What is the aim of treatment? (part 3)

If the aims of treatment are to live as long as possible and as well as possible, it may be that these aims are not compatible. We can make you live longer but you won’t be as well or we can keep you well but you won’t live quite so long. What I mean is you may have to compromise.

There’s a quote from Edmund Burke, “All government, indeed every human benefit and enjoyment, every virtue, and every prudent act, is founded on compromise and barter.”

The compromise is this. Left alone CLL will probably kill you. Even in the most benign cases the ability to respond to infection seeps slowly away. On the other hand the treatment is harmful too; the harm it does also damages the immune system.

Let us examine these questions. Unless the Lord returns first we are all going to die. Someone once said, “Life is a sexually transmitted condition that is universally fatal.”

Death is caused by violence or disease. Assuming we are not murdered, hit by a bus or some other traumatic intervention our body will get a disease and no longer be able to sustain itself. Infection, cancer, heart disease, brain failure; we used to call it old age. We can dissect out the cause of old age, but we can’t do much about it. It’s like running an old car; replace the brakes and the muffler blows, the gaskets leak, the tyres are threadbare, the pistons rattle, bodywork rusts. These bodies wear out. With CLL they wear out quicker. My oldest survivor was 106. Without CLL she might have lived to 107.

CLL can kill in fairly obvious ways. Marrow failure opens the way to infection, bleeding and, without transfusion, heart failure from anemia. Infection is probably the single commonest cause of death. Another cancer, whether a melanoma, squamous cell cancer of the skin, lymphoma or lung cancer may seem just another bit of bad luck, but though it’s hard to prove, it probably wouldn’t have happened without the CLL. But no-one can put their hand on their heart and say that the treatment of the CLL didn’t make these outcomes more likely.

Sometimes the CLL gallops. It becomes inevitable that you have to put a halter on it to slow it down. But more often it canters, trots or walks. Sometimes it seems to stand still like a dressage pony making grandmother’s footsteps, now forward, now back. Then you have to decide how much treatment and when.

Except in the most virulent cases I prefer to take the long view. I’m not much interested in treating a blood count. Treating a blood count is like polishing the bodywork while the engine is disintegrating. I have two concerns. I want the bone marrow to go on making blood cells, and I want to stop the immune system falling apart. So unless the bone marrow is threatened I prefer to avoid treatment. The CLL will eat away at the immune system, but it will do it slowly. Every treatment that I know will make the immune system worse. There is no way of treating the CLL that will restore the damaged immune system.

So, supportive care is the first thing. Blood transfusion or erythropoietin to keep the haemoglobin high. Surgery for an uncomfortable spleen or one that is consuming red cells or platelets. Irradiation of large or uncomfortable peripheral lymph nodes. Antibiotics for infections. And when infections are caused by low serum immunoglobulins then intravenous immunoglobulin infusions on a regular basis. Do what you can to avoid having to have treatment.

If treatment is inevitable, my choice would be the treatment that is least harmful. At the moment this is rituximab. It only works in about half the patients, and it does lower the levels of normal B cells, but this is transient and they quickly return. Rituximab plus a growth factor like G-CSF or GM-CSF may well be more effective. So if it works for you and gives you a year off treatment then go for it, and don’t be afraid to repeat it. True rituximab resistance is very rare. In some patients increasing the dose will turn a non-responder into a responder.

It’s after that that you have to think about chemotherapy, and that is the subject of another article.

Strata

Pushing through the holly-prickle teeth
Of the quick, ambitious wind,
I trickle like the lock gates trickle,
Shut against the higher level;
And pull at my stickle back nest;
Where the best grass grows
And everybody knows and is known.
I lie alone and think how to atone
For the mind and manners I have grown;
And how I can be free
From the wreathes of tiredness claiming me.

The doctor's time

My grandmother lived in a small house without plumbing, electricity or gas. There was an outside lavatory shared between three houses and a pump at the end of the road for water. Rooms were lit by either oil lamps or candles. Cooking was over an open fire. She was a sort of unqualified nurse who went round looking after people in the neighbourhood and relied on gifts to live. She died in 1948, old before her time.

My father had TB as a teenager, which cut short his education; was apprenticed to a tailor, followed the military to practise his job, and ended up as a bar steward in an officers’ mess. He moonlighted doing alterations for tailor shops and before he died had accumulated one thousand pounds in savings. He died from a medical mistake.

I was fortunate to be brought up in a country with free universal education and no barrier to a working class child rising to the top of one of the great professions. I have never been hungry, never cold or unsheltered, never the victim of more than trivial crime, never unloved, never friendless, never the subject of prejudice or unfairness. Although I lived through part of one of the worst wars the world has seen, I have never been bombed or shot at and never lost a relative through war. When I have been ill I have been expertly treated without charge. I have lived in a safe, generous and peaceful country in which to marry and bring up my children.

The idea that I should measure the time that I spend helping people and calculate how much I should charge them for knowledge that has cost me nothing is alien to me.

I heard of a doctor who was tired of being approached at parties with requests for remedies for bad backs, rashes or fatigue. He shared his moan with his friend the lawyer. The lawyer replied, “You should do what I do. I give them the advice they need and the next day I send them a bill.”

The doctor was thrilled with the advice and the next day at work set about sending accounts to all the would-be patients who had accosted him at the party. He was interrupted by the arrival of the post which included an invoice from his friend the lawyer for ‘advice given to deter medical enquiries – 50 guineas’.

What is the aim of treatment? (Part 2)

What about a long remission?

There are lots of cases of acute leukemia that we can’t cure. Most people over 40 for a start. Does that mean we don’t treat them? Certainly not. We try and get them to live as long as possible in the best possible health. If you have acute leukemia then quality of life in remission is much better than quality of life in relapse, so this equates to wanting the longest possible time in remission. How about this as an ambition in CLL?

But in CLL you can have a very good quality of life in relapse. Most patients with CLL are asymptomatic. So starting treatment is delayed until symptoms start and restarting treatment is delayed until symptoms restart. In acute leukemia the first remission is the main deal. Subsequent remissions are questionable and short. In CLL it is quite usual to be able to get several remissions, many of which are long lasting. In acute leukemia the rule is to give it your best shot first because for many patients you are only going to get one shot. In CLL you may have to eke out the treatment over many years.

