Tom Treasure Weblog

Over the past few years, this question has become more pressing, both for the profession and for me as a surgeon. However long and hard I look at the problem I come to the same conclusion – we need a proper controlled trial.

For the twenty years until 2001 did a very broad range of work as a cardiothoracic surgeon. My cardiac surgery, in addition to the full range of elective and emergency surgery for ischaemic and valvular heart disease, included an increasing tertiary referral practice in aortic surgery and a period of some years in transplantation. Consequently in thoracic surgery, to somewhat limit my range, I left oesophageal surgery and chest wall reconstruction, for example, to full time thoracic colleagues. As for Mesothelioma, it was rare when I started and I was content to see the few cases that came along go to the pure thoracic surgeons for an opinion. Now two things have changed. Mesothelioma has become much more common and, having been invited back to Guy’s Hospital, my alma mater, as a General Thoracic Surgeon, I have had to take a position on this challenging problem.

The problem: Mesothelioma now kills more people a year than either melanoma or cancer of the cervix. The death rate will rise for 10-15 years. About 60,000 new cases are projected in the UK over the next 45 years. The same is true in Europe. The epidemic may be declining in the USA but in many countries in Asia and South America asbestos is still uncontrolled and there is bound to be a huge burden of illness.

Is there any hope of cure? Extrapleural pneumonectomy (EPP) promulgated in the 1970s by the British surgeon Eric Butchart is the radical surgery on offer in which the parietal pleura, mediastinal pleura, pericardium and the diaphragm are taken en bloc with the lung inside the envelope. If surgery alone had a self evident role it would probably have been established by now – or would it?

An historical digression: Consider the history of mitral valvotomy for rheumatic mitral stenosis. In the 1940s the proposed operation of valvotomy was authoritatively declared to be not only dangerous to the point of recklessness but also misconceived since any physician knew that it was the myocardium that was the problem; the stenosed valve was a non-contributory epiphenomenon. Within a few years of Bailey, Harken and Brock’s operations in 1948 it was universally accepted. Surgery had been first proposed fifty years earlier in 1898. It took fifty years to become established (Treasure T, Hollman A. The surgery of mitral stenosis 1898-1948: why did it take 50 years to establish mitral valvotomy? Ann R Coll Surg Engl 1995; 77:145-151).

The case for EPP: The best survival has been reported by David Sugerbaker in a subset of 31 patients who had three prognostically significant variables: epithelioid cell type, clear resection margins, no positive extrapleural nodes (JTCVS 1999). Their median survival was 51 months. No reference population anywhere has survival figures with a median in excess of four years. On the strength of these results, Sugerbaker’s team offer patients who meet these criteria radical surgery preceded usually by chemotherapy and followed by radical radiotherapy. Not to do so would be to deny 50% the chance of cure. They add weight to their case for EPP (or weaken it, depending on one’s point of view) by adding an argument ad hominem, accusing the other side (and this is an issue where sides are taken) of therapeutic nihilism and surely nihilism in this and all cancers must be a thing of the past?

The case against EPP: To perform EPP is to base a lot on just 31 patients retrospectively selected. It may all be a consequence of retrospective exclusion of the patients with unfavourable features. Let me explain. If one establishes favourable features from a data base, and redefines the groups on the basis of significantly favourable and unfavourable features, there will be a difference in favour of the better group. That is a statistical inevitability, leading to a circular argument. That is why in developing a risk model the data are randomly divided into a first test set to devise the risk model and the remainder are used to test its reproducibility.

Is it likely that the results will be replicated prospectively? Let us look at that again in clinical terms. You have identified the favourable features for longer survival. You do not operate on those without favourable features and confine your efforts to those most likely to survive. You then look at survival for the selected group operated on. They will probably do less well than the artificially selected group in the retrospective analysis but they may well do better than historical controls. But the historical controls are dominated by the very sort of cases that you elected to not operate on. Again, it becomes circular and self-serving, say the doubters.

Like those in favour, those against EPP seek to bolster their arguments with emotive language, answering the charge of therapeutic nihilism with references to quality of life. They emphasise the inescapable fact that trimodality therapy will take six to nine months. Perhaps it is inhumane to use up the best remaining months of someone’s life this way.

The basis of equipoise: So this is the situation I found as I took up my tools as a born again general thoracic surgeon. Which policy to adopt? The disease was becoming more common and we were diagnosing cases ever more frequently, sometimes several a week. Which camp was I in? Either way I faced a personal problem of integrity. Could I, as a sceptic, deny active treatment without the evidence to back up that decision or, as an enthusiast put patients through extreme treatment on a judgement made outside the evidence? Whichever of these two opposing views is espoused, and however well intended, the evidence is simply not there to support either. Are we entitled to a free for all, each side engaging in highly charged rhetoric?

My colleague Jules Dussek invited me to a meeting of his European Thoracic Surgical Club in 2001 soon after I joined him at Guy’s. On the programme was the Italian surgeon Maggi who related his EPP experience. Also present was the epidemiologist Julian Peto who had correctly predicted the epidemic in the The Lancet in 1995. Peto saw a randomised trial as the only way to address the uncertainty. He even had an acronym ready for the trial - MARS (Mesothelioma and Radical Surgery). Independently of Peto, the English surgeon David Waller and the Irish oncologist Ken O’Byrne had proposed a trial, so we joined forces.

One compelling reason for a trial is that the numbers of cases in years to come will place a heavy burden on resources. If treatments are effective we must fight to have them at our disposal. But what if they are not? The medical philosophers Brody and Miller have laid down the gauntlet with this strong challenge:

“So long as all the physician had to offer the patient was his own time and advice and a few herbs and powders, both medicine and society could comfortably claim that the physician’s duty of fidelity was owed solely to the individual patient. When physicians can, with the stroke of their pens, literally bankrupt the community, the community may no longer be able to tolerate that view of the physician’s duty. (J Med Philos. 1998;23:384-410)

The physician’s perception of where duty lies can lead to some anomalous situations. Respiratory physicians are often the first point of contact with patients, putting them in a powerful position to effectively veto the trial in their area, whether on the grounds of science or ethics. At the other end of the control chain is the surgeon. When presented with information about the trial some surgeons say it is “unethical” to offer this operation, others claim it is “unethical” to deny it to the patients who in their judgement might benefit. Other than quibbling with their casual use of the strong charge that colleagues are “unethical” I cannot argue convincingly against either.

The trial design: A trial which looks like “a lot” versus “a little” is hard for doctors and patients, hence the attempt to balance the arms. In the MARS trial EPP is sandwiched between chemotherapy and radiotherapy as that is how the best survival rates have been achieved. In MARS, the control patients are also given full active trimodality therapy; every treatment is available to the patient - short of EPP.

Is it ethical? The commonest objection we receive is on this basis. Yes, it is ethical. This trial has been extensively discussed in National and International meetings on many occasions during its development phase. It has passed through all the hoops to gain ethical acceptance (MREC) as well as scientific approval (CTAAC and NCRI) and funding (Cancer Research UK). Its ethics have been carefully considered.

Consider the alternative. What can be “ethical” in deliberately choosing to remain in uncertainty and thus consistently use treatments that fail to help - or are actively harmful? It is beyond any individuals clinical judgement to unravel cause and effect. There is a widely variable course in this disease, only the best cases are selected for radical treatment, the treatment has three components, all severe, and not all patients complete all three. Any multivariate analysis is beset with confounding. Whichever way I look at it, I come to the same answer – we need controlled trials. MARS has started as a small scale feasibility study. It is the first proper trial of EPP and it should not be the last.