Mesothelioma Recurrence After Pleurectomy Decortication

Page Profile
Recurrence After Pleurectomy/Decortication (P/D)
Anchor study	Paajanen et al., Ann Surg 2026 (PMID 39813065)
Cohort	N=436 verified recurrences (of 551 evaluable, 79%)
Local recurrence	85% of recurrences; sole site in 29%
Median DFI	9.8 mo (95% CI 9.0–10.7)
Median PRS	12.7 mo (95% CI 10.6–14.4)
Salvage surgery (PRS)	HR 0.46 (95% CI 0.29–0.74, P=0.0013)
IOHC effect (DFI)	HR 0.60 (P<0.001); PRS HR 0.56 (P<0.001)
Dominant genomic features	BAP1 alt 44%; CDKN2A HD ~49–75%; NF2 33%
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Mesothelioma recurrence after pleurectomy/decortication (P/D) is virtually universal in long-term follow-up. The largest dedicated analysis to characterize the pattern — the 2026 Brigham and Women's Hospital cohort by Juuso Paajanen and colleagues, published in Annals of Surgery (PubMed identifier (PMID) 39813065) — examined 436 patients with verified tumor recurrence from a population of 551 evaluable patients who underwent P/D with macroscopic complete resection (MCR) between 1998 and 2022. The dominant finding is that local recurrence occurred in 85% of patients (N=370) and was the sole site of first recurrence in 29% (N=129), making P/D-associated relapse predominantly a locoregional rather than distant event. This page synthesizes the Paajanen anchor study, comparative recurrence geography after extrapleural pneumonectomy (EPP), the histologic and molecular predictors that shape post-operative trajectory (including BAP1, CDKN2A homozygous deletion, and tumor mutational burden), the role of intraoperative heated chemotherapy (IOHC), and the salvage options — including re-resection (Paajanen hazard ratio (HR) 0.46), hemithoracic intensity-modulated radiation therapy (IMRT), and second-line systemic therapy informed by CheckMate 743, MAPS, RAMES, and ATOMIC-Meso.

Recurrence and post-P/D recurrence at a glance:

• Recurrence is virtually universal — 436 of 551 evaluable (79%) P/D patients in the Paajanen Brigham cohort developed verified recurrence during a median follow-up of 88.5 months.
• 85% local pattern — local recurrence occurred in 85% of recurrent cases (N=370) and was the sole site of first recurrence in 29% (N=129); residual thoracic cavity (72%), ipsilateral chest wall (55%), and diaphragm (22%) were the leading anatomical sites.
• Histology dominates trajectory — sarcomatoid tumors relapsed earlier and more distantly (P=0.003 for time-to-recurrence; P<0.001 for distant spread); epithelioid tumors relapsed later and predominantly locally.
• Intraoperative heated chemotherapy (IOHC, also known as Hyperthermic Intrathoracic Chemotherapy (HITHOC)) extends survival — IOHC was independently associated with longer disease-free interval (DFI; HR 0.60, P<0.001) and longer post-recurrence survival (PRS; HR 0.56, P<0.001).
• Salvage re-resection is independently survival-prolonging — among patients with distant or distant+local recurrences, recurrence surgery showed HR 0.46 (95% CI 0.29–0.74, P=0.0013) for PRS.
• 9.8-month median DFI; 12.7-month median PRS — in the recurrent cohort overall; 1-year recurrence-free survival 39%, 3-year 9%.
• P/D ≠ EPP geography — contralateral chest recurrence is roughly half as common after P/D (18%) than after EPP (38%) from the Brigham comparison cohort; abdominal recurrence is 24% after P/D vs. 54% after EPP.
• Modified Response Evaluation Criteria in Solid Tumours (mRECIST) — the Byrne and Nowak modified RECIST criteria are the standard for measuring tumor change in post-treatment surveillance imaging.
• Soluble Mesothelin-Related Peptides (SMRP / MESOMARK) — the only U.S. Food and Drug Administration (FDA)-cleared blood biomarker for monitoring biphasic and epithelioid mesothelioma; sensitivity is limited in sarcomatoid disease.
• Circulating tumor DNA (ctDNA) — Johns Hopkins phase 2 perioperative immune checkpoint blockade trial (PMID 40921804) showed that undetectable ctDNA after neoadjuvant immunotherapy correlated with significantly longer event-free and overall survival, establishing molecular residual disease monitoring as feasible.

Educational disclaimer: This page is for medical education and is not a substitute for individualized advice from a treating oncologist, thoracic surgeon, or palliative care team. Treatment decisions after P/D recurrence require multidisciplinary evaluation at a specialized mesothelioma program.