Most doctors who design clinical trials for CLL have trained as acute leukemia doctors. Faced with a disease that may span decades they revert to type. Pharmaceutical companies are not much interested in a clinical trial that may last 20 years – their patents will have run out. Current clinical trials, by common consent, have abandoned overall survival as an end-point; instead they have adopted complete response rate and progression free survival as surrogates.

There are problems with both of these. A German trial reported last year assessed complete response rates. They compared the complete response rate without bone marrow biopsy confirmation, complete response with bone marrow biopsy confirmation and thirdly, with CT scan confirmation. For each successive group the CR rate diminished. Their conclusion was the harder you looked for residual disease the more you found. When PCR is used to look for MRD, the ‘true’ CR rate falls even further.

Progression-free survival is even less reliable. What counts as progression? When the MRD test becomes positive? When the CLL becomes clinically detectable? When the CLL is bad enough to need treatment again? Some trials have used ‘treatment-free interval’ as the interval. But different units have different criteria for restarting treatment.

The biggest problem with these end-points is that they don’t correlate with overall survival. It is common ground that fludarabine produces more remissions than chlorambucil however the remissions are defined. It also produces longer remissions, however defined. But no trial has ever shown a longer survival for fludarabine than for chlorambucil.

The fludarabine people say that that’s unfair, because patients are allowed to crossover. Patients who fail chlorambucil are allowed to get fludarabine, and indeed, if you do fail chlorambucil you have a very good chance of responding to fludarabine; but vice versa the chances are very small. But this isn’t a game. Fairness doesn’t come into it. This is real life and in real life, patients want to live as long as possible no matter what order they take the drugs in. If someone could show that taking chlorambucil first and then fludarabine later shortens your overall survival compared to having fludarabine first then there would be no question. But the trials do not show that. Of course we will have to wait to see whether fludarabine combinations first are better than chlorambucil first, but so far in the British CLL4 trial the overall survival for chlorambucil first is no worse than for fludarabine plus cyclophosphamide first.

What is the aim of treatment? (Part 1)

Is it to cure?

We want to cure cancer. That was my ambition when I became a cancer doctor. Can cancer be cured? Clearly some cancers can. If you have a skin cancer and you cut off the piece of skin, the chances are it won’t come back. Sure, if it’s a melanoma it may have spread, but most skin cancers aren’t melanomas. In fact insurance policies aren’t loaded if your only history of cancer is non-melanomatous skin cancer. Surgery does cure cancer. The hiccup came with breast cancer. Women who had their breasts off 20 years ago suddenly reappear with bony secondaries. It wasn’t dead; only sleeping. The idea that a cancer could be dormant for many years sowed doubt. Can we ever say you’re cured?

The acute leukemia model

In 1966 everybody with acute leukaemia died – adults in six weeks, children in ten. But 10% went into remission. Remission meant that the patient was well. Not anemic, not apt to bleed, not prone to infections. A complete remission meant that the blood count was back to normal and in the bone marrow no leukemic cells could be seen. Daunorubicin and Cytarabine were new drugs in 1968 or so that turned that 10% into 60% and then 80% by the 1970s. Instead of 9 month remissions, they lasted 2 years or 5 years and one paper said no-one who has survived for seven years has ever relapsed. Was this a cure?

Another false dawn. A few months before I left the National Health Service we admitted a young woman with leukemia 22 years after she was ‘cured’ as a child. She died a few months later with unresponsive disease. Treatment for acute leukemia has got better; patients live for longer and some are apparently ‘cured’ but who can tell?

The numbers

A patient with acute leukemia typically has between 10 to the power of12 and 10 to the power of 13 leukemic cells in his or her body. When he or she goes into remission there may be fewer than 10 to the power of 9. That’s 1,000,000,000 - a billion cells. With that many, the disease will be back in nine months. Further rounds of chemotherapy or perhaps high dose treatment with an autograft will reduce the number further, but below 100,000 we won’t be able to detect them even with the most sensitive techniques. We just have to hope that there are many fewer than one hundred thousand, or that our defensive troops are up to handling an invading army that big. Acute leukemia cells are usually relatively accessible, being in blood and bone marrow, but there are some sites denying access to chemotherapy. With acute lymphoblastic leukemia these sites are the testicles and the brain. Unless these sites are treated separately the leukemia will relapse. Unless we have some reason to suspect leukemia in these sites and deliberately look for them – by doing a lumbar puncture, for instance – we will not know that we have to treat them, so for the brain at least, we routinely irradiate it.

Does the acute leukemia model fit CLL?

What about CLL? Until recently we didn’t have any drugs capable of producing a complete remission, even if defined in a rather looser way than it is in acute leukemia. Then came fludarabine and its various combinations. For the first time we were getting sizeable numbers of CRs. Even with the supersensitive techniques like the polymerase chain reaction (PCR) or multi-channel flow to detect minimal residual disease (MRD) some patients seem to have no detectable disease. And when we add in Campath these MRD negative patients increase in number. These patients seemed to have fewer than one hundred thousand leukemia cells. Perhaps the defending immune system could mop up the rest?

Immune surveillance

One thing we know about CLL is that the defending immune system ain’t much cop. If you’re relying on that to save you it’s like relying on the Newcastle back four. (Sorry, a soccer allusion. Substitute the worst defense in the NFL). And most types of treatment make it even worse. You could try using somebody else’s immune system – ie a bone marrow transplant, but only a few are eligible and it’s a pretty dangerous undertaking.

Secret sites

Then there are all those secret sites. Not the brain and testicles this time, but just about everywhere else. Small lymphocytes are wandering cells. Not just in blood and bone marrow, but all those thousands of lymph nodes, and in the gut and the skin and the thyroid and the prostate and the eye sockets – you’d be surprised where I’ve found CLL cells. How are you going to examine all those? CT scans will pick up big lymph nodes but if they are less than half an inch in diameter they won’t be seen. PET scanning will pick them up if there’s a Richter’s transformation, but quiet old CLL cells won’t be seen.

