Aggressive, Tri-Modality Therapy for Mesothelioma

Howard (Jack) West, MD, Founder, President and CEO

Thus far, when discussing malignant pleural mesothelioma (MPM), a cancer of the normally onion skin-like lining around the lung, I’ve primarily talked about the role of chemotherapy. In general, that makes sense, because only a small minority of MPM patients have such good health and early enough stage disease, plus the availability of a surgeon able to perform an extrapleural pneumonectomy – the aggressive surgery generally preferred for eligible patients with MPM, in which the lung is taken out with all of the lining around it. Although there are small series of patients who have undergone aggressive surgery, and a few have shown prolonged survivals of some patients that go out several years, these trials are subject to major selection bias: essentially, only quite fit, disproportionately younger patients, with less aggressive cancers, who have the motivation and ability to travel to one of a handful of major medical centers that do this work are enrolled on these trials. So while many people (and I suspect the vast majority of lung surgeons) take it as a foregone conclusion that the most aggressive surgery is definitely the way to go if it’s a possibility, it’s not clear, at least not to me, that surgery and an extremely aggressive approach confer a clear benefit over other alternatives. I’ll describe a trial that gives me reason to question whether the presence of a few long-term survivors with MPM is definitely because of their treatment, or whether it’s more because these trials enroll an unrepresentative group of patients most likely to fare well.

At ASCO this year, Dr. Krug from Memorial Sloan Kettering Cancer Center in NYC, one of the most respected centers for mesothelioma work (along with most other cancers), presented the early results of a trial of tri-modality therapy (abstract here). This is a strategy in which patients with stage I – III MPM received a combination of chemotherapy followed by aggressive surgery and then radiation to the now empty half of the chest that previously contained the lung with the MPM around it. That’s a LOT of treatment, and it wasn’t for the faint of heart. But there is reason to thing that this version of tri-modality therapy might be worth the challenge: while older trials have shown that it’s possible, this was the first tri-modality study that incorporated the combination of cisplatin/alimta, the first and only regimen proven to produce a survival benefit for patients with unresectable disease (described in detail in a prior post) for four cycles before surgery. There is also limited evidence that suggests that patients who received post-operative radiation to the same side of the chest may have improved survival (abstract here). So this trial planned four cycles of cisplatin/alimta chemotherapy, then extrapleural pneumonectomy in patients who showed no evidence of progression and who were healthy enough for surgery, all followed by extensive radiation to half of the chest over a 5 week period:

KRUG MPM schema

(Click to enlarge image)

All of that treatment sure sounds daunting to me, and in fact, even with the selected patients who were enrolled, it was more than many could get through. Starting with 75 patients, 62 (83%) got through four cycles of cisplatin/alimta without dropping out because of progression, bad side effects, or just refusing to continue. After chemo, 29% had a significant (>50% shrinkage) of measurable cancer, and another 51% had at least stable disease and no progression. That left 56 (75%) to go to surgery, of whom 6 (11%) couldn’t have the planned resection once the surgeon got in and evaluated the extent of disease. Finally, only 42 patients, or 56% of the initial 75, went on to post-operative radiation as the trial intended:

Krug attrition

In looking specifically at how patients did, there were 3 patients who had no evidence of disease at the time of surgery, of whom one appeared to have no disease on pre-operative scans, and the 2 others appeared to have had a partial response. Unfortunately, two of those three patients subsequently died during follow-up, one of progressive MPM after 13 months on study, and the other dying of respiratory failure, presumably due to the extensive treatment, after about 8 months. Just one of the three patients with no evidence of disease was still alive, being followed 8.7 months after enrolling. To me, it’s a bad sign when two of three patients who have no evidence of disease when they go to surgery die within 13 months on the trial. It suggests to me that maybe this approach could be too much for some patients. The median progression-free survival was 13 months, and the median overall survival was 16.6 months. Many patients are still being followed, with it too early to tell what will happen with them. Not surprisingly, the patients who had significant responses to four cycles of initial chemotherapy had a survival that was much better than that of patients who had stable disease or progression (29.1 vs. 13.9 months, p = 0.0764). So to restate the obvious, the patients who are doing the best with chemotherapy before going to surgery also do the best. They have the most favorable disease.

Krug outcomes

Finally, the table below helps to put these results into context:

Krug trimodality table

The trial by Krug and colleagues is the largest ever reported for trimodality therapy for MPM. All of the preceding trials gave cisplatin or carboplatin with gemcitabine, the previous general standard for MPM (without any survival benefit shown, but some activity). Although the numbers are too small to draw any conclusions, the results of this trial with cisplatin/alimta don’t look clearly better than the preceding trials. What is perhaps most intriguing and troubling is that the median survival of 16+ in this small trial of highly selected patients isn’t much better than the median survival of about 13 months in the larger, real world experience with cisplatin/alimta or carboplatin/alimta in an unselected population of MPM patients. The places that conducted this trial were among the most experienced in MPM management in the world – including Memorial Sloan Kettering, University of Chicago, the Harvard system, MD Anderson, and others – but still the results don’t look convincingly better than chemo alone in a general population (at least not to me). Of course, many patients who have MPM will still jump at the chance for surgery, and most surgeons won’t hesitate to believe that it’s the best treatment. But I look at the results in a very highly selected group of patients and see that the patients who have the least cancer and respond the best to chemo are also the ones who do best overall. And I also see patients experiencing a wide range of serious side effects from such aggressive treatment, even dying from treatment. I’m just not quite sure that surgery is providing more benefit than harm for a significant fraction of the patients offered surgery. Especially with greater attention on offering more second line and later chemo options for MPM, I think we can continue to improve on our non-surgical options for MPM and compare well with the most aggressive options.

 

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