That is, if that even works. I first attempted this a week ago and although I was called by one of my doctors within a day with the results, I still have not received them myself. And this is a small hospital with not a lot of records processing to keep track of.

I think the area of medical records may also be one of the only contexts in which people still must use fax machines (that is, if they want to move things along a bit faster than the mail will provide). In any context, to release my own medical records to myself, I have to fill out a form, sign it, and either mail it or fax it. (Because I live in a rural area and do not live close to most of my health providers, I can’t just deliver it in person).

And if what I want is a scan, sent either to me or to a doctor, it must be sent on a physical CD.

Even if you have not experienced this yourself, you can probably imagine how difficult it is, when someone confers with multiple doctors, for each of those doctors to actually have a full record of that patient’s treatment. This is because making sure everyone gets everything becomes nearly a full time job. (Keep in mind that not only do the forms need to be sent, but follow-up phone calls as well to make sure they were received and acted upon.) And incomplete records create pretty good starting conditions for potential mistakes to be made.

And if mistakes are made in this context, who is at fault?

The current push for computerizing medical records (finally at least getting more emphasis) is both incredibly slow, and unfortunately, being done completely the wrong way. Because while hospitals are finally getting stuff on their internal computers, this does not solve the above problems: patient access to records, which is an essential requirement for many of us trying to wend our way through the medical wilderness, will still be just as difficult and bureaucratic as it ever was. And there is, of course, no need for it to be this way, given current technology.

Imagine now a world in which all test results, scans, and doctor’s notes are uploaded to a central database for each patient, accessible via the internet, with the patient having complete access and complete control over access. Patients could thus assign a username and password to anyone he or she wants, in order to see all the records immediately – or even have different levels of access, if you want the person only to see one relevant part of the record. (For example, insurance companies could only see what you allow them to see – the privacy and access halves of the equation both work for the patient.)

For the doctors who still rely on hand-written notes, well, they just need to join the 21st century, or at least hire someone to do it for them. This is not an outrageous expectation, given how computers already infiltrate every other aspect of our existence, including medically.

In this world, I wouldn’t always have to be FedExing CDs of scans all over the world; I could actually just email a username and password to the doctor in question, and be done. (There is, to be fair, at least one third-party service that provides medical record storage, but the patient would still be responsible for getting all the records there in the first place, and it’s unclear that there is any way to upload scan CDs.)

But the world we live in right now is one in which most patients don’t even have a clue what’s in their files, let alone have the know-how and/or energy to find out, because you can’t even just ask your doc’s receptionist for a copy of your own records as you leave.

And yet, here we are, finally acknowledging that patient records need to all be on the computer, but there is still a catch – I can’t even look at my own records without the filter of a doctor or a bureaucrat. Does anyone else find this ludicrous?

Why is it this way? It’s possible there is some component of foot-dragging. After all, as far as getting records on computer in the first place, there is an up-front cost, which is why most hospitals and doctors have to be ordered to do it through Obamacare.

But I think there is something more, which is that the medical community just can’t let go of their legacy of paternalism. I’m guessing there are doctors out there who hate the idea of their patients having easy access to their own records. I’m sure fear of lawsuits underlies some of this, which is why I agree with those who support real tort reform (as long as it still guarantees clear ways to censure doctors who make real, avoidable mistakes). But I doubt that is the only reason. I honestly think it never crossed the mind of anyone developing electronic records software to figure out a way to allow patient access to it. In fact, they probably spent a lot of time making it ultra-secure and as inaccessible as possible.

It’s tough being a full-time patient. We’ve all heard the calls to “take charge of your own health care” but if you haven’t permanently entered the Medical Industrial Complex yourself, or with a loved one, you don’t know the half of it, especially in an area such as oncology in which the “standard of care” delivered dutifully by doctors is pretty much guaranteed to have few long-term effects beyond a miserable death. Well, if the Complex can’t do better than this, then why make my life doubly hard by making me waste so much of my time left on earth filling out forms and placing endless phone calls to make sure the instructions on those forms have actually been carried out? Why?

While any oncologist is familiar with the problem of acquired resistance to previously effective chemo drugs, it seems that the field of clinical oncology as a whole has failed both to examine carefully the mechanisms for this or to explore possible methods to overcome or delay resistance (other than by the ultimately useless blunt instrument of switching drugs), in order to extend meaningful life in metastatic patients.

There are two important facets to this failure. The first, briefly, is cultural. Our society’s Cancer Machine has an odd, collective cognitive dissonance in which the idea of “curing” late-stage patients, understood rationally to be nearly impossible, exists alongside treatment techniques theoretically designed to cure, but which never have come close to this ideal. (This dovetails with the other cognitively dissonant dichotomy in which the continued propaganda of “cure” overlays the fear of cancer as inevitable death in early-stage patients.) So doctors, particularly specialists such as surgeons and radiologists treating one part of the body, often imply that the goal of a given treatment is cure, even while their own data show that cure is essentially never achieved by their treatments.

But the focus of the discussion here is the science of tumors:  their heterogeneity and ability to evolve, which oncologists again understand in the abstract, but generally fail to respond to, because they do not seem to understand evolutionary biology. This is not for lack of researchers encouraging the approach to tumors in these terms (Gerlinger and Swanton 2012; Greaves and Maley 2012; Marusyk et al 2012). And it’s not doctors’ fault that medical schools that their training does not include the basic principles of evolution and population biology (although in the case of oncologists at least, it clearly should).

Here is an oversimplification of the essential problem (for more nuances and explanations showing how much more complicated it actually is, see the references below): malignant tumors are heterogeneous populations of cells which actually compete with each other for resources. Tumor cells are mutating all the time, via several mechanisms such as drift and varying selection pressures, which include exposure to different chemical microenvironments, oxygen levels, etc. (which can even be different in different parts of the same tumor, not just between different tumors).

Although there are many selective pressures driving tumor evolution that we have no known control over, the use of chemotherapy is a big one that we do. That is, our misuse of chemotherapy for cancer treatment is similar to the misuse of pesticides in agriculture. In the latter case we create resistant pests by imposing a strong selection pressure on a heterogeneous population of insects, most of which are susceptible to the poison but a few of which by chance are resistant. Once all the susceptible individuals are destroyed, the resistant ones have no competition and can take over, and the pesticide is now useless.

In a way, chemotherapy is even more insidious because of the evidence that chemo itself increases the mutation rate of cancer cells, which is abnormally high. The implications of this should be sobering: misuse of chemo drugs can actually hasten the evolution of one’s tumors to a more aggressive form (although it has been argued that the changes occur more on a phenotypic than genotypic level [Germain, 2012]). In any case, the end result is that the current paradigm of chemotherapy treatment, the delivery of “highest tolerated dose” (HTD), while intended to circumvent resistance by the use of overwhelming force (as the use of high levels of antibiotics for ten days to two weeks wipes out an infection so that it will not return), in reality almost never works, mainly because the levels of drugs truly needed to wipe out all populations of cancer cells would be much too high for the patient to survive. So, we continue to deliver drugs at a sublethal level which promotes resistance, and probably shortens lifespan much more often than currently acknowledged. The effects of even those drugs identified in trials as providing “complete response” for some patients are nearly always only temporary, and extend life in many cases by less than a year, by which time resistant (untreatable) tumors come roaring back (the dreaded “progressive disease”), ultimately killing the patient for whom there are no more treatment options.