So can we cure CLL?

If you really want to cure someone with CLL you really need to start when there aren’t many CLL cells to kill and blast them with the most effective drugs you’ve got. The problem with that is that the available evidence suggests that there is no benefit in treating asymptomatic, early-stage disease until symptoms develop. Now, that may be because you have got to use more effective treatment than chlorambucil to show a benefit and you have to avoid treating patients who are never going to progress. This is certainly a question worth asking and there are clinical trials in Europe asking it.

So I ask again. Can we cure CLL? Saving an allograft, I don’t think so.

More on Revlimid

In Athens I had the opportunity to question Dr Giagounidis who was heavily involved in the MDS Revlimid trial about the 11 deaths that occurred in that trial. About half the deaths occurred in Germany. He went through them one by one and was able to satisfy me that they were all unrelated to the treatment apart from one patient who developed neutropenic sepsis.

At Athens Alone

At Athens alone. Some may recognise the phrase from Paul's first letter to the Thessalonians chapter 3 verse 1.

I was in Athens to attend a meeting of the Oncology Network Europe on hematology cases. It was all a bit mysterious. The e-mail arrived promising an all expenses paid trip to Greece. Most people who received it were highly suspicious, thinking of it as some sort of Timeshare entrapment. In fact it seems to be all above board. You can check them out at their website at
http://www.oncologynetworkeurope.com . I was very pleased that I went.

First, although the funders of the enterprise are clearly pharmaceutical companies, this was not drug company propaganda. The programme was set around difficult cases of myeloma, MDS, CLL, CML, and follicular lymphoma - just the diseases that I have spent my life dealing with. The speakers were experts from Sweden, Greece, Germany, Italy and the UK. Their expertise is unquestioned and they were completely up to date. There have been major therapeutic advances in all these disease in recent days, so it is important that physicians should be aware of them. But we were informed, not by a company representative, but by oncologists who have dissected the clinical trials and the scientific evidence.

The location was splendid and the hotel very comfortable. Those attending (I can't abide 'attendees' - 'ees' are always the object not the subject of the verb, as in employers and employess) those attending were mainly from southern and eastern Europe - Romania, Croatia, Greece, Italy, Georgia, Turkey. Most had kept up with the literature, but perhaps they were self selected (giving up a Saturday).

I was particularly interested in the role of immuno-radiotherapy with Bexxar and Zevalin. I had always disregarded these agents in CLL because they cannot be given if there are more than 25% B cells in the bone marrow. But, of course , after therapy the B cells count in the bone marrow may be far less than that. There is still the question of whether marrow reserve is sufficient after chemotherapy to withstand the radio-isotope. I would need to consult an expert on this.

There were a couple of hours of light left after the meeting finished. The Acropolis closes at 3pm so I went to the Areopagus (or Mars Hill - if you read the KJV). It was where Paul preached his famous sermon, "Men of Athens, I perceive that in every way you are very religious." It is nearly 30 years since I last went there and the only change is that they have put in a steel staircase to replace the worn and slippery stone steps. You can see a picture of it at
http://www.padfield.com/2001/areopagus.html .

It was warm enough to walk around without a coat, and quite sunny. On the plane home I finished the Terry Pratchett children's book "A Hatful of Sky". Two useful snippets. I'm not, as I thought, afraid of heights. I walk past tall buildings and massive trees every day without the slightest feeling that they might fall on me. On the other hand I am afraid of depths. When I looked down from Mars Hill I felt sure I would fall in. The second is this: Life is like a balloon; it is important to hold on to the string.

I returned to 200 emails. Somebody had doubted that the lurkers were really lurking on the ACOR list and threatened them with bile beans. They wrote back pleading not to be purged.

PC Plod

I am fan of Michael Connelly. I have read all the Harry Bosch books and have just finished his latest, "The Lincoln Lawyer". It exposes the flaws in the adversarial system of law. An attorney's job is to give his client the best possible defense - justice is irrelevant. In fact, the lawyer would rather not hear his client's view on whether he was innocent or guilty, since he cannot tell a lie in court. He doesn't want the facts to interfere with the defense. In The Lincoln Lawyer the defendant is a real estate dealer - what we in England call an estate agent.

Now there are hundreds of jokes about lawyers. Like the one in Spielberg's Peter Pan that Robin Williams tells - I hear that lawyers are replacing rats in animal experiments; the public is less concerned when they hear of lawyers having their eyes put out or being operated on without anesthetic and they've found that it's possible to get lawyers to do things that even rats won't do.

In England those sorts of jokes are told about estate agents. When the AIDS epidemic began the New Scientist published a cartoon that showed an old man with a beard on a cloud in the sky talking to an angel having just thrown a lightening bolt down to earth. He is saying, "That's done for the homosexuals, now can we think of something worse for the estate agents?"

It raises the interesting question of who can be the butt of humor in these politically correct days. 22 years ago the left leaning New Scientist could gaily make jokes about homosexuals (or was it a joke against estate agents or a joke against God or against fundamentalist Christians and Muslims?) John Cleese takes the mickey out of the Germans in "Don't mention the war!" one of the sublime episodes of Fawlty Towers, and Yes Minister has a wonderful episode where the civil servant explains that the real reason for the British nuclear bomb was that the French have one; the French have always been the real enemy ever since 1066. Then there is the story about Italian Tanks, with 14 reverse gears and one forward gear in case they are attacked from behind.

We can no longer make jokes about Africans - there were certainly jokes about Idi Amin - it is this inhibition that allows tyrants like Robert Mugabe to thrive. Bin Laden is fair game, but we have to be careful that we don't apply the punch line against all Muslims, all Arabs, all Asians, all people with different colored skin. Ethnic jokes are out. I tell a lot of jokes against the English but then I'm English. Don't you try! I once got into trouble for telling a joke against the IRA (Irish Republican Army - nothing to do with the Inland Revenue. Now there's a target.)

