Today we’re sharing another piece from our medical contributor, “Doc Gumshoe” — we have added the stock tickers to the companies he mentions for your researching convenience, but this survey of the state of cancer research — which will hopefully be good background help to folks trying to understand the basic science behind pitches for cancer cure stocks — is not a recommendation to buy or sell any company and, as always, the words and opinions here are his own.
In the past few weeks there have been a couple of news items that define the spectrum of cancer treatment today. At one end is the news that everyone has heard about – Angelina Jolie’s decision to undergo a double mastectomy, based on her genetic profile. At the other end is the sentencing of a Los Angeles physician, Christine Daniels, to fourteen years in the slammer for putting her patients on a totally fraudulent cancer “cure” that resulted in the deaths of several patients.
I won’t say much about Angelina’s decision itself, except that to my admittedly skeptical viewpoint, it was more a matter of peace of mind than of medical necessity. Many oncologists have weighed in with the perspective that careful monitoring would in all probability have detected breast cancer in time for successful treatment. In other words, they would not recommend a similar course for all women with the BRCA1 gene.
Following Big Data
However, what her decision was based on illustrates a powerful trend in cancer treatment, and, indeed, in current medical practice: that is, increasing reliance on Big Data, in this case, on sequencing the patient’s genome and looking for correlations with genetic information about cancers. The cancer establishment likes this. They know how to do it. There is already a repository of genetic information about cancers, The Cancer Genome Atlas (TCGA), funded by the National Cancer Institute. According to some experts, including Dr Michael Yaffe of MIT, the new data that is being dug up by further genomic analysis isn’t much different from the old data already in TCGA, but the NCI is spending about a quarter of a billion dollars a year on this approach, which may or may not lead, eventually, to improved treatment. And let us not forget, please, that treatment is what it’s about. Not more data.
But it’s hard to wean human beings from doing what they know how to do. If you’re a hammer, you want to solve the problem by pounding on a nail. If you’re a drunk looking for your house keys, you look under the street light, because that’s where the light is better, even if you dropped your keys a hundred feet away.
And this approach is safe. There are no failures. The researchers program their computers, the results emerge, grants are renewed, and everybody is happy. Except, maybe, the cancer patients who are waiting for news of a cure!
Why Are People Willing To Be Fooled by the Likes of Dr Christine Daniels?
From where I sit, the short answer is that after being promised a “cure for cancer” by lots of people, from Nixon’s declaration of “War on Cancer” more than 40 years ago on, no “cure for cancer” has turned up, and the news that comes out from the medical establishment promises nothing like a genuine cure for cancer. So it’s not exactly unexpected that when someone with a legitimate medical degree promises a cure, people would believe it. Of course, there have always been fraudulent cures, pitched by hucksters and crooks of nearly infinite varieties. But the underlying soft spot they aim for is the public’s disappointment. There’s a widespread view that mainstream medicine doesn’t have really effective cancer treatments. Cancer treatment, overall, gets a bad rap.
There May Never Be “A Cure for Cancer.”
That’s because, essentially, there isn’t any such thing as “cancer” in the singular. There are many, many different cancers. Therefore it’s highly unlikely that there will ever be a “cure” in the singular. What links these multiple cancers is the propensity of cancer cells to continue to subdivide and multiply indefinitely, and also their greedy, invasive, destructive character. These common characteristics do provide a target for treatment, however, as we’ll see later.
Possible Reasons for People’s Dim View of Current Cancer Treatment
More Heart Disease Survivors Means More Cancer Fatalities
Cancer mortality rates are down, but not that much. One reason is a sort of statistical artifact: death rates from the chief killer, cardiovascular disease (CVD), are down sharply. According to the NIH, yearly heart disease mortality declined from 307.4 per 100,000 population in 1950 to 134.6 per 100,000 in 1999, and it has continued to decline steeply since then. For example, in my home state of Connecticut, mortality from heart attacks was 66.6 per 100,000 in 1999 and 41.5 in 2006. The American Heart Association calculates that if the CVD mortality rate had remained at its 1963 peak, 621,000 additional CVD deaths would have taken place annually from about 1996 onward – that’s almost 10 million people. But those folks who escape dying of heart attacks don’t live forever – lots of them survive to succumb to something else, frequently the big C.
