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Trimodality Therapy (Chemotherapy, Surgery, and Radiation) for Malignant Mesothelioma: Can Some Patients actually be Cured?

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Malignant mesothelioma is a relatively rare but particularly deadly malignancy that arises from the lining of the pleural (chest) cavity or peritoneal (abdominal) cavity. About 70% of cases of mesothelioma are directly related to asbestos exposure, usually with about 30 or 40 years between exposure and diagnosis. While there are only about 2200 cases per year in the USA, this number is expected to increase over the next decade, as workers exposed to asbestos earlier in their lives eventually begin to manifest symptoms of the malignancy. After 2015 or so, this may begin to decline due to laws regulating exposure to asbestos in recent decades, but these laws don’t exist in the developing world, so mesothelioma is likely to be a worldwide problem for the foreseeable future.

The usual patient with mesothelioma presents with chest pain and/or shortness of breath, with x-rays showing thickening of the pleural lining with as associated pleural effusion. Many times the fluid around the lung contains no cancer cells, so a biopsy of the pleura is necessary to make the diagnosis. It usually occurs only on one side; distant spread is unusual. So if it is technically “localized”, why is it so hard to cure? The main problem with mesothelioma is that most patients present with advanced disease that has no chance of curative treatment with surgery. In fact, mesothelioma is a malignancy that classically is not thought to be really “curable” at all. Surgery is usually used for palliation, to drain the fluid and peel the malignant rind away from the lung so that the patient can breathe easier and with less pain. Of course there are case reports or case series of patients with limited disease who can be aggressively treated with surgery and have lived >5 years (most oncologists’ definition of cure), but the reality is that these patients are few and far between. To date, studies of patients treated with surgery have shown about the same average overall survival as patients treated palliatively with chemotherapy alone (about 9-12 months).

This brings us to the study published this week in the Journal of Clinical Oncology by Dr. de Perrot and colleagues (abstract here). Since 2001, select patients with mesothelioma at Prince Margaret Hospital and Toronto General Hospital in Toronto, Canada, have been treated with an aggressive regimen that begins with 3 cycles of cisplatin-based chemotherapy followed by staging to see if they were still possibly resectable. If so, they underwent a surgery called extrapleural pneumonectomy (EPP), which is a huge surgery that removes an entire lung with the surrounding pleural cavity, pericardium, and hemidiaphragm as a single piece. After the surgery, patients were then given fairly high doses of radiation (50-60 Gy) to the entire half of their chest where the lung used to be. You can imagine that you would have to be pretty healthy to be considered for this treatment. In addition to having no metastatic disease and being healthy enough for surgery, all patients had to have what is considered to be favorable histology (epithelioid or mixed) with no sarcomatoid histology, which has a dismal prognosis.

All in all, 60 patients since 2001 were found to be eligible for this regimen. We don’t know how many patients with mesothelioma were seen in Toronto to get down to these 60 patients, but my guess is that this was less than half of all comers. 53 of them made it through three cycles of chemotherapy, 45 patients made it to surgery, and 41 were able have all visible tumor removed. Only three patients died from the surgery, which is actually pretty impressive, although 1/3 of patients had major complications. 30 patients (down to 50% already) underwent the post-operative radiation course.

The median overall survival for this group was 14 months. To compare, the median survival in the only phase III randomized trial of chemotherapy alone (cisplatin and Alimta) in mesothelioma was 12.1 months. Let’s look at the curves from the 2 trials (trimodality on the left, chemo alone on the right), highlighting only the first 2 years.

Meso Composite NP figure (Click to enlarge)

If you’re saying “Gee, those look pretty similar”, you would be correct. The difference is in the tail of the curve (red box). Essentially no patients treated with chemotherapy survive even to 2 years, much less 5 years, whereas in the de Perrot paper 10% of patients were still alive at 5 years! By looking even closer at the patients in the study, they were able to piece out which patients had a better chance of long-term survival with trimodality treatment. Turns out it is the patients who had no involvement of the mediastinal lymph nodes (N2 nodes) who did well (see below), with a median survival of 59 months with trimodality treatment versus 8 months if they were unable to complete the treatment.

Meso KM Curve 2

They also found that less invasive tumors (T1-2) did better than more invasive tumors (T3-4), and that epithelioid histology did better than mixed histology. So what can we take away from this? It would appear that it is possible for some patients, specifically those with no mediastinal nodal involvement, to be cured of malignant mesothelioma with aggressive trimodality therapy. But I think is important to emphasize that this is a tiny proportion of the mesothelioma patients who walk in the door who would be eligible for this treatment. Only 50% of this highly selected population made it through all of the treatment, and if they couldn’t complete the regimen they had an identical survival to patients who had chemotherapy alone. In conclusion, I do think there is a role for surgery in mesothelioma and any advancement that leads to cures in this terrible disease is fantastic, but until this can be applied to a larger percentage of the patients I think it will remain out of reach for most patients.


2 Responses to Trimodality Therapy (Chemotherapy, Surgery, and Radiation) for Malignant Mesothelioma: Can Some Patients actually be Cured?

  • Dr. West says:

    I think you raise several important points, and one that remains undefined is whether the fact that the patients who completed all of the therapy had a very good survival means that the treatment caused the good survival or that the people who get through initial chemo and have done well are exactly the ones who would do well even without surgery. The other point, which you mention, is that surgery is an option that is generally offered only to the patients with more limited spread of mesothelioma. Not only would you expect that patients with less bulky/lower stage disease will do better, but you could also envision that the patients who have their mesothelioma detected when it is stage I or II could have a fundamentally slower-growing, less aggressive cancer that is fundamentally different from the more typical, more extensive mesothelioma we see in patients who aren’t good candidates for surgery.

    Unfortunately, to test the value of surgery, you’d need to do a randomized trial, but I can’t imagine that patients would accept the possibility of being randomly assigned to receive surgery or not for potentially resectable mesothelioma. But in the meantime, I think it’s appropriate to ask whether multimodality therapy or being a good candidate for multimodality therapy is what drives the more favorable prognosis in this group.

    -Dr. West

  • Dr Pennell says:

    This is an interesting debate, and applies to lung cancer as well. Do the patients with truly indolent cancer (assuming we could identify them somehow) need to be treated aggressively, or would they do just as well with more conservative treatment? A great example is in the area of screening.

    People who argue against the benefit of lung cancer screening often propose that many (or even most) of the multitude of stage IA lung cancers found and removed in CT screening trials represent indolent cancers that would never cause problems. This is termed “overdiagnosis”, and is definitely a real phenomenon in the prostate cancer world. My feelings are that even indolent lung cancer is still lung cancer, and even if an indolent cancer doesn’t kill you in the normal 12 months, 5 years seems like a long time to survive without curative treatment. I think these patients will eventually die from their disease if they live long enough.

    In the case of mesothelioma: I don’t believe too many patients, even marathon-running stage 1 epithelioid histology patients, are still around 5 years from diagnosis. So I guess what I am trying to say is that, yes, healthy patients with better cancer biology do better no matter what you do to them, but when you can improve on a true “cure” rate in a deadly disease it still has real value in patients likely to live several more years.

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