sunlight). Dietary choices are important; among risk factors are obesity and excessive intake of animal fats and probably red meats, whereas protective measures appear to include diets rich in fruits and vegetables. “Eat your broccoli” is sound maternal advice in light of that vegetable’s content of isothiocyanate compounds with inhibitory effects on cancer development. These examples are illustrative rather than comprehensive. Many reference sources provide more inclusive lists.
Inhibiting cancer development constitutes “primary prevention.” The term “secondary prevention” refers to measures employed to detect and remove cancers before they become dangerous. These are not all equally effective. Pap smears for cervical cancer, and colonoscopy for colon cancer almost certainly save lives—colonoscopy is particularly useful for its ability to detect precancerous growths, “polyps”, before they have become malignant. Similar benefits have been reported for the use of mammography to screen for breast cancer, but these findings have been disputed and the benefits, if any, are likely to be modest. Other screening modalities have proved useless to date, or questionable, including PSA screening for prostate cancer. In selected high risk populations, PSA screening may be warranted, but increasing evidence indicates that its value may be negligible for general population screening, particularly if false positive tests in patients without prostate cancer or with cancers unlikely to be life-threatening result in needless anxiety and unnecessary procedures, some of them with hazards of their own..
The differences between high risk and general populations define the nature of criteria that screening tests must satisfy to be useful. This is particularly the case for cancers with low population prevalence. To illustrate the point, I will end these remarks with the hypothetical example of a cancer present in one person out of 100,000 apparently healthy individuals. Screening accuracy is typically expressed in terms of “sensitivity” and “specificity”, where sensitivity denotes the percentage of individuals with the disease who are identified by screening—i.e, they test “positive.“ Conversely, specificity denotes the percentage of individuals without the disease who are correctly classified as negative. In our example, let us assume a test has succeeded in achieving 99 percent sensitivity and 99 percent specificity.
These are enviable attributes, one might assume, and if applied to a high risk population, might thoroughly validate the use of the test. Applied to our hypothetical population of 100,000 low risk individuals, however, the test turns out to be less useful than one might intuit. How much less? The 99 percent sensitivity tells us that it would be 99 percent likely to detect the one cancer in that group—we can round that off to conclude we would find one true positive result. On the other hand, the 99 percent specificity signifies that 1 percent of a group of individuals without cancer will also test positive. In this case, it would be 1 percent of 99,999 individuals, or 999.99 false positives. Again, rounding would make it 1000 false positives for every one case of cancer detected. Those who are interested can calculate the levels of specificity that would normally be required to justify screening for conditions as rare as the one cited in this example. On the other hand, the same type of calculation should make clear why our hypothetical 99 percent specific test might prove valuable when the disease is present in as many as one out of every twenty individuals.
Frederick L. Moolten, M.D.
How much of the high cost and lack of results is due to incremental research, you know, the type that gets funded and is approved of by peer-reviewers, vs. unconventional breakthrough type work?
Does the NIH grant system reward ongoing research or does it reward research that changes medicine and creates cures?
Joe – That’s an important question, but nobody knows the answer. The NIH has generally attempted a balance, by utilizing both traditional grants (R01s) as well as other mechanisms designed to support more innovative research (e.g., R21 type grants). With the advent of the stimulus funding, additional support mechanisms for unconventional, “high risk, high payoff” projects have been implemented. I’ve had a chance to review some of these proposals, and my perception is that they will only marginally expedite our efforts to control cancer better, but I hope I’m wrong. In any case, I support these efforts.
In my view, research into cancer prevention, and greater utilization of prevention strategies already known to work, hold more promise than improved cancer therapy for reducing the impact of cancer over the next few decades. Prevention isn’t as glamorous as basic molecular biological studies, such as the work on telomerase that just won a Nobel Prize for Drs. Greider, Blackburn, and Szostak, but it probably deserves more attention than it currently receives.
For perspective on prevention vs therapy, consider that we still are unable to treat most viral infections effectively, but we are able to prevent the large majority of them by vaccination. One scourge, smallpox, has already been eradicated from the face of the earth by appropriate public health measures that included vaccination. Cancer is not equally amenable to a vaccine strategy, but we know enough about environmental exposures that contribute to its development to plan preventive strategies that could reduce its incidence dramatically. Smoking cessation efforts are only a start.
