The Chemo Question

This morning in our thoracic oncology tumor board discussion, we reviewed a case of a 72 year-old man who is now diagnosed with malignant pleural mesothelioma (MPM) that is too advanced to consider surgery, and who is rather debilitated from emphysema and other longstanding medical problems. The best studied treatment for MPM is the chemotherapy combination of cisplatin and Alimta (pemetrexed), which has a proven survival benefit compared with cisplatin alone1. But cisplatin is an older chemotherapy agent that is notoriously challenging for even many fit patients to tolerate. This raises the question of whether there might be an alternative approach for patients who are unlikely or unwilling to tolerate the anticipated side effects of a cisplatin/Alimta combination, which often include nausea/vomiting, possible kidney damage, hearing loss, peripheral neuropathy (numbness and tingling from nerve damage), and sometimes other issues not typically seen with carboplatin. The data from a large European registry2 provide reassurance that the generally better tolerated combination of carboplatin/Alimta can provide comparable benefit for patients who are not candidates for the standard cisplatin-based regimen.

The report available describes the experience of a total of 1704 patients with confirmed and unresectable MPM who received Alimta with either cisplatin (in 843 patients) or carboplatin (861 patients) in an expanded access protocol that made Alimta available to appropriate patients and collected data on how patients fared on this treatment. Despite the median age of the carboplatin/Alimta group being 4 years older than the recipients of cisplatin/Alimta (66 vs. 62), the efficacy of the carboplatin doublet was completely comparable to that of the more established but more challenging cisplatin/Alimta combination. Specifically, carboplatin/Alimta and cispatin/Alimta were associated with a nearly identical median time to progressive disease (6.9 and 7.0 months, respectively) and overall survival at one year (64.0% vs. 63.1%, respectively), with just a relatively modest difference in the response rate on imaging (26.3 vs. 21.7%, respectively).

It is important to note that this isn’t a true randomized trial, so it isn’t a pure comparison of nearly identical groups. There may be differences in the patients who were recommended to receive carboplatin or cisplatin, but one would expect that the bias would be that the more fit patients were more likely to receive cisplatin, while patients felt less likely to be able to tolerate the standard treatment of cisplatin might have been recommended to receive carboplatin instead. In fact, the four year difference in median age, with younger patients more likely to be assigned to receive cisplatin, is consistent with this idea. But this would only be expected to bias results in favor of the cisplatin/Alimta recipients if they were more likely to be younger and more fit. Despite this presumed bias, those receiving carboplatin performed just as well.

Another important point is that the results in this “real world” expanded access protocol were every bit as good, and in fact in many ways a little better, than the results in the well-controlled randomized trial that led to the approval of Alimta as a treatment for MPM. This illustrates that both the cisplatin/Alimta and carboplatin/Alimta treatment strategies are both feasible and effective for MPM in less selected patients than those eligible for the controlled trial – that regular patients and presumably those with more medical problems can still benefit from these chemotherapy combinations.

My personal preference is still to favor cisplatin/Alimta as the preferred and better studied combination for patients I believe are well enough to tolerate it. But when faced with the common scenario of a patient who is not a strong candidate for the potentially rigorous FDA approved combination, I’m happy to know that an acceptable substitute has been demonstrated in hundreds of patients to provide a very comparable utility for MPM.