Now there are lots of Jewish jokes. You can Google them if you like. I particularly like the one about the Jewish princess who asks her father if she can visit Harrods now that it's owned by an Egyptian - but then I'm only one sixteenth Jewish so I can only tell you one sixteenth of the joke.

Precious people

A precious people, dearly loved,
Chosen by God for holiness;
May Christ’s compassion clothe our hearts
And fill our lives with gentleness.
Ah, Christ, who splendour cast aside,
Puncture our pompous vanity!
Give us to face our daily tasks
With patience and humility.

How hard we find it to forgive!
We nurse our wounds in secret store.
We cling to grievances long past
And cultivate our bitter core;
Yet Jesus died to rescue us
While we were drowning in our woes.
Forgiven, how can we withhold
A like forgiveness for our foes.

The world has known no greater love
Than that my saviour gives to me,
That other virtue supersedes
And lasts throughout eternity.
The Golden chain that binds his church
And captures sinners perfectly
That links our lives in gratitude
And holds our hearts in harmony,

Family matters

Today I watched as my daughter was admitted to membership of the Royal College of Physicians of London. It took me back 35 years to when I was admitted. It was a great pleasure to see her welcomed in by the President, Carol Black. 44 years ago when I first met Carol she was Lady President of the Union among the students at Bristol University. She was a final year student, in English I think, but having met the medics she changed courses and started again as a medical student. I have followed her career. She became a Professor of Medicine at the Royal Free Medical School and one of the leading experts in the world on scleroderma. She is only the second woman to become President of the College.

Also today my eldest son was awarded a fellowship to support a sabbatical year in the States later this year. I'm not sure where he will go, but it means I will have an excuse to spend some time in America this year.

Sick transistor, Gloria.

We will not let the world complain
For hearts beating hard, for joy turned to pain,
For tears shed to trickle in twos down the drain,
For the glory of England, the might that was Spain,
For Tobrouk and Montgomery El Alemain,
For all that once was;
For moments of mind,
For fragments of love,
For a second of art ticked away;
For the catch of a voice,
For the touch of a hand,
For the sound of a hot summer’s day;
For Florentine David dissolved by the rain,
For the sound of a horn, for dead Dennis Brain,
For all not the same
Be happy they came;
For all that is transient may happen again

Who needs treatment?

It seems a strange question to ask; surely everybody with cancer needs treating? Let me tell you a story about prostate cancer. This has suddenly got a lot commoner than it was. In the US it about 6 times as common as it was 30 years ago and in the UK about twice as common. The reason, of course, is prostate specific antigen (PSA) testing. Not everybody with a raised PSA has prostate cancer; in fact two thirds of men with a raised PSA don’t have prostate cancer. But the only was to be sure of that is to do a prostatic biopsy.

Said quickly that sounds simple. In practice it is most off-putting. A plastic probe one centimeter in diameter and nine inches long is covered in KY jelly and inserted through the anus. When positioned correctly by ultrasound guidance it is pressed against the front of the rectum and a biopsy needle fired. It feels like a dull thud hitting the prostate gland, but it doesn’t hurt exactly, unless it happens to catch a nerve. If it does then it causes an eye watering pain extending from the prostate down to the tip of the penis. When this has subsided, the operator does it again. Nine times.

You get the result a week or so later. Likely it will be benign, but if it shows cancer you then have the agonizing decision of whether to have surgery or just watch and wait. If you choose surgery you’d better choose your surgeon and carefully scrutinize his complication rate. For among the complications of successful surgery are incontinence and impotence. I remember a featured article in Reader’s Digest. The author was so grateful that he had a PSA test. He made a point of stressing how much his wife sympathized with him over his impotence.

Prostate cancer is currently three times as common in the US as in the UK. But the death rates in the two countries are exactly the same. Better surgeons in the US? Or better case selection in the UK?

With CLL the CBC is the screening test and people get one, not because they are looking for CLL, but for any and every other reason. Three-quarters of patients diagnosed with CLL have no symptoms referable to CLL when they have that first blood test.

In 1999 a large meta-analysis of several trials with 10 years of follow-up proved that there was no advantage for early treatment over waiting until symptoms began. Indeed in 1995, after 6 years of follow-up there was a possibility that those treated early did worse.

The problem with this analysis was that the treatment offered was old fashioned chlorambucil. Not only that, but the trial took in all comers; had they selected only those with bad prognostic markers the outcome might have been different, especially had they used one of the more recent treatment that give more complete remissions. This is a question still waiting to be answered, but trials are going on now in Europe to try and answer it.

In the meantime we are all signed up not to treat until the NCI guidelines are fulfilled. These are the NCI guidelines:
One of the items on the following list must be present:
1] Weight loss of more than 10% of body weight in the previous 6 months;
2] Extreme fatigue so that the patient cannot work of perform usual activities;
3] Fevers of greater than 100.5°F for at least 2 weeks without evidence of infection;
4] Night sweats without evidence of infection. They have to be severe.
5] Evidence of bone marrow failure shown by the development of, or worsening of, anemia or thrombocytopenia.
6] Autoimmune hemolytic anemia and/or thrombocytopenia poorly responsive to corticosteroids.
7] Massive splenomegaly (>2.5 inches below the ribcage).
8] Massive lymph nodes or clusters of nodes (>4 inches in longest diameter).
9] Increase in lymphocyte count by >50% over two months or an anticipated doubling time of <6 months.

However, a high lymphocyte count is not in itself an indication for treatment. For everybody else it is wait and worry or join one of those European trials of early treatment, or find a physician who likes to bend the rules a bit.

War of the Worlds

I finally got around to seeing the Spielberg/Cruise movie, albeit on DVD. I read the book45 years ago and saw the old film. This one has modern special effects, a modern marriage, and modern sound. The moving scene where Cruise abandons his son to go to his daughter was lost to me because I could hear a word that was said.

There were some typical Spieberg moments, most paricularly when the long proboscis goes hunting round the cellar for survivors.

It was a three out of five movie. I might watch it again, but not if I had a choice of watching Edward G Robinson or Humphrey Bogart.