For perspective on prevention vs therapy, consider that we still are unable to treat most viral infections effectively, but we are able to prevent the large majority of them by vaccination.
Fred this got me thinking about chemotherapy. If the body can prevent viral illnesses through the immune response, how much is the immune response needed in fighting or preventing cancer. To put it another way, chemotherapy must almost destroy the immune response, so might chemotherapy also have a negative effect on the body’s ability to fight or prevent cancer growth?? I can see other modalities of treatment for existing cancers such as surgery or localized radiology, but how really helpful is radical chemotherapy, as used up to now, to the bodies ability to fight the cancer itself??
NG – Although some incipient cancers may be eliminated by the immune system because they are strongly immunogenic, cancers that successfully grow to the stage where they are clinically detectable tend to differ only slightly from normal cells, and therefore elicit only weak immune responses. As you surmise, chemotherapy will often abrogate those responses, but this disadvantage is offset by the ability of the drugs to kill large numbers of cancer cells. Alternation of chemotherapy with attempts to stimulate antitumor immune responses are being explored to exploit both mechanisms. To date, they have not yielded dramatic improvement in treatment results, but efforts to bolster these effects are continuing.
The ultimate tragedy is, and only time will tell, is that the course of oncology therapy has been driven not by compassion or true concern for the patient, rather, the perpetuation of a research culture that cannot conquer a disease, or for that matter, ever embark on that process for fear of putting themselves out of work.
Bert Berkson said it best: “Nothing will keep a man from understanding a new idea quite like his income depending on his not understanding it.”
I keep holding out hope that clinical level oncology will eventually shift from gatekeeper to integrative medicine, and with that shift will come a more imaginative approach to therapy models and treatment plans.
To beat down cancer mortality, oncologists need to target all the many cancers that make up a cancer – the dozens of different pathways that cells use to proliferate and spread.
That is the leading edge of research today, determining how this patient’s tumor cells work and hitting those pathways with multiple drugs, simultaneously or sequentially, each chosen because it targets one of those growth, replication and angiogenesis pathways.
The hope is to match tumor type to drug. We need to make the next leap, getting the right drug to the right patient.
Gregory – I’m not sure how to respond to your comments. I believe you’re absolutely right that we can improve cancer treatment by targeting multiple pathways, and that substantial current research is proceeding in that direction. Even so, these pathways are not unique to cancer cells, but rather altered in their level of expression in those cells. Targeting them is therefore likely to surmount only partially the challenge of finding a modality with sufficient cancer selectivity to eliminate the cancer without exposing the host to intolerable toxicity.
However, while I agree with your point about the appropriate direction of research, the suggestion in your first paragraph that progress is impeded by fear within the research culture that it will be put out of work is incorrect. It is inherently illogical, considering the enormous profitability that would ensue from finding one or more cancer cures (not to mention the Nobel prize dollars). Logic aside, I can state that it’s wrong because as a member of the culture, I know their motivations intimately; they include scientific curiosity, compassion, a wish to succeed, and other forces, but not the fear of unemployment. For more on motives, see – http://tpmcafe.talkingpointsmemo.com/talk/blogs/fredmoolten/2009/06/prescription-drug-costs-can-be-2.php.
Your second paragraph contains a misattribution. The statement, “It is difficult to get a man to understand something when his job depends on not understanding it” should be attributed to the novelist Upton Sinclair.
The link in my comment to Gregory may not work. Instead, try
The link in my comment to Gregory may not work. The following one seems to be intact –
Just wanted to weigh in to say that this is a very good thread–readers talking to each other, sharing information, asking each other questions.
Thanks to Fred for writing the post.
I urge layman (people like me who know little about cancer but have many questions about cancer reserach) to weigh in and ask him (and others) questions.
Fred. Then Upton Sinclair it is!
In regards to your response about research culture, perhaps it is the mindset of rewarding academic achievement and publication over all else. The aurora that organizations, government agencies, scientists, researchers and even practitioners working together, sharing information for the benefit of patients.