New Drugs Are Usually Tested Only In Patients with Terminal Cancers
Another reason is that the new drugs for cancer have a huge hurdle to surmount to get approval from regulators, here or abroad. They have to demonstrate that at least they are not inferior to established treatments, which they can do only in clinical trials in patients with cancer. But these cannot be placebo-controlled trials, because it would be hugely unethical to put cancer patients in the placebo arm. Also, patients with newly-diagnosed cancers for which there are established treatments that work reasonably well are not going to consent to go into a trial where they might be on an experimental drug that might be a bust. So most new cancer drugs are studied initially in patients in whom other treatments have failed. That’s why sometimes you see that a new drug, approved by the FDA, results in only a few months longer life than the drug it was compared to. An example is a very promising drug from a booming biotech, Regeneron. Zaltrap improved survival by only a few months, and Memorial Sloan-Kettering decided not to use it, because it costs about twice as much per month ($11,000) as Avastin. But that doesn’t mean that in recently diagnosed, early stage cancers, drugs like Zaltrap might not be a significant improvement.
What Are the Real Numbers?
Here are the incidence & mortality figures for the most common cancers, according to the National Cancer Institute. These are what’s known as SEER Statistics (Surveillance, Epidemiology, and End Results), and SEER data from the NCI are very well respected.
|Type of cancer||Projected new diagnoses 2012||Expected deaths 2012||Current fatality rate|
(Note that the fatality rates are not part of the NCI SEER statistics – the expected deaths in 2012 are in patients whose diagnoses were made in previous years. The fatality rates in the new diagnoses are unknown at this time; those are my own calculations.)
The huge differences in predicted fatality rates are due to many factors – the aggressiveness of the cancer, the efficacy of the treatment modalities that are available, and the accuracy of the means of detection. The low prostate cancer fatality rate is partly due to the fact that this form of cancer progresses slowly, that detection of prostate cancer is effective (despite the efforts of the USPSTF to discourage PSA testing), and that radiation or, especially, surgery, for prostate cancer is curative in most cases. This is also true of breast cancer (and also despite the effort of the USPSTF to discourage mammograms in women in their 40s). The low melanoma fatality rate is also due to the relative ease of detection of this form of cancer. The high fatality rates for pancreatic, liver, and ovarian cancer probably have at least as much to do with the difficulty of detecting those cancers as with absence of effective treatment.
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According to the National Cancer Institute, fatality rates have slightly declined in the past ten years – nothing spectacular, perhaps 1.5% over a ten year period, likely due to a combination of better detection and somewhat better treatment. Cancer prevalence in the US is about 12 million – or rather, that’s the estimated number of persons who have been diagnosed with cancer as of 2008. The NCI designates them as “cancer survivors,” meaning that they have been diagnosed and treated.
Current Cancer Treatment
If the cancer is an identifiable, locatable solid tumor, the plan is to kill it or cut it out, and poison any remaining cancer cells so that they don’t have a chance to recur. The effectiveness of surgery has greatly improved, owing mostly to enhanced imaging capabilities, as well as improved surgical skills. Surgery is often the most direct, immediate, and definitive treatment for some cancers, i.e., solid tumors that have not spread or metastasized. In some cases, surgery does not need to be followed up by any kind of drug therapy. The patient goes home, is monitored for signs of recurrence, and can genuinely be considered “cured.” However, I repeat, that’s “in some cases…”
Chemotherapy consists of giving the patient toxic chemicals that the cancer cells absorb more avidly than do the patient’s non-cancerous cells. The calculation is that the cancer cells greedily take in more of the poison than do the normal cells, so that the cancer cells die while the healthy cells survive. Nonetheless, chemotherapy can be exceedingly rough on patients and, by itself, is rarely completely curative. However, in combination with surgery, chemotherapy can result in long-term remission amounting, in effect, to a cure. A widely used cytotoxic drug is cyclophosphamide, marketed as Cytoxan, by Boehringer-Ingelheim, Bristol Myers-Squibb, Mead-Johnson, and others.