There is already a fairly rich literature on the mechanisms of the evolution of resistance in tumors, although ideas to overcome it are still largely theoretical and remain untested. One study, however, provides not only a mathematical model for how resistance could possibly be overcome, but tests the model successfully in mice in a laboratory setting, with a quite intriguing result. Gatenby et al. (2009) developed a mathematical model that showed that it should be possible to maintain a low tumor burden with a single effective chemo drug, by continually adjusting the rate and levels (and thus the selective pressure on the tumor cell population) at which the drug is delivered.  The key to the new paradigm is that it does not aim for a cure, but rather management of tumors at a non-life-threatening level. To shift to such a paradigm would not be unreasonable scientifically, since cure of metastatic disease via conventional treatments is essentially nonexistent (no matter how much we pretend it is not). The authors find that lifespan can be extended indefinitely by using this protocol that is individualized to how the patient’s tumors are responding to the drug.

The important assumption of the model is that resistance implies a metabolic cost, which allows susceptible cells to outcompete resistant cells in the absence of the selective chemo agent. While this may not necessarily be true for all forms of resistance (Germain, 2012) there is a lot of evidence that it is much of the time (including from Gatenby et al.’s subsequent laboratory experiment). Given that assumption, chemotherapy treatments are adjusted downward when there is a strong response from a tumor — i.e., when the tumor shrinks quickly as the majority population of susceptible cells is killed. This allows susceptible cells to remain and continue to compete with resistant cells, keeping them suppressed to a relatively small population size.

What strengthens Gatenby et al.’s paper is that they followed up their mathematical model with an in vivo mouse study, testing the model’s predictions. Human tumors implanted in mice are convenient for this purpose because they can be measured easily (see picture). In the authors’ treatment group, tumors were measured and the chemotherapy dose adjusted, while for comparison a group of mice was administered the typical static dose of the same chemo drug, regardless of tumor size. Not only was a low tumor burden maintained in the dynamically treated mice (which resulted in a greatly increased lifespan), but the amount of the drug required to maintain the tumors at a low level dropped to 17% of the normally administered levels of the drug, suggesting that much lower toxicities are needed under this protocol. In other words, it’s a win-win: longer life at a higher quality. The only thing that is being given up in return is the misguided hope for a cure that does not exist anyway.

The time when cancer for many more people can be managed as a chronic disease is thus possible with the tools we already have. This pre-clinical result needs to be followed up with human data, in order to establish how to make such a protocol work in a situation where the tumors cannot be so easily measured with a pair of calipers. Refining this will clearly take time, given all the permutations of cancers and drugs, but now is the time to start, and no doubt there are many stage IV patients who would be willing to try something different from the hopeless alternative. What is clear is that for all the reasons stated here and in the last post, standard chemotherapy regimens for metastatic patients are clearly not only a waste of time, but worse, are killing a lot of us more quickly and miserably than if we just died of our cancer.

There’s no need to throw out the chemo baby with the bathwater, as shown by this paper; we just need to be a lot more intelligent with its use, and that will start by cancer doctors listening to what evolutionary biologists have to offer in their understanding of tumor biology.

References

Gatenby RA, Silva AS, Gillies RJ, Frieden BR, 2009. Adaptive therapy. Cancer Res. 69(11):4894-903. doi: 10.1158/0008-5472.CAN-08-3658.

Gerlinger M, Swanton C 2012. How Darwinian models inform therapeutic failure initiated by clonal heterogeneity in cancer medicine. Br J Cancer. 103(8):1139-43. doi: 10.1038/sj.bjc.6605912. Epub 2010 Sep 28.

Germain, P-L., 2012. Cancer cells and adaptive explanations. Biology & Philosophy 27(6):785-810.

Greaves M, Maley CC 2012. Clonal evolution in cancer. Nature. 481(7381):306-13. doi: 10.1038/nature10762.

Marusyk A, Almendro V, Polyak K 2012. Intra-tumour heterogeneity: a looking glass for cancer? Nat Rev Cancer. 12(5):323-34. doi: 10.1038/nrc3261.

Why is this? There are three main strikes against chemotherapy as a cancer treatment.

1. Chemotherapy kills immune cells
First, most people know that chemotherapy drugs suppress the immune system. In fact, two of the most common chemotherapy drugs, cyclophosphamide (Cytoxan) and methotrexate, are used as immunosuppressants in people with autoimmune diseases (Zitvogel et al., 2008). A primary reason for this is that chemo drugs are designed to target proliferating cells, because of the general but crude idea that tumor cells are dividing much more at any given time than normal cells. The immune system depends on rapid proliferation to be effective, so we are immediately undermining it with chemotherapy. (Sometimes this is done to the point at which the compromised immune system is what actually kills a cancer patient, rather than the cancer itself.)

It isn’t just the primary chemo drugs themselves that suppress the immune system. The common use of drugs called glucocorticoids (e.g. prednisone) as part of chemotherapeutical regimes is a typical example of the fairly indiscriminate use of drugs without consideration of all their potential effects. Prednisone has been used in combination with other drugs to treat lymphoma, leukemia, and breast cancer. The added benefit appears essentially to be in reduction of side effects, so that patients can be treated with a higher dose of poison. Hence, there is sometimes a better tumor reduction associated with its use — but only temporarily (Kufe et al., 2003).

The problem with using prednisone is that this class of drugs has a strong immunosuppressive effect — something anyone who has taken them for a severe allergy outbreak can already tell you. So, in the case of both standard chemo drugs and glucocorticoids, to obtain a short-term gain in tumor suppression, a drug is administered which greatly reduces the body’s ability to achieve long term control of cancer through a healthy immune system (Zitvogel et al., 2008).

2. The way chemotherapy kills cells keeps them invisible to the immune system
Second, a huge reason why chemotherapy does not, most of the time, help stimulate the immune system is because of the way in which it kills cells. There are two main ways that cells in the body experience death. The first is called apoptosis, or programmed cell death, where the cell essentially commits suicide by winding down in a predictable manner. The second is called necrosis, and this can be thought of as more of a violent death against the cell’s will. One might assume that poisoning through chemotherapy would result in necrosis, but as it turns out, the majority of chemo drugs disrupt a cell process during division that causes a cascade resulting in apoptosis.

The reason this is important is due to the way our immune systems work. It should make sense that we do not want our disease-attacking killer T cells on the scene every time a cell dies, because cell death is a normal part of an organism’s life. Cells undergoing apoptosis essentially just call for the cleaning crew: macrophages, or white blood cells that engulf and remove dead cell parts. This is why apoptosis is considered a non-immunogenic process, or one that does not stimulate the immune system to attack. Necrosis, however, stimulates a quick immune response.

Necrosis can be caused by a sudden injury, such as a cut. In this case part of the immune response is inflammation, which helps the healing process, and alerts the immune system against the possibility of invading bacteria. Necrosis can occur internally as well. For instance, when a virus injects itself in our cells, it multiplies and the many virus particles lyse, or break up, the cell, so that they can go infect other cells. The uncontrolled release of cell proteins out of the dying cell alerts the immune system to a potential problem, and kicks the T cells into high gear, seeking out infected cells and killing them before the virus can multiply and spread.

