Combined Modality Treatment in Mesothelioma

A Systemic Literature Review With Treatment Recommendations

Charlotte De Bondt; Ioannis Psallidas; Paul E. Y. Van Schil; Jan P. van Meerbeeck


Transl Lung Cancer Res. 2018;7(5) 

In This Article


We recognize several flaws in the reporting of combined modality treatment series. As malignant mesothelioma is a relatively rare disease, the volume of patients being treated in any given center is low. A small number of specialized institutions tend to dominate the publications and as a result, the published outcomes do not mirror the real-life outcomes. Recording data in (inter)national registries could help in overcoming this selection bias.

Treatment protocols also tend to be amended and adapted depending on findings during therapy, e.g., PORT is sometimes added based on operative findings. This lack of standardization makes retrospective comparison of different series hazardous.

Aside from this heterogeneity in treatment protocols, there is also the issue of bias in the definition of resectable disease. The availability of experienced surgeons or radiotherapists plays an important role in this interpretation. Patient characteristics such as N2 disease and histological subtypes are also not routinely documented and considering how significant these prognostic factors are, omitting them is casting a bias on the results.

Time-to-event outcomes such as median overall survival and progression free survival, are estimated from different starting points in different trials, making comparison between individual series and trials difficult and confusing.

Retrospective series suffer from immortal time or guarantee time bias. This arises when the analysis includes the time period before or in between treatment(s) as part of follow-up, as is often the case in multimodality treatment trials.[40,41] Nelson et al. attempted to overcome this by implementing propensity matched analysis when studying the National Cancer Database.[42] Vogl pointed out that this analysis is still biased in favor of the multimodality treatment group. A tell-tale sign of this statistical wizardry is the fact that the survival curve of the multimodality treatment group starts out flat. Only the patients that complete the entire treatment protocol are included in the analysis. As they have to be alive to undergo the different treatment modalities any patient who drops out of the trial ahead of completion is not taken into account when analyzing the treatment group. As a result an overestimation will occur favoring the treatment group. Unfortunately, in any disease with a prognosis as dismal as that of malignant mesothelioma, patients will die in between treatment modalities or even before any treatment is given, as such a plateau in the survival graph is inaccurate and misleading.[41]