by Henry Marsh
The operation on Ludmilla took eight hours and was a great success. The first operation on Tanya took ten hours, and then there was a second operation that took twelve hours. Both operations were complicated by terrible blood loss. With the first operation she lost four times her entire circulating blood volume but she emerged unscathed, although with half of the tumour still in place. The second operation – to remove the rest of the tumour – was not a success. She suffered a severe stroke. She had to stay in the hospital for six months before she was, more or less, well enough to return home to Ukraine. I drove her and her mother to Gatwick, with the help of Gail and her husband. We stood by the Departures gateway. Tanya’s mother, Katya, and I kept on looking each other in the eyes – she with desperation, I with sadness. We embraced, both of us crying. As she started to wheel Tanya in her wheelchair through the gate she ran back to me and hugged me again. And so they left – Katya pushing her mute and disfigured daughter in her wheelchair, and the Ukrainian doctor Dmitri beside them. Katya probably understood better than I did what the future would bring.
Tanya died eighteen months after her return home. She would have been just twelve years old. Instead of a single, brilliant operation she ended up having to undergo many operations and there were serious complications – ‘complications’ being the all-encompassing medical euphemism for things going wrong. Instead of a few weeks she had ended up spending six months in my hospital, six horrible months. Although she did eventually get home she returned more disabled than when she had left it. I don’t know exactly when she died and I only got to hear of it by chance from Igor. I had telephoned him from London to discuss another brain tumour case. I had asked in passing, a little anxiously, after Tanya.
‘Oh. She died,’ he said. He didn’t sound very interested. I thought of all that Tanya and Katya had been through, of what we had all been through in our disastrous efforts to save Tanya’s life. I was upset, but his spoken English is limited and broken and perhaps something was being lost in translation.
I had last seen her shortly before her death, after her return from England, on one of my regular trips to Kiev. Katya, her mother, had brought her to see me all the way from her home in Horodok. She could just walk if somebody held her, and her faint, lopsided smile had returned. For the first few months after the operations her face had been completely paralysed. This had left her at first not just unable to talk but also with a face like a mask, so that it seemed she had no feelings at all – even the most intense emotions were hidden, unless sometimes a tear rolled down her expressionless cheek. It is sad how easy it is to dismiss people with damaged or disfigured faces, to forget that the feelings behind their mask-like faces are no less intense than our own. Even then, a year after surgery, she was still unable to talk or to swallow although she could now breathe without a tracheostomy tube in her throat. Katya had been with her in London throughout those endless six months, and when I had seen them off at Gatwick Airport, Katya had sworn to give me a present whenever we next met. She now came not just with Tanya but with a large suitcase. This contained the family pig, which had been slaughtered in my honour and turned into dozens of long sausages.
A few months later Tanya was dead. She probably had died from a blocked shunt. After the catastrophic second operation on her brain tumour I had had to insert an artificial drainage tube into her brain and this might well have blocked, causing a fatal increase in the pressure inside her head. Living, as she did, far away from modern medical facilities, it would have been impossible to deal with this. I will never know for certain what actually happened. Nor will I ever know whether I had been right to uproot her from her home in impoverished, rural Ukraine for so many months, and to operate on her in the way that I had done. For the first few years after Tanya’s death Katya would send me a Christmas card – coming all the way from Horodok it did not usually reach me until the end of January. I would put it up on my desk in my windowless office in the huge, factory-like hospital where I work. I would leave it there for a few weeks as a sad reminder of Tanya, of surgical ambition and of my failure.
Several years after Tanya’s death a documentary film about my work in Ukraine was being made and I suggested that it should include a visit to see Katya. The film crew and I were driven in a minibus the four hundred kilometres from Kiev to Horodok. It was in late winter and much of the filming had gone on in deep snow and in temperatures of minus 17 degrees centigrade but as we drove west the snow faded away and, although all the rivers and lakes we passed were frozen solid, often with men fishing through holes sawn in the ice, there was a distinct feeling of spring in the air. I wanted very much to see Katya again – during the six months she and Tanya had been in London I had come to feel very close to them, even though we had no language in common. I also felt very anxious as I could not help but blame myself for Tanya’s death.
Horodok, as with so much of rural western Ukraine, was impoverished and depopulated. Since the fall of the Soviet Union the economy had collapsed and most of the young people had left. There were the rust-coloured, derelict factories that are to be found all over Ukraine and rubbish and broken machinery were scattered everywhere. Katya lived in a small brick-built house beside a muddy yard – when we arrived she seemed as nervous as I was, although she was clearly very happy to see me. We waded across the mud and puddles to reach the little house where there was an enormous meal laid out for us. We sat down with her family round the table as the film crew filmed us. I was so intensely moved to see Katya again that I could scarcely talk, and was quite unable to eat, much to Katya’s distress. I managed to stumble through giving a toast as we followed the Ukrainian tradition of proposing toasts with vodka, accompanied by short speeches.