T cells attack tumors as well. Normally, immune cell scouts, known as “antigen presenting cells” (including dendritic cells, which are more commonly being used in cancer immunotherapy), are circulating around all the time, ready to activate a process which alerts the killer T cells to abnormal tumor cells. This is known as “immunosurveillance” and is the reason we don’t all have invasive cancer all the time: although cancer cells are continually forming in our bodies, our immune system usually recognizes them and kills them without us even knowing that they were there.

It is unclear why some cancer cells escape this process and are allowed to form tumors; probably there are different reasons in different people. Unfortunately, once there are invasive tumors, cancer cells end up with lots of mechanisms for hiding from the immune system. So the ideal cancer treatment is not only one that helps strengthen a patient’s immune system, but one that also takes aim at the immune defenses thrown up by tumors. Unfortunately, by the very mechanism by which it causes cell death, chemotherapy usually does nothing to help our immune systems find and destroy cancer cells.

3. Systemic chemo is not likely any more effective than targeted chemo
The third main reason why chemotherapy treatment is making life worse for cancer patients is mainly due to how we deliver it, which is systemically. This means that most of the time, chemo drugs are not injected into tumors to kill them; they are delivered directly into the blood stream, which is why people on chemo get sick all over.

This is done because of the still-mistaken idea that chemo can cure cancer by killing all the cancer cells in your body (including those forming tiny tumors that we can’t see, and those just circulating around your lymphatic system or blood stream). Except perhaps in the occasional case of dose-dense adjuvant chemotherapy (which is designed to hit the cancer with as many poisons as possible as once without killing the host), even when chemotherapy appears to cure cancer, it almost certainly isn’t the chemotherapy that did it, but rather the immune system which somehow got stimulated along the way. This has been borne out by studies in which the tiny percentage of mice that were cured with chemo later had tumor cells injected back into them: even though tumors easily established in these mice before treatment, they would not grow back in the cured mice (Lake and Robinson, 2005).

When an immune response is properly provoked, it happens itself on a systemic level. This means that when necrosis occurs in one tumor, if this succeeds in recruiting killer T cells, those cells will attack all tumor cells in the body, not just those in the specifically injured tumor (Tanaka et al., 2002 [yes, this effect has been known for at least ten years]).

All of this should make it clear that if one’s goal is to cure cancer, a systemic dose of chemotherapy is not only completely unnecessary, but ineffective and in many cases more liable to kill sooner than the cancer itself.

Naturally, there are some gray areas here, some of which suggest that it’s not quite time to toss all chemotherapy entirely, but rather, try to mitigate the immunosuppressive effects somewhat by adjusting dosage levels. In fact, there is a lot of evidence that when chemo works to induce an immune response, it does it through the mechanism of secondary necrosis. This can happen if so much apoptosis occurs at once (due to sensitivity to a chemo drug) that it overwhelms the body’s macrophages (the cleaning crew) which can’t get to all the cells before they start to fall apart from decay (Lake and Robinson, 2005). But this doesn’t change the fact that primary necrosis is much easier to achieve (for example through physical damage to tumors such as with local heat treatments) than getting there by hoping to induce apoptosis on a large scale through chemotherapy (which won’t work for most people on most drugs).

This all begs the question, of course: if chemotherapy is no good, why does it shrink tumors and appear to extend the lives of at least some people? This is the crux of the matter, because if chemo never did anything more than induce immune-mediated remission in 5% of cancer patients, these dozens of drugs never would have been approved in the first place. Unfortunately, it works just often enough in the short term to have gotten these drugs approved, and to keep the clinical oncological community in their treatment boxes, unwilling to face head on the fact that chemo is nearly inevitably useless over the long term, because tumors will nearly always grow back, stronger than before. Why chemo works this way will be the topic of my next article.

References

Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003. Corticosteroids in the Treatment of Neoplasms. Available from: http://www.ncbi.nlm.nih.gov/books/NBK13383/

Lake RA, Robinson BW, 2005. Immunotherapy and chemotherapy–a practical partnership. Nat Rev Cancer. 5(5):397-405.

Tanaka F, Yamaguchi H, Ohta M, Mashino K, Sonoda H, Sadanaga N, Inoue H, Mori M, 2002. Intratumoral injection of dendritic cells after treatment of anticancer drugs induces tumor-specific antitumor effect in vivo. Int J Cancer. 101(3):265-9.

Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G., 2008. Immunological aspects of cancer chemotherapy. Nat Rev Immunol. 8(1):59-73.

The first thing you might look at is what is already known about what actually has cured cancer in the past (focusing primarily on metastatic (advanced, or late-stage) patients, who are pretty much presumed as a group to be inevitably killed by their cancer within months to at best, a few years). You would discover that before anyone had even heard of chemotherapy, some people were cured of late-stage cancer after they got sick from infectious diseases. You might be surprised when digging through current literature referring to cured patients that the general consensus is that all permanent cancer remissions, whether spontaneous or on the heels of chemotherapy, are brought about by an immune system response.

If you dig through this literature some more, you realize that it has been established for decades that whatever its initial cause, invasive cancer clearly represents an immune system failure. You learn that everyone has cancer cells forming all of the time, but that our immune systems are generally pretty good at finding these cells and destroying them before they can form invasive tumors (which are what ultimately lead to cancer-caused sickness and death, via organ failure).

So you might then ask why in some people (seemingly more all the time), the immune system has failed. This is a complicated question, and you realize fairly on in your research that it probably fails for different reasons in different people, because immune responses are incredibly complex and involve lots of steps, any of which could be the weak point. But at least it’s clear that in general, an important strategy to keep cancer from killing people is to try to get their immune systems back to where they are capable of recognizing cancer cells as dangerous and destroy them. It’s especially clear that with billions of dollars being spent on cancer research and education, and a lot of the groundwork having already been laid over decades, research focusing on clinical applications of cancer immunology promises to produce one of the biggest bangs for the buck (perhaps second only to research and education coupled with legislative action that focuses on how cancer can be best prevented in the first place).

But instead, the following illustrates our society’s current approach to cancer:

You break your right leg. You go to a doctor, who enthusiastically tells you that research has shown that putting a cast on the left arm heals 25% of patients with Broken Limb Syndrome, so he puts a cast on your left arm.

You might then ask him, “But how do I find out if I am in that 25%?” Your doctor responds, “There’s actually no way to know. We could also try a cast on your right arm, but we can’t do both because it would be too debilitating for you, and there would still be no guarantee that you would get better. Since there’s no way to know if either of these will work, I’ll just let you choose: would you like me to put a cast on your right arm, or your left arm?”

Baffled by being given the task by a doctor of arbitrarily choosing your treatment, you can’t help persisting: “But can’t we figure out ahead of time if either one of these will work, so that I don’t have to be stuck in a cast for nothing?” Your doctor assures you, “Well, some time in the near future, we expect that treatment of broken limbs will become much more individualized, but that’s just not available now. The good news is that we’ve made a lot of recent progress in treating Broken Limb Syndrome, and we find that we are getting much better results these days. For example, it used to be that we’d just cut off your left arm in cases such as yours, but now we know from lots of scientific data that that’s not usually necessary. So don’t worry; wearing a cast for six weeks may be uncomfortable and have somewhat of an impact on your life, but it is generally very well-tolerated for someone of your age and general health.”

