Radical Surgery for Mesothelioma: Still Controversial

Zosia Chustecka

April 22, 2014

The role of radical surgery in the treatment of malignant pleural mesothelioma has been the subject of much heated debate in the last few years, as thoracic surgeons argue over the details of a small but landmark clinical trial that failed to show any benefit from a highly complex operation, extrapleural pneumonectomy (EPP).

That operation has now largely fallen out of favor, and has been replaced to some extent by a slightly less radical operation, but the role of surgery in the management of mesothelioma is still very controversial. This approach "remains experimental," experts said recently at the 2014 European Lung Cancer Conference (ELCC), while others believe that it belongs only in clinical trials.

"There is doubt about whether there is any survival or symptomatic benefit from surgery, but we know that there is harm," say a group of experts in a recent editorial in Thorax (2014;69:194-197).

When mesothelioma patients ask about surgery, the "default position for clinicians should be to encourage recruitment into clinical trials," they wrote. The authors were Avijit Datta, MD, from the Department of Respiratory Medicine in York Teaching Hospital, and 3 colleagues from the United Kingdom, including senior author Tom Treasure, MD, from the Clinical Operations Unit at University College London.

The issue is growing in importance, as mesothelioma, while rare, is increasing in incidence. Europe is nearing the peak of an epidemic, but the burden of disease is likely to continue to rise in the large areas of the world where asbestos remains unregulated, the editorialists comment.

Large Physiological Insult

EPP is a very radical surgery, which involves removing the lining, as well as the lung and diaphragm, on one side, "so it's quite a big physiological insult to the body," David Waller, MD, consultant in cardiothoracic surgery and respiratory medicine at Glenfield Hospital, Leicester, United Kingdom, explained to Medscape Medical News in an interview.

It was developed in England (first described by Butchart et al. [Thorax. 1976;31:15-24]), and was then popularized in the 1990s in a number of papers authored by David Sugarbaker, MD, from the division of thoracic surgery, Brigham and Women's Hospitals, Boston, and colleagues.

EPP became the standard of surgical care for mesothelioma, along with chemotherapy and radiation, Dr. Waller commented. There were a few publications in the late 1990s reporting long-term survivors, and he himself has had patients on whom he carried out this procedure who lived for 3 to 4 years after surgery (whereas the overall average survival for mesothelioma is about 1 year).

However, Dr. Waller said there were always doubts about the procedure. It was difficult to replicate the long-term survival data in all patients, and this surgery has a relatively high mortality and considerable morbidity risks.

"We needed to know if it was worth doing the operation," he said.

Hence, they conducted a randomized feasibility trial (Mesothelioma and Radical Surgery [MARS]) in 50 patients with mesothelioma, in which all patients received chemotherapy and/or radiotherapy, but only 1 group of patients also underwent EPP. (The surgery was carried out mainly at 2 centers, one of which was in Leicester where patients were operated on by Dr. Waller and colleagues.)

The MARS results (published in Lancet Oncol. 2010;12:763-772) showed that "there was no benefit for EPP and, in fact, when you stratify for risk factors, the results suggested that EPP was harmful," Dr. Waller said.

Because of this suggestion that EPP may be harmful, it was considered unethical to move onto a larger phase 3 randomized trial, which would have been powered to answer the question, he added. Another issue was that recruitment into the feasibility trial had been very slow; it took over 3 years to recruit the 50 patients, mainly because most patients were not fit enough for this surgery, Dr. Waller commented. The average age at diagnosis is about 70 years, and many patients have comorbidities, including other lung diseases such as chronic obstructive pulmonary disease.

At the same time that the MARS study was ongoing, "we were also experimenting with another surgical technique, which preserves both lungs while attempting to remove all visible tumor by stripping the lining — known as extended pleurectomy/decortication, the EP/D procedure," Dr. Waller said.

"We had started using EP/D in patients who were not fit enough for EPP, and when we compared the results for both types of surgeries retrospectively, we found that the results with ED/P were just as good and maybe even better than with EPP, and that wasn't just us in England, it was also in other countries, including the United States," he said.

"The main comparison was retrospective, but we did look at a few case-matched comparisons, and overall the results for EP/D were similar if not better than with EPP, but as the EP/D procedure spares the lung, it is safer, and hence probably the better option for most patients," he said.

"But there is still doubt over whether the surgery provides an added benefit, and so another randomized study is now planned — MARS 2 — which will investigate the role of EP/D," he said. "The plan is to conduct a 50-patient feasibility study, and we already have funding [from Cancer Research UK] and ethical approval to go ahead," Dr. Waller commented. The surgery will be performed at 3 centers with a proven track record of doing this procedure — in Leicester by Dr. Wallace and his colleague Apostolos Nakas, MD, and then in Sheffield and Oxford by surgeons who have trained with him.

The next step after that would be a phase 3 trial in 300 patients.

However, there has been some argument over whether EP/D is a better operation. A retrospective analysis of data on 3000 mesothelioma patients who had been surgically treated around the world, published in the Journal of Thoracic Oncology (2012;7:1631-1639), suggested that there may be an advantage with EPP in a certain subgroup of patients.

