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Housman et al. J Cancer Metastasis Treat 2021;7:69 https://dx.doi.org/10.20517/2394-4722.2021.159 Page 3 of 12

Years of subsequent studies have investigated the virtue of EPP for MPM. Treatment paradigms have long
involved a combination of systemic and local therapy, and studies are often described in this multimodal
[16]
context .

[19]
For example, a phase II trial conducted by Flores et al. investigated a protocol of neoadjuvant
gemcitabine/cisplatin chemotherapy, followed by EPP and radiotherapy. Median survival was 33.5 months
[19]
in the patients who underwent surgery vs. 9 months in patients determined to be unresectable .

Another study by Yan et al. retrospectively examined 70 patients undergoing EPP followed by
[20]
chemotherapy and/or radiation. They reported a morbidity rate of 37%, a mortality rate of 5.7%, and a
median survival of 20 months. Survival in patients who received adjuvant radiation was 90 months vs. 14
months, and in the recipients of adjuvant chemotherapy was 60 months vs. 14 months .
[20]

[21]
Sugarbaker et al. examined 183 patients who underwent EPP followed by adjuvant chemotherapy and
radiation. The perioperative morbidity rate was 50%, and the mortality rate was 3.8%. Overall median
survival was 19 months, and among 31 patients with a combination of positive prognostic factors - epithelial
histology, negative margins, and uninvolved mediastinal nodes - this increased to 51 months .
[21]

Weder et al. also investigated the use of neoadjuvant platinum-based chemotherapy and EPP followed by
[22]
adjuvant radiation. A total of 18 patients received preoperative chemotherapy, and 16 patients underwent
EPP with a 31.5% morbidity rate and 15.7% mortality rate. Of the original cohort, only 13 received
postoperative radiation and completed the treatment protocol. Overall median survival was 23 months, and
two patients remained free of disease 41- and 38-month following therapy. The authors note that the plane
of dissection was obliterated by dense fibrosis following induction chemotherapy compared with primary
surgery, and recommended caution during post-induction procedures .
[22]

The same author conducted a similar study on 61 patients in a multicenter prospective trial . A total of 58
[23]
(95%) completed induction chemotherapy, 45 (74%) underwent EPP, and 36 (59%) completed at least part
[23]
of planned radiotherapy . Median survival was 19.8 months and 23 months for the 45 patients who
received EPP .
[23]
More recently, a phase II study by Cho et al. , the “SMART” trial, investigated patients undergoing EPP
[24]
following induction radiation and receiving adjuvant chemotherapy for node-positive disease. A total of 96
patients underwent surgery 2-12 days following completion of radiation (median 5 days) to avoid radiation-
[24]
induced pulmonary toxicity before surgery . Median overall survival was 24.4 months. Disease-free
survival was 18 months. The 5-year incidence of local recurrence was 17 (20.1%), distant recurrence was 62
(63.3%), and at the time of publication, 24 patients had no disease recurrence. There were 4 deaths (4.2%); 1
in hospital from pneumonia, and 3 after discharge .
[24]

These examples also illustrate the problem with MPM research: heterogeneity in study design, the number
of subjects, and reported outcomes. All despite purported similarities in chemotherapy, radiation treatment,
and surgical approach. This may be influenced by variation in chosen time to progression, reported patterns
of recurrence, and chosen endpoints which influence statistical evaluation and may compensate for small
numbers of subjects . Combined with differences in follow-up practices, diagnostic modalities, and the
[13]
definitions of progression and recurrence, research into mesothelioma outcomes is sometimes limited by a
lack of standarization .
[13]