British Editorial: Randomized Controlled Trial Needed to Verify Whether Radical EPP Surgery BestOption for Mesothelioma

© Société Internationale de Chirurgie 2003

Editorial Update

Radical Surgery for Mesothelioma: How Can We Obtain Evidence?

Tom Treasure, M.D., M.S.¹, Simon Swift, M.B.B.S.¹ and Carol Tan, M.B.Ch.B.¹

Abstract: Asbestos exposure in industry and construction sites in the 1960s and 1970s has left a legacy of mesothelioma, a diffuse pleural cancer, with a lag time of 40 to 50 years and due to peak around 2015 to 2020. Some surgeons believe that by radical surgery they can prolong life and relieve symptoms, but the evidence comes from very carefully selected series. How do surgeons respond to demand for evidence of benefit? In this article we explore how evidence for major surgical operations has been gained and how mesothelioma fits into this history.

Diffuse malignant pleural mesothelioma is a remorseless cancer that progressively surrounds the lung and traps, restricts, and invades it. After some months, or at most a very few years, the disease is uniformly fatal. Gnawing pain and incapacitating breathlessness mark its relentless course. Modest palliation is all that can be offered to most patients, but some doctors hold out the hope of cure achieved by very radical surgery. Patients with mesothelioma can search the World Wide Web with a few keystrokes and mouse clicks that easily lead to a description of a theoretically curative operation called extrapleural pneumonectomy [1]. The operation aims at extirpation of all the tissues that might be involved, including the whole lung, all the pleura, the diaphragm, and the pericardium. The operation may be preceded and followed by chemotherapy. The empty hemithorax is then the target of radiotherapy to complete what is called trimodality therapy. The article about surgery for mesothelioma on the Web is written by the principal champions of the operation, Sugarbaker and his colleagues [1, 2]. The evidence provided is from a one surgeons case series of well-selected patients with no control group, but it is the leading series in the world and is widely recognized as the standard for those who believe that radical surgery might help sufferers with this terrible disease.

But a word of caution is warranted. The history of medicine is full of well-intentioned doctors who hold a belief in a treatment that they themselves promote. It may be a drug, a diet, or an operation. The task they set themselves is not only to offer a treatment to their own patients but also to convert their colleagues, to spread the belief, so that their cure may reach more sufferers. There is an important difference between promulgating surgery in this way and proposing nonoperative remedies. The effects of drugs and diets, beneficial or harmful, are usually gradual. Treatment may be modified or withdrawn, the dose halved or doubled, and any instantaneous or irreversible hazard is uncommon. By contrast, an operation, once performed, may be regretted but cannot be undone. Gradualness is not an option in operations of the type offered for mesothelioma. It is a great leap of faith to undergo-or indeed to perform-this type of surgery.

The problem we face is enormous. There is an epidemic of mesothelioma. There are 2,000 to 3,000 cases each year in the United States, a 50% increase during the 1990s [1]. Peto et al. have monitored the epidemic in Europe, and in the UK he predicts a steady rise from the present rate of about 1,500 deaths per annum to peak at about double that around the year 2020 [3, 4]. The condition is being recognized more readily and diagnosed earlier in its course. A Google or Altavista search quickly leads to a list of Web sites devoted to mesothelioma. Most of these are for law firms offering to fight compensation claims, but among these advertisements it is easy to find that an operation is on offer, with the prospect of cure implicit in the description. Knowing how ineffective their own and the best available local treatments are for this terrible disease, kind doctors help patients find their way to the few surgeons who undertake these cases. Being informed and given choice, consumers will want the chance of cure, but there have been no randomized trials or even case-matched comparisons. It is in the nature of case selection that surgery is offered to the fittest patients, with the earliest and least aggressive disease, so the proponents of radical treatments can show sufficient long-term survivors (up to 5 years) to promote their cause. A critical analysis of the evidence falls short of proof of efficacy- nor is there sufficient evidence to reject the claims for benefit [5].

Faced with a steady increase in the number of cases and growing patient awareness that some surgeons offer hope, we are faced with a difficult dilemma. Those surgeons who have not adopted radical surgery wonder if they are denying their patients relief from a terrible disease. Unconvinced surgeons and their pulmonologist and oncologist colleagues would much prefer to have evidence to support their negative advice rather than just point out that there is no evidence on which to base action. Conversely, among the minority of surgeons who have taken on this surgery, some wonder if they are really justified in performing such high-risk, mutilating, and disabling operations. They too would like evidence to support their action.

