Wednesday, November 14, 2007

The complexity of cancer

Today I went to a lecture by Nick Cross on tyrosine kinase inhibitors in chronic leukemias. The lecture was a tour-de-force, but I came away profoundly depressed. Nick runs an excellent genetics unit and is extremely erudite. He has managed to identify 43 chromosomal translocations in the chronic leukemias in which conjoined genes result in a constitutively activated tyrosine kinase that has the effect of causing the leukemic cell to continue to divide even when it is not receiving an appropriate signal from its environment.

This has nothing to do with CLL, by the way, the pardigmic disease is chronic myeloid leukemia in which the BCR/ABL tyrosine kinase is always in the switched on mode. Nick has looked at a variety of atypical chronic myeloid leukemias and has sorted out the molecular mechanisms.

Excellent though the science was there were several depressing features. First, in one case they had identified a Gleevec-like inhibitor which switched the tyrosine kinase off and would have had the effect of controling the leukemia, but so few patients suffered from this particular variant that no pharmaceutical company would spend the money to manufacture the product. Second, although he had identified 43 molecular mechanisms these represented less than 10% of all cases of atypical chronic myeloid leukemia. This is a rare variant of a rare disease; there are only 750 new cases of chronic myeloid leukemia in the UK every year.

The chronic myeloproliferative diseases are single gene disorders - there is usually only one molecular mistake. The common cancers, on the other hand, have 6, 7 or 8 molecular mistakes. If single gene diseases are so complex, how much more complex must the common cancers be?

When Gleevec was discovered I was very excited. The age of molecular therapies was dawning. That was 9 years ago. All we have done since then is produce one failed drug - Iressa - for common cancers. It is still the case that the most effective treatment for cancer is surgery, a treatment 150 years old.

The third depressing feature came from a meeting I went to the day before. WE were proposing a trial of mini-dose Revlimid for maintenance therapy in CLL. This was being opposed on the grounds that as the drug was so expensive, no matter how effective it might be, it would never pass NICE, and therefore there was no point in doing the trial. If Revlimid (a relatively easy to make molecule) is too expensive, what hope is there for new drugs in cancer.

The fourth thing that depressed me was seeing a doctor smoking. I have always refused to work on lung cancer on the grounds that the problem is already largely solved. Just stop tobacco smoking. As we unravel these molecular mechanisms at huge expense, society as a whole is unwilling to give up the thing that causes the commonest type of cancer. Why should we bother?


Anonymous said...

Are there any circumstances NICE would approve a life-saving drug?

Does it pay for Gleevic? Avastin?

Terry Hamblin said...

Actually NICE does pay for Glivec (as it is spelled in the UK). The addition of Avastin to irinotecan, fluorouracil and leucovorin on metastatic colorectal cancer has been shown to significantly improve median overall survival from 15.6 months to 20.3 months.
The cost of an average of 141 days extra survival worked out at $34,000 or about $240 a day.

There are circumstances where people would be prepared to pay for that delay in death. Would you be prepared to pay that much for somebody you did not know?

In America there are perhaps 50,000people who might benefit from that treatment. If I have got my decimal points in the right place, I think the total bill comes to 1.7billion dollars a year. That is the total GDP of a small country.

Still prepared to pay?

The money could be found, but either taxes would rise or healthcare prmiums would rise; business would take another hit, more downsizing, jobs exported to China, more absolute poverty, more welfare, more benefit-culture. Not an easy decision.

Anonymous said...

I do pay the $240 per day for people I don't know.

Besides the sizable charitable contributions (many church related, btw), my Blue Cross insurance pays for Avastin for some folks, and I pay a portion of that insurance (a sizable portion, my employer pays the rest).

Drug development costs are sizable (I've read close to a billion dollars per drug!), and drug companies are for-profit enterprises, so they have to charge considerable money for the ones that make it to market.

Every day is precious to a cancer patient.

The US pays the most per capita for health care, and I think we have the best system in the world.

Not to get into another tedious debate, but surely NICE goes too far the other way, don't you think?

They won't pay for other drugs, such as drugs for blindness, heart disease, and, of course, CLL.

Don't you really feel that CLL patients in the US have more and better choices than those in the UK?

Terry Hamblin said...

The US has the best healthcare system in the world? I don't think so. There are a large number of people who have a very poor health service, relying on ER rooms at County Hospitals because they are not insured and not eligible for medicare. From my post bag I hear of insured patients being denied appropriate stem cell transplants by their insurers. Others are offered completely inappropriate treatment by oncologists who don't know the disease as well as they should, especially where there are perverse incentives to give intravenous therapy where oral would be better.

There are lots of things wrong with the US system just as there are with the UK system. The American system is inefficient, wasting money on bureaucracy to a much greater degree than the UK NHS. Health costs are a burden to many companies.

I agree that many special units in America are among the best in the world, but not every superlative unit is there. Consider this: where would you go for gene therapy is you had a child with severe combined immunodeficiency syndrome? The unit with the most experience is the Necker Hospital in Paris, who have done 11 cases but four have developed a subsequent acute leukemia. Great Ormond Street in London have done 10 and all are alive and well. Two units in America have also treated patients - one four and one two. These patients have also all done well, but the FDA have suspended further gene therapy in this group of patients.

The truth is that there are good and bad things in every system, but is also true that to provide the very best for everybody when and where they want it runs into problems of cost. As new medicines get more and more expensive this cost has to be borne by taxpayers (and US taxpayers pay at least as much as British ones) and/or companies (who pay a large proportion of medical insurance premiums). Either way it is a drag on the economy. Heavily taxed companies cannot compete and jobs are exported. Heavily taxed electors vote out governments or else lose incentives to earn. Every government faces a problem.

