Mesothelioma

Overview

• Epidemiology: ~2,500 to 3,000/yr in US. M:F 5:1 in pleural; 1:1 in peritoneal. ↓ incidence in countries with asbestos bans.
• Distribution: pleural ~80%, peritoneal ~20%, rare sites (pericardial, tunica vaginalis testis) ~1%.
• Asbestos: ~80% of cases. Latency 20 to 40 yrs. Crocidolite (blue) > amosite (brown) > chrysotile (white) for risk. Fibers resistant to cellular enzymes accumulate in lung → mutagenic DNA strand breaks/deletions, ↑ EGFR, ↑ inflammatory cytokines.
• Other risk factors: erionite (Turkey/Cappadocia), prior thoracic RT, germline BAP1 (BAP1 tumor predisposition syndrome).
• Smoking: does NOT increase mesothelioma risk (but does ↑ lung ca risk in asbestos-exposed).
• SV40 controversy: polio vaccines 1955 to 63 contaminated with SV40 (monkey kidney cells), link to mesothelioma not established.

Histology & subtypes

• Epithelioid (~60 to 70%): mOS ~15 to 20 mo. Most chemo-responsive; smaller IO benefit than non-epithelioid (CheckMate 743 HR 0.86). Best prognosis.
• Sarcomatoid (~10 to 20%; rarest): mOS ~4 to 7 mo. Chemo-resistant, poorest prognosis of all types. Greatest IO benefit (CheckMate 743).
• Biphasic (mixed): mOS ~12 mo. Behavior depends on % sarcomatoid component.
• Benign variants:
  • Well-differentiated papillary mesothelial tumor (WDPMT), formerly WDPM. Cured with surgery alone.
  • Benign multicystic mesothelioma, F predominance, large grape-like cystic clusters, indolent (survival in years), surgery alone.
• IHC (positive): calretinin, WT-1, CK5/6, D2-40 (podoplanin), mesothelin, HBME-1 (antimesothelial cell antibody), vimentin; BAP1 LOSS supports mesothelioma.
• IHC (negative; rules out adeno): CEA, TTF-1, Ber-EP4, MOC-31, claudin-4, CD15; diastase-resistant PAS-positive mucin favors adenocarcinoma (plain PAS can be positive in mesothelioma from glycogen).
• SMRP (soluble mesothelin-related peptide): ↑ in >60% at presentation but useful only in epithelioid disease; supportive, not diagnostic.

Genomics

• Low TMB overall (low neoantigen load). No approved targeted therapy.
• Most commonly altered genes: BAP1, NF2, TP53, LATS2, SETD2, CDKN2A.
• BAP1 (BRCA1-associated protein 1):
  • Tumor suppressor. Somatic mutation in ~20 to 60% of mesothelioma.
  • Germline BAP1 (~1 to 3% of unselected cases; higher in familial or young-onset) → BAP1 tumor predisposition syndrome (mesothelioma + uveal melanoma + RCC + cholangiocarcinoma + cutaneous melanoma).
  • Loss of nuclear BAP1 by IHC supports mesothelioma diagnosis (vs benign reactive process).
• CDKN2A loss (homozygous deletion, ~70%): supports mesothelioma dx by FISH.
• No FDA-approved targeted therapy. PARP inhibitors (olaparib, niraparib) studied in BAP1-mutant disease, modest activity, NOT standard.

Presentation & diagnosis

• Pleural: dyspnea, chest pain, unilateral pleural effusion/thickening, weight loss. ECOG declines fast.
• Peritoneal: abdominal distention, ascites, pain, weight loss; rarely mets outside abdomen.
• VATS/thoracoscopic biopsy is diagnostic in ~95 to 98% (image-guided core-needle biopsy ~80 to 90%; blind needle biopsy and pleural fluid cytology only ~20 to 30%).
• Tract metastasis risk: mesothelioma can seed biopsy/drainage tracts, minimize invasive procedures and consolidate access points.
• Imaging:
  • CT chest/abdomen/pelvis with IV contrast, initial.
  • PET-CT, assess distant disease, guide biopsy.
  • MRI chest, chest-wall and diaphragm invasion if surgery considered.
  • Brain MRI, only if symptomatic.
• Operative workup: PFTs (FEV1, DLCO), V/Q scan, cardiac stress test. Mediastinoscopy +/- abdominal laparoscopy (evaluate underside of diaphragm) as needed.

