Cancer: the problem.

I read an interesting blog recently entitled “The War on Cancer” (http://sten.astronomycafe.net/the-war-on-cancer/). Apparently, in the US a little under 600,000 people die of it each year. The author, Dr Sten Odenwald, then set out to illustrate that funding for cancer research is far too low. I think it was President Nixon who coined the phrase, “war on cancer”, and set it as an objective, in the same way Kennedy had set the Moon landing as an objective, but this was doomed to fail, at least in the spectacular way. The reason is the nature of cancer, which, as an aside, is not one disease. We have been trying to cure this for a very long time, but with mixed results. Gaius Plinius Secundus recommended a poultice of broccoli for breast cancer, and asserted it works. There are indeed agents in broccoli that will deal with some breast cancers, but by no means all, and even then, the cancer would need to be near the surface. There are at least twenty different types of breast cancer. Drugs like tamoxifen stop the growth of at least one type, monoclonal antibodies help in some others. So we have made some progress, but there are still severe problems, especially if the tumour metastasizes (dislodges cells to other parts of the body).

It is the nature of cancer that is the problem. Cells grow around nucleic acid, and nucleic acids reproduce by base pairing, then splitting, each strand now being the frame for the production of more nucleic acid. Thus after splitting, when a new double helix is finished being assembled, the amount of nucleic acid has doubled, so a new pair of cells is possible, the old cell having been destroyed. So what can go wrong? You will usually read that copying is not correct, or something is added to the double helix, but I don’t believe that. It is the peculiar nature of the hydrogen bonding that either the correct nucleic acid goes onto the growing strand or nothing does. That is why reproduction is so accurate. In the double helix, the reactive sites are protected, as they are in the interior of the helix, and the outside is the phosphate. A further substitution on the phosphate to make a tri-ester would be a nuisance, but it would not be very stable, and it would repair itself. Further, it would require a highly reactive reagent to do this, as it is exceedingly difficult to make phosphate esters in cold water other than through enzymatic catalysis. No, I think the problem probably arises during the splitting stage when the reactive sites become exposed. If something happens to the nitrogen functions, then that will block the formation of the next double helix at that point.

At that stage, the body will attack the nucleic acid at that point, and the next usual outcome will be that the various parts of the strand will be degraded, and the bits reused or excreted. But if the problem occurred in certain places, it may be that what is left can start reproducing. If that happens you have something growing that has no function for you, BUT it looks like it is part of your body, because up to a point it is. The growth just keeps growing, and reproducing itself. The reason there are so many different cancers is there are so many places where a nucleic acid could go wrong, and each different place that can reproduce will lead to a growth that is slightly different from any others. Because it looks like part of your body, your natural defences ignore it.

So far, we have largely relied on surgery, radiation or drugs. So, how is progress? In some cases, such as leukemia, progress is good, and it is often curable. In other cases, life can be extended, but according to Wikipedia, since Nixon declared war on cancer, the US alone has spent $200 billion on research. Between 1950 and 2005, the death rate, adjusted for population size and age has declined by five per cent. On the other hand, while in remission many patients have had life extended.

However, we should ask, are we doing anything wrong? I think we are, and one problem relates to intellectual property rights. Here is an example of what I mean. In the 1980s I was involved in a project to extract an active material from a marine sponge. My company developed some scale-up technology and made a few grams of this material, which, from reports I received, if the odd microgram was introduced to a solid tumour, the tumour blistered and died, leaving a well-repaired skin outside wherever the organ was. This property was limited to studies on rats, probably with external carcinoma. Anyway, the company that hired us ran into difficulty with its source of funds and went bankrupt, however, somehow ownership of the intellectual property lived on. At the time, there was no known technique of introducing a material as reactive as this to internal tumours, nor did we know whether that would even be beneficial. Essentially, the project was in an early stage, and maybe the material would not be beneficial. Who knows? The problem is, now we don’t know and nobody is likely to work further because the patents have expired. Any company working on that will have all the expense, and then somebody else can come in and take the benefits. In my opinion, this is not a desirable outcome. We should not have a situation where promising knowledge simply gets lost because of formal procedure.

