MADRID — High-dose radiotherapy adds no survival benefit after chemotherapy and radical surgery in patients with malignant pleural mesothelioma, according to a phase 2 study presented here at the European Society for Medical Oncology (ESMO) Congress 2014.
"We wanted to see if the adjuvant therapy could prevent relapse or at least delay it," said current ESMO president and lead author Rolf A. Stahel, MD, from the clinic and policlinic for oncology at the University Hospital Zurich. "We aimed for a 6-month delay in local recurrence, which would be meaningful because it's an aggressive treatment for patients."
"To our disappointment, there was no significant improvement," he said.
Mesothelioma continues to be challenging to treat, Dr. Stahel noted. At the beginning of the 1990s, a treatment regimen of chemotherapy followed by radical surgery was developed. The surgical mode adopted was a highly complex operation —extrapleural pneumonectomy (EPP) — which involves removing the lining, as well as the lung and diaphragm, on one side. However, this surgery is highly controversial and is now being phased out, as reported previously by Medscape Medical News.
"Radical surgery for cancer generally means you have a safety margin, and you can't do this when you have a tumor on the chest wall," Dr. Stahel explained. "That is the reason there is often a relapse in that area, because you can't remove the chest wall."
No Difference in Relapse Rate
Dr. Stahel presented results from the phase 2 multicenter trial of 153 patients treated with 3 cycles of cisplatin and pemetrexed, followed by restaging and EPP. Overall, 125 of these patients underwent surgery, 99 of whom had a complete macroscopic resection.
In the second part of the study, 54 patients were randomized to receive either radiotherapy or no further treatment. The primary end point was the duration of relapse-free survival.
Median local relapse-free survival was shorter for patients who received chemotherapy and surgery than for those who received radiation therapy (7.6 vs 9.4 months), as was overall relapse-free survival (5.7 vs 7.6 months). These differences were not significant.
Still a Role for Radiotherapy
This might not be the end of the story, said Paul Baas, MD, from the Department of Thoracic Oncology at the Netherlands Cancer Institute in Amsterdam.
The study shows that radiation does not improve time to disease recurrence, but this is a phase 2 study, Dr. Baas pointed out.
This does not mean that there is no role for adjuvant radiation in this setting. Selecting patients with different pathology, stage, and performance could influence outcome, he suggested.
"Times are changing, and this is also true for the way radiation therapy is administered to the patient. New approaches (intensity-modulated radiation) can improve local control and reduce toxicity," Dr. Bass explained.
Better Treatment Needed
During a discussion of the study, Dirk De Ruysscher, MD, a radiation oncologist at University Hospitals in Leuven, Belgium, noted that it "could be argued that the study may be underpowered," making it difficult to detect very small differences in outcomes.
More important, Dr. De Ruysscher emphasized the need for better treatments. "The long-term results are pretty poor," he said. "Even in this highly select group of patients, overall survival is still unsatisfactory."
At this time, "we can say that we don't have a proven treatment," he said.
Dr. Stahel said he agrees that "we have really pushed the treatment," and noted that now it is time to look ahead to the next steps.
For example, the role of radical surgery has been the subject of heated debate in the past few years, and a recent small but landmark clinical trial failed to show any benefit from radical EPP. Although EPP has been replaced to some extent by a slightly less radical operation, the role of this surgery itself in the management of mesothelioma is still very controversial, Dr. Stahel explained.
Dr. Baas noted that finding a good treatment for mesothelioma has been a challenge for many years and has led to many disappointments. He explained that there is a need to investigate new approaches, such as the use of immune checkpoint inhibitors that target the PD-1/PD-L1 pathway, which was the subject of another study presented at the ESMO meeting.
About 20% of patients with malignant pleural mesothelioma have cancer cells that express PD-L1, which is associated with poorer outcomes.
The results suggest that this population of patients could be treated with therapies targeted at PD-L1, but several key issues would need to be addressed, such as identifying the best antibody and platform to find tumors with increased expression of PD-L1, and deciding which treatment approach to take, Dr. Bass added.
The authors have disclosed no relevant financial relationships.
European Society for Medical Oncology (ESMO) Congress 2014: Abstract 37LBA_PR. Presented September 29, 2014.
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