Mesothelioma Treatment Cost Facts (Reference, Verified 2026-05-13)

Cost dimension	Typical range (United States Dollars (USD))
First-year cost (total typical first-year billed cost of mesothelioma treatment)	$150,000–$1,000,000+
Immunotherapy / year (FDA-approved nivolumab + ipilimumab, CheckMate 743 regimen)	$150,000–$200,000
Surgery (Pleurectomy/Decortication, P/D) (procedural cost; EPP costs similar or higher)	$30,000–$100,000+
Chemotherapy course (standard cisplatin/pemetrexed course; typical full course 4–6 cycles)	$10,000–$30,000 per cycle
Average settlement (average mesothelioma civil lawsuit settlement per Mealey's industry benchmark)	$1,000,000–$1,400,000

Recurrence and post-P/D recurrence at a glance:

• Recurrence is virtually universal — 436 of 551 evaluable (79%) P/D patients in the Paajanen Brigham cohort developed verified recurrence during a median follow-up of 88.5 months.
• 85% local pattern — local recurrence occurred in 85% of recurrent cases (N=370) and was the sole site of first recurrence in 29% (N=129); residual thoracic cavity (72%), ipsilateral chest wall (55%), and diaphragm (22%) were the leading anatomical sites.
• Histology dominates trajectory — sarcomatoid tumors relapsed earlier and more distantly (P=0.003 for time-to-recurrence; P<0.001 for distant spread); epithelioid tumors relapsed later and predominantly locally.
• Intraoperative heated chemotherapy (IOHC, also known as Hyperthermic Intrathoracic Chemotherapy (HITHOC)) extends survival — IOHC was independently associated with longer disease-free interval (DFI; HR 0.60, P<0.001) and longer post-recurrence survival (PRS; HR 0.56, P<0.001).
• Salvage re-resection is independently survival-prolonging — among patients with distant or distant+local recurrences, recurrence surgery showed HR 0.46 (95% CI 0.29–0.74, P=0.0013) for PRS.
• 9.8-month median DFI; 12.7-month median PRS — in the recurrent cohort overall; 1-year recurrence-free survival 39%, 3-year 9%.
• P/D ≠ EPP geography — contralateral chest recurrence is roughly half as common after P/D (18%) than after EPP (38%) from the Brigham comparison cohort; abdominal recurrence is 24% after P/D vs. 54% after EPP.
• Modified Response Evaluation Criteria in Solid Tumours (mRECIST) — the Byrne and Nowak modified RECIST criteria are the standard for measuring tumor change in post-treatment surveillance imaging.
• Soluble Mesothelin-Related Peptides (SMRP / MESOMARK) — the only U.S. Food and Drug Administration (FDA)-cleared blood biomarker for monitoring biphasic and epithelioid mesothelioma; sensitivity is limited in sarcomatoid disease.
• Circulating tumor DNA (ctDNA) — Johns Hopkins phase 2 perioperative immune checkpoint blockade trial (PMID 40921804) showed that undetectable ctDNA after neoadjuvant immunotherapy correlated with significantly longer event-free and overall survival, establishing molecular residual disease monitoring as feasible.

Key Facts

Metric	Finding
Anchor study	Paajanen J, Richards WG, Xie Y, Mazzola E, Sidopoulos K, Kuckelman J, Gill RR, Bueno R. Annals of Surgery 2026 (PMID 39813065). Single-center retrospective cohort, International Mesothelioma Program, Brigham and Women's Hospital / Harvard Medical School.
Recurrence rate	436 of 551 evaluable (79%) over median follow-up 88.5 months (95% CI 80.9–127.0).
Local recurrence rate	85% of recurrent cases; sole site of first recurrence in 29%.
Median disease-free interval (DFI)	9.8 months (95% CI 9.0–10.7); 1-year recurrence-free survival 39%, 3-year 9%.
Median post-recurrence survival (PRS)	12.7 months (95% CI 10.6–14.4).
Salvage surgery effect on PRS	HR 0.46 (95% CI 0.29–0.74, P=0.0013) in patients with distant ± local recurrences.
Chemotherapy at recurrence effect on PRS	HR 0.69 (95% CI 0.54–0.92, P=0.005).
Histology distribution	Epithelioid 63%, biphasic 31%, sarcomatoid 6%.
Genomic landscape (Bueno 2016)	BAP1 44%, CDKN2A 49%, CDKN2B 42%, MTAP 34%, NF2 33%, TP53 18% in 216 mesothelioma tumors.
Germline BAP1 survival advantage	~7-fold improved long-term survival in germline BAP1 carriers (5-year survival 47% vs. 6.7% in SEER controls).
CheckMate 743	First-line nivolumab + ipilimumab vs. chemotherapy in unresectable MPM (N=605); median overall survival (OS) 18.1 vs. 14.1 months; HR 0.74; P=0.002.
MARS2 trial	Extended P/D + chemo vs. chemo alone in resectable MPM; median OS 19.3 vs. 24.8 months; restricted mean survival difference −1.9 months; serious adverse events more common in surgery arm.
Imaging modalities at recurrence	Computed tomography (CT) 51%, Positron Emission Tomography–CT (PET-CT) 45%, magnetic resonance imaging (MRI) 2%, physical exam 1%, exploratory surgery 2%.
Standard response criteria	Modified RECIST (Byrne and Nowak, Lung Cancer 2004, PMID 14760119); mRECIST 1.1 revision (Armato, J Thorac Oncol 2018).
Approved biomarker	Soluble Mesothelin-Related Peptides (SMRP / MESOMARK), FDA-cleared for monitoring biphasic and epithelioid mesothelioma.

