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Slow progress in advanced mesothelioma: Is the FDA winning the battle with the EPA?
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Last month, I mentioned my favorite new oxymoron — “Environmental Protection Agency” — and am concerned you might have missed it if you were on vacation ... so I raise the topic again.
You may recall that we discussed the recent liberalizing of asbestos regulation in one of the less progressive modern nations, thus potentially exposing the future U.S. population (our children and their children) to an increased level of risk from a well-established biohazard. The topic is on my mind, as I recently lost a classmate from medical school who was exposed to asbestos as a young woman and sustained an advanced mesothelioma.
Variable presentation
This month, as a practicing oncologist partly within the VA system (and Navy personnel have been at risk for mesothelioma), I thought I should focus on the tools available to treat those who have been sufficiently unfortunate to sustain chronic (or sometimes acute) exposure to asbestos, with the resulting evolution of a malignant mesothelioma. Over the next several years, I expect there will be an expansion of the patient population, and we need to review what we will have to offer (beyond a change of leadership at the EPA).
The presentation of mesothelioma is quite variable. The more fortunate patients will be diagnosed early, sometimes because they have been employed by a company that previously used asbestos and has created early diagnosis programs for potentially exposed employees.
There is no standard operating procedure, but reasonable approaches include regular history and physical with a CT scan to assess changes that might signal an emerging mesothelioma. In parallel, the occasional diagnosis of mesothelioma may be made on a CT or MRI scan (or, rarely, a chest X-ray) obtained as part of a diagnosis for an unrelated problem. The imaging is followed by some form of open (or closed) biopsy.
The more fortunate patient will have localized disease, which is amenable to resection, although this is complex chest surgery that involves careful clinical mapping of the extent of disease with stripping of the tumor tissue, which usually extends along the pleural surface and sometimes into the pulmonary parenchyma.
It is well-established that malignant mesothelioma can be potentially cured by surgical resection. To my knowledge, the roles of radiotherapy and cytotoxic chemotherapy are unproven in the management of early-stage or localized disease, although there are some new approaches that may well be applied to this setting in structured clinical trials (discussed below).
Many patients present with advanced disease — sometimes they have suffered from a chronic cough as their occupational exposure also has been associated with cigarette smoking (which increases the carcinogenic impact of asbestos), and the gradual change of coughing associated with the mesothelioma is simply not noticed.
In some cases, the pleural space can be quite silent, and thus the other hallmark feature of pleural pain does not occur until late. The onset of dyspnea can be variable, either associated with very advanced and bulky disease — sometimes compounded by chronic obstructive pulmonary disease — or with the development of a pleural effusion, which usually, but not always, signals quite advanced disease.
Because of the peripheral location of this tumor, symptoms like hemoptysis usually don’t occur until late, if at all. The constitutional, nonspecific features, such as fever, sweats, anorexia and weight loss, usually don’t occur until the disease is advanced.
Thus, the majority of cases of malignant mesothelioma present with advanced disease, where surgery and perhaps radiotherapy are merely palliative.
Emerging treatment options
Decades ago, I published a phase 2 trial that showed that carboplatin has some activity against malignant pleural mesothelioma and that the occasional response can be sustained for periods of 1 to 2 years or more. More recently, pemetrexed, with or without a platinum complex, has produced remissions in about 30% to 40% of cases.
The FDA — perhaps trying to offset the negative effects of the EPA — reviewed data from a phase 2 trial, conducted by Novocure, testing the antitumor effect of pemetrexed plus a platinum complex with the addition of the company’s tumor-treating fields device (Optune). This trial included 80 patients with unresectable disease and reported median OS of 21.2 months for patients with epithelioid mesothelioma and 12.1 months for nonepithelioid disease; the overall response rate was reported to be 40%. The FDA approved this combination earlier this year.
Another interesting development is the suggestion from Japan that nivolumab (Opdivo, Bristol-Myers Squibb) also may be active. In the MERIT study, investigators administered nivolumab to 34 patients with various types of malignant mesothelioma and observed an ORR of 29% and median OS of 17.3 months, including responses in the sarcomatoid variant of the disease. There was preliminary evidence that PD-L1 expression predicted for a higher response rate. It should, however, be noted that other immuno-oncology trials have been negative.
The good news is that there are emerging options for the management of advanced mesothelioma, and studies are being established to define whether any of the novel approaches may have application to increase the cure rate of early-stage disease.
Reduction of mesothelioma incidence 10 to 20 years from now by responsible EPA action would be even more effective, but it is troubling that this is not likely to happen in this political climate. This should impact our voting choices in November 2019 and 2020.
References:
Ceresoli G, et al. J Thoracic Oncol. 2018;doi:10.1016/j.jtho.2018.08.416.
Okada M, et al. Clin Cancer Res. 2019;doi:10.1158/1078-0432.CCR-19-0103.
Raghavan D, et al. J Clin Oncol. 1990;8(1):151-154.
For more information:
Derek Raghavan, MD, PhD, FACP, FRACP, FASCO, is HemOnc Today’s Chief Medical Editor for Oncology. He also is president of Levine Cancer Institute at Atrium Health. He can be reached at derek.raghavan@atriumhealth.org.
Disclosure: Raghavan reports no relevant financial disclosures.