Each group has its own priorities and its own agenda. Moreover, the image of cooperation between these different groups only gives the illusion that reform isn’t needed. The present system exists to serve academic achievement and publication, but not to serve the best interests of people.
The demise of the “discoverer” type with its not so well organized risk-taking, in favor of the “investigator” culture, well organized, exhaustive analysis of trivial hypotheses, is a perfect example of thirty years of the “trial and error” mind-set that has occupied cancer research.
A dysfunctional culture that pushes tens of thousands of physicians and scientists toward the goal of finding the tiniest improvements in treatment rather than genuine breakthroughs, that rewards academic achievement and publication even though their proven activity has little to do with “curing” cancer.
Gregory – Both you and “Joe Says” before you ask legitimate questions about the relative role of incremental research advances vs risky projects with “breakthrough” potential. I don’t think anyone knows what the best balance should be, but let me give you my perspective as (1) and insider, and (2) a risk-taker throughout my research career, even as far back as a time when my NIH application was rejected as “science fiction”, but subequent results I achieved based on VA funding were incorporated into NIH clinical proposals accompanied by deafening promotional fanfare from the NIH public relations people.
The NIH has always striven for some balance, using the R21 grant mechanism and other formats to encourage innovative research. With the influx of stimulus money recently, additional programs have been established to encourage potential “paradigm shift” proposals. In addition, it may not be well known, but the DOD (Dept. of Defense) has been a robust supporter of cancer research from some years, and has included within its portfolio “idea awards” requiring no preliminary data but rather innovative concepts that deserve at least a brief trial to determine whether they merit further support.
Here’s the problem. I’ve reviewed many of these. Some are excellent, but at the end of the day, what remains is that there have not yet been “breakthroughs” in our ability to conceive approaches that circumvent the problem of selectivity – cancer cells and normal cells are very similar, differing mainly in quantitative levels of function, and thereby making it exceedingly difficult to devise a means to target the cancer cells without undue damage to the normal ones. Our adversary here is not the research culture, but nature, and she is a formidable adversary indeed. I do foresee progress, but breakthroughs are another matter. In another time and place, I might explain how I’ve conceived a strategy to overcome the selectivity barrier, but that strategy, in the literature for decades, is still waiting to develop into something practical.
To summarize, you won’t find me belittling the need for “discoverer” types, but it’s equally important to understand that intellect and imagination must still deal with the universe we inhabit rather than one more to our liking.
At the risk of belaboring the point I made earlier about the virtues of prevention, it temains true that we really can’t cure any viral illnesses (an easier challenge than cancer), but for an interval ranging from decades to centuries, we’ve known how to prevent them. Even the toughest, HIV, may be starting to yield to vaccine efforts. It’s been estimated that environmental variables might account for as much as 80 percent of the variation in cancer incidence worldwide, and so, as we strive to advance treatment, we should also work to apply preventive measures in ways that reduce cancer rates to those in low incidence environments.
Thank you for the indepth and informative post. There are those who do believe we’re holding back a cure for cancer, but this is not logical based on the fact that health care professionals as well as scientists and pharmaceutical executives all face the dangers of cancer and have lost love ones to cancer. Who has not been touched by cancer? There’s this idea out there that we’ve cured nearly everything….there are many diseases and conditions that have gone unexplained and uncured (not only cancer). We’re just fortunate that there have been cures and preventative methods in many areas.
Well the main thing is we are in an era where nothing is healthy anymore. the fertilizers and others things do help us providing things in bulks but a unnatural process is unnatural it do come with many plus n negative things. we have to adopt natural things if u want to stay away from cancer
Thank you very much for this detaşled review on cancer and cancer research. Having worked for around 10 years there is nothing much left for me to mention.
I have 2 hopes. The first one is that the pharma industry will change its habbits and invest more into cancer research. Pfizer only invested 5% of its budget into cancer research so far (http://www.americangenes.com/node/241).
The second is the near future impact of human genome sequencing. Cancer research will be another chapter in 5 years when İndividual genome sequencing is around $1000.
Thak you for your comment.
“There’s this idea out there that we’ve cured nearly everything….there are many diseases and conditions that have gone unexplained and uncured (not only cancer). We’re just fortunate that there have been cures and preventative methods in many areas.”
This is very true–and something that more Americans need to understand.