Alcohol

Charles Kennedy's battle with the bottle is out in the open. For him it is probably the first step on his road to recovery. I doubt that he will survive as Liberal Party leader, but his liver might recover. Drunks are very plausible characters. Amiable, amusing, daring, smart; they impress the people around them until they shamble into incoherence.

No-one should be surprised that Charles lied about his dependence on alcohol; lying is what alcoholics do. I remember the Ray Milland film "Lost Weekend". He was willing to do anything to get a drink - lie, cheat, steal, betray. It is an accurate picture.

My daughter is a junior doctor in a busy medical unit. She has been astounded at the number of young women admitted to hospital in terminal liver failure. We used to think that it took 20 years of heavy drinking to develop cirrhosis. She believes that for women, three years is sufficient.

I once had a patient in his forties who came to see me because he had large red blood cells. It was immediately apparent that he was both a heavy drinker and a heavy smoker. he had recently remarried. His second wife was a woman aged 23. I explained to them both that they had to change his lifestyle. We decided to try one thing at a time. His 60 cigarettes a day habit was the first target. I referred him to the Stop-Smoking Program. Two weeks later he was admitted to hospital with acute pancreatitis and died. His wife pummelled me on the chest, "I could put up with the smoking; why didn't you stop him drinking?" As if I could.

In the past ten years mortality from cirrhosis of the liver has doubled in Scotland and increased by more than two thirds in England and Wales. Although, England and Wales still have among the lowest cirrhosis death rates in Europe - similar to Holland, Ireland, Norway and Sweden, Scotland has among the highest, similar to Austria, Germany, Denmark, Portugal, Spain and France. However, alcohol consumption and cirrhosis have been reducing in many of the European wine-producing areas, but both are increasing in the UK. The problem is greatest in Scotland. Kennedy is, of course, Scottish. (See Leon and McCambridge. Liver cirrhosis mortality rates in Britain from 1950 to 2002: an analysis of routine data . The Lancet, 2006, 367:52-6.)

The British government is suspiciously friendly to both the tobacco and alcohol lobbies. The notrious gift from Bernie Ecclestone which coincided with the decision to allow tobacco advertising to continue on Formula One racing cars, the 'open-all-hours' policy for pubs and clubs despite widespread opposition, the failure to do anything about the widespread smuggling of wine and tobacco from France (supply of French Hypermarkets is a major outlet for British tobacco and alcohol producers), and even the downgrading of cannabis (if it ever becomes licensed the tobacco manufacturers stand to make a killing) all suggest to me that the British governement is in hock to the unacceptible face of capitalism.

It also helps to explain why despite unprecedented increases in funding the national health service is failing.

Beta Glucan to enhance rituximab

How rituximab kills CLL cells is not known for certain. It could do it by invoking direct apoptotic mechanisms. (Apoptosis = programmed cell death, a means by which cells suicide at the end of their useful life) It could do it by activating complement. (Complement is a cascade of proteins - each one activating the next one in the cascade - that is used to kill cells attacked by the immune system) But most people believe that it does it by antibody-dependent-cellular-cytotoxicity or ADCC. This means that antibody on the surface of the CLL cell invites killer cells to destroy the CLL cell. The killer cell might be an NK cell or a monocyte/macrophage or even a polymorph, all of which have Fc receptors that recognize part of the antibody molecule that sticks out when it binds to the cell. The use of G-CSF or GM-CSF with antibody is to try and activate the killer cell.

Although it is very unlikely that CLL cells are killed by the full activation of complement components from C1 to C9, resulting in the so called membrane-attack-complex punching a hole in the cell, some activation of the complement components is likely with the deposition of part of C3 (known as C3b) on the cell surface. This is quickly converted to iC3b. There is a receptor for iC3b on phagocytes and NK cells, called CR3. Binding of iC3b to CR3 enhances the Fc binding and increases the likelihood of ADCC.

There is another mechanism of killing using CR3, known as CR3-dependent cellular cytotoxicity (CR3-DCC), but it isn't normally used for killing tumor cells, only yeast cells. Yeast cells have beta glucan exposed on their surface. CR3-DCC requires the binding of CR3 by both beta glucan and iC3b. The yeast cell wall beta glucan binds to a part of the CR3 called 'the C-terminal lectin domain of CD11b', and primes the CR3 for efficient cytotoxic degranulation responses after it binds the iC3b by an other site known as 'the N-terminal I domain binding site of CD11b'. But tumor cells lack beta glucan on their surface and cannot trigger CR3-DCC.

However, if you do the experiment in a test tube, and add soluble beta glucan to the reaction mixture, the beta glucan binds to CR3 on monocytes and granulocytes and primes the receptor, enabling the effector cell to kill tumor cells. The next step after showing something works in glass tubes (in vitro = in glass) is to show that it works inside a live animal (in vivo = in life). The late professor Gordon Ross from Louisville, Kentucky looked at this. In mouse models (mouse tumors growing in laboratory mice) monoclonal antibodies were used to treat mice with and without beta glucan given intravenously. The regression of the tumors was much greater when the beta glucan was added than with antibody alone, and the mice lived for significantly longer. These experiments also showed that neutrophil granulocytes were the principle effector cells, that mice deficient in CR3 had no enhancement, nor was there any benefit in mice deficient in complement (C3). The paper is available on Medline Hong et al Cancer Res 2003, 63:9023-31.

But mouse tumors are very different to human tumors. The next step is to look at human tumors. The way this is done is to grow a human cell line in an immunodeficient mouse. These mice with severe combined immunodeficiency (SCID mice) are like test tubes on legs. They have no immune system of their own although they have normal numbers of effector cells. Cells from foreign species can grow well in them when they are injected. They are not rejected the way a normal mouse would reject them. In this case the tumor cells were Daudi cells, a tumor line that is driven to divide by the presence of the EB virus. It carries large amounts of CD20 on its surface, and the monoclonal antibody used was rituximab. The beta glucan was fed to the mice by mouth. The result was that the mice that had beta glucan and rituximab lived nearly twice as long as the mice that only had rituximab. This paper is available on Medline Modak et al Leuk Res 2005, 29:679-83.