This analogy is actually a big understatement, of course. After all, cancer treatments themselves can easily turn deadly, while casts generally don’t. But the reason the analogy seems so silly is that it’s been obvious to people for millennia how to heal a broken leg, while it’s also obviously not at all a trivial problem to figure out what exactly the problem is when someone has cancer.

So when we did not yet have the tools to figure out complex physiological mechanisms, it did actually make some sense to attack tumors themselves; after all, they are what kills us, and we can see them, so surely removing them one way or another was the way to go. The problem is that although we now have those tools, and researchers have used them to make enormous progress in our scientific understanding of cancer, as far as the clinical setting is concerned, those tools and knowledge don’t exist.

Everyone knows from personal observation that physically or chemically attacking tumors only takes you so far, but we’re completely stuck in that paradigm. Sometimes it seems as though the only two things one can say for sure about advanced cancer treatment is that mortality rates have barely budged in decades, and that the entire oncological community appears to be in utter denial about it. (Early cancer mortality has dropped, but much of that drop may be attributable to newer scanning technology that allows us to see many more early cancers than we could before it existed.)

What has happened over several decades is that we have continued down the cut, burn, and poison road into a cul-de-sac, and we have not yet figured out how to turn around and get on the right road, even though there is a new road just waiting for us to drive down it in the right direction. The oncological community barely acknowledges that we’re in a cul-de-sac at all.

Okay, that’s enough metaphors. To see the magnitude of this problem, let’s go back our original question, and ask, how does systemic chemotherapy, still the dominant treatment continuously making millions of generally healthy people extremely sick, fit into current knowledge that what cures all cancers is ultimately, the immune system?

The short answer, unfortunately, is that chemo is pretty much the worst possible “treatment” you can give someone if your ultimate goal is to cure their cancer. The long answer includes several unassailable reasons as to why this is true, and these will be explored in detail in the next post.

The question of why the cancer treatment paradigm is so inertial, seemingly much more so than with other medical treatments, has its own complicated answers, which Bioblog has begun to address (browse the “Cancer” category), and which will occupy a lot more space in the future.

Source: MedicalInfrard via Wikimedia Commons

Even with all we know already about cancer over-treatment, just having this discussion remains controversial. It was fully three years ago that the USPSTF updated its official guidelines to suggest that having a mammogram should be a point of discussion between a woman and her doctor based on individual risk factors and family history, rather than a blanket recommendation for routine screening that has been the dogma for years. They concluded, based on a review of current research, that screening has not had an overall benefit for women under 50, and those over 50 need only be screened every other year. This is because the panel recognized that there are not only benefits to routine mammography; there are costs too that can be serious, and potentially outweigh the benefits for a given individual.

The panel’s 2009 recommendations were greeted by a shrill, hyperbolic reaction by the American College of Radiologists who countered with an aggressive campaign to undermine them, without any qualification about their strong financial interest in continuing routine mammograms. Predictably, they have responded to the latest finding by Bleyer and Welch (2012) similarly:

Debra L. Monticciolo, a physician who chairs the American College of Radiology’s Quality and Safety Commission, questioned many of the study’s methods, including the data used to account for fluctuations in the underlying incidence of breast cancer due to factors like the use of hormones.

“It stuns me that this got through peer review,” said Monticciolo.

She added that as a physician, she found it hard to believe that such a large share of screenings produce false positives. If that were the case, there would be countless tales of miraculous recoveries by women who refuse traditional treatment after being diagnosed with early-stage breast cancer.

Yes, the response by a spokeswoman for ACR to a data-based study is that she “found it hard to believe” and that it “stuns” her that it got through peer review. Now, Bioblog sympathizes with her low assessment of peer review of medical papers, but ironically there never seems to be an equivalent outcry when a questionable paper recommends a new drug or treatment or scan that will make someone a lot of money. This paper, on the other hand, could result in industry losing a lot of money, and so this data-free objection by an industry group just isn’t credible.

And her claim about the lack “countless tales of miraculous recoveries” is just bizarre. How many women do we personally know who got a positive cancer diagnosis from a mammogram and chose to do nothing? How many papers have you seen lately comparing the outcomes of women with early stage breast cancer who were treated vs. those who were untreated?

It’s hard to even imagine the thinking of someone who is apparently immersed in cancer culture, but imagines that we are currently conducting some grand (yet undocumented) experiment in which “countless” women are choosing non-treatment of their diagnosed cancers. In fact, those of us who have unfortunately entered the cancer machine as patients know all too well that anyone who even considers non-treatment as an option has to push back against incredible pressures from family, friends, and medical staff to make her case, and only the most stubborn have a chance to prevail in this environment (see previous articles on the cancer culture and the pressures to undergo hellish chemotherapy, even in settings in which it has not even been shown to provide any benefit).

This physician speaking for radiologists across the country does not sound like she knows anything about science, and that she herself makes medical decisions based on anecdote, rather than data, which is extremely disturbing if true.

But here’s the most amazing thing about this new article, which after all (Bioblog readers at least will recognize) is not a new, earth-shattering result. Nobody responding to the study (including the American Cancer Society, which is supposed to be an advocate for patients, but apparently could muster no response other than that the study “must be viewed with caution”) has taken the most obvious point away from it, which is that our ability to scan and find tiny incipient cancers has gotten too far out ahead of our ability to know what to do with these cancers.

Bioblog is a big supporter of H.G. Welch’s previous work in this area, which include the recommended book Should I Be Tested for Cancer?: Maybe Not and Here’s Why and a newer more general treatise, Overdiagnosed: Making People Sick in the Pursuit of Health.

Welch has thus been slowly raising awareness about the problems of overscreening for a decade, but he (and the people now commenting on his work in the mainstream media) should not be stopping there.

Rather than simply encouraging people to think more clearly about the pros and cons of screening, we should be working furiously to change the balance of that equation. In short, routine screening is probably not going to be reduced significantly, and indeed if we take a long view, that should not be the goal, because we know that for at least a small subset of people, screening has indeed been effective in preventing more serious disease — by Bleyer and Welch’s calculation, this number is 8 out of 122 women screened via mammography, or 6.6 percent of those screened. One thing presumably we can all agree with is that we don’t want to see those 6.6 percent end up as collateral damage in the quest to save 93.4 percent of women from useless suffering from overtreatment.

The real root of the problem, therefore, is not overscreening per se; it is screening without having in place an appropriate treatment, or non-treatment, plan for those who are diagnosed with early-stage cancer. While Welch continues to mention in passing that we don’t know yet which early-stage cancers will progress, he doesn’t pursue that line of thought with calls for the necessary research to actually figure it out.

We have incredible tools now available in molecular biology, biochemistry, and physiological research. We have had computers for decades that can conduct complex multivariate analyses. The problem is that despite the billions spent on the “war on cancer” we have put negligible resources into the two main areas of research which promise the greatest benefit: more sophisticated biopsies to determine with precision who needs to be treated and how; and effective alternatives to toxic chemotherapy and radiation treatments which probably kill almost as many people as cancer itself.

The biggest bang for our buck is not the next chemo drug which statistically adds two months to a person’s life; and yet that’s what the research money is being spent on, because most of the research money comes from pharmaceutical companies. Pumping a lot more funding into sophisticated pathology should be a no-brainer for the feds, because in the end they promise to save a lot of money (not to mention suffering) by eliminating over-treatment. We have treasure troves of data coming in every single day in the thousands of tumors that people are having biopsied and surgically removed, and which are going right into the biowaste cans in hospitals to be incinerated shortly after.