Anonymous said...

I wish I could remember who pointed this out, but, paraphrasing, 'what better to spend money on but your health?'

I acknowledge that European researchers are adding to the knowledge of CLL. More please!

As far as the heavily taxed industries are concerned, that's true to some extent, but surely you aren't arguing that we should have a health care system like Bangladesh, are you?

Drugs are expensive, as you know. However, eventually, most drugs go generic and the price drops. But companies need to sell product to fund research.

BTW, did you know that generic drugs in the US are cheaper than those in Canada, according to an FDA study?

Anonymous said...

Very nicely said concerning the U.S. health system. I am always flabberghasted by the vocal American's who really think our health care system is the best in the World. Someone must have put out the best propaganda newsletter in the Universe to these people. We can't even get oral Fludarabine because it is too cheap. The pharmacuetical lobbyist's would rather infuse Fludarabine here because of the profit margin. and that is coming from the best health care system in the World?

Anonymous said...

These are a few random thoughts related to this post and comments.
I want to preface this with the comment that I am tremendously grateful for the gifts I have related to medical care: I am in the US, I have very good medical insurance, my employer is generous with their benefits, I am still able to work full-time.
That being said I have a number of concerns related to health care--
1. The US is a nation of those who have health care and those who do not. This should concern all of us in the US. No, I don't have a solution.
2. The rapidly increasing costs and the ignorance of those costs. I am only more aware because of my job in Human Resources and I make it my business to check things out both for our organization and my personal situation.
Don't even get me started on the drug commercials that make people think they need stuff that they don't need (little purple pill, anyone?)
3. As far as my CLL situation, I have gone to a number of doctors. Without the CLL community, including Dr. Hamblin, I would have accepted care that would have actually made my situation worse. I don't think I am alone in this.
4. My sister was a victim of a Medicare part D situation/failure of the medical system. She was doing well, had her medications cut and it resulted in a lengthy hospitalization (like 2 months) and ongoing care. It was gut wrenching watching this situation play out. Because it was a mental health issue it also ended up in court with her being committed.

No solutions here except some observations that we need to take responsibility for our health care and help those who cannot. We need to educate ourselves about our own medical situations (even if we NEVER wanted to do work in the medical field).

Oops...I think I have "RLS"--restless leg syndrome...I need to sign off (Okay that was a feeble joke and hopefully it didn't offend anyone).


Terry Hamblin said...

The problem in Bangladesh is one of poverty. It would be ludicrous for the Bangladeshi government to spend money on rituximab when what it really needs is clean water. Every country has to prioritize its health needs. It is an invidious choice, because the doctor wants the best for the patient in front of him. None of us likes to suggest that we have to cut our cloth according the needs of the nation. These decisions sometimes have bite to them. Would you accept that Avastin should be available to all if it meant fewer helicopters in Iraq or less protection against IEDs in Afghanistan or a waiting list for hip replacements or shorter prison sentences for murderers or more expensive gas or garbage collection every 2 weeks instead of every week? Nothing is free. I would quite happily see the price of cigarettes and alcohol go up for more health care, but not necessarily the price of food or gas.

Anonymous said...

I want to comment on your statements concerning lung cancer.

First of all, not all lung cancer patients have a history of smoking. Secondly, when the older generation started smoking, there was no clear link to lung cancer.

I personally would have no problem helping a smoker face lung cancer. You can shake your head when you see a smoker, but you must realize it is highly addictive, and, again, a certain percentage of patients have never smoked, yet are diagnosed with lung cancer. I suppose air pollution has a lot to do with it.

On the question of the health care system in the US, I curious to know which country has a better health care system.

Terry Hamblin said...

If everybody smoked lung cancer would be regarded as a genetic disease. Even in heavy smokers 7/8 don't get lung cancer, but in non-smokers it is a very rare disease indeed. Without smoking it would not be on the top of the agenda. Small groups of sufferers would be campaigning about how this rare disease is neglected.

I agree that nicotine is highly addictive - there should be more clinics to help with the addiction, and access should be restricted, but it simply is not true that the evidence wasn't there. 56 years ago the first report demonstrating the risk was published. It was enough to make Sir Richard Doll, previously a heavy smoker, give up and to make me, eight years old at the time, never start. There have been numerous reports ever since, but the tobacco companies have spent billions trying to cover them up, bad-mouth them, lie about them and use whatever propaganda they might to discredit them. Governments have been too dependent on tobacco money to resist them.

Air pollution? The proof against that being the cause is in the Island of Jersey which has the highest incidence of lung cancer in teh British Isles. It is entirely rural with few cars and no industry and consequently no air pollution. There is also no tax on cigarettes.

Countries with better healthcare than the US? France, Germany, Spain, Sweden, Denmark, Finland - where would you like me to stop? Most are insurance based, but lack the special interests that build in perverse incentives.

Would the pharmaceutical companies produce new drugs without the lucrative American market to drive it? Possibly not, but new classes of drugs are produced by universities not pharmaceutical companies. The alkylating agents, antibiotics and monoclonal antibodies all came out of British Universities, purine analogues out of American Universities.

Anonymous said...

You write:

"Would the pharmaceutical companies produce new drugs without the lucrative American market to drive it? Possibly not"

That is frightening! Since America will soon have government-paid health insurance, there will be few if any new drugs.

I also wonder what country will become the country of last resort for foreigners who have the money to pay for their own treatment.

Most Americans hate the rich and want them to suffer for being successful.

Maybe they will go to one of the European countries. I think China will be the biggest powerhouse in health in a few years. They have a three-thousand year head start.

Terry Hamblin said...

It is usually possible to get any drug in the UK if you are prepared to pay for it. NICE only controls what teh NHS will pay for.