Radiation therapy has also greatly improved in effectiveness, due principally to the immensely improved accuracy of imaging techniques. External-beam radiation, which is used in solid tumors only, can now pinpoint the tumor precisely, and by changing the angle of the radiation beam in all dimensions, most of the radiation passes through the tumor only, with surrounding tissue getting much less exposure. In some cancers (e.g., prostate cancer), it’s possible to implant tiny pellets of radioactive material directly in the tumor, killing the cancer while minimizing damage to surrounding tissue.
Other Strategies for Treating Cancer
As oncologists have learned more about cancer cells, they have tried to devise ways of getting rid of them without causing harm to neighboring non-cancerous cells.
Inhibiting the reproduction of cancer cells
Cancer cells, like all cells, reproduce by mitosis, or splitting. The difference between cancerous and non-cancerous cells, however, is that non-cancerous cells are subject to apoptosis, or programmed cell death. This sounds like a bad thing, but it’s actually a good thing for the health of the host organism – we grow new cells, so that most of cells in our bodies are relatively young and healthy.
However, cancer cells, left to their own insidious devices, will continue to reproduce endlessly. The process by which they do so is complex, but it involves dividing some of the cancer cell’s crucial components, such as chromosomes and microtubules. A number of drugs can significantly inhibit the process, and have shown great clinical benefit in some cancers. Many of these drugs are descendants of a compound which was first discovered in the bark of the Pacific yew tree and named “taxol” after that tree; since then, a number of taxol-based drugs have been developed. Taxol-based agents using this mechanism include paclitaxel (Taxol, Bristol Myers Squibb (BMY)); docetaxel (Taxotere, Sanofi-Aventis (SNY)), Abraxane (a newer formulation of paclitaxel from Celgene (CELG)) and others. Other anti-mitotic agents with different mechanisms include vinorelbine (Navelbine, from Abbott (ABT)), capecitabine (Xeloda, Genentech), which inhibits DNA synthesis, and others.
Another way of preventing cancer cells from reproducing indefinitely is targeting telomerases in cancer cells. These protect the ends of genes (telomeres), but if the telomeres are damaged, the cancer cells stop replicating. It is indeed a promising mechanism of action, but the only agent so far that has shown any promise in that area is Geron’s (GERN) imetelstat (GRN-163L).
Inhibiting the capacity of cancer cells to foster the growth of blood vessels
Like all cells, cancer cells need nourishment to survive, and they get it by inducing the growth of blood vessels (i.e., angiogenesis). Several strategies have been developed to inhibit tumor angiogenesis and thus starve and kill cancer cells. One is to target vascular endothelial growth factor, or VEGF, which cancer cells release in amounts far greater than ordinary cells. Alternatively, the receptors for VEGF can be targeted.
A widely used drug targeting VEGF is bevacizumab (Avastin, from Genentech and Roche, RHHBY). Avastin is FDA approved in the US for a range of cancers, but breast cancer approval has been problematic. It was originally approved for breast cancer in 2004, but approval was revoked in November 2011 because, although it did target VEGF, it failed to show survival or quality of life benefit in breast cancer patients. Genentech/Roche are currently conducting more than hundred clinical trials with Avastin to try to regain the breast cancer license; many or most of these are in combination with other established or emerging drugs. Avastin is approved for ovarian cancer in the European Union, but not in the U. S.
A breast cancer variant in which tumor growth is fostered by another kind of growth factor is HER2 breast cancer, which is more difficult to treat than others. HER2 stands for human epidermal growth factor type 2, which is triggered by tyrosine kinase. A few agents in particular target this cancer type – lapatinib (Tykerb, from GlaxoSmithKline), which is typically used with capecitabine (Xeloda, from Genentech), also trastuzumab (Herceptin, from Genentech). Both of these agents inhibit angiogenesis.