We (that is the medical profession and health care providers) have to make a decision about surgery for mesothelioma. Should we offer it or should we declare it ineffective? There is an epidemic upon us, and we do not know what to do. It may be helpful to reflect on how the process of acceptance or rejection has been achieved for other major operations. The problem can be no worse than that which faced thoracic surgeons in the late 1940s in the years following the Second World War surrounded by patients with mitral stenosis.

In the face of not only considerable skepticism but outright hostility, only a few surgeons believed that surgery might be the answer [6]. There had been tentative suggestions at the turn of the century that mitral stenosis might be surgically relieved [7, 8]; then in the 1920s Souttar [9] in London and Cutler [10] in Boston each performed a successful operation, but then after a series of early postoperative deaths Cutler wrote a final report drawing a line under the episode. There was a surgical moratorium, as later occurred after the 1960s run of heart transplants [11]. During the 1930s and 1940s the standard medical textbooks by Price and Conybeare referred to these ten or so operations first as a record of clinical facts, then as an interesting experiment, but in successive editions they were increasingly scathing, although in fact no more evidence had accumulated to support the increasingly negative opinions expressed.

The doyen of clinical science, Sir Thomas Lewis, wrote [12]:

"Surgical attempts to relieve cases of mitral stenosis . . . have so far failed to give benefit. I think they will continue to fail, not only because the interference is too drastic, but because the attempt is based upon what, usually at all events, is an erroneous idea, namely, that the valve is the chief source of the trouble."

Surgeons were operating around (but not within) the heart on coarctation of the aorta (1938) and persistent ductus arteriosus (1944), and to relieve the cyanosis of certain forms of congenital heart disease by the Blalock-Taussig shunt (1944). At the American army hospital in Cirencester in wartime England, Dwight Harken was retrieving bullets and other missiles from the chest, 13 of them from within the chambers of the heart [13]. If bullets could be retrieved, the narrowed mitral valve could be relieved within the beating heart. By the end of 1948 Harken, Charles Bailey in Philadelphia, and Russell Brock in London had performed the operation with success [6]. In 1952 Baker et al. published results on 100 cases [14], and successful series were being reported from all over the world. Mitral valvotomy was taken up worldwide without a trial of any description. This was conversion like the light on the road to Damascus [15]. There is no evidence in the literature of carping from the doubting Thomas Lewis or the other physicians who now turned their energy to distinguishing pure mitral stenosis with a mobile valve, for these were the cases that most benefited.

Sir Thomas Lewis, although a great man, on the matter of surgery for mitral stenosis was wrong in every respect. His summary of the evidence was incorrect. The two patients who survived did get benefit, and the surgical target, the stenosed valve, was indeed the chief source of trouble. However, skeptics use similar arguments now to make a case against radical surgery for mesothelioma. They argue that ever more radical surgery to encompass a disease that is of its nature diffuse is flawed in its objective. Why should a patient lose a lung (the intervention is too drastic) for a diffuse cancer of the pleura, while the cancer itself is rarely (if ever) eradicated? They might well pour scorn on the concept of cytoreductive surgery [16] and argue that it is based on an erroneous idea, that debulking at this price can have any benefit, and again that the interference is too drastic for what (if any) good might be achieved. As far as mitral stenosis was concerned, all of these criticisms were leveled at the surgeons who saw it as a surgically relievable condition.

What can we learn from the precedent of surgical relief of mitral stenosis to help us decide how to consider surgery for mesothelioma? Should we be impressed by the zeal and tenacity of the highly skilled and passionately committed surgeons who take on these desperate patients with mesothelioma to give the patient a chance? There is an argument put forward for doing everything possible to get rid of a cancer, even though the operation may be futile, in order to give hope. Aberg rejects this concept in the case of metastasectomy as being without justification [17]. Surgical zeal is open to the same doubt in the example of mesothelioma surgery.

