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SOURCE: Medscape

New Directions for the Treatment of Mesothelioma: An Expert Interview With Nicholas J. Vogelzang, MD


Malignant pleural mesothelioma (MPM) is an aggressive, yet relatively rare cancer; about 2000 new cases are diagnosed in the United States each year. Standard treatment is generally not curative, with median survival for local disease reported as 16 months and median survival for extensive disease reported as 5 months. Treatment options vary by extent of disease, but typically consist of surgical resection, chemotherapy, and/or palliative radiotherapy.

Over the past few years, some progress has been made in the management of MPM, as new agents and combinations of agents have demonstrated improved survival rates. In an attempt to expand upon these improvements and to identify ever more effective diagnostic and treatment strategies, 3 studies on the management of MPM were reviewed during an Oral Presentation Session at the 39th Annual Meeting of the American Society of Clinical Oncology. After the Session concluded, Medscape's Shira Berman sat with Nicholas J. Vogelzang, MD, Director of the Cancer Research Center at the University of Chicago, to discuss the findings presented and to review their significance in the treatment of the disease.

Intracavitary Hyperthermic Cisplatin

The first study in the Session, presented by Dr. David Sugarbaker of Brigham and Women's Hospital in Boston, Massachusetts, evaluated the use of an intracavitary lavage consisting of hyperthermic cisplatin followed by intravenous thiosulfate in patients who had undergone pleurectomy, but who were not candidates for extrapleural pneumonectomy. The average age of the 44 patients evaluated in the phase 1/2 study was 70 years, and 88% were older than age 65.

Three dose levels of cisplatin were used: The lowest dose level was 50-100 mg/m2; the intermediate dose level was 175-200 mg/m2; and the maximum tolerated dose (MTD) was 225 mg/m2. Across all dose levels, the median overall survival (OS) was 10.5 months, or 13 months among those who survived surgery; when divided by tumor type, patients with epithelioid disease fared better than did those with mixed or sarcomatous disease.

The median OS seen with the lowest doses was 6 months, and the recurrence-free survival (RFS) was 3.6 months; at the intermediate dose level, the median OS was 11 months and the RFS was 7.6 months; at the MTD, the median OS was 22 months and the RFS was 20 months. Dose level of cisplatin was an independent predictor of survival, and each successive lower dose level conferred a 22% greater risk of death on the patient. Although 23 patients treated with the MTD showed no grade 3/4 toxicities, the rate of atrial fibrillation (AF) was 32%, and the rate of deep venous thrombosis was 11%.

Medscape: What did you see as the key findings in this study?

Dr. Vogelzang: This feasibility study was clouded by 3 things. One, it's highly technical and therefore difficult to export. It will probably be replicated in several technical centers around the country, but I think it's unlikely to be used outside of those settings. Two, the side effects that were seen may be directly related to the high temperature and the high dose of chemotherapy, although we weren't given a lot of data on the evolution of the regimen. When I asked [Dr. Sugarbaker] what his plans were beyond this hypothesis-generating phase 1/2 study, he didn't answer directly. I suspect they're pausing before continuing this.

The third issue is that the median survival is not that good. A cluster of mesothelioma mavens gathered after the sessions, and we all agreed that we could reach this survival rate with regular chemotherapy. I suspect they'll extend it to the extrapleural pneumonectomy patient population because it offers a fully empty cavity, and very few people do just a decortication and pleurectomy; it's not a commonly done procedure.

Medscape: So given the limited application, what does a study such as this add to the overall body of knowledge on mesothelioma?

Dr. Vogelzang: It's not a blind alley, but a very steep canyon that very few people would try to cross. It's highly appropriate for this kind of research to go on; it's very creative. But it will require a consensus that this is the path to take. There will be a few brave souls who will try this canyon up over the mountains, but I think that this is not the way to go. It requires a very skilled surgeon; in truth, this can probably be done only by a handful of surgeons across the country. And when the skill level is that high, it just isn't translatable.

Predicting Survival With FDG-PET

The second study in the Session, presented by Dr. Raja M. Flores of Memorial Sloan-Kettering Cancer Center in New York, NY, evaluated the feasibility of using the FDG-PET standardized uptake value (SUV) to predict urvival. Of the 65 patients evaluated, 54 were men and 11 were women; the median age was 65 years. The median SUV in the 46 patients with epithelioid disease was 6.5; the median SUV in patients with mixed disease was 6.8; and the median SUV of patients with sarcomatous disease was 3.8.

A nearly perfect inverse relationship was seen between SUV and survival, such that a greater SUV correlated with a shorter survival. The median survival in patients with an SUV < 4 was 24 months vs a median survival of 14 months in patients with an SUV > 4, demonstrating a 3.3% greater risk of death with the higher SUV. When evaluated by tumor type, 80% of patients with epithelioid disease and low SUV were alive after 36 months vs 0% of patients with mixed or sarcomatous disease and a high SUV after only 18 months. In the highest-risk group, there was a 3.2% greater risk of death with the combination of a high SUV and mixed or sarcomatous disease. Stage of disease did not independently predict survival in these patients.

