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Page 8 of 12 Housman et al. J Cancer Metastasis Treat 2021;7:69 https://dx.doi.org/10.20517/2394-4722.2021.159

greater resistance to postoperative complications [10,28,41] . In fact, additional chemotherapy is administered in
64% of patients after P/D and only 25% of patients after EPP [28,41] .

Other studies have observed that surgical intervention does not provide any meaningful benefit. In a
retrospective multicenter Italian study of 1365 patients, the median survival was not different between EPP,
P/D, and chemotherapy alone (20.9, 24.6, 18.6, P = 0.596) .
[12]
[42]
Batirel et al. in 2018 published that MCR is not associated with improved survival. A group of 154
patients was examined; 90 underwent P/D, 42 EPP, and 22 partial pleurectomy. MCR was achieved in 75
patients (49%), 19 in the P/D group, 38 after EPP, and 18 after partial pleurectomy. A total of 133 patients
received adjuvant therapy, 45 of whom had chemotherapy and radiation, 33 after MCR, and 12 without
MCR. The study found no statistically significant difference in survival between those who had surgical
MCR and those who did not (21.4 months vs. 16.3 months).

The MARS 2 study, a phase II randomized control trail of P/D vs. no surgery for patients undergoing
[43]
platinum and pemetrexed-based chemotherapy, is ongoing .

RECURRENCE
Even following radical surgery and multimodal therapy, recurrence is unfortunately expected in patients
with MPM . Early studies estimated that up to 85% of patients died within the first 3 months of
[13]
[44]
recurrence . However, the addition of second-line chemotherapy and repeat surgical intervention
increases survival with recurrent disease [41,45,46] .

While the reporting of recurrence varies greatly between studies, the pattern of recurrence is consistently
related to the index procedure . Disease predominantly recurs in distal sites following EPP and the
[13]
ipsilateral hemithorax after P/D [13,22] .

[13]
In their retrospective study, Flores et al. describe a 56.9% recurrence rate in EPP and 47.8% in P/D with a
median follow-up of 17 months. Local recurrence was found in 33% of patients undergoing EPP vs. 65%
after P/D. Distal recurrence - including the contralateral hemithorax, peritoneum, abdomen, bone, brain,
skin, and “other” - occurred in 66% of EPP patients vs. 35% in P/D . In one series, the ipsilateral
[13]
[47]
hemithorax and/or mediastinum was the site of the first recurrence in 95% of patients undergoing P/D .
In the previously mentioned study by Nakamura et al. , the overall recurrence rate following P/D was
[30]
63.3%, with a 1- and 3-year recurrence-free survival of 69.7% and 34.0%. Median recurrence-free survival
was 19.0 months. The 1-year post-recurrence survival was 59.5%, and the median post-recurrence survival
[30]
time was 14.4 months . Interestingly, the hazard ratio of treatment post-recurrence was 0.2, a finding that
reinforces the observation that survival after recurrence is better in patients with P/D than EPP [30,48] .

One exception may be external beam radiation. In some guidelines, radiation has been contraindicated
following P/D due to the concern for postoperative pneumonitis in the preserved lung [10,49,50] . Surgeons who
utilize intensity-modulated pleural radiation therapy (IMPRINT/IMRT) or intraoperative radiotherapy may
[16]
be more likely to perform P/D due to the lower risk of pneumonitis . On the other hand, some surgeons
elect to perform EPP in anticipation of radiation due to the greater pleural exposure permitted by an empty
hemithorax . Other studies have reported the opposite concern; high rates of fatal pneumonitis with
[16]
[51]
radiation therapy following EPP in the remaining lung .