Why Is the Paajanen 2026 Study the Anchor for Post-P/D Recurrence Care?

The Paajanen 2026 paper is the largest dedicated analysis of P/D-specific recurrence patterns and the first to demonstrate an independent survival benefit from recurrence surgery using multivariable analysis in a P/D-only cohort.

Study population and design

From 1,920 patients in the Brigham International Mesothelioma Program (IMP) surgical database, 709 (37%) underwent complete (extended) P/D. After excluding 148 patients with insufficient endpoint data, 4 with non-diffuse pleural mesothelioma (PM) diagnoses, and 6 with concurrent metastatic malignancies, 551 patients were available for analysis. Of these, 436 (79%) developed verified recurrence and form the analytical cohort. Median follow-up from surgery was 88.5 months (95% confidence interval (CI) 80.9–127.0). Mean patient age was 68 ± 9.7 years; 76% male; histology distribution was epithelioid 63% (N=275), biphasic 31% (N=136), and sarcomatoid 6% (N=25).

Anatomic recurrence map

Among the 436 patients with verified recurrence:

Recurrence category	Frequency (N, %)
Local — residual thoracic cavity (pleura)	N=314 (72%)
Local — ipsilateral chest wall	N=241 (55%)
Local — diaphragm	N=96 (22%)
Local — interlobar fissures	N=69 (16%)
Local — pericardium	N=57 (13%)
Local — direct lung invasion	N=43 (10%)
Local — mediastinal soft tissue mass	N=28 (6%)
Local — spinal cord/thoracic vertebrae (adjacent)	N=20 (5%)
Local — direct abdominal extension (liver)	N=30 (7%)
Lymphatic — any nodal recurrence	N=217 (50%)
Lymphatic — mediastinal lymph nodes (specifically)	N=177 (41%)
Hematogenous — abdomen	N=105 (24%)
Hematogenous — metastatic lung nodules (ipsilateral)	N=91 (21%)
Hematogenous — contralateral hemithorax (CHT)	N=77 (18%)
Hematogenous — distant musculoskeletal	N=27 (6%)
Hematogenous — central nervous system (CNS)	N=18 (4%)
Port-site recurrence (any port)	N=65 (15%)
Multifocal recurrence (more than one site)	N=402 (92%)

Multivariable predictors

Multivariable Cox proportional hazards modeling identified the following independent predictors:

Predictor	Outcome	Hazard ratio (HR) (95% CI)	P-value
Age (continuous)	Shorter DFI	1.02 (1.00–1.03)	0.015
Preoperative tumor volume (TV)	Shorter DFI	1.00 (1.00–1.01)	<0.001
Epithelioid vs. biphasic	Longer DFI	0.62 (0.49–0.77)	<0.001
Intraoperative heated chemotherapy (IOHC)	Longer DFI	0.60 (0.45–0.79)	<0.001
Tumor-Node-Metastasis (TNM) Stage IV vs. I	Shorter DFI	4.69 (1.69–13.01)	0.003
Eastern Cooperative Oncology Group performance status (ECOG PS) >1 at recurrence	Worse PRS	2.01 (1.50–2.70)	<0.001
Sarcomatoid vs. biphasic	Worse PRS	1.81 (1.09–3.01)	0.021
Epithelioid vs. biphasic	Better PRS	0.62 (0.49–0.80)	<0.001
IOHC (yes)	Better PRS	0.56 (0.42–0.75)	<0.001
Multifocal recurrence	Worse PRS	1.74 (1.08–2.82)	0.024
Recurrence surgery (distant ± local)	Better PRS	0.46 (0.29–0.74)	0.0013
Chemotherapy at recurrence	Better PRS	0.69 (0.54–0.92)	0.005

Abstract conclusion (verbatim)

"PM is frequently associated with local recurrence. Repeat surgical resection is feasible and can achieve good local control in selected cases."

How Does P/D Recurrence Differ From EPP Recurrence?