We’ve all heard that a definition of insanity is doing the same thing over and over and expecting a different result. In that respect, the world of cancer screening and treatment is absolutely certifiable. It’s time to start making real progress, not keep repeating the same arguments about why one failing strategy is better than an unlikely, but bleak alternative.

Reference

Bleyer A, Welch HG., 2012. Effect of three decades of screening mammography on breast-cancer incidence. N Engl J Med. 22;367(21):1998-2005. doi: 10.1056/NEJMoa1206809.

The article is centered around the following questions:

Can patients in the throes of getting this terrifying news really make an informed choice about whether they want the test? Are they able to understand at such a fraught time that, for now at least, there is nothing that can save them if they get the bad prognosis?

Of course these are not necessarily trivial questions, and are certainly worth discussing.  But the question that was not asked speaks to our society’s collective tunnel vision about cancer:  why aren’t we using genetic data to inform patients whose cancer can be treated?

Research on this topic has been unfortunately spotty, for which we can thank the FDA.  Trials looking for new ways to poison cancer patients are a dime a dozen these days, and the FDA routinely approves drugs which provides benefits on the order of a two-month extension of life in cancer patients.  (This is not an exaggeration; after writing that sentence, the first link I clicked at random on a list of recent drug approvals was a new one called Inlyta from Pfizer, which improved median progression-free survival versus a previously approved drug by exactly two months.)

Here’s what most people don’t understand about clinical trials, because most people (including it seems, most doctors actually running clinical trials and on FDA panels) don’t understand probabilities and statistics:  In a clinical trial, drug companies look for an end result in a heterogenous group of people who all share some easily defined characteristics.  For example, they might all have late-stage breast cancer and have tried several different chemotherapy treatments previously that did not work.  Then, they test the new drug on a large number of patients (723 in the study above — yes, that is a lot, if you are trying to show a clear and clinically significant difference between treatment groups.)  Then, they measure the time it takes for those people to die.  If their (usually most forgiving) statistical test shows a statistical difference in the groups, usually they end up with FDA approval, and doctors very quickly add the drug to their list of treatments.

What’s the matter with this protocol?  Well, a lot.  First, it is fairly easy to magnify a very slight difference in effects to a large one by just using a larger sample size.  What’s funny is that most people going through basics statistics courses are told that the bigger the sample size, the better.  But they don’t understand the context of that admonition.  All it means is that you are more likely to find a statistical difference in your treatment groups with a larger sample size.  It does not speak at all to the relevance of that statistical difference.  As explained in the link above, the bigger the sample size you need to find a difference, the more meaningless that difference is.  And as it turns out, there is no standard in the medical literature for defining the relationship between statistical significance, and biological (or clinical) significance.  Put most succinctly, you make the most money if you assume a standard 1:1 correspondence of these two, an assumption which clearly has no clear evidence to support it.

But the most egregious part of these studies is that one can generally classify all the participants into one of three groups based on their response to a drug.  A drug either worked really well, sort of worked, or did not work at all.  This is then translated to the general “median” response data on which approval is based.  The dirty FDA/pharmaceutical company secret is that there is absolutely no requirement in these studies even to attempt to figure out why a given person was in a given group.  What that means for you, as a cancer patient who is an individual person, not a probability, is that you have no idea if a given drug will work for you.  This might not be so bad if even one or two of the following were true:  the drug is cheap, side-effects are negligible, or it works for, say, 80 or 90 percent of patients.  Unfortunately, when it comes to all the dozens of chemo drugs out there, pretty much none of these are true.

The general misunderstanding of probability and statistics by both laypeople and doctors fuels this problem.  When pressed, an oncologist will probably throw out a probability that a given drug will work for you.  But the truth is that either it will work or it won’t; individuals are individuals, while probabilities deal only with populations.  The nearly criminal part of this is that we should be putting all kinds of resources into looking for characteristics not only to determine prognosis in general, but also in drug responders vs. nonresponders. This is the obvious angle that the NY Times article should have taken.  Instead of couching this information, fairly easily obtained for ocular melanoma, as some sort of ethical or moral issue, the writer of this piece should be shouting from the rooftops that the molecular tools now available, demonstrated by this particular case, should obligate that similar information be obtained for all types of cancers.  Characterization of cancers not only for prognosis, as in this case, but to evaluate the most effective forms of treatment, could easily have been a standard part of the biopsy process by now.

Think I’m exaggerating?  Then look at this paper from 2006 about one of the most common cancer treatments out there and get back to me.  In English, what it says is that the researchers’ set of 30 molecular markers predicts sensitivity to the chemo drugs tested (the well known spirit-killers paclitaxel and doxorubicin) at a 92% level.  And yet, if you go to the doctor today, in 2012, to decide on your cancer treatment, your oncologist will almost certainly never offer you a test to tell if the drug s/he wants to give you will actually work.  It’s truly astounding.

Why is this?  Part of the problem is that the American Society of Clinical Oncology continues to issue reports that do not recommend the use of chemotherapy sensitivity assays for clinical use, mainly because supportive studies in the literature that meet their standards are few and far between.  The problem is likely a combination of their standards being too narrow, and not enough studies being done.  (But they are not really that hard to find.  Bioblog reviewed some research two and a half years ago on doxorubicin [Adriamycin] that established clear markers for its effectiveness, and yet the author was subjected to that drug 18 months later without being offered any way to predict whether or not it would work; it did not.)

What is clear, however, is that it is simply not in the financial interests of those running drug trials to gather the added data necessary to ask the question of why the drug works for some but not for others.  That is not to say that those running drug companies are evil people who are withholding information that would negatively impact their bottom line, but rather that given the lack of financial incentive, it might not even occur to most of them to do it, since the FDA doesn’t make them.

Of course, that’s the rub.  Why doesn’t the FDA make them?  There are probably multiple complex reasons, but none of them should trump the bare economic fact that the government could save itself a ton of money (not to mention years of suffering by American citizens) if they did.  This suggests serious structural deficiencies in how the FDA operates, which probably include undue influence over their policy by moneyed interests.

As it turns out though, chemosensitivity tests, such as offered by this company, are available despite the ASCO’s reports; it is simply incumbent upon the savvy patient to find out about them and make sure they happen.  If you are concerned that there must not be enough evidence that these tests can work, there is a publication list you can peruse.  But I will draw one in particular to your attention: Bosserman LD, Rajurkar SP, Rogers K, Davidson DC, Chernick M, Hallquist A, Malouf D, Presant CA, 2012. Correlation of drug-induced apoptosis assay results with oncologist treatment decisions and patient response and survival. Cancer. Oct 1;118(19):4877-83. doi: 10.1002/cncr.27444. Epub 2012 Feb 21.