Equally, we should not have the situation where drugs become ridiculously expensive. Why should the unfortunates who get a rather rare cancer have to pay the huge prices of drug companies? I am not saying drug companies should not get a fair return, but I think society should pay for this. Think of it as compulsory insurance. The alternative is a family might have to decide whether to bankrupt themselves, kill the grandchildren’s education prospects to buy a year or so for grandmother, or whether to just let her die. What sort of society is it that allows this?

Cancer is one of those diseases that everybody comes into contact with one way or another. In my case, my father died of pancreatic cancer, and I am a widower because of cancer. Yes, these things happen, but isn’t it in everybody’s interest to try and do what we can to at least minimize the harsh effects?

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Happenings!

Since my last post, things have been happening and there has been material for several posts. I have been in hospital getting a hip replacement, but that is of little importance, other than to me. The United States elected a new President, after what I thought was one of the most bizarre campaigns, and then there was . . . But more of that below.

The surgery and the follow-up care were carried out with professionalism, skill and commitment, and I can assure anyone wondering that New Zealand does have good skilled medical care. One can argue about the politicians’ involvement with health care (and many of us Kiwis do), but I could not have asked for more. While recovering, the election results were coming in, and I had nurses pausing and discussing. Many Americans probably do not appreciate the importance many ordinary people in other countries attribute to their political scene. Of course there is no personal involvement, so we could make our comments in a detached sort of way. I am sure all who are following my blog, or other writings, will have seen enough comments on the actual result, so I shall leave it at that, other than to add that only too many of such comments show some ugly aspects of the writer that probably should not have been shown.

Then it was time to come home. My daughter thought I was being silly coming home because I have some fairly steep steps to climb, but no problem. The hospital had the rule, if you cannot climb up and down steps, you cannot come home, and I had practised. A lot of people commented on how well I was doing, bearing in mind . . . I put that down to three things. First, for weeks before going in I had been doing exercises to strengthen hip muscles. You cannot do anything about what is to be cut, but with bad hips, the muscles around them tend to atrophy through lack of use. You can do something about that. The second, I was determined to do what had to be done, and I think attitude helps. Finally, I had some long-term goals. Simple goals, like being able to walk down the beach in our up-coming summer. Be that as it may, I mention it just in case anybody else is to face such surgery. One can imagine all sorts of things, but it helps if you can focus on the desirable.

So, the day I came home we had, in a 24 hr period, the total average rainfall for November, and here was me hobbling up towards the house. Any moss on concrete, when wet, tends to get slippery, and you need slipperiness under crutches like you need the plague. So, the end of the bad luck?

Nope. I came home on a Saturday, and had a quiet Sunday, but then shortly after midnight, the house started shaking: a 7.8 earthquake. (Equivalent, I have been told, to 5.35 Mt of tnt.) This was centred at Waiau, which is about 40 % of the way between Christchurch and Wellington. This has apparently got international attention, especially “cow island” – three cows stranded on a pillar where the rest of the land had subsided. In one sense it was good this happened at Sunday/Monday midnight because many of the high-rise buildings in the Wellington commercial district lost sheets of glass, and there would have been serious casualties had there been people wandering about down below. Meanwhile, the electricity to the house went out. For me, there was worse to come – just as I was getting back to sleep, the sirens for a tsunami warning started up. No real likelihood of a tsunami where I live, because I am about 70 meters up a hill. But these sirens went on and on.

Then on Tuesday I had to go back and get dressings changed. No problems, except there was a serious storm going on, a number of roads were closed, and I had to hobble both down and up my path to my house. Of course my inconvenience is nothing compared to others’. Apparently, the whole town of Kaikoura has to be evacuated by sea because all land routes to and from it are blocked by huge rock slips. These road closures are all over the country. Earthquake/storms have closed at least 7 roads in the Lower Hutt area where I live, and a good number of houses have had to be evacuated. Then, of course, the aftershocks; 2000 of them. These have ranged as far north as Taupo, (half-way up the north Island) and a number directly under Wellington. A number of high-rise buildings there are under suspicion.

