Second-Line Mesothelioma Treatment: “Uncertain” Evidence

3110504_scientistsA trio of researchers from England and Italy say the evidence for second-line treatment of malignant pleural mesothelioma is “uncertain at best”.

In a new article in JAMA Oncology, the three point out flaws or weaknesses in several of the most often-cited second line mesothelioma treatment studies and call for better-designed clinical trials in the future.

First-Line and Second-Line Treatments of Mesothelioma

Most pleural mesothelioma patients receive first-line chemotherapy with a combination of pemetrexed (Alimta) and cisplatin.

A second-line mesothelioma treatment is a treatment that is administered when cancer recurs after first-line therapy. At present, there is no accepted second-line treatment for pleural mesothelioma.

“Early case study reports including some pretreated patients had provided evidence that additional responses are possible with the use of further chemotherapy,” writes Dr. Alfredo Addeo of the Bristol Cancer Centre in Bristol, England “Unfortunately, the evidence supporting the efficacy of second-line treatment in this setting is globally weak.”

Problems with Existing Second-Line Trials

The article points to a 2008 Polish study including 243 mesothelioma patients which compared second-line treatment with pemetrexed to best-supportive care.

According to Dr. Addeo and his colleagues, the biggest problem with this trial is that it enrolled only mesothelioma patients who had first-line treatment with a drug other than pemetrexed.

Given that pemetrexed is now the most common first-line mesothelioma treatment, the authors contend that the results of this trial (significant disease control but no survival advantage), are of questionable value.

Another trial conducted at a London hospital in 2009 tested second-line mesothelioma treatment with a weekly dose of vinorelbine. That trial, however, included only 63 relapsed mesothelioma patients all of whom had otherwise good overall health (known as performance status) and had a median age of just 59. There was also no control group.

The authors of the JAMA Oncology article say the results of this trial, though encouraging, are unlikely to be reproducible in unselected older patients with a worse performance status.

Even a 2011 Italian study of pemetrexed “rechallenge” in patients who did well on the drug during first-line treatment was deemed “weak” because it included both patients who got pemetrexed only and those who received a combination of pemetrexed and cisplatin. Again, there was no control arm.

Redesigning Second-Line Mesothelioma Studies

To determine whether second-line treatment really can extend mesothelioma survival, Dr. Addeo and his co-authors Lucio Buffoni, MD, and Massimo Di Maio, MD, of Italy’s University of Turin say studies must be redesigned.

They recommend that second-line studies stratify mesothelioma patients according to how well they responded to first-line treatment since those who did well on a platinum-based treatment the first time (3 months or more without recurrence) may be more likely to respond to second-line treatment.

They also contend that it is crucial for second-line mesothelioma trials to include a control arm – a group of mesothelioma patients to provide a basis of comparison by receiving a placebo rather than the drug being tested.

“Clinical research is vital to obtain progress in this setting, and well-designed clinical trials are strongly needed,” concludes the article.

Second-Line Mesothelioma Treatment: The Official Stance

Current recommendations about second-line treatment for pleural mesothelioma differ between countries.

In the US, the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines support second-line chemotherapy while acknowledging that data on the practice is limited.

The European Society of Medical Oncology and the Third Italian Consensus Conference for MPM both recommend that relapsed mesothelioma patients consider enrolling in clinical trials.


Addeo, A, et al, “Is there room for second-line treatment of pleural malignant mesothelioma?”, January 19, 2017, JAMA Oncology, Epub ahead of print

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