The authors found positive results — that is, higher treatment success rates — with patients who used a particular chemosensitivity assay (the MiCK assay provided by the above company) to guide their treatment.  Their results are particularly striking because they used a reasonable sample size, meaning dozens rather than hundreds or thousands of patients, which had all different types of cancer, and a statistical difference in survival and relapse-free intervals was found.  That’s not really so surprising, because if you have a way to determine which of several drugs work best for you, and you take that advice, you are generally going to do better.  But one part of the discussion in particular leapt out at me:

In 1 breast cancer patient whose results were important to note, the patient had received 8 prior lines of chemotherapy before a MiCK assay was performed. The physician had recommended hospice based on early pro- gression on the last 2 lines of therapy and declining per- formance status. The patient and her husband initially had declined hospice because she had done well years earlier and they wanted to keep fighting. After the assay was performed, results demonstrated a low amount of apoptosis (0-1.5 KU) from 4 different drugs she had not previously received. The physician discussed these results with the patient and her family, which indicated only a low chance of response based on the MiCK assay results, and the likely associated toxicity with ineffective therapy. With this additional knowledge, the patient elected to receive hospice care and stated that her decision was largely based on the low MiCK assay results. The MiCK assay may therefore be able to reduce inappropriate use of chemotherapy at the end of life and increase use of hospice services.

It is fortunate that this anecdote was included in the paper because it highlights one of the choices that every patient has but that few actually consider: declining further treatment, particularly after multiple attempts at treatment have failed. As patients we are constantly pressured to undergo brutal treatments based on absolutely no scientific evidence, but rather on a slim ray of hope, because they are considered the only remaining option. (It is ironic that the political term “death panels” is used to apply to fanciful instances in which life-saving treatment is denied by faceless bureaucrats; rather, the true death panels are those at the FDA which approve treatments that for a given individual, have a probability approaching 1 for pain, suffering and deterioration of general health, along with a completely unknown probability of effectiveness.)

So it’s high time that cancer patients were provided with the information that we need if we want treatment that will actually help us, instead of martyr us.  It’s a win-win-win for patients, insurance companies/Medicare, and oncologists (who have to watch their patients suffering every day).  The only losers are the pharmaceutical companies, but if their goal is really to give people better living through chemistry, as they profess, they should be happy to embrace a sharper definition of their client base than they currently do.

But the only way this will happen is if we — the patients and our families — start asking our oncologists to tell us if the treatment they just prescribed will work.  If the answer is “we can’t know for sure,” we should ask them why they can’t tell us that.  And we should not accept the response that there are no alternatives to us rolling the dice while we lose all our hair and puke our guts out for days, because there are.

There are several major differences between lifestyles and policy shaped by government in Europe and those in the U.S.; all together they spell out that Europe is on a much more sustainable path with regard to resource use and health than the U.S. Europe is in a very different place from the U.S. in terms of transportation, food distribution and waste, and health (especially obesity). Europe’s solutions to these problems are much more sustainable over the long term.

For example, public transportation is well known to be much more comprehensive in European cities than American cities of equivalent populations, and this probably has a lot to do with population density. For comparison, here are the population densities in all cities with between 1 and 2 million people.

The obvious American outlier is Philadelphia; it is surely no accident that it is the oldest city on the list, founded two hundred years before industrialization and cheap oil. (Without Philadelphia, the American average density is 1,291.)

It is impossible to serve a large portion of the public with public transportation at such low densities. Thus, Americans have much lower access to public transportation, increasing our dependency on cars. Obviously one reason for this is that the U.S. simply has more land to use; Europe has higher population density because it has a much smaller area. In addition, most European cities were built before industrialization, and thus were not designed to be dependent on cars and cheap oil.

But current government policy continues to support this trend. For decades, gasoline has been two to four times as expensive in Europe, due to taxes. This encourages use of other modes of transportation than by private automobile (and helps to fund them). European cities also have superior bike-path systems; they are crowded with bikes as a result, and the benefit is twofold, as many more Europeans save energy and are in better physical shape by using bikes as their primary transportation mode. In fact, it is standard policy in German cities for employers to offer employees either a parking space or fully funded public transportation. Many choose the latter.

As Europe has progressed toward government policies which discourage the most wasteful vehicle use, the U.S. has done exactly the opposite. Americans howl with outrage when gasoline gets over $3 per gallon, while it costs as much as $10 per gallon in Europe (e.g in Norway, right now — note prices in euros/liter; the average here translates to about $8 per gallon). But if we had the will to implement it, government price control would have an effect on Americans too; at the $4 threshold, which we first saw in the last year of Bush’s presidency, Americans began to drive a lot less, even without a good public transportation system. Not only would price controls keeping U.S. gas at a minimum of $4 per gallon save fuel and make us healthier (reducing those easily walkable car trips that Americans routinely take without a second thought), but it is argued that greater stability in gas prices is better for national security and business planning, and thus would help the economy as well.

Oil is a finite resource, being consumed at exponentially greater rates now that China and India are taking their piece of the pie, and Europe is in a much better position than the U.S. to transition away from it.

Another striking difference between American and European lifestyles is in how we produce and store food. The amount of food wasted in America, even as Americans (let alone the multitudes in other countries) go hungry, is nothing short of appalling. And it is wasted for exceedingly idiotic reasons.

First, fresh produce is often a money loser for supermarkets because the profit margins are lower than for packaged, processed foods, and because most throw fruit and vegetables out at the first sign of a blemish. Of course, the USDA grading standards ensures that produce that is found to have the slightest amount of damage before it leaves the farm is thrown out before it even makes it as far as the supermarket.

(As an aside, it is instructive to do a spot perusal of the pdf documents at the above USDA site listing standards for produce. After checking several, and doing searches on the words “appearance”, “damage”, “taste”, and “nutrition”, I found dozens of instances of the first two, and exactly zero of the last two words. Not only do these standards contribute to huge amounts of wasted food (not to mention huge amounts of tasteless and nutritionally devoid food), but they encourage very high levels of pesticide use. They have also made it more difficult for organic products to compete by getting Americans used to unrealistic, even unnatural fruit and vegetable appearances, so that we are assumed to be squeamish about the slightest sign of insect damage.)

Why do supermarkets even bother to sell produce then? Because it gets people into the store. While everyone likes the look and idea of fresh produce, once in the store most people buy primarily packaged foods. (If you don’t believe this, just take a moment next time you are in a supermarket checkout line to see how much fresh produce relative to packaged food is in everyone’s carts.)

American consumers end up throwing out enormous amounts of food as well, and this is where another important comparison between the U.S. and Europe comes in. Americans have giant refrigerators and freezers, and are encouraged by pricing to buy in bulk perishable items such as dairy products and meat, and some produce that can be bought bagged such as potatoes, apples and oranges. Buying milk by the quart just isn’t cost-effective given its price by the gallon. So Americans stuff their refrigerators full of bulk food, much of which spoils before we eat it, because we feel compelled to “save” money by buying the larger size. (This surely also contributes to higher-than-adequate portion sizes at home.)

In European cities, you would be hard pressed to find milk containers more of more than one liter (about a quart). Larger quantities of items don’t tend to be cheaper, and refrigerators are much, much smaller, half the size or less of the average American fridge. But it’s not a problem, because there are grocery stores everywhere, probably within a ten-minute walk of most homes, and so people go to the store much more often, and just buy what they need for the next few meals.

The one American city I have spent time in that is the most similar to this model is New York. Doubtless there are several others that at least in parts of the city, have similar access to groceries. Most or all of these cities are either pre-industrial in age or much larger than 2 million. But the chart above provides the telling data that American cities smaller than that are very low density compared to European, and thus in addition to weak public transportation, do not provide a grocery store every few blocks. In essence, in the European model, consumers are not made responsible for food storage as they are in the U.S., and much less food is wasted.
But the role of government in policies that reduce waste is strong. The European Union is taking positive steps to reduce food waste further. (They also are way ahead on recycling: in Germany, all plastic packaging is sent back for recycling. You don’t have to hunt around for miniscule numbers to figure out which things you can recycle, you just put everything from potato chip bags to yogurt containers in there, and all plastic bottles go back to the store for deposit.) The U.S. government is not only ignoring the fact that we throw out 40% (almost half!) of our food, but if someone in it tried to propose any measures, he or she would surely be accused by the tea party of violating our constitutionally protected right to waste whatever we feel like.