P/D leaves the visceral pleura in situ (a macroscopic-only, R1, resection) and so cannot achieve microscopic margin-negative (R0) clearance. That anatomy dictates a local-dominant recurrence pattern, in contrast to the more contralateral and abdominal pattern seen after extrapleural pneumonectomy (EPP), which removes the entire pleura, lung, ipsilateral diaphragm, and pericardium en bloc.

A 94-patient Swiss comparative recurrence analysis by Bellini and colleagues, reporting separate first-relapse patterns for P/D (N=45) and EPP (N=49) groups, found local-only relapse rates of 42.2% (P/D) versus 16.3% (EPP) and combined local+distant rates of 48.9% versus 36.7%, mirroring the Brigham pattern. A Japanese single-center series by Nakamura and colleagues of 90 P/D patients reported 68.4% local, 10.5% distant, and 21.1% local+distant recurrences among 57 patients who relapsed. The Brigham EPP comparison cohort had contralateral chest recurrence in 38% (vs. 18% after P/D) and abdominal recurrence in 54% (vs. 24% after P/D), the most direct cross-procedure comparison from a single institution.

For comparison of the operations themselves, see Pleurectomy/Decortication and Extrapleural Pneumonectomy. For the MARS2 trial controversy on whether extended P/D produces a net survival benefit, see MARS Trial and the MARS2 results published by Lim and colleagues in Lancet Respiratory Medicine 2024 (PMID 38740044).

What Are the Predictors of Recurrence After P/D?

Histologic subtype dominates

Histology is the single most consistently validated prognostic and recurrence-pattern predictor across all mesothelioma surgical series.

Epithelioid mesothelioma (63% of the Paajanen cohort) is independently associated with longer DFI (HR 0.62 vs. biphasic, P<0.001) and better PRS (HR 0.62 vs. biphasic, P<0.001). Epithelioid tumors recur later and predominantly locally.

Sarcomatoid mesothelioma (6% of the Paajanen cohort) is independently associated with worse PRS (HR 1.81 vs. biphasic, P=0.021) and more frequent distant spread (P<0.001). Among sarcomatoid patients, 76% experienced early recurrence (DFI < 9.8 months).

Biphasic mesothelioma (31% of the Paajanen cohort) shows intermediate behavior; higher sarcomatoid component proportion correlates with worse outcomes in pathology series.

BAP1 (BRCA1-Associated Protein-1)

Somatic BAP1 alterations occur in approximately 44% of pleural mesothelioma cases per the landmark 2016 comprehensive genomic analysis by Bueno and colleagues of 216 tumors (PMID 26928227, Nature Genetics). A subsequent review of genomic landscape in pleural mesothelioma confirmed BAP1 alteration rates near 44% and identified CDKN2A alterations in 49%.

Germline BAP1 mutations define the BAP1 Tumor Predisposition Syndrome (BAP1-TPDS), first described in the 2011 Nature Genetics paper by Testa, Carbone, and colleagues (PMID 21874000). Mesothelioma patients with germline BAP1 mutations show an approximately 7-fold improved long-term survival compared with sporadic mesothelioma, with 5-year survival of 47% versus 6.7% in Surveillance, Epidemiology, and End Results (SEER) Program controls (Carbone et al., PMID 25380601, Carcinogenesis 2015). Patients with a personal or family history of mesothelioma, uveal melanoma, or early-onset disease should be referred for genetic counseling per the medical and surgical care guidance published by Carbone, Pass, and colleagues in Journal of Thoracic Oncology 2022.

CDKN2A (p16/INK4a) homozygous deletion

Homozygous deletion (HD) of cyclin-dependent kinase inhibitor 2A (CDKN2A), detectable by fluorescence in situ hybridization (FISH), is the most prevalent genetic modification in mesothelioma. HD CDKN2A is an independent negative prognostic indicator (median 34 months without deletion vs. 10 months with, on univariate analysis) and is strongly associated with sarcomatoid differentiation and aggressive behavior. Co-deletion of methylthioadenosine phosphorylase (MTAP), occurring in approximately 90% of cases with CDKN2A HD, is detectable by immunohistochemistry (IHC) and serves as a practical surrogate marker for CDKN2A status in pathology workflow.

Intraoperative heated chemotherapy (IOHC / HITHOC)

Intraoperative heated chemotherapy — typically heated cisplatin perfused at 175 milligrams per square meter (mg/m²) over one hour after P/D — was administered in 80% of the Paajanen cohort (N=349) and was independently associated with both longer DFI (HR 0.60, P<0.001) and better PRS (HR 0.56, P<0.001). A National Cancer Database analysis of 1,632 patients undergoing radical surgery confirmed HITHOC's overall survival advantage (HR 0.72, P=0.004 in propensity-matched radical surgery subgroup). Prior dose-finding work from the Brigham group has reported that higher cisplatin doses in P/D-plus-intraoperative-lavage protocols correlate with a longer recurrence-free interval and overall survival, providing dosimetric rationale for the 175 mg/m² standard.