The following day we went to visit Tanya’s grave in the local cemetery. It was some miles away from Katya’s house, standing on its own beside a wood. The road to it wound along country lanes, lined with bare winter trees, passing through battered and dishevelled villages, each with a pond, frozen over with blue-grey ice, with geese and ducks standing at the edges. Orthodox cemeteries are wonderful places. The graves are decorated with dozens of brilliantly coloured artificial flowers and the gravestones all have photographs behind glass or portraits etched in stone of the deceased. Everything was in perfect order and in marked contrast to the dilapidated houses in the villages of the living which we had passed through on our way to the cemetery.
Tanya’s grave had a six-foot-high headstone from which her carved face appeared – odd, perhaps to western eyes, but beautiful. The sun was shining, the artificial flowers glittered and shook in a light wind and in the distance I could hear the chickens in the local village. The snow had melted and only a little was left, showing up as white lines in the furrows of the ploughed field which we had crossed to reach the cemetery. There was birdsong everywhere. As the film crew set up their equipment I wandered round the cemetery, looking at the gravestones and their portraits. Most of the people buried here would have lived through the most terrible times – the Civil War of the 1920s, the famine of the 1930s (though it had been worst in central Ukraine), Stalin’s despotism and the unspeakable horrors of the Second World War. At least a quarter of the population of Ukraine died violently in the twentieth century. I wanted to ask these dead faces what they had done during those years, and what compromises they must have made to survive, but it seemed to me that they looked back at me as though to say: ‘We are dead. You are still alive. And what are you doing with the time that you have left?’
The film about Igor and me was a great success. It has been shown all over the world and won many awards. At the end of the film I was shown standing in front of Tanya’s grave. I was looking sad not just because of Tanya’s death but because next to her grave, and unbeknown to any viewers, was her father’s grave. He had gone to Poland a few months earlier to make some money as an agricultural labourer since he and Katya were desperately poor. He had managed to earn a thousand dollars and w
as about to set out for home for Christmas when he was found murdered. The money had gone. I had wanted to see Katya not just because of Tanya but also because of her father’s death. Life in Ukraine is not easy.
23
TYROSINE KINASE
n. an enzyme that acts as an on/off switch in many cellular functions. Drugs to reduce its activity, known as tyrosine kinase inhibitors or TKIs, are used in the treatment of many cancers.
‘Are we quorate?’ the chairman asked. A rapid head count showed that we were, so the meeting began.
The chairman, after making a few brief jokes, got to the business of the meeting.
‘We have patient representatives from the Support Group for the technology we are discussing today,’ he said, looking towards three elderly grey-haired men who sat on one side of the hollow square of tables around which the Technology Appraisal Committee was seated. ‘Welcome!’ he said, with an encouraging smile. ‘We have our clinical experts,’ – he pointed to two grave-looking men next to the patient representatives – ‘and we have representatives from the company whose drug for this cancer we are considering,’ he continued, in a slightly more formal voice, looking towards two anonymous-looking men in dark suits with large box-files on the floor in front of them. They sat a few feet behind us, away from the tables.
‘Mr Marsh is the Clinical Lead and will tell us about the evidence for the effectiveness of the drug, but I thought we might first start with statements from the patient representatives.’
The first of the three elderly men cleared his throat a little nervously and, with a sad and resigned expression, delivered his statement.
‘I was diagnosed with the cancer two years ago,’ he began, ‘and at the moment am in remission. I have been told that it’s bound to start growing sooner or later and the only possible treatment when that happens will be this new drug you are considering today . . .’
As he spoke, the committee listened in complete silence. It was difficult not to admire his bravery in talking to a room full of strangers in this way. He went on to explain that he had started a support group for patients with this particular disease.
‘There were thirty-six of us to begin with but now there are only nineteen of us left. I would ask you to remember when you consider this drug,’ he added, with a slight note of despair as he finished, ‘that life is precious, that every day counts . . .’
The next elderly man spoke of how his wife had died from the cancer, and he told of us of her suffering and the misery of her final months. The third elderly man opened the briefcase in front of him and pulled out a sheaf of papers. He looked very determined.
‘I am only here,’ he began, ‘in my opinion, because of this drug. I was first diagnosed twelve years ago – and as you all know most people die from it in less than five years. The doctors here had nothing to offer me so I read up about it and went to America and was enrolled in various drug trials. The last drug was the one you are looking at today – I started it eight years ago. The NHS would not give it to me. It has cost me three hundred thousand pounds of my own money so far. Gentlemen . . .’ he looked around the room at us all, ‘I hope you will not consider me to be a statistical outlier.’
After a brief pause the Chairman turned to me. ‘Mr Marsh will now tell us about the clinical effectiveness of the drug in question.’ He pushed the laptop in front of him towards me.