Yes, this has been a period where things have been happening. I just wish they would slow down, or happen somewhere else. I know that is hardly fair to someone else, but I have felt that a quiet spell for recovery would be good.

A disastrous example of free market economics

Do we see crises coming, and if so, are we in the habit of preventing their arrival? Is our free market system of economics capable of preventing their arrival? In answer to the first question, I think some of us do. As the second, no, especially if it means we do not make so much money so fast. Climate change is an example. The scientific community has made it fairly clear that our addition of infrared absorbing molecules into the atmosphere is causing the planet to warm. The politicians, or at least some of them, wave their arms and say we have to burn less carbon, but who says we have to stop using spray cans? A device that led to air creating the spray would be fine, but hydrocarbons, fluorocarbons, etc are not. How about stopping the manufacture of sulphur hexafluoride? Or reducing the level of application of nitrates to the soil?

So, we are at best a quarter hearted about climate change, but what about other impending problems? It is here I think the answer to my third question is no, and in fact the free market is more than just a part of the problem. One such problem that I think needs more thought is the question of antibiotic resistance. How does this come about? Basically because when antibiotics are used, the surviving bacteria are more likely to be resistant, after all, how else did they survive? This is evolution at work; the survival of the adequate, and being adequate to survive in the presence of antibiotics is to develop resistance to the antibiotic. And the problem is, the resistance can be transferred to further bacteria.

So, how does that come about? The most obvious example comes from agriculture, where antibiotics at low levels are used to promote growth. This helps the farmer’s and the drug company’s profits. The object is not to kill off all the bacteria, but rather to reduce their number, hence the low levels. (If you kill off the lot, digestion is impeded.) So, we have a little fermentation pot where resistant strains can develop, and then be transferred to the general environment. Why is this permitted? Because there is more money to be made by the companies, and a bit more by the farmers. Up to 80% of the antibiotic usage in the US has apparently gone into agriculture, and the big pharmaceutical companies are not going to give away that market. The chances of the farming sector turning down the quicker bringing of stock to the market are somewhat slight. Some do not use them, but only because they can then sell meat that can be advertised as “grown antibiotic-free”. So, maybe the consumer is at fault. Are we prepared to pay a bit more to prevent antibiotics being used this way?

Does it matter? I think so. If antibiotics no longer work, or if there is a reasonable risk they will not work, then medicine goes back a hundred years. The more advanced surgery developed during that period may well have to be abandoned. Surgery in the late 19th century was not something many would want to see their family undertake, let alone themselves. Additionally, many cancer treatments seriously suppress the immune system, and antibiotics are needed to deal with adventitious infection.

Now, for the moment we still have a slate of antibiotics, and while resistance is growing, it is rare to get superbugs resistant to just about all of them. Accordingly, our society is responding to this problem in its usual way: we ignore it, and assume we can find a way around it. The way around it is to have a “last resort” antibiotic, or preferably, more than one. The problem is, what used to be the antibiotics reserved for the most serious problems are now being used loosely and widely. But we can discover more, can’t we? Well, probably not. The first problem is, who is going to do the discovering?

The usual answer would be, big pharma. Nevertheless, success there is somewhat unlikely because by and large big pharma is not looking. The problem is, drug discovery has become hideously expensive, and suppose one was discovered and put away as a drug of last resort, usage would be incredibly small compared with the costs of getting it. The reason, of course, is that to prevent getting resistance to this, it too would be used very rarely. The company would never get its money back. Big pharma wants drugs to treat chromic conditions.

There is another problem. One drug that has had a dramatic increase of sales to the agricultural sector is tylosin, and it, by and large has little use in human medicine, but it is in the class known as macrolides, and if resistance is developed to tylosin, it is quite plausible that resistance will be developed to all those in the macrolide class. The use of third and fourth generation cephalosporins in animals has jumped seriously, and these are essential to human medicine. Why are they used? Almost certainly because of direct marketing. These drugs are convenient to use, but they are by no means the most suitable. There have been large increases in the use of tetracyclines and aminoglycosides in the agricultural sector, the latter class includes streptomycin. This report shocks me because of direct experience. When she was about 40, my wife got severe brucellosis, and the only cure then was serious doses of both tetracyclines and streptomycin. At the time it was a close call what would die first: Claire or the bacteria. Fortunately the bacteria did, but brucella live in animals, and I would hate to see that become resistant.