For more on the genomic landscape, see BAP1 and Mesothelioma and Genetic Testing for Mesothelioma.

How Are Patients Monitored for Recurrence After P/D?

Imaging surveillance

The U.S. National Comprehensive Cancer Network (NCCN) Guidelines for Mesothelioma: Pleural (Version 1.2024) provide recommendations for post-treatment follow-up, summarized in the NCCN Insights publication in Journal of Thoracic Oncology (PMID 38503043). The European Respiratory Society (ERS) / European Society of Thoracic Surgeons (ESTS) / European Association for Cardio-Thoracic Surgery (EACTS) / European Society for Radiotherapy and Oncology (ESTRO) 2020 guidelines (PMID 32451346) recommend structured follow-up with imaging, tailored by histology and stage.

In the Paajanen 2026 dataset, recurrence was detected by CT in 51% of cases, by PET-CT in 45%, by MRI in 2%, by physical examination in 1%, and by exploratory surgery in 2%, with pathologic or cytologic confirmation obtained in 42% of cases.

Modified RECIST (mRECIST)

Standard World Health Organization (WHO) and Response Evaluation Criteria in Solid Tumours (RECIST) criteria do not apply to pleural mesothelioma because of its non-spherical, rind-like growth pattern. Byrne and Nowak developed the modified RECIST (mRECIST) system, published in Lung Cancer 2004 (PMID 14760119): tumor thickness perpendicular to the chest wall or mediastinum is measured at two positions at three separate levels on thoracic CT, creating a six-point unidimensional sum. A revised mRECIST 1.1, published by Armato and colleagues in Journal of Thoracic Oncology 2018, formalizes measurement-site selection and provides further standardization. The phase III LUME-Meso trial (ClinicalTrials.gov identifier NCT01907100, PMID 31103412) used mRECIST as the primary progression-free survival endpoint, validating its ongoing role in clinical trials.

Soluble mesothelin-related peptides (SMRP / MESOMARK)

SMRP — the Mesomark® assay — is the only U.S. Food and Drug Administration (FDA) 510(k)-cleared blood biomarker for monitoring mesothelioma patients and is FDA-labeled for monitoring biphasic and epithelioid mesothelioma for progression or recurrence following primary chemotherapy. Serial SMRP increases may precede radiographic recurrence detection in epithelioid disease, though sensitivity in sarcomatoid histology is limited because of low mesothelin expression. Fibulin-3 (EFEMP1) was reported by Pass and colleagues in New England Journal of Medicine 2012 as a candidate biomarker, with subsequent independent validations reporting substantially lower sensitivity (8–13%). Its role in post-P/D recurrence monitoring is not established and the assay is not FDA-cleared for mesothelioma surveillance.

Emerging: circulating tumor DNA (ctDNA)

The first perioperative ctDNA trial in resectable pleural mesothelioma was published by the Johns Hopkins Kimmel Cancer Center team in Nature Medicine (PMID 40921804). The phase 2 trial combined neoadjuvant immune checkpoint blockade with ultra-sensitive tumor-informed whole-genome sequencing of cell-free DNA to detect minimal residual disease. Patients with undetectable ctDNA after neoadjuvant immunotherapy, or ≥95% ctDNA decline, had significantly longer event-free and overall survival. ctDNA is not yet standard post-P/D surveillance practice; the Johns Hopkins data establish feasibility and clinical relevance.

How Is Recurrence Treated After P/D?

Local recurrence — salvage surgery

Re-resection for local or combined recurrence is associated with the largest independent survival benefit in the Paajanen 2026 dataset (HR 0.46, 95% CI 0.29–0.74, P=0.0013 for PRS, in the distant ± local subgroup). A systematic review by Bellini and colleagues of second surgery for recurrent pleural mesothelioma — 9 studies, 89 total re-resection patients — reported median PRS after recurrence surgery ranging from 14.5 to 23.5 months, with chest wall resection the most common procedure (70.8%). Patient selection prioritizes good ECOG performance status, epithelioid histology, a singular or limited recurrence, and a technically resectable lesion. Surgery was performed in only 33% of patients with local-only recurrence and 13% of those with distant ± local recurrences, underscoring the selectivity required.

For the operative considerations and the natural history of the index P/D operation, see Pleurectomy/Decortication. For salvage operative outcomes published by Mount Sinai with 0% 30-day and 4.2% 90-day mortality in a contemporary cohort, see the ASCO Post coverage referenced in the MARS2 controversy.