In that study, a graph showing survival of patients according to the their stage of mesothelioma shows that the survival curves after EPP and EP/D were superimposable for stage III and stage II patients, with a median survival of 18 to 20 months. But for patients in stage I disease, there was a better survival seen with EPP, with a median of around 4 years, when compared with EP/D, with a median of 2.5 years.

But Dr. Waller commented that there was some question over the comparable staging that had been carried out in the EP/D patients. Less accurate nodal staging may have resulted in some of the EP/D patients being classified as stage I when in fact they were stage II, which would have skewed the results, he said.

"This to me defined the role of EPP," Dr. Waller told Medscape Medical News. "There was absolutely no reason to carry this out in stage II and III patients, and the only potential role for this operation may be in stage I patients, and even then, that is questionable," he said.

Dr. Waller is convinced that there is no role for EPP anymore. At the ELCC meeting in Geneva, at an educational session discussing the role of radical surgery in mesothelioma, he stood up and announced to the audience that "EPP is dead," adding, "I will say this even if you won't." The comment was directed at the presenter, Loic Lang-Lazdunski, MD, PhD, FRCS, from the Department of Thoracic Surgery at Guy's Hospital, London, United Kingdom, who was one of the surgeons who carried out EPP in the original MARS trial. At the meeting, Dr. Lang-Lazdunski said he had personally stopped doing EPP in 2008, but added that there are still surgeons who are doing this operation.

Dr. Waller reminded the audience of the conclusions from the MARS trial, which showed no benefit and suggested harm: "There is no need to take out the lung.... This is a dangerous procedure and patients may be dying from the operation rather than the disease," he said.

Pushback on MARS Conclusions

There was a lot of push back after the MARS results were published.

The subject was discussed at length and in some very heated debates at conferences, including the International Mesothelioma Interest Group Congress held in Boston in September 2012. A summary of that meeting was published in the Journal of Thoracic and Cardiovascular Surgery (2013;145:909-910). First author Valerie Rusch, MD, from the Department of Surgery at the Memorial Sloan-Kettering Cancer Center, New York City, senior author Dr. Sugarbaker, and a number of other signatories noted that there were "numerous shortcomings" and "deficiencies" in the MARS 1 trial, which "make drawing any conclusion from MARS 1 regarding the therapeutic efficacy of EPP impossible."

The group also staunchly defended the role of radical surgery in mesothelioma.

"Surgical macroscopic complete resection and control of micrometastatic disease play a vital role in the multimodality treatment of malignant pleural mesothelioma, as is the case for other solid malignancies," they wrote. "The type of surgery [EPP or EP/D] depends on clinical factors and on individual surgical judgment and expertise."

Not surprisingly, the MARS researchers, headed by Dr. Treasure, have written stiff rebuttals of the criticism levied at the trial, including a letter to the Journal of Thoracic Oncology (2013;8:e48-e49). "The MARS results have broad clinical face validity," they wrote, and they came "as no great surprise to all except a number of proponents of EPP."

In an interview with Medscape Medical News, Dr. Treasure said that the fiercest criticism of the MARS has come to a large extent from eminent thoracic surgeons who have staked their reputations on carrying out this type of surgery, and the trials results, showing no benefit and suggesting harm, are "an inconvenient truth."

There are occasional good survivors after radical surgery, Dr. Treasure acknowledged, but there are also occasional good survivors among mesothelioma patients who have not undergone surgery, he pointed out. He personally has had mesothelioma patients who have lived 7 years after diagnosis, so the big question is: "Would those patients who survive after surgery have survived anyway, without the surgery?" he said.

"Perhaps the patients that we are selecting as fit enough for surgery are the very patients that we should leave alone," he said. There is a complication in that surgery is only part of the picture; these patients will also have received chemotherapy and/or radiotherapy, and these components "cannot be disentangled, so it becomes very difficult to ascertain which intervention made which contribution."

"There is no proof as yet that surgery provides a benefit," Dr. Treasure said, and he emphasized that patients need to be informed about this lack of data.

"In my opinion, EPP has been proven to have net harm but has not been proven to have any benefit and, on average, it does not prolong life," Dr. Treasure said. He also admitted that, while he has carried out many other thoracic surgical procedures, he has personally never done an EPP, because it is drastic surgery "that made no sense at all.... I thought it was irrational, and the evidence was never there."

His impression is that EPP is now not being carried out to any extent, and while there still are surgeons who are talking about their right to do this operation, they are not actually doing it anymore. Part of this talk, he feels, is to protect themselves against criticism and maybe even legal action, especially for any such surgery that has been carried out after the MARS results were published (in 2010).

The "milder and gentler" option of EP/D spares the lung, which enables the patient to breathe better for longer, so it may allow patients to have a better quality of life for the time they have left, Dr. Treasure said. There is also the "even milder" approach of debulking keyhole surgery, as explored in the MesoVATS trial, which has shown that this surgical approach improves quality of life, although it does not prolong survival.

It may be a case of "less is more," Dr. Treasure commented, but he added also that it may be the case that "nothing at all is better than less."

There are ongoing trials that are addressing this question, and hence he believes that "if patients are to be considered for surgery, given the lack of good quality evidence, recruitment into clinical trials should be considered the default position by respiratory physicians, surgeons, and oncologists."

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