Will the worst-case scenario actually happen? I don’t know, and hopefully it won’t. Nevertheless, from a strategic point of view, don’t we want to optimize our chances of avoiding disaster? And it is here that the problem is most apparent, because the sufferers of the disaster scenario are not the current beneficiaries. We have an economic model that is almost designed to maximize the chances of disaster. It is not time to panic, but equally, it is also not the time to continue being stupid. If we want to insure our medicine does not descend into the state where serious surgery is to be avoided, should we not be cautious and defend what we have? Or do we say, let the corporations make what they can now, and not worry, and hope we never need the antibiotics?

The day after first posting this, the Huffington Post reported: ‘THE END OF THE ROAD FOR ANTIBIOTICS’

Are drug prices fair?

Recently in the Huffington Post, Allen Frances wrote a blog asking, “Why are most cancer drugs so expensive and so ineffective?” The link is below for those interested.
(http://www.huffingtonpost.com/allen-frances/why-are-most-cancer-drugs_b_8294392.html?utm_hp_ref=science&ir=Science )
That is most certainly a good question. A summary of his points includes that the pharmaceutical industry is essentially a monopoly, in that only one company will make any given patented product. In the US, it exerts far too much political pressure, and as an example, he claimed Congress denied the Medicare program the right to negotiate drug prices. He claims there is a price monopoly, for even when generic drugs can be made, the pharmaceutical companies buy up the companies. He claims patent lives are extended with phoney variations. But in my mind, even worse, drug companies test their own products, but do not have to release the data for analysis by neutral observers. The companies hype the benefits and minimize disclosure of any risks.

He then cites some data from a Dr Prasad. Some of his findings include, the price of Gleevac rose from $30,000 in 2001 to $70,000 today, despite the fact the cost to make it is $200 (for a year’s course). However, at least Gleevac actually works. According to Dr Prasad, the median improvement in survival for 71 drugs for solid tumours produced in the last decade is 2.1 months. That may well be an overestimate because only 36% of those over 65 yrs old were in the trial, but that age group represents 60% of the patients in the wider community. Another interesting question is, given that many of these drugs have very severe consequences to the patient, is that 2.1 months worth it?

So, how do the companies do? Seemingly, remarkably well, with returns of between 10 – 42%. I saw a recent article that stated one product that had been sold for $20 per prescription had it raised to $1,000. When asked why, a spokesman said they wanted to make more money. Well, yes, I suppose they do. Don’t we all? The products are grossly overpriced, and only too often it appears they don’t really work all that well. There is the argument that research costs a lot. Yes, it does, but despite this, these companies are hugely profitable. In my view, this is simply price gouging, and it shows the ugly side of capitalism. A further interesting question would be, how much tax do they pay on these profits? Given that some large companies pay very little, one suspects the answer is, not much.

Usually, economic theory works on the basis that if there is a bad product, people will not buy it. However, with cancer drugs, that theory goes out the window. The average person has no hope whatsoever of deciding whether the product is any good, and you find out it is not when you die, or come close to it. Earlier this year, my wife died of cancer, so I know the pressure on the relations. Who can tell someone dying that product B is a waste of money, and it will bring penury to the remaining family members? And no, this situation did not arise for me. Claire was diagnosed in November, some simple treatment was provided as a holding measure while various things were done, and proper treatment was to start after Christmas. As it happened, her funeral was on the day scheduled for the start of treatment. Nevertheless, when someone you love is dying, you cannot really think rationally. There is a temptation to grasp at straws, but think what the grasping is like if you hear promising things from the drug companies? The very least we could ask for is a fair and open discussion of the prospects, and the basis for saying that. And we should expect that where there is little to substantiate the claims, at the very least the straw to be grasped should involve only reasonable expenses. Price gouging for performance is, in my view, not justifiable, but price gouging for what may be little better than snake oil is in my view criminal.