Hemithoracic intensity-modulated radiation therapy (IMRT)

Hemithoracic pleural IMRT after P/D was evaluated in a phase II study by Rosenzweig and colleagues (PMID 25442335) of 24 patients receiving 45 Gray (Gy) to the involved hemithorax: little high-grade toxicity, progressive declines in pulmonary function, and superior overall survival and progression-free survival relative to a matched EPP-IMRT cohort. The IMPRINT phase II study by Rimner and colleagues evaluated hemithoracic IMRT as part of multimodality P/D-based treatment (median progression-free survival 12.4 months, median overall survival 23.7 months) with acceptable radiation pneumonitis rates.

Stereotactic body radiation therapy (SBRT) for focal chest wall recurrences is used case-by-case at high-volume centers; mesothelioma-specific SBRT prospective data are limited.

Photodynamic therapy (PDT)

The Penn Medicine team led by Joseph Friedberg has pioneered intraoperative PDT combined with lung-sparing pleurectomy. The 38-patient Penn series (PMID 22541196) reported median overall survival of 31.7 months for all patients and 41.2 months for epithelioid disease. PDT uses porfimer sodium as photosensitizer with intraoperative light delivery and is hypothesized to stimulate anti-tumor immune responses in addition to direct cytotoxicity. PDT-at-recurrence specifically is not yet published as a distinct series.

Systemic therapy for distant or distant+local recurrence

CheckMate 743 (nivolumab + ipilimumab)

Baas, Scherpereel, and colleagues reported the phase III CheckMate 743 trial in Lancet 2021 (PMID 33485464): N=605 unresectable mesothelioma patients; first-line nivolumab plus ipilimumab vs. platinum + pemetrexed chemotherapy. Median overall survival 18.1 vs. 14.1 months; HR 0.74; P=0.002. Three-year overall survival 23% vs. 15%. CheckMate 743 enrolled only unresectable MPM patients without prior systemic therapy; its relevance to post-P/D recurrence is an extrapolation. The Paajanen cohort showed no statistically significant survival difference between immune checkpoint inhibitor (ICI) therapy and chemotherapy at recurrence (P=0.900), likely reflecting selection bias and the long study window rather than true equivalence.

MAPS — bevacizumab + cisplatin/pemetrexed

Zalcman and colleagues reported the phase III Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS) trial in Lancet 2016 (PMID 26719230): N=448 unresectable MPM; bevacizumab 15 mg/kg every 21 days added to cisplatin/pemetrexed vs. cisplatin/pemetrexed alone. Median overall survival 18.8 vs. 16.1 months; HR 0.77; P=0.0167. Bevacizumab addition is included in current ERS/ESTS/EACTS/ESTRO and NCCN recommendations for eligible patients without contraindications.

RAMES — ramucirumab + gemcitabine (second-line)

The phase II RAMES trial reported by Pinto, Zucali, and colleagues in Lancet Oncology compared gemcitabine plus ramucirumab vs. gemcitabine plus placebo in the second-line setting after first-line platinum-based chemotherapy. Median overall survival 13.8 vs. 7.5 months in the ramucirumab arm; 1-year overall survival 56.5% vs. 33.9%. Benefit was observed regardless of histologic subtype and prior treatment outcome.

ATOMIC-Meso — pegargiminase (ADI-PEG 20)

Szlosarek and colleagues reported the ATOMIC-Meso phase II/III randomized clinical trial (NCT02029690, PMID 38358753) in JAMA Oncology. Pegargiminase (pegylated arginine deiminase 20, ADI-PEG 20) plus pemetrexed/cisplatin vs. placebo plus pemetrexed/cisplatin in non-epithelioid mesothelioma — most of which is deficient in argininosuccinate synthetase 1 (ASS1) and therefore arginine-dependent. Results: a ~1.6-month median survival extension, ~35% reduction in progression risk, and a quadrupled 3-year overall survival rate vs. placebo.

KEYNOTE-028 — pembrolizumab in PD-L1-positive previously treated mesothelioma

Alley and colleagues reported the phase Ib KEYNOTE-028 mesothelioma cohort in Lancet Oncology 2017 (PMID 28291584): N=25 programmed death-ligand 1 (PD-L1)-positive previously treated MPM patients; objective response rate 20%, median duration 12 months, median progression-free survival 5.5 months, median overall survival 18.7 months.

LUME-Meso (negative trial)

Scagliotti and colleagues reported the phase III LUME-Meso final results in Lancet Respiratory Medicine 2019 (PMID 31103412): nintedanib + pemetrexed/cisplatin vs. placebo + pemetrexed/cisplatin in N=458 chemotherapy-naïve epithelioid mesothelioma patients. Primary progression-free survival endpoint was not met (median 6.8 vs. 7.0 months). Nintedanib is therefore not a standard salvage option.

