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Among the many challenges in treating malignant pleural mesothelioma (MPM) is the limitation we have in not really being able to do larger, randomized trials easily, particularly in the small subset of patients who are really strong candidates for more aggressive treatment options (like surgery, which is typically a big procedure even by the standards of lung surgery.) The most aggressive protocols involve a sequence of chemotherapy, surgery, and chest radiation. What these studies tend to show is that there are certainly some patients who do extremely well after the most aggressive “multimodality therapy” for MPM. But do they do well because of the aggressive therapy or because they qualified for it?
Specifically, this issue comes up because the average person with MPM doesn’t receive this aggressive course of treatment. Yes, it’s uncommon, but if there are 2000-3000 patients diagnosed with MPM per year in the US, only a few dozen will undergo this treatment in all of the mesothelioma centers of excellence that are doing this work. Those people are often the most proactive, fit, younger patients, who then must travel to the centers that are doing MPM work (most people diagnosed with MPM don’t have one of these top 5-10 centers as their closest cancer clinic) and then be screened for their candidacy for such an aggressive approach.
To qualify, most doctors reviewing the treatment options for MPM will be looking at a patient’s general health and also the features of their MPM. Not only do the patients who are considered good candidates for aggressive therapy need to be quite a bit younger and stronger than an average person with MPM, they typically have an unusually limited amount of cancer – a smaller tumor burden than most people newly diagnosed with MPM. After that hurdle, many experts advocate several months of pre-operative chemotherapy as the first treatment approach…and only the patients doing well in terms of non-progression and tolerating treatment well go on to surgery and further therapy from there.
To illustrate this issue in more detail, a report from Dr. Lee Krug and colleagues1, coming out of Memorial Sloan-Kettering Cancer Center, one of the pre-eminent cancer institutions on the planet, and certainly a leader in MPM as well, describes the experience from nine MPM referral centers in the US, where they treated 77 patients with MPM. The plan consisted of initial “neo-adjuvant” (pre-operative) cisplatin/Alimta (pemetrexed) for four cycles, followed by an extrapleural pneumonectomy (removal of the lung and surrounding pleural lining on one side), then radiation to that side of the chest after surgery. Of the 77 selected patients who started that journey, 57 made it through the chemo and proceeded to surgery, 44 got to the point of starting the post-operative radiation, and 40 got through all of the planned treatment. The group that started the process was unusually young, fit, and motivated, but about half dropped out along the way.
And at the end of the day, which patients had the longest survival? Not surprisingly, it was the patients who had the earliest stage of disease, the least nodal involvement, and the best response to chemotherapy. Perhaps these patients did especially well because they received such aggressive care, but which patients do best with an approach of chemotherapy and no surgery? The patients with the earliest stage of disease, the least nodal involvement, and the best response to chemotherapy.
It’s hard to do randomized trials for these questions, because patients and physicians don’t want to accept randomization when we all have biases. But I see patients who are reluctant to pursue surgery because they have minimally symptomatic MPM with a small tumor burden and that appears to be growing slowly. That’s not most patients with MPM, but there’s a lot of variability in how MPM behaves, and some patients are destined to do well regardless of what we do to them (sometimes despite what we do to them). I try to tell my patients who appear likely to have a prolonged survival with less intensive therapy and who are reluctant to accept more aggressive treatment that they shouldn’t feel pressed to accept the potential challenges of multimodality therapy just because they happen to have such a limited amount of disease that they’re a good candidate for surgery.
In the end, it’s just important for patients and caregivers reviewing the options for MPM to be aware that the patients receiving the most aggressive MPM therapies aren’t like the broader population of people diagnosed with MPM. They are a self-selecting group, and then they are further selected by the treating centers, so that only those most likely to do well anyway are recommended to receive the most aggressive treatments. These multimodality strategies may be a key to the long survivals seen in some patients, but some patients are likely harmed by treatments that can be extremely challenging, so that the treatment is actually worse than their own particular version of the disease.
1) Krug LM, Pass HI, Rusch VW, et al. Multicenter phase II trial of neoadjuvant pemetrexed plus cisplatin followed by extrapleural pneumonectomy and radiation for malignant pleural mesothelioma. J Clin Oncol 27: 3007-3013, 2009.
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