Should surgery dominate as the standard of care for mesothelioma or be in reserve for a select group of pts?

Surgical intervention for mesothelioma has become widely accepted, but controversy persists: Should surgery be the standard of care or should it be offered only to select patients? According to scientific literature, surgery decreases morbidity and mortality while also improving outcomes compared with adjunctive therapy alone.

The merits of surgery for mesothelioma were debated at the 2009 World Conference on Lung Cancer in San Francisco by David J. Sugarbaker, MD, chief of the division of thoracic surgery at Brigham and Women’s Hospital in Boston, and Nick Pavlakis, PhD, head of the department of medical oncology at the Royal North Shore Hospital in Sydney, Australia.

Surgery for long-term survival
Surgery for mesothelioma, particularly extrapleural pneumonectomy, decreases the risk of local failure and metastases and allows for cytoreduction that enhances the effectiveness of adjunctive therapies, according to Dr. Sugarbaker. Thus it improves survival in mesothelioma patients, he said. Surgical resection also allows the most accurate pathologic staging and will soon be paired with genomic classification of tumors, enabling clinicians to target therapies to individual patients, Dr. Sugarbaker said. “What are the advantages of surgery? It allows cytoreduction and extrication or resection of primary disease, as well as control of micrometastatic disease,” Dr. Sugarbaker said. In addition to relieving symptoms, surgery can help optimize adjuvant therapy, providing mesothelioma patients with the best chance for survival, he said.

Many studies have shown improved survival of patients who undergo extrapleural pneumonectomy or pleurectomy/decortication. An analysis of outcomes in 945 patients showed that those who had undergone surgery had improved outcomes, although tumor histology, asbestos exposure, and other factors predicted survival as well. Multimodality therapy was associated with a median survival of 20.1 months (J Thorac Oncol 2:237-242, 2007).

By contrast, studies that have analyzed single-modality therapies without surgery have shown median patient survival of 12 months or less. A phase III study of 456 mesothelioma patients treated with pemetrexed (Alimta) in combination with cisplatin compared with cisplatin alone showed a survival of 5.7 months in the pemetrexed/cisplatin arm and a survival of only 3.9 months in the cisplatin arm, Dr. Sugarbaker noted (J Clin Oncol 21:2636-2644, 2003).

Surgery reduces the potential sites for recurrence, which is an important consideration, since local failure is the most important barrier to long-term survival in mesothelioma patients. “Macroscopic complete resection is the goal in mesothelioma surgery, and if you can leave patients with zero visible disease, that’s not bad,” Dr. Sugarbaker said.

Removal of the tumor in mesothelioma surgery also allows the most accurate pathologic staging, which helps clinicians select the best adjunctive therapies for their patients, Dr. Sugarbaker noted. He also said that the need for tissue samples is growing with the ability to study tumor genomics, and scientists will soon be able to target therapy based on genetic profiles of individual tumors. Instead of debating the merits of surgery, clinicians should be focused on how to target adjunctive therapy to best prevent recurrence, Dr. Sugarbaker said. He noted significant advances in understanding the genetics of mesothelioma. A recent study found that a ratio based on expression of four genes in the tumors of 120 patients was a significant factor that distinguished between patients at low risk and those at high risk for recurrence (J Natl Cancer Inst 101:678-686, 2009).

Surgery relieves symptoms in many patients and improves quality of life. Complication rates from surgery have also decreased greatly in the past 20 years, Dr. Sugarbaker said.

Most important, surgery offers patients their best shot at improved survival, especially when combined with adjunctive therapies. “That’s the Holy Grail: having long-term survivors,” he said.

Not the be all, end all of treatment options
Dr. Pavlakis argued that the scientific literature in favor of mesothelioma surgery is flawed by lead-time bias and uneven patient selection. He also noted that surgery can affect morbidity and decrease patient quality of life.

Dr. Pavlakis centered his argument on the deficiencies of the scientific literature regarding surgery for mesothelioma, and questioned whether extrapleural pneumonectomy or pleurectomy/decortication should be the standard of care.

“Should this be the policy of all people with mesothelioma or should it only be offered to unique highly select patients in special circumstances?” he said.

When comparing therapies for mesothelioma, many researchers cannot or did not control for prognostic factors such as clinical stage, histology, and epithelial subtype, Dr. Pavlakis pointed out. He also noted that the selection criteria for surgery eliminate those likely to have poorer outcomes. Those who receive surgery are often very fit with clinically limited disease, he said.

In a 2007 paper, the researchers found that surgical resection when used with other modalities improved survival. Yet the researchers also admitted that other factors affected survival, including histology, gender, smoking, and asbestos exposure. “We have to look at radical therapy as a package and we can’t be sure what component of the package contributes most to the long-term survival of patients,” Dr. Pavlakis said. He also noted that the literature suggests that multimodality therapy is better for mesothelioma patients than surgery alone (J Thorac Oncol 2:237-242, 2007).

Another problem with scientific studies that have analyzed mesothelioma surgery outcomes is that most of this research has been done in large medical centers, where morbidity and mortality rates are kept low by expert surgeons. Most patients and clinicians do not have access to this same level of expertise, and so surgery may not be as successful in the larger community, Dr. Pavlakis said. There are also problems with scientific literature on the outcomes of chemotherapy for mesothelioma patients. These studies tend to capture patients later on in their treatment than do surgery trials.

“Again, that lead-time bias may be a large part of the explanation for the difference in survivorship,” Dr. Pavlakis said. While conceding that modern surgery can effectively debulk disease in mesothelioma and can provide tissue samples for accurate pathologic staging, Dr. Pavlakis also highlighted the risks associated with surgery. The morbidities associated with extrapleural pneumonectomy are particularly well documented and affect quality of life. “There’s a risk of morbidity, and whether it’s worth the effort depends on the patients’ preferences,” he said.

He also noted that clinicians have a tendency to view the decision not to do surgery as “passive acceptance of the inevitability of death.” However, Dr. Pavlakis emphasized that it’s important instead to pursue other avenues of therapy, including chemotherapy and radiotherapy, with a sense of hopefulness.

Finally, Dr. Pavlakis pointed to the MARS (Mesothelioma and Radical Surgery Randomized Controlled Trial) study as one that could definitively address the problems inherent in the scientific literature on surgery for mesothelioma. In the MARS study, extrapleural pneumonectomy will be compared with no surgery. So far, 50 patients have entered the evaluation and induction phase of the trial and have been randomized, according to early results (J Thorac Oncol online, August 5, 2009).

“The evidence base on surgery is really subject to bias, and the research that shows its benefits is really in the eye of the beholder,” Dr. Pavlakis said. “The MARS trial will address the impact of this sort of surgery in mesothelioma, and hopefully the trial will be completed.”

Questions about surgery for mesothelioma really revolve around uncertainties over whether patients who receive radical surgery or simply other modalities would have the same outcomes if they were treated at the same time point, Dr. Pavlakis said. n