Intracavitary CAR-T cell therapy (investigational)

Adusumilli and the Memorial Sloan Kettering (MSK) team have led intrapleural delivery of cluster of differentiation 28 (CD28)-costimulated mesothelin-targeted chimeric antigen receptor (CAR) T-cells. The phase I trial (ClinicalTrials.gov identifier NCT02414269, PMID 34266984): 27 patients (25 with MPM) received 0.3 million to 60 million CAR-T cells per kilogram intrapleurally. No CAR-T-related toxicities exceeded grade 1. CAR-T cells were detected in peripheral blood beyond 100 days in 39% of patients. Eighteen of 27 patients subsequently received pembrolizumab; in the 16-patient subset with minimum 3-month follow-up after pembrolizumab, 12-month overall survival was 80% and best overall response rate was 63% in MPM patients.

Intrapleural delivery — via pleural catheter or interventional radiology image-guided injection — makes this approach directly applicable to post-P/D local recurrence with residual pleural cavity or recurrent effusion. Evidence remains phase I, single-center, and not yet phase II/III.

Intrapleural gene therapy

Sterman and colleagues at the University of Pennsylvania (now New York University Langone) have led intrapleural adenoviral-mediated interferon gene transfer trials. The pilot/phase I/II of adenoviral interferon alpha-2b (Ad.IFN-α2b) plus celecoxib plus chemotherapy in 40 unresectable mesothelioma patients (PMID 26968202) showed an overall response rate of 25% and a disease control rate of 88%, with overall survival significantly higher than historical controls in the second-line group. A phase III INFINITE trial of TR002 (recombinant adenoviral interferon alpha-2b, rAd-IFN α2b) plus gemcitabine plus celecoxib as second-/third-line therapy was initiated.

When Should Goals-of-Care and Palliative Care Conversations Happen?

The Paajanen 2026 multivariable PRS model identifies the clinical features that should trigger early palliative care consultation at recurrence: ECOG performance status >1 (HR 2.01, P<0.001) — the single strongest PRS predictor — multifocal recurrence (HR 1.74, P=0.024), sarcomatoid histology (HR 1.81, P=0.021), and original TNM Stage III or IV (HR 1.49–5.00). When three or more of these are present simultaneously, median PRS approaches or falls below 6 months, making early goals-of-care discussions appropriate.

Symptomatic re-accumulation of pleural effusion after P/D may be managed with indwelling pleural catheter (IPC) placement. The Second Therapeutic Intervention in Malignant Effusion Trial (TIME2), reported by Davies and colleagues in Journal of the American Medical Association (JAMA) 2012 (PMID 22610520), was a randomized controlled trial (N=106) comparing IPC vs. chest tube plus talc pleurodesis for symptomatic malignant pleural effusion: both strategies were equally effective for dyspnea relief (>75% achieved clinically significant improvement), with IPC avoiding hospitalization but requiring home drain management.

For the broader symptom management framework, see Palliative Care for Mesothelioma and the foundational Temel and colleagues 2010 NEJM trial on early palliative integration in metastatic non-small cell lung cancer that informed the American Society of Clinical Oncology (ASCO) Provisional Clinical Opinion on early palliative care integration.

What Should Patients Know Before Choosing P/D?

The Paajanen 2026 dataset and broader literature support the following informed-consent points before P/D:

1. Long-term recurrence is highly probable — 79% of evaluable Brigham P/D patients developed verified recurrence during a median 88.5-month follow-up. The 3-year recurrence-free survival in the MCR cohort was 9%.
2. The median DFI in the Paajanen recurrent cohort is 9.8 months (95% CI 9.0–10.7); ranges across other large series are approximately 10–19 months, reflecting differing denominators.
3. Histology defines trajectory — epithelioid patients recur later, predominantly locally, and have better PRS; sarcomatoid patients recur early (76% within 9.8 months), distantly, and have the worst PRS.
4. IOHC independently extends DFI and PRS and should be part of pre-operative planning at centers that offer it.
5. A small but meaningful fraction of patients are candidates for salvage surgery — those with good performance status, epithelioid histology, and singular or limited recurrence with distant ± local pattern had a median PRS of 26.6 months in the Paajanen dataset.
6. P/D produces more local and less contralateral or abdominal recurrence than EPP — a meaningful consideration if salvage may later be needed.
7. The phase III MARS2 trial reported by Lim and colleagues in Lancet Respiratory Medicine 2024 (PMID 38740044) found that extended P/D was associated with shorter 2-year survival than chemotherapy alone (median overall survival 19.3 vs. 24.8 months; restricted mean survival difference −1.9 months, 95% CI −3.4 to −0.3, P=0.019), with more serious adverse events. Patient selection, quality assurance, and center volume remain points of debate in the surgical community.

Mesothelioma claimants and their families considering surgical options should also weigh the long-term financial planning required to support multimodality care; Danziger & De Llano's intake team coordinates a free consultation that examines both the medical pathway and the legal-financial recovery pathway in parallel (free Danziger & De Llano case evaluation).