Mobilizing viruses to attack cancer cells
Strange as it may seem, this approach has shown some success, and some of the big pharmaceutical companies have anted up hefty sums to acquire biotechs that have promising oncolytic viruses – “oncolytic” because they lyse, or destroy, cancer cells by attacking the cell wall. The trick is to mutate the virus, so that it’s less dangerous to the human host and more lethal to the cancer cells. In 2011, Amgen (AMGN) made a deal with a company called BioVex for $1.1 billion for an oncolytic virus called BioVex, which has the capacity of attacking melanomas that cannot be treated by surgery and are consequently exceedingly difficult to treat. BioVex has demonstrated a fairly high success rate in treating these melanomas. It is based on the cold-sore virus, which is not a huge threat to the host.
There are quite a few other oncolytic viruses currently under investigation. An outfit called Cold Genesys, Inc, in California, is working on recombinant adenoviruses to target bladder, breast, ovarian, colon, and prostate cancers. Another California outfit, Genelux, is looking at attenuated vaccinia viruses, which have shown effectiveness in head and neck tumors and advanced solid tumors. (The vaccinia virus is used to vaccinate people against smallpox.) A Canadian firm, Oncolytics Biotech (ONCY), has an agent, Reosyn, based on one of the reoviruses, which is now in Phase 3 trials against head and neck cancers and is being studied in lung, colorectal, and pancreatic cancers. And an Australian biotech, Viralytics Ltd (VLA in Australia, VRACY pink sheets, teensy), has a couple of agents in clinical trials, based on the coxsackie virus, against ovarian, lung, gastric, and pancreatic cancers. An advantage of some of these agents is that they don’t have to be injected into the tumor cell, but can be given intravenously.
My guess is that some of these will turn out to be effective drugs.
The T-cell strategy
Yet another mechanism that is getting considerable attention is mobilizing the human immune system, especially T-cells, to attack cancer. There has been one very successful (as well as highly publicized) foray in this area, and the news is that the NCI is focusing a lot of attention, and spending a lot of money, on this approach. There was a New Yorker article by Jerome Groopman in April of 2012, which described this approach in three patients with leukemia. The approach entails harvesting a patient’s T-cells, modifying them so that they target the patient’s specific cancer cells, and then reinfusing them. The three patients had failed standard treatment and were not offered much hope, but the T-cell treatment has resulted in remission thus far.
This strategy would not in any way lead to the development of a drug that could be more widely used in cancer patients. And it sounds to me like a “last resort” type of treatment – maximally individualized and extremely expensive, but certainly worth further investigation. It’s an example of the “data-driven” approach that I mentioned earlier, and is perhaps its single success story.
Why Doesn’t Mainstream Medicine Pay Much Attention to “Miracle Cures?”
Most physicians have seen patients recover from serious illnesses for reasons they don’t understand. When you’re talking about cancer patients, the usual term is “spontaneous remission.” If the patient happened to be using some alternative treatment, not sanctioned by the medical establishment, that cuts no mustard with most doctors – they attribute it to the “post hoc propter hoc” fallacy, meaning that if event B takes place after event A, it’s tempting to say that event A caused event B.
However, it’s worth taking a look at the phenomenon of “spontaneous remission.” I don’t think it’s good science, or common sense, to accept that something happens without a reason. Something, or a combination of somethings, brings about spontaneous remission. A reasonable conjecture is that spontaneous remissions, as well as recovery from many illnesses, has a lot to do with our immune system, which is exceedingly complex and far from being completely understood.
So there may be components in some of those miracle cures that boost the immune system and result in those mysterious spontaneous remissions. However, before mainstream medicine accepts those alternative treatment forms, the mechanism of action has to be understood, and the results have to be able to be replicated. When that happens, the alternative treatments will be alternative no longer – they will enter the mainstream.
A miracle-touting website that popped into my inbox starts out with the scare headline – “did you know you have a 1 in 4 chance of dying of cancer?”
My answer: you have a 4 in 4 chance of dying of something. Our goal should be to postpone that eventuality, and to live a long, healthy, and happy life in the meantime.
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I’m having a good time writing these pieces, and I’m particularly enjoying the stream of responses. I’m gathering up some of these very interesting questions and responses and will try to address them in a future commentary. My best to all.
Michael Jorrin (aka Doc Gumshoe)