Medscape: What did you see as the key findings in this study?

Dr. Vogelzang: The results were relatively modest, although the approach was correct -- trying to understand the biology beneath the disease. The best biologic study is the microarray, or other similar mechanism, so perhaps this is molecular biology at the visual limit edge. We know that some cancers are very hot and that some are very cold. What [Dr. Flores] showed is that those cancers that are hot -- with a higher SUV -- are "bad," and those that are cold -- with a lower SUV -- are "good." This suggests that the growth rate of the cancer is somehow related to outcome. I think it's real, I think it's biologic, and I think it's a very nice step forward.

The problem is that Medicare won't pay for PET scans, and they're expensive, so it might not be practical to implement. However, the PET scan would be perfect for a clinical trial setting -- if people can arrange for a PET scan to be done before and after chemotherapy, I think it would be a very nice addition. You can't do biopsies on everyone, but if the PET scan correlates with the molecular biology, then this could be a useful tool.

Effect of Chemotherapy on Quality-of-Life Parameters

The third study in the Session, presented by Dr. Richard Gralla of Columbia-Presbyterian Medical Center in New York, NY, evaluated the impact of pemetrexed plus cisplatin on quality-of-life (QOL) parameters defined by the validated LCSS-meso tool. The median age of the patients enrolled in the phase 3 trial of the combination vs cisplatin alone was 60 years, and most patients had stage III or stage IV disease.

At the start of the trial, the median score recorded by the patients on a visual analog scale was in the third quartile, indicating moderate severity. In addition, 3 or more symptoms were noted on presentation. Over the course of the trial, evaluations were collected weekly in all participating centers; initial and follow-up data were available for 96% of patients. Differences in QOL parameters began at 6-9 weeks with the combination, despite no improvements in survival data at this point. After 18 weeks of therapy, at which point survival was significantly improved vs cisplatin alone, significant improvements were seen with the combination in all thoracic parameters, as well as in fatigue, anorexia, and level of activity. These improvements were also significant in the summary evaluation completed by the patients at trial completion.

Medscape: What did you see as the key findings in this study?

Dr. Vogelzang: First, 93% of these patients are symptomatic. That's a very high percentage; I didn't expect it to be that high. So the patients are telling us that they're sick, and we're no longer able to say that our patients have a performance status (PS) of 0. Technically, they're PS 0, but they're telling us that there's still something wrong. Second, there was an extremely high questionnaire completion rate, which makes this a very powerful study.

Third, the symptoms of pain, dyspnea, and cough were significantly improved even before the general symptoms of fatigue, anorexia, and activity, indicating that their symptoms are referable to the local cancer, and are not necessarily due to the cancer spread throughout the body. Also, it's interesting to note that an improvement in the global measure of QOL was present at 12 weeks and was significant by 18 weeks, suggesting that the improvement is, although not abrupt, certainly modest.

The one thing we don't yet know is if QOL predicts survival -- if people who have a higher QOL also have a longer survival. Also, it isn't clear if cough and shortness of breath improve before pain or if they're all getting better at around the same time. It may be a general trend, so by the time you measure each parameter, they've become generally better; the symptoms are all probably correlated with anticancer activity in general.

Medscape: How would you translate these data for the average patient?

Dr. Vogelzang: I think the biggest issue is that patients don't have to fear the chemotherapy. And if they're getting this combination, they're almost certainly going to feel better -- even the nonresponders, even the progressors, even those who have drug toxicity feel better. So you can honestly say to the patient: Even if your tumor doesn't shrink, you're going to have some improvement in your symptoms. That's not bad at all.

From a QOL perspective, when you compare the intensity of a pleurectomy with chemotherapy, I think patients are going to choose chemotherapy over surgery. Chemotherapy offers a more global improvement, whereas surgery may be helpful in only a selected population. Ultimately, chemotherapy offers something for everyone; surgery offers a lot for a small number of patients.


Medscape: Putting all of this together, where do we go from here?

Dr. Vogelzang: Based on the data from these studies and from what was presented in the poster sessions, we've learned a number of things. Chemotherapy now has an established role in the treatment of mesothelioma. Almost everyone, even if they're surgical candidates, should get chemotherapy. Also, giving chemotherapy in the second line is valuable and needs to be tested in a prospective trial setting. Although we all thought that chemotherapy helps, we now see that it's like breast cancer -- if you give a second round after the first one doesn't work, you still get a benefit. That's pretty remarkable.

Finally, we have to focus more on the molecular biology of the disease to learn who's going to improve most on the different treatments. We're pretty good at predicting who's going to do poorly -- we just have to work more on predicting who's going to do well.

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