These results are sufficiently encouraging for the people at Sloan-Kettering to start a clinical trial in children. These are the details:

Phase I Study of Beta-Glucan and Rituximab in Pediatric Patients With Relapsed or Progressive CD20-Positive Lymphoma or Leukemia or Post-Allogeneic Stem Cell Transplant-Related Lymphoproliferative Disorder
Primary Objectives are to determine the maximum tolerated dose of beta-glucan when given in combination with rituximab in pediatric patients with relapsed or progressive CD20-positive lymphoma or leukemia or post-allogeneic stem cell transplant-related lymphoproliferative disorder; to determine the toxicity of this regimen, with special emphasis on the degree of B-cell depletion and immune suppression, in these patients; and to determine the effects of beta-glucan on leukocyte-mediated cytotoxic effects in patients treated with this regimen.
The secondary objective is to determine the anti-tumor effect of this regimen in these patients.
This is a dose-escalation study of beta-glucan. Patients are assigned to 1 of 2 treatment groups according to diagnosis.
Group I (lymphoma or leukemia): Patients receive rituximab IV on days 1, 8, 15, and 22 and oral beta-glucan once daily on days 1-28 (days 8-28 of course 1). Treatment repeats every 42 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Group II (post-allogeneic stem cell transplant-related lymphoproliferative disorder): Patients receive rituximab IV on days 1, 4, 8, 15, and 22 and oral beta-glucan once daily on days 8-28. Beginning on day 42, patients with responding disease may receive monthly rituximab prophylaxis until their CD4 cell count is > 200/mm^3.
Cohorts of 6 patients receive escalating doses of beta-glucan until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. Patients are followed every 3 months for 2 years. A total of 6-24 patients will be accrued for this study within 2 years.
Memorial Sloan-Kettering Cancer Center, New York, New York, 10021, United States; Shakeel Modak, MD 212-639-7623

What makes a good doctor?

All doctors are different and none of them are perfect, but there are characteristics that make some better than others.

First, the doctor must be able to hear. I was going to say listen, but there is that expression “ever listening but never hearing”. A doctor can get by appearing to be a good listener. One partnership I knew was very popular with the patients. Both the doctors (now long retired) were very good listeners. Unfortunately, they didn’t understand what they were listening to. Despite their incompetence, their patients got a very good service because almost everybody who went to see them was referred to a specialist – and this was in the days when specialists did home visits. Of course, they were often referred to the wrong specialist, but specialists were known to play Happy Families with the referrals. They would meet at a local café and the cardiologist would bid two hernias for a chest pain and the surgeon would swap.

It is important to listen to the patient and hear what he or she is saying because patients tell you what is wrong with them. This is the advantage we have over veterinary surgeons, who just have to poke and guess. Television’s Dr House says that patients always lie. So they do, but they don’t mean to. They leave things out that are important and they try to interpret things so that they make a pattern. In order to make things fit with their erroneous diagnosis they create false memories. That is the skill in taking a history; you ask leading questions to discover what seems trivial to the patient but meaningful to you. Don’t be afraid to interrupt the flow. Students tend to write down verbatim what the patient tells them. The result is wordy and repetitive, and comes up with the patient’s own diagnosis. If the patient were able to diagnose he wouldn’t need a doctor, and this is especially true when the patient is a doctor. I know that when I am a patient I’m always jumping to the wrong diagnosis. The doctor needs to be objective, to listen dispassionately, and to hear what is being said. The patient needs to tell the truth in plain English, not medical jargon. When the doctor hears medical jargon he first has to translate it back into plain English and then back into his own medical jargon. Does the patient mean the same by ‘chronic’ as I do? Or does she just mean that the pain is very bad?

Second, the doctor needs to be able to see. That’s stupid; how many blind doctors do you know? Everybody sees. No, everybody looks but it’s often a case of “ever looking but never seeing”. Even a blind man sees better than that. Dr House is, of course, a play on “Dr Holmes”. Arthur Conan Doyle was said to have based his great detective on a famous Edinburgh doctor, so a doctor named House making use of Sherlockian observation is doubly amusing. I do not expect the doctor to look at the mud on a man’s boots and deduce that he was once a corporal in the 14th Lancers serving in India and that the enlarged spleen must therefore be an infection cause by bathing in some obscure tributary of the Ganges, but I do expect him to notice that the patient is frightened or nervous, or embarrassed or holding something back. I expect him to know how to look for pallor, and what pigmentation of the skin creases means, and to know that you must look at armpits before you feel them.

The old medical student story is of the teacher who tells the class that the most important skill in medicine is observation and the second is testing the urine. “Now watch me,” he says, and proceeds to dip his finger in a glass of yellow liquid and then suck it. The students hesitantly copy him, grimacing as they suck. The professor chides them, “You will remember that I told you that the most important skill was observation. Had you been observing carefully you would have noticed that I dipped my index finger in the urine and sucked my middle finger.”

Consultation by telephone or via the internet is dangerous because you can’t see the patient. Everybody who asks me for remote advice needs to remember this. You are asking a blind man to help you.

The doctor also needs to be able to see in order to read. I am amazed at how little doctors read. The incompetent partnership that I referred to earlier was castigated by a local surgeon. “One of them doesn’t read letters, he complained, “and the other one can’t!” Reading is the only way to keep up to date. When I qualified, a child with acute leukaemia survived for on average 10 weeks and an adult for 40 days. Things have changed so completely that we might be living on a different planet. I was dismayed when the improvement happened that physicians were still reluctant to offer patients chemotherapy as it “only made the dying more dreadful”. More than seven years after I introduced VH gene mutations as a prognostic factor in CLL many oncologists have never heard of them. Indeed, some oncologists don’t seem to have heard of Rai staging.

If you don’t read, you don’t know the limits of your own competence. No doctor can possibly know everything. But unless you know what you don’t know you are dangerous.

It goes without saying that a doctor must be skilful. But skills can be learned by almost anyone. The best at bone marrow trephines are the nurses at MD Anderson who do 60 a day. Practice makes perfect. Our Hickman lines are put in by a radiologist. He also does prostatic biopsies. A different radiologist is the most skilful colonoscopist I know.