Surveillance Protocol Synthesis

No mesothelioma-specific randomized trial of surveillance intervals exists. The following framework reflects the integrated guidance of NCCN v.1.2024, ERS/ESTS/EACTS/ESTRO 2020, and the Paajanen 2026 anatomic data (evidence level: expert opinion / guideline-based).

Patient profile	Recommended CT interval	PET-CT role	Additional notes
Epithelioid MCR + IOHC	CT chest/abdomen/pelvis every 3–4 months × 2 years, then every 6 months	For equivocal CT findings or rising SMRP	Baseline CT at 4–8 weeks post-operation; serial SMRP per FDA labeling
Biphasic MCR	CT every 3 months × 2 years, then every 6 months	Consider PET-CT every 6 months	Symptom vigilance (chest pain, dyspnea)
Sarcomatoid MCR	CT every 2–3 months given early-recurrence pattern	PET-CT every 3 months or with symptoms	Early palliative care integration; performance-status monitoring; lower SMRP utility

Frequently Asked Questions

How likely is recurrence after pleurectomy/decortication?

In the largest single-institution series — the 2026 Brigham analysis of 551 evaluable P/D patients — 436 (79%) developed verified recurrence during a median follow-up of 88.5 months. The 1-year recurrence-free survival was 39% and the 3-year was 9%, meaning that most P/D patients should expect some recurrence in long-term follow-up.

Where does mesothelioma recur most often after P/D?

The Paajanen 2026 data show that 85% of recurrences are local (the same hemithorax that was operated on), with the residual thoracic cavity (72%), ipsilateral chest wall (55%), and diaphragm (22%) being the leading anatomical sites. Distant spread — most commonly to the abdomen (24%) or contralateral chest (18%) — is less common after P/D than after extrapleural pneumonectomy.

Does salvage surgery for recurrence work?

In the Paajanen 2026 dataset, recurrence surgery was independently associated with improved post-recurrence survival in patients with distant ± local recurrences (HR 0.46, 95% CI 0.29–0.74, P=0.0013). Surgery was performed in only 33% of patients with local-only recurrence and 13% of those with distant ± local recurrence, indicating that careful selection is required: good performance status, epithelioid histology, and a technically resectable lesion are the key criteria.

What is the role of intraoperative heated chemotherapy (IOHC)?

IOHC (also called HITHOC) — typically heated cisplatin at 175 mg/m² perfused for one hour after P/D — was administered in 80% of the Paajanen cohort. On multivariable analysis it independently extended both disease-free interval (HR 0.60, P<0.001) and post-recurrence survival (HR 0.56, P<0.001).

Does the BAP1 gene affect recurrence after P/D?

Somatic BAP1 alterations occur in about 44% of pleural mesotheliomas per the Bueno 2016 Nature Genetics analysis. Germline BAP1 mutations define the BAP1 Tumor Predisposition Syndrome and are associated with approximately 7-fold improved long-term survival (5-year survival 47% vs. 6.7% in SEER controls), suggesting that germline-mutant patients may have a more indolent course — though recurrence-specific data are not yet published.

What new approaches are being investigated for recurrent mesothelioma?

Three avenues are advancing. First, perioperative immune checkpoint blockade combined with circulating tumor DNA (ctDNA) monitoring — the Johns Hopkins phase 2 trial published in Nature Medicine (PMID 40921804) showed that undetectable ctDNA after neoadjuvant immunotherapy correlated with longer event-free and overall survival. Second, intrapleural mesothelin-targeted CAR T-cell therapy (MSK NCT02414269, PMID 34266984) — directly applicable to post-P/D local recurrence with residual pleural cavity. Third, pegargiminase plus chemotherapy in non-epithelioid disease (ATOMIC-Meso, PMID 38358753), which quadrupled 3-year overall survival.

Related Resources at WikiMesothelioma

• Pleurectomy/Decortication — the operation itself: indications, technique, perioperative outcomes.
• Extrapleural Pneumonectomy — the alternative operation and its distinct recurrence geography.
• MARS Trial — the MARS and MARS2 trials and their implications for surgery selection.
• BAP1 and Mesothelioma — germline and somatic BAP1 alterations.
• Immunotherapy for Mesothelioma — CheckMate 743 and second-line ICI options.
• Chemotherapy for Mesothelioma — pemetrexed/cisplatin standard-of-care and second-line options.
• Radiation Therapy for Mesothelioma — hemithoracic IMRT and SBRT for focal recurrences.
• Clinical Trials Mesothelioma — finding active trials at recurrence.
• Palliative Care for Mesothelioma — symptom management framework and early integration.
• Mesothelioma Prognosis — overall survival benchmarks across histologies.
• Danziger & De Llano mesothelioma practice — free case evaluation, including for newly diagnosed patients and families navigating multimodality care decisions.

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