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to nodules < 1 cm, cytoreduction, macroscopic complete resection, en bloc chest wall resection,
diaphragmatic and pericardial resection “when indicated”, and organ sparing when frank invasion was
[32]
identified . Some studies had multiple forms of extirpation being performed in the same population, which
made reporting of outcomes even more challenging. Though some papers reported promising outcomes,
Teh et al. ultimately drew no conclusions with regard to overall survival or symptomatic benefits. It was,
[32]
however, one of the earliest studies to codify the descriptive difficulties in mesothelioma research. Later that
same year, Rice et al. published their paper with the IASLC calling for formal definitions of cancer-
[6]
directed mesothelioma procedures.

EPP vs. P/D
The EPP remained the gold standard of mesothelioma surgery for decades . Unfortunately, despite
[33]
improvements in technique and supportive care, a considerable volume of research has revealed a high
morbidity rate and mortality associated with the EPP [13,16] . In some studies, the outcomes are so poor that
undergoing surgery with curative intent actually reduces overall survival [10,13,34] .

In one of the most widely referenced studies on the EPP, the original MARS trial - now referred to as MARS
[34]
1 - randomized 50 patients to EPP and no EPP treatment arms . Median survival was 14.4 months in the
EPP group and 19.5 months in the no EPP group. The authors found that the hazard ratio for overall
survival - when adjusted for sex, histologic subtype, stage, and age at randomization was 2.75 (1.21-6.26, P =
0.016). There were also five times the number of adverse events in the EPP group (10 vs. 2), which was likely
[34]
reflected in a lower median quality of life scores in the survivors .
Arguably the decision to continue to perform the EPP over P/D has been based on surgeon preference,
historical inertia, and the intuition that more tissue resection confers better oncologic outcomes [10,14,16] . But
despite the greater radicality of the procedure, and possibly because of it, numerous studies since the 2000s
have shown equal or better survival after P/D than EPP [10,13,35-37] .

Flores et al. , in what remains one of the largest retrospective studies of MPM, investigated outcomes of
[13]
663 patients undergoing EPP vs. P/D. The EPP group was more likely to receive multimodality therapy and
had a higher proportion of epithelioid histology. The patients undergoing P/D had earlier stage tumors, but
also significantly greater age. These represent a constellation of factors that should have favored outcomes
in the EPP group. They nevertheless found that operative mortality was 7% for the EPP group and 4%
following P/D. Additionally, serious respiratory complications occurred in 10% of EPP patients and 6.4% of
P/D patients. In a cox proportional hazard model controlled for histology, stage, gender, and multimodal
therapy, EPP had a hazard ratio of 1.4 compared to P/D.

A meta-analysis performed by Taioli et al. examined 1391 patients undergoing EPP compared to 1512
[38]
undergoing P/D. They found 2.65 times higher 30-day mortality rate associated with EPP (4.5% vs. 1.7%).
Median survival appeared to be equivocal, with 53% of studies reporting longer survival after PD vs. 47%
[38]
after EPP (see Figures 1 and 2) . However, of the 7 studies reporting at least 2-year survival, there were no
significant differences between the two procedures .
[38]
A combination of higher rates of complications - including acute respiratory distress syndrome,
reintubation, bleeding, bronchopleural fistula, unexpected reoperation, sepsis, and mortality - all contribute
to hazard ratios in EPP of up to 10-times the surgical alternatives, and have forced many practitioners to
advocate against it as the procedure of choice [10,13,34,38,39] .