My near namesake, Dr Hamlyn, was a missionary doctor in Ethiopia. A major problem he and his wife encountered was the leaky young woman. The African girls had their first baby at a very young age and traumatic births left them with vesico-vaginal fistulas. Their urine leaked from their vaginas. They were disowned by their husbands and kicked out of their villages because they were smelly. Dr Hamlyn set up a service repairing the fistulas. He and his wife dressed them in a brightly colored dress and sent them back to their villages, clean and dry, and they were mostly accepted. Some were not and found their way back to the Mission Hospital where they were put to work as cleaners and cooks and then as nursing or even operating theater assistants.

One young woman began assisting in the theater and eventually began to do the operation herself, first with the assistance of Dr Hamlyn and eventually alone. Now, still unqualified, she trains surgeons from all over Africa to do this one operation. Nobody is better at it than she.

The point is that the technical skill is not enough. Surgeons are revered by the community. What they do is very impressive. Not as impressive as driving a Formula One car around Monte Carlo, but then, they are not paid so much. When you get down to it, surgeons are basically plumbers (and these days they’re not paid as well as them, either). One surgeon told me, “It’s not knowing how to operate that matters; it’s knowing when.”

This is all a roundabout way of defining what the third requirement is for a good doctor. He or she must be a human being. I’ve known surgeons (and physicians – let’s not get partisan) who were really robots. Automatons, they go through the same procedure with every consultation. Every operation is carried out with meticulous skill, but the anesthesiologist manages their care. That’s what a good doctor must do: care.

The doctor must be interested in the patient; not as a case but as a person. He has to show it, too. Someone told me that during their time as a student at St Barts they were taught two things: always have shiny shoes and always get up from your desk and shake hands with the patient when he enters the room. There are worse things to learn; not as a ritual, but as a token of interest, of care. Doctors who take a history while staring at the notes are performing a chore, not showing an interest. It mustn’t be feigned; that always shows. Doctors who care are available. Doctors who care are truthful. Doctors who care call back, answer e-mails, look things up, hold your hand, offer comfort in distress, time in grief. Doctors who care do not stand on their dignity, are not too proud to listen to your views or refer you on; and they keep an open mind on new ideas.

CAT scans

Should you have a CAT scan as part of your diagnostic work up?

A CAT scan uses a computer to produce pictures of what thin slices through your body would show if you were put through a bacon slicer. There is no doubt that they have revolutionized the practice of medicine. When I was a lad the abdomen was a mystery. You could feel things with your hands through several layers of flesh, and you could try to figure out what they were by tapping, listening, ballotting and guessing. X-rays were pretty hopeless, and frequently we resorted to opening it up to have a look. The chest was easier - the stethescope allowed you to listen to snaps, crackles and pops coming from the heart or lungs and chest X-rays showed shadows that could be interpreted by some. The pelvis could only be examined by sticking your finger in various orifices. Pity those with short fingers. What went on inside the head had to be guessed at by very indirect signs. Neurologists were the super-diagnosticians, able to deduce a diagnosis from the merest hint of an absent knee jerk. Of course, they had no treatments; that would spoil the fun.

Then came the CAT scan and most people gave up on clinical signs. You could see what was happening; you didn't have to guess. Head scans revealed a wonderful picture of the brain. Neurologists nowadays ask for a CAT scan first before offering an opinion, and if you already have one they ask for an MRI. I have a colleague who is whizz at chest CTs. Listening to him demonstrate a case opens new vistas of understanding. I am most used to abdominal scans. You can get a clear picture of abdominal glands in the lymphoid tumors.


The problem with CAT scans is the amount of X-irradiation they use. Radiologists used to joke that they were no longer mere diagnosticians; with the amount or radiation a patient received they could now be thought of as radiotherapists. They were exaggerating, but there is certainly a concern that too many CAT scans can damage your health.

The public's attitude to radiation seems to go through phases. Immediately after World War II there was a nuclear hubris. The atom bomb had won the war and everybody wanted the benefits of X-rays. They even had X-rays in shoe shops to see that your shoes weren't too tight. It was interesting that President Eisenhower couldn't pronounce 'nuclear' - it came out as 'newcular' and several American Presidents have followed suit.

Then came the nuclear disarmament movement, generously funded from the Soviet Union and many people turned against anything nuclear. Then Three Mile Island, and especially Chernobyl really put the hoodoo on the whole nuclear question. In the UK we rejected irradiated food, even though it was quite harmless and wouyld have saved thousands of cases of food poisoning. Now with greenhouse gases, global warming and Russian gas supplies cut off, nuclear power stations are back on the agenda.

As with most things radioactive, the risk of CAT scans is greatly exaggerated, but there is a risk and they should be used sensibly.

Are they of any value in CLL?

The first thing to say is that staging of CLL does not involve a CAT scan. Lymph node enlargement only counts if you can feel it with your hand. An enlarged spleen is not enlarged unless you can fel it below the ribs. It's the same with the liver. If you started to stage according to the CAT scan, then patients who are stage O would be called stage I or II, and the prognosis of stage I and II would be much better than we think it is. All the rules on how to treat it would have to be changed. So for staging CAT scanning is out.

There are moves afoot to make CAT scanning part of the work-up for patients entering clinical trials, and I can see the merit in this. Watch this space.

I think that patients with unexplained symptoms who appear clinically to have early stage disease should have a CAT scan. It could reveal much more extensive disease than had been imagined and would add to the understanding of what is going on.

So the answer is - as a screening test, I would not advise CAT scanning, but to investigate unexplained symptoms then it is a useful test.

The perfect off-break

The perfect off-break has drift and dip. The idea is to deceive the batsman into thinking that the ball will pitch closer to him than it will and secondly to separate his bat from his pad.