Assisted death

In New Zealand, unlike some other places, assisted death has some probability of the assistant being charged with homicide, and recently the question of assisted dying was raised by a legal case initiated by a lawyer Lecretia Seales, who was dying as a consequence of an inoperable and untreatable brain tumour. Her case was, she wanted to be permitted to have a doctor assist her death when the pain became intolerable without the doctor being liable for being charged with homicide, and her case was based on the Bill of Rights. In the end, Justice Collins refused her case, based, correctly in my opinion, on the fact that the Courts are there to implement the law, and not to change it. Justice Collins argued that it is the role of the politicians to change the law. As it happens, the politicians have had this issue raised many times, but they invariably ignore it. Lecretia happened to be known by relations of mine by marriage, and I have written letters to papers on this issue, and this post summarizes the arguments I believe are relevant.

To be clear here, the arguments I am putting forward apply only to the case of people with terminal illness that cannot be cured, there is pain that cannot be avoided, and no improvement is reasonably in sight.

First, why do the politicians duck the issue? In my opinion, because they fear losing votes from the minority that hold life sacred and are prepared to vote on that single issue alone. That is the curse of our form of government, which is in fact, if not in name, a Republic. A republic form of government is where the people elect their representatives; a democracy is where the people vote on the issues. More on politicians and governance in later posts. However, one comment here: the government is prepared to spend $26 million on a referendum on whether we should have a new flag. Why cannot a question be included where polls suggest 70% of the population would approve of a change? Is not letting the people vote an example of the democracy we claim to have?

The case for assisted death is simple: why should people have to put up with insufferable pain? The counter argument that there is palliative care does not apply because if that works, there is no pain. A recent survey of doctors carrying out palliative care showed that in a few per cent of the patients there was clear and intense pain, no matter what, and for some of the others, pain was avoided only by putting the person into such a sedated state that they were unaware of their surroundings. Exactly what is the point of that? What is the real difference between death and being totally unaware of your surroundings, from the point of view of the patient. The problem arises when the palliative care no longer works, and the evidence is incontrovertible that this happens for the unfortunate few. Exactly how many examples of “insufferable pain” there are is unclear because only the clearly worst cases will be acknowledged. That is because it requires a confession that palliative care has failed, and doctors are usually unwilling to admit they have failed. I believe the solution is simple: it is the person suffering the pain that determines whether it is sufferable, and not someone else, who really has no standing in the specific death.

There seems to be an argument, Let nature take its course. Well, we do not do that in general. The people that make this argument presumably die young with the pain of rotten teeth, but I suspect, hypocrites that they are, they go to the dentist. Similarly, I expect they will have surgery when an appendix flares, and take various pharmaceuticals to alleviate various troubles. We interfere with nature frequently to make our lives better, so why not improve them by stopping things that make lives worse?

There are a number of other arguments against assisted death, such as people will rush to it. As far as I know, there is no evidence of that, and in any case, it should be available only to people for whom there is no reasonable possibility of a cure. There is the argument that relatives will push for it. Again, there is no evidence, but again the assistance should only be available for people who are lucid enough to ask for it, or to set down the conditions in a living will. One of the more callous arguments that turned up in the Seales case was that if granted, more people with insufferable pain would request it. Why should a person bear insufferable pain? We do not allow our pets to. There are also examples of patients who do what they can to kill themselves rather than suffer, and, perforce, make a rather more unpleasant ending of it. There is one other point. If the patient knows he can pull the plug anytime, he can stop worrying about future pain and better enjoy what time he has left. Is that not desirable?

To me, there are two questions. Why should the views of others, of religious, “moral” or whatever origin, be imposed on those who are suffering? Why should not the purpose of medicine be to maximize the quality of life, including the quality of the end of life? We all die; why not make it avoid long and unnecessary torture? What do you think?

As a final comment, Lecretia died within 24 hours of hearing of the failure of her case. I am writing this to give her final case perhaps a little more meaning.