ATLANTA – New treatment approaches are emerging in the treatment of malignant pleural disease.
Until recently, talc pleurodesis, the standard of care, and repeated thoracentesis were the only options for treating symptomatic patients with malignant pleural disease established by cytology or biopsy, Dr. Najib Rahman said at the annual meeting of the American College of Chest Physicians.
"We need more novel, less toxic, and more effective agents," Dr. Rahman said, noting that these are exciting and important areas of research, especially given how common malignant pleural disease is – and how the incidence is increasing because of the aging of the population.
One newer option is the use of an indwelling catheter, said Dr. Rahman of the University of Oxford (England). "We can completely bypass the whole idea of pleurodesis and go for an indwelling catheter." As for the continued use of talc pleurodesis, the focus should be on identifying the best agents and improving upon current practices.
"All of us feel talc isn’t as good as it could be," he said, noting that the procedure is painful and is associated with various toxicities.
Nonetheless, talc pleurodesis is considered the most effective agent for the treatment of patients with malignant pleural effusion, and data suggest that the success rate is about 75%.
In a meta-analysis of 46 randomized controlled trials comprising more than 2,000 patients, talc was shown to be superior to bleomycin and tetracycline (risk ratios of 0.63 and 0.50, respectively).
However, some questions remain about how to best use talc pleurodesis. For example, it is unclear whether poudrage or slurry is the best approach for instillation, he said. Further, talc is associated with significant toxicity; 8 (4%) of 196 patients in one study experienced acute respiratory distress syndrome and 5 of those patients died, and 41 of 4,030 patients (1%) in another study experienced acute respiratory failure.
Although studies have suggested better safety with graded talc (French talc), compared with non-graded talc (U.S. talc), limitations of those studies raise questions about the findings. Also lacking with respect to talc is information on the best analgesic strategy, appropriate tube size, and predictors of outcomes, he said.
Newer options under consideration for pleurodesis include the bacterial proteins OK-432, staphylococcal super antigen, and Lipoteichoic Acid (LTAT).
Bacterial proteins are promising for pleurodesis because they are proinflammatory and potentially less toxic than other agents.
OK-432, or Picabinil, is a bacterial protein commonly used in Japan (where talc is not available), but not yet available in the western hemisphere, Dr. Rahman said.
In a single randomized controlled trial, the radiological complete response rate in 23 treated patients was 73%, compared with 41% for those treated with mitomycin C. OK-432 was associated with a longer effusion-free survival (7 months vs. 1.5 months) but was also associated with greater toxicity.
"So, clearly there are some interesting ideas there, but certainly no definitive data," he said.
Staphylococcal super antigen has been shown to induce cytotoxic T-cell differentiation in animal models of melanoma, and is associated with anti-tumor cytokine production, as well as with evidence of tumor regression and metastasis treatment. The complete response rate was 79% in one small study in 14 consecutive patients with non–small cell lung cancer. Patients were treated with repeated intrapleural instillation of staphylococcal super antigen at 100-400 pg once or twice per week until effusion resolved.
Furthermore, median survival was 2.0 months for 13 patients with malignant pleural effusion treated with talc pleurodesis, compared with 7.9 months for 14 patients treated with staphylococcal super antigen. While this is not comparative data, the survival with staphylococcal super antigen was better than one might expect in this patient population.
"Potentially there are some interesting signals here that might suggest this stuff may do more than just seal the pleural space, and may help to regress the cancer," Dr. Rahman said.
LTAT also shows promise. It has various immune effects, including activating toll-like receptor pathways. In a dose escalation study, he and his colleagues found that at 1-month follow-up, the overall success rate was 75%, while the success rate among those receiving greater than 750 mcg of LTAT was 86%, suggesting that this treatment is "doing something to pleural fluid production," he said.
No significant toxicity occurred at doses below 3,000 mcg. This early evidence of efficacy requires confirmation in additional studies, he said.
Another innovative area with respect to the treatment of malignant pleural disease involves the direct biological control of pleural fluid production with profibrotic cytokines such as TGF-beta.
"So rather than sealing the cavity, this is turning off the tap at the source," Dr. Rahman said.