Cricket is a sideways-on game. To bowl a perfect off-break it is necessary to be very sideways-on. The tendency is to look at the batsman beneath the left arm; on the contrary you must look at him over the left shoulder. The length of the run up is immaterial. Bob Appleyard used to bowl off-breaks from a run-up as long as Freddie Trueman's: Jim Laker took only a few paces. You hold the ball across the seam and apply clockwise rotation to it at the time of delivery. The ball has to be given some air. These flat-jack off-spinners are just trying to bore the batsman out. The rotation of the body in delivery, the high arm necessitated by the over-the-shoulder presentation and the rotation of the ball will provide the drift and dip.

The batsman will see it as a half-volley and be drawn into the drive, the the dip means that he doesn't get to the pitch of it. He will think he has got the line right but the drift will deceive him. As the ball drifts to the off he has already planted his front foot and can't move that so he follows the ball with his bat, opening the gate between bat and pad. Then as the ball pitches it breaks back and takes the off peg.

I bowled my last perfect off-break eleven years ago next September. The memory lingers.

Bone marrow aspirates and trephine biopsies

Everyone has seen a marrow bone. The inside of a bone is colored red or yellow, depending on how much fat there is. On the butcher's slab it looks like a jellied honeycomb, but in life its temperature is 98.6 and it is a liquid surrounding a network of bony spicules. It is the site of blood production, and under the microscope you can see all the precursor cells of the blood. There are also the cells of the supporting structures, but the commonest cell is a fat cell. The long bones in the legs and arms mainly have fat cells in their bone marrow. A small proportion of the marrow cells are stem cells; they can mature into any type of blood cell, but some have the possibility of maturing into cells of other tissue. Just how complete this plasticity is, is still a matter of conjecture.

To examine the bone marrow there are two separate procedures, though they are often combined in a single operation. Marrow aspiration involves sucking out the liquid marrow through a small hole in the bone; marrow trephine means taking a core of bone through a hollow needle. It is usual to take a specimen from the iliac bone. This is the large flat bone that forms part of the pelvis. Either the front or back of that bone is a suitable site. I learned to take marrow aspirates from the sternum or breast bone, which in my view is very much easier, but being in front of the patient's nose, is perhaps more frightening.

The marrow aspirate needle follows a design by Salah or Klima (the difference is how the guard that stops you going in too far) is fastened. It is a hollow needle with a solid insert that is removed after it has been inserted into the bone. A syringe is fastened to the needle and suction is applied. This is a painful procedure. I am told that there is a special sort of pain when the suction is applied. However, it is a very rapid procedure that can be over in about 30 seconds after the needle is inserted. Anesthetic is essential. The skin and periosteum (the membrane that surrounds the bone) have nerve endings that must be dulled. Before the procedure begins lignocaine (lidocaine) is infiltrated at the site. Now comes the mistake that is most common. you have to wait until the local anesthetic works. Many operators are too hasty.

The marrow trephine needle is based on a design by Jamshidi. I learned to do trephines with a Sacker-Nordin needle. This was a horrific implement, about a half in diameter; it comprised a saw and a spike. We seldom did trephines in those days. The Jamshidi is another hollow needle with a solid trochar, but about 3 times the size of an aspirate needle. The trick is to have a tapered end so that after a core of marrow is cut out, it is retained within the needle while the needle is withdrawn. A trephine is generally taken from the back of the iliac bone at the top. It is more painful and takes longer than an aspirate. Good analgesia is essential. Some people prefer to be put out with a shot of midazolam; others prefer a pre-med with pethidine (meperidine). Again it is very important to wait long enough for the local anesthetic to work. Some people have tough bones and it takes considerable force to get the needle through the outer table of the bone. It is not an easy technique and beginners should always render their patients unconscious before they have perfected the method. Patients should always opt for an experienced operative if they intend to stay awake for the operation. Ideally it should be possible to obtain a core of bone at least an inch long.

The purposes of the two procedures are different. The trephine obtains a sample for histology. The core of marrow can be sliced and stained and examined down the microscope, but first it has to be decalcified, otherwise it would damage the knife. The decalcification process alters the structure of the marrow and it may mean that certain immunostains don't work well. The histology allows an accurate assessment of the anatomy of the bone marrow and a good assessment of how much of the marrow is replaced by tumor. The aspirate obtains a suspension of cells, which may be spread on a slide rather like a blood smear or used for other examinations like flow cytometry or cytogenetics or bacterial culture. You get a much better picture of the nature of the cells and their immunoreactivity, but not their relationship to each other. It is also subject to sampling error, so the assessment of percentage of a particular cell is not so accurate.

What is the need for a bone marrow in CLL? In most cases a bone marrow is not needed to make the diagnosis, which is made perfectly well from the blood smear. In cases of SLL, diagnosed by lymph node histology, a bone marrow trephine may be done to see if the bone marrow is involved (it almost always is). A bone marrow trephine used to be used to determine the prognosis, but this is now out of date. Four histological patterns were described: interstitial, nodular, nodular and interstitial, and diffuse. Only the diffuse pattern carried a poor prognosis. However, this has now been superseded by the modern prognostic factors.In clinical trials it is important to document the state of play before and after the treatment. Bone marrow trephines are recommended before and after treatment. It is impossible to attain a complete remission according to the NCI criteria if a bone marrow is not done. Trials that have declared CRs without a bone marrow trephine consistently get a 'better' success rate than those that insist on one. Outside clinical trials there is some debate as to whether a trephine should be done. If it is the intention of treatment to get the best possible remission then a trephine should be done so as to know when to stop treatment. However, it may be that in the future estimation of MRD will replace the trephine.

Movie sound

Is it only me or do others find that the volume in movie theaters is set too loud? There is an imbalance between the speech and the music. Actors seem to believe that they must sound natural, and that naturally people mishear or don't hear what others are saying. I have taken to watching foreign fims with subtitles so that I can read what the actors are saying.

The other evening I saw a bit of Olivier's Henry Vth. It was a joy to hear English spoken as if the words were meant to be heard and understood.

I am sure that the spectacle of films like Lord of the Rings and Narnia is meant to be appreciated in a theater, but give me a DVD any time, where I can turn the volume up for the speech and down for the music and battle sounds, and hit the pause button for comfort breaks.