(As another aside there is also much reduced consumption of plastic bags in Europe now, at least in Germany; one very quickly learns the habit of bringing reusable shopping bags to the market because you have to pay for store bags. This is clearly a much better way to reduce bag waste than the feeble efforts by American grocery stores to credit customers 5 cents or even just 1 cent per bag they reuse, which means hardly anyone bothers. Fortunately though, some states, e.g. California and Hawai`i, are finally taking steps on their own to eliminate plastic bags and the huge amount of litter they cause.)

A free market is good at a lot of things. It allows many people to prosper economically over the short term, but it is clearly terrible at promoting any sort of path toward sustainable energy use and health. The great majority of businesses, particularly large corporations, have one metric that matters to them — the quarterly profits report. Planning for the long term is almost nonexistent, because it doesn’t make any money now. This is one of the main functions, even responsibilities of government, to steer society in a direction that will keep future generations healthy and happy. The EU is far short of true socialism, despite what its detractors say, and although there is always more to be done it has been quite successful in nudging people toward lifestyle choices that make them healthier and help to reduce waste of energy.

By contrast, right now the American political system seems incapable of addressing problems that will arise in the next month, let alone the next decade. It wasn’t always so. But while there are clearly some historical reasons why each region ended up on its current trajectory, the EU is making the most of an opportunity to imagine a better future. The U.S. though is clearly headed for a hard fall in the decades to come. The part of the government telling us how to eat healthily and exercise can’t even convince the part providing obscene subsidies for processed (but not fresh) food, let alone can we wave a magic wand and turn exurbs dependent on cheap oil into energy-efficient cities. Although there are lots of small steps we could take to head off disaster if there were a modicum of political will, instead it looks like the crazy End Times crowd may actually get their self-fulfilling prophecy.

Researchers at Imperial College London are working on a project to make steerable needles for medical applications, particularly procedures involving the brain.  When tissue deep in the brain needs to be accessed, such as a brain tumor for a biopsy, it is usually a problem, because the act of inserting a tool into the brain such as a biopsy needle — let along trying to operate to remove a tumor — could obviously cause more brain damage.  The objective of the project, led by Ferdinando Rodriguez y Baena, is to make certain procedures possible that are currently considered not by the use of a flexible needle.

Sirex noctilio (courtesy insectimages.org)

This is where the horntails come in. Horntails, or woodwasps in the genus Sirex, drill into tough wood using their ovipositors, in order to lay eggs.  Their larvae feed inside trees, and in fact are considered a serious forest pest in areas where they have been introduced outside their natural range.  Horntails (which are an evolutionary more basal relative of parasitic wasps such as the walnut fly parasitoid Diachasmimorpha juglandis) have a particular construction to their ovipositors, the tubes through which they lay their eggs, because they drill up to 20 mm through wood with them, although they are less than 0.5 mm wide.  At the same time, the ovipositors are quite flexible, and can be directed.

The ovipositor needle

The engineers in London used a paper from 1995 detailing the physiological mechanism by which S. noctilio completes this task (J. F. V. Vincent and M. J. King, 1995. The mechanism of drilling by wood wasp ovipositors. Biomimetics, 3(4):187–201) to design a flexible needle which can be directed around obstacles in the brain.  Their needle, like the woodwasp’s ovipositor, consists of two interlocking valves which slide relative to each other.  Each valve has external teeth which allows it to be anchored while the second valve slides.  That stabilization allows great force in movement of the long thin tube.

Schlettererius cinctipes (courtesy insectimages.org)

Some other wasp species demonstrate that it doesn’t matter how long such a flexible tube is, it can easily penetrate long distances.  A parasitoid of Sirex (in the family Stephanidae, right) must find a woodwasp larva deep in the wood to lay an egg on it, and also needs a maneuverable ovipositor that can follow the larval tunnels to the host.  So it needs even a longer ovipositor to find the larvae which have tunneled deeply — I have seen such ovipositors up to 15 cm long. They likely use a similar principle as the ovipositors of Sirex.

The research has now reached the stage of animal testing, after development of an algorithm to determine the best paths to take to a tumor through healthy brain tissue.  Hopefully in a few years this breakthrough will be available to people with brain tumors who might have otherwise been told that it would be unsafe to investigate their tumors further.  With a better diagnosis through biopsy, perhaps the chances for a better outcome will increase for these patients.

But I’m obviously in the minority.  Seafood is big business, and our growing ability to use technology to harvest vastly higher quantities of fish than were possible historically has put entire oceanic ecosystem at risk.  Fortunately, the U.S. is finally taking the lead on the attempt to impose catch limits (see the pdf fact sheet about the new rules) in order to at least slow this process down.  There is now another piece of good news as well:  Some fish stocks are showing signs of recovery (based on a pdf NOAA report), which means our policies are headed in the right direction.

Pretty much all resource extraction industries are about making as much money as possible, with no thought or care about the future.  The mentality is, “if I don’t get it first, someone else will anyway.”  Conservatives use this “tragedy of the commons” argument to support private vs. public ownership of resources — even though there is plenty of evidence that people are often no more protective of resources they own than those they don’t, because the short term is always weighted economically much higher than the long term. But even if that argument actually held, there is no real way to allocate ownership of oceanic resources.  Even when countries maintain sovereignty of their coastal waters, these “borders” are impossible to defend.  There is no way to prevent overfishing other than by government-mandated catch limits, because there is no way for this system — like nearly all extractive industries, I would argue — to self-regulate for sustainability.

We can’t control the rules other countries make, but there’s no doubt that when the U.S. fails to weigh in on an environmental issue, or actively spurns an international effort to deal with one (such as the Kyoto climate change agreement), that significantly reduces the likelihood that other countries will continue to do the right thing.  Although containing just 5 percent of the world’s population, the U.S. consumes roughly a quarter of the world’s resources, and so any claims about why we should not be held to the same standards as the rest of the world ring hollow.  So U.S. policy positions on world ecological problems carry a lot of weight, whether we like it or not, and we may already be seeing the fruits of this in the 2011 fisheries report, which classifies six fish species now as “rebuilt.”  This contributes to a promising trend of higher sustainability in the way we are fishing (details on how the FSSI index is calculated can be found in another pdf):

This comes with caveats, of course.  First of all, the definition of “rebuilt” has nothing to do with historical levels, but rather is calculated as current biomass divided by the maximum sustainable yield (which also must be determined for every species).  Any number above 80% is assumed to be within “normal” fluctuations.  So “rebuilt” is not truly “rebuilt” in ecological terms, just in economic terms. According to Lee Crockett, director of federal fisheries policy for the Pew Environmental Group, this corresponds to 40% of historical levels (although that number must be different for different species, so one assumes he means on average). There’s no understanding (let alone consideration) of what levels are sustainable ecologically.  All creatures exist as part of the greater food web, not as separate, distinct populations, and in the longer term, economic sustainability is dependent on ecological sustainability.