I had volunteered my services to NICE, the National Institute of Clinical Excellence, two years earlier. I had seen an advertisement in one of the medical journals for a consultant surgeon to join one of the NICE Technology Appraisal Committees. I thought the word ‘technology’ would mean interesting things like microscopes and operating instruments but it turned out, to my dismay, to mean drugs. The only exam I ever failed in my prolonged academic career was in pharmacology. The popular press often accuses NICE of being an organization of callous bureaucrats – in America right-wing politicians refer to it as a ‘Death Panel’. These are wholly unfair accusations and as I have become familiar with the process by which new drugs are appraised by the committee, and a decision made as to whether the NHS should use them or not, I have become increasingly fascinated. Once a month I will take the train to Manchester, where the all-day meeting is held in the NICE head office. The members take it in turns to present the evidence about the drugs being considered. On this occasion it was my turn.
The slides for my presentation were projected, one by one, on three of the room’s four walls as I spoke. They were rather dull slides, plain blue letters on a white background, with facts and figures and the long unpronounceable names of chemotherapy drugs, over which I stumbled as I read. I had prepared the slides in a frantic rush with the help of the NICE staff over the preceding few days. The meetings are open to the public and there can be none of the jokes and pictures trawled off Google Images with which I usually decorate my medical lectures. My presentation took about ten minutes.
‘The conclusion,’ I said as I finished, ‘is that this TKI works for this particular cancer in the sense that it significantly reduces the size of the patient’s spleens but this is only a surrogate outcome. It is not clear from the trials whether patients lived longer or had a better quality of life. Many of the patients were lost to follow-up and the quality of life data is largely missing.’
There was then a ten-minute break for coffee. I found myself standing next to the chairman. I told him that I had been in Ukraine two weeks earlier and had been told that drug trials there are a good little money-spinner. Many of the hospitals are involved in trials for the big drug companies and I was told that the same patient might be put into several different trials since the doctors get paid for every patient they enter. If that is true, I said, the results are therefore meaningless. The chairman chose not to comment.
The next presentation was by a health statistician and dealt with the cost-effectiveness of the drug – in other words the question of whether the benefits for patients dying from the cancer are worth the drug’s cost. He had the hesitant delivery of an academic and he stumbled and hesitated as he went through his complex slides. His presentation was a series of graphs and tables and acronyms, using the various models that health economists have developed in recent years to analyse this question. I quickly became lost and furtively looked around me, trying to guess if the other committee members understood his presentation any better than I did. They were not giving anything away and were all watching the projection screens with expressionless faces.
In this kind of economic evaluation the extra life that patients may, or may not, get from a drug is adjusted to make allowances for the fact that the extra time might, or might not, be of only poor quality. Most patients dying from lung cancer, for instance, will be in poor health – short of breath, coughing blood, in pain, in fear of death. If they were to live an extra year (which is unlikely with that particular cancer once it has spread) and were in good health, that extra year would be given the value of one year. If they were in poor health, that value would be correspondingly reduced. This value is called a Quality Adjusted Life Year and it is calculated using ‘utilities’. In theory this involves asking dying patients how they feel about the quality of their life, but it has proved very difficult to do this in practice since it often involves openly confronting dying patients with their imminent death. Not surprisingly this is something from which both doctors and patients shy away. Instead, healthy people are asked to imagine that they are dying, that they are coughing blood or in pain, and then asked how much they feel this would reduce the quality of their life. Their replies are used to calculate the quality of the extra life gained by using the new cancer drug. There are various ways of doing this – one is based on a technique from game theory called the ‘standard gamble’. It was invented by the great mathematician von Neumann who – it is perhaps worth pointing out – also recommended on the basis of game theory a pre-emptive nuclear strike against the Sovi
et Union in the days of the Cold War. Some might conclude that the standard gamble is not necessarily the best basis for human decision-making.
The degree of uncertainty that surrounds all these calculations must also be measured, which makes matters even more complicated. At the end of all this, a final figure is generated – the Incremental Cost Effectiveness Ratio, which is the cost of one extra quality-adjusted life year which the new treatment achieves when compared to the best current alternative. If this is more than £30,000 NICE will not approve the use of the drug by the NHS, although exceptions will sometimes be made for patients dying from rare cancers. Whenever NICE refuses to approve a drug there is an inevitable outcry from patient groups and the drug companies. Patients dying from various distressing diseases will appear on the television news accusing the NHS and NICE of abandoning them. NICE will be accused of being a Death Panel.
The health economist, who looked more like a harmless drudge than a sinister death panellist, trudged through his complex slides. The talk seemed to consist of nothing but acronyms and I constantly had to ask the friendly analyst next to me what they meant. Once he had finished, the chairman of the committee asked the visiting experts for their opinion and the committee members then questioned them.
‘How can we judge the value of the drug if the trials don’t really tell us how the patients were doing and only how long they lived?’ I asked.
There was a grave and bearded professor of oncology attending the meeting as an expert witness.
‘If you look at the Manufacturer’s Submission,’ he said in a very soft voice, which I could scarcely hear, ‘you will see that the quality of life data wasn’t collected because the clinicians running the trial felt it would be bad for the patient’s welfare. It’s a standard problem with cancer chemotherapy trials – it’s difficult to get dying patients to complete questionnaires. One has to use standard utilities instead. But it’s one of the few chemotherapy agents we have for this cancer that has very few side effects,’ he added.