Most success stories in surgery start with an historical resumé, a tale of vision in the face of skepticism, of the courage to fail, and the tenacity of man on a mission. Will history praise those determined to offer radical surgery for mesothelioma in the face of considerable skepticism as Bailey, Harken, and Brock are now admired? Who knows? The understanding of medical history as steady progress, onward and upward, based on foresight, forgets the more numerous instances of failed operations that were promoted with equal enthusiasm but that were never adopted and have been appropriately passed over [18]. The case for mitral valvotomy was made not because of the weight of authority of the surgeons who undertook these operations but quite simply because the state of the patient relieved of mitral stenosis is very evidently different from that which existed before. Even the enthusiasts for radical operations on mesothelioma could not make that claim. Case series of extrapleural pneumonectomy have been written up since the 1970s [19, 20]. There have been few converts among the body of thoracic surgeons. In the year 2000–2001 in the UK only 26 radical extrapleural pneumonectomy operations were performed in 10 centers, a fall in numbers from the previous year [21]. Eight centers did just one or two operations. Radical surgery for mesothelioma is one of those areas of medical endeavor where there is a lot more said than done; nonetheless, we are being presented with the rising curve of an epidemic and are being increasingly pressed to do something for these patients who will die miserably and painfully with mesothelioma.

Compared with the common surgical operations performed in the largest numbers in developed countries, the number of operations for mesothelioma is insignificant. How have the common operations such as cataract surgery, coronary artery bypass, and joint replacement been promulgated and adopted? It has rarely been on the basis of high-quality clinical trial evidence. In a highly critical attack on UK surgeons, John Yates titled his book Private Eye, Heart and Hip because these represent the largest numbers and the biggest financial outlay in the National Health Service [22]. Neither he nor any other informed and rational person doubts the efficacy of these procedures. His gripe was that the Health Service wanted more of these operations because their benefit was immediately evident.

The evidence for joint replacement and cataract surgery depends essentially on a before-and-after comparison of symptoms. Quite simply the lame walked and the blind recovered their sight [23].

The bulk of the evidence for these operations is not from comparative studies but from before-and-after evidence. Conversion was a more gradual process than for mitral valvotomy, but as results improved the number of cases operated increased. The evidence was not grade A, but it was compelling.

After 25 years of accounts of low-volume selective application of radical surgery for mesothelioma, there is no proof one way or the other. Whether we should or should not perform radical surgery for mesothelioma has not so far been helped by the process of following cases after surgery and comparing them with the natural history of the disease. Our own work to establish a reference population showed a large difference in survival (nearly twice) between two tertiary referral hospitals (both in London) offering similar care [24]. We attribute this to lead time bias in the referrals. Sugarbaker, who has contributed the most to the surgical management of this lethal disease, has published an article on a series of 183 patients operated upon over a period of 18 years [25]. The median survival was 19 months, and 15% were alive after 5 years. Other groups report similar results [26]. Given the highly selected nature of the cases he operates upon, this result may not be any better than the natural history of the disease in this cohort of patients. Some compassionate colleagues equate skepticism with nihilism and argue that at least the surgeons who take on these cases offer the patients hope, as if that were reason enough [17]. Many patients have subjected themselves to painful, futile, and damaging surgery in the name of hope. Many terminal cancer patients have used and will continue to use the last weeks of their lives-and the personal and material resources of their families-pursuing unrealistic hope, and paying for it in fees and foreign travel. And yet in the case of mesothelioma and radical surgery, we do not have the quality of evidence to persuade them against this course of action or to justify surgeons turning their backs on this disease.

The answer to the dilemma seems to be clear-we should do a trial. We will have increasing numbers of cases for the next 20 years and we have insufficient evidence to guide us. There is at present no consensus and there are strongly held and diametrically opposed views. Other means of adopting evidence on which to base surgical practice (such as the mitral stenosis road to Damascus conversion, or the weight of clinical efficacy as in hip and cataract surgery) have not helped us decide on the benefits of mesothelioma surgery. The difficulties and obstacles in the design of a trial of surgery are enormous, but interestingly the opposition to performing such a trial does not come from thoracic surgeons themselves; most of them would dearly love to have the dilemma resolved. One common argument is that patients will not accept randomization because the difference in the treatment offered (that is radical surgery or not) is so great. But this has yet to be put to patients, and it can be argued that with so little evidence and at best moderate benefit from surgery the scales are finely balanced. We have an obligation as a profession, a health service, and a society to work toward a rational basis for how we use expensive and limited surgical resources.

So we end with a solution to the dilemma that we face. With colleagues in oncology and epidemiology we have obtained funding from the national charitable trust Cancer Research UK to embark on a randomized controlled trial (RCT) called the Mesothelioma And Radical Surgery (MARS) trial. This is due to start in the next few months, and we believe it is a major step forward. There are very few major operations to have been evaluated in an RCT to an equivalently rigorous and scientific standard [5]. We hope to return to the journal in 5 years with evidence. Meanwhile we express no opinion on how best to care for these patients-with or without radical surgery.