The second problem is that inevitably, labeling a stock as “rebuilt” will cause political pressure to increase catch limits again, pretty much the opposite of what you want to do in the case of a recovering species.  Politics is injected into nearly all resource decisions, even when the government tries to rely on science, so any gains should be considered fragile, and the constant pressure short-term economic gain makes long-term planning difficult.  But you can follow yourself how this story progresses at the NOAA site.

Addendum:  Like clockwork, the GOP and their moneyed interests are trying to eliminate funding to help regulate catch shares.  Ironically, the commercial fishermen have seen clearly the value of the program and wish to keep it in place; it is the recreational fisherman (and their guides dependent on rich people) who have decided that  “catch shares are no different than any other inside-the-Beltway-style tactic determined to destroy every aspect of American freedom under the guise of conservation.”  That’s right; once more, any attempt, no matter how tepid, which represents an effort to slow down the exploitation and degradation of our planet so that there is something left for future human generations (let alone other species) is an attack on freedom, or better yet, an attempt to “destroy jobs.”  We are in deep do-do if these people are allowed to hold onto power this fall.

But as it turns out, indiscriminate use of ineffective chemotherapy may also be undermining other treatment options, in more than one way.  A big new area of research is on how to convince our immune system to attack and destroy cancer cells without them attacking healthy cells.  From one perspective, invasive cancer can be considered an immune system failure, because somehow immune cells are diverted from doing what should be their job and clearing out these defective cells.  Of course, it’s asking a lot of our immune system to recognize cells originating from our own body as foreign, especially given that cancer cells are very good at manipulating our natural immune response (Whiteside 2006).  Immune function is also very complicated.  But recently, more studies are helping scientists to manipulate the immune system in a way that shows very promising preliminary results that could significantly impact the way we treat cancer.

One trick is to train our immune system in a very similar way that we do with any regular vaccine against a disease.  Of course it’s a lot more difficult to train our immune cells to selectively attack our own cancer cells while leaving healthy cells intact, because our immune cells work by targeting specific proteins on cell surfaces.  One you have been exposed to an invader such as a virus or bacterial pathogen, your immune system “learns” what those cells look like based on their surface proteins, and produces a whole line of special cells designed to attack and kill any cells in the body with that specific protein signature.  We never get sick from the same cold virus twice, because each time we develop immune cells ready to attack a previously experienced viral strain, before it multiplies enough to cause symptoms (unfortunately, in the case of cold viruses, there are hundreds of strains, and so there is always a new one we can catch).  In the case of serious foreign pathogens such as those causing flu, measles, polio, hepatitis, and other life-threatening diseases, we can often pre-train our immune system by introducing a small amount of the pathogen into our bodies — usually it’s a killed version of the pathogen that cannot harm us but which still retains the identifying surface proteins.

The hard part of enlisting our immune systems to attack cancer cells is identifying surface proteins that are unique to the cancer cells.  Fortunately a lot of progress has been made on this front.  Adding to previous extensive work in this area (Cheever et al. 2009), Willingham et al. (2012) have found that some cancer cells overexpress a protein (called CD47) that sends a “don’t eat me!” message to white blood cells (immune cells) that are phagocytic, or cell-eating.  In fact, the higher the level of expression, the lower the survival rate for someone with that cancer.  The researchers exposed tumors in mice to a CD47 antibody, which enabled the mouse’s immune system to destroy the tumor cells.  They also transplanted human tumor cells into mice and got the same effect — in several cases the tumors completely disappeared, making the mice cancer-free.  They tried it with several types of cancer.  When they gave mice tumor cells known to aggressively metastasize, the CD47 antibodies also prevented metastasis compared with controls.

Another step in this problem was alluded to earlier: researchers had to establish that the antibody attacking this protein, which is also expressed in some normal cells (to a lesser degree than in tumor cells) would not work as a toxin by causing the destruction of healthy cells (as most chemotherapeutic compounds do).   They found that the primary side effect was anemia and neutropenia — a temporary killing off of red and white blood cells.  And, they have reason to believe that the doses of antibody that they used in the mice were much higher than might be necessary, which reduces the probability that toxicity would be a problem in a therapeutic setting.  (And let’s not forget that the neutropenia associated with commonly used chemotherapy regimens at this time has been deemed acceptable despite its danger, partly because we have drugs such as neulasta which mitigate the problem by stimulating overproduction of white blood cells.)  A cancer treatment that could be applicable across a wide range of different cancers has truly been the holy grail of the “war on cancer.” Now it seems possible that the grail could exist.

Also interesting are the studies going on looking the anti-cancer effects of recombinant pox virus vaccines (Mohebtash et al., 2011).  These work by the addition of genes into a pox virus that stimulate the immune system to attack other proteins associated with cancer cells, such as MUC1.  This treatment also has essentially no side effects because it targets cancer cells. Their preliminary data from a human trial shows promise, with the interesting effect so far that the treatment worked better in patients who had not undergone previous chemotherapy.  Given the damage that chemotherapy causes to immune systems, these therapies certainly wouldn’t work in conjunction with chemotherapy, but results raise questions about whether or not chemotherapy is causing longer term immune damage that we may be ignoring. At the same time, to make happy those wedded to continuing the use of chemotherapy are results showing that chemotherapy can actually be synergistic with immunotherapy, if treatment is manipulated with precision (Lake and Robinson, 2005; Ramakrishnan and Gabrilovich, 2011).

What few people realize is ideas relating the immune system to anti-cancer effects are hardly new, having existed for well over a hundred years.  Infections themselves have been demonstrated to halt cancer progression, perhaps partly due to the fever response (Hobohm, 2009) but over the last several decades, this avenue of research has been essentially ignored (except by a few curious academics) in favor of a focus on chemotherapy.  It’s hard not to think that the profit motive that has a huge influence on biomedical research has a lot to do with this.

Researchers are much further than most people realize at converting immunologcial research into clinical treatments, some of which are already being used outside the U.S, and others of which are currently being tested in a lot of trials around the world. These are hopeful signs that medical scientists are finally seeing the routine and usually useless poisoning of millions of people every year for the therapeutic dead end that it clearly is, and that this will be enough eventually to fight back against the inertia and competing interests contributing to the stagnation of progress in cancer treatment.

References

Cheever MA, Allison JP, Ferris AS, Finn OJ, Hastings BM, Hecht TT, Mellman I, Prindiville SA, Viner JL, Weiner LM, Matrisian LM, 2009. The prioritization of cancer antigens: a National Cancer Institute pilot project for the acceleration of translational research. Clin Cancer Res. 15(17):5323-37.

Hobohm, U., 2009. Healing Heat: Harnessing Infection to Fight Cancer. American Scientist, 97(1):34-40.

Lake RA and Robinson BW, 2005. Immunotherapy and chemotherapy–a practical partnership. Nat Rev Cancer 5(5):397-405.

Mohebtash M, Tsang KY, Madan RA, Huen NY, Poole DJ, Jochems C, Jones J, Ferrara T, Heery CR, Arlen PM, Steinberg SM, Pazdur M, Rauckhorst M, Jones EC, Dahut WL, Schlom J, Gulley JL., 2011. A pilot study of MUC-1/CEA/TRICOM poxviral-based vaccine in patients with metastatic breast and ovarian cancer. Clinical Cancer Research 17(22):7164-73.

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