Pleural mesothelioma, resectable disease

• EPP (extrapleural pneumonectomy): en bloc resection of parietal/visceral pleura, lung, ipsilateral diaphragm, pericardium.
• Extended P/D (pleurectomy/decortication): similar to EPP but lung remains in place.
• P/D: removes parietal and visceral pleura, no diaphragm or pericardial resection. Lung-sparing.
• Partial pleurectomy: palliative, partial removal, leaves gross tumor behind (for diagnosis or palliation).
• Modern preference: lung-sparing (P/D or extended P/D) over EPP, lower morbidity/mortality, similar or better OS.

• MARS (2011): randomized feasibility trial of EPP plus postoperative hemithoracic RT vs no EPP, after induction platinum-based chemo. EPP arm had WORSE mOS 14.4 vs 19.5 mo. EPP largely abandoned.
• P/D vs EPP (comparative data): mOS 22 vs 12.8 mo and 2-yr OS ~50% vs 20% favoring P/D; 30-day mortality and postoperative complications ↑↑ in the EPP group.
• MARS-2 (2024 update): P/D + chemo vs chemo alone. Surgery did NOT improve OS (HR 1.28 favoring chemo alone, P=.03), with ↑ AEs (~3×) and ↓ QOL. Routine P/D is being reconsidered.
• Hemithoracic radical RT (Trovo phase 3, IJROBP 2020): after lung-sparing surgery + chemo, radical hemithoracic RT (50 to 60 Gy) vs palliative RT in pts with proven gross residual disease, mOS 25.6 vs 12.4 mo, 2-yr OS 58% vs 28% (HR 0.54, P=.031). ~20% radiation pneumonitis.

• Adj/neoadj chemo: cisplatin + pemetrexed × 4 cycles, either before or after surgery (per Vogelzang regimen).
• Adj RT: palliative for pain or part of multimodality. Hemithoracic RT (50 Gy) selectively post-EPP.

Pleural mesothelioma, unresectable / advanced disease

• Nivolumab + ipilimumab (CheckMate 743):
  • Efficacy (initial): mOS 18.1 vs 14.1 mo (cis/peme), HR 0.74. Benefit independent of PD-L1.
  • Histology subgroups:
    • Non-epithelioid: mOS 18.1 vs 8.8 mo, HR 0.46, strong benefit (NCCN category 1).
    • Epithelioid: mOS 18.7 vs 16.5 mo, HR 0.86, modest and NS in subgroup, but still NCCN category 1.
  • 5-yr update: 5-yr OS 14% vs 6%; HR 0.74 sustained at 66.8 mo follow-up.
  • FDA approval: Oct 2020 (1L unresectable malignant pleural mesothelioma). Preferred 1L for sarcomatoid/non-epithelioid.
• Pembrolizumab + cis/peme (KEYNOTE-483 / IND.227):
  • Efficacy: mOS 17.3 vs 16.1 mo, HR 0.79. ORR 62% vs 38%. 3-yr OS 25% vs 17%.
  • FDA approval: Sept 17, 2024 for pembrolizumab + pemetrexed + platinum, 1L unresectable advanced/metastatic MPM (Chu QSC et al, Lancet 2023; PMID 37931632).
• Cisplatin + pemetrexed (Vogelzang 2003, historic SOC):
  • Efficacy: mOS 12.1 vs 9.3 mo (cis alone), ORR 41% vs 17%.
  • Folate + B12 supplementation required (reduces pemetrexed toxicity).
• Cis/peme + bevacizumab (MAPS, 2016):
  • Efficacy: mOS 18.8 vs 16.1 mo, HR 0.77; PFS 9.2 vs 7.3 mo.
  • Use: consider when IO contraindicated (e.g., autoimmune disease, transplant).
  • Stage-migration curiosity: the identical cis/pemetrexed regimen gave mOS 12.1 mo (experimental arm, Vogelzang 2003) but 16.1 mo (control arm, MAPS 2016), a ~4 mo delta over 13 yrs from better supportive care and patient selection.
• Tumor treating fields (TTFields, NovoTTF), STELLAR phase 2: mOS 18.2 mo with TTFields + cis/peme. Not yet RCT-validated; FDA HDE approved 2019.
• DREAM3R / PrE0506, durvalumab + cis/peme phase 3, results pending (phase 2 DREAM and PrE0505 promising single-arm data).

• Sarcomatoid / biphasic / non-epithelioid: ipi + nivo PREFERRED (greatest benefit; chemoresistant histology).
• Epithelioid: pembro + chemo OR ipi + nivo OR cis/peme +/- bev, discuss with patient (toxicity vs efficacy trade-off).
• IO contraindicated: cis/peme +/- bev.

• Re-platinum (cis/peme): if progressed on IO (ipi/nivo).
• Ipi/nivo: if progressed on chemo (and IO-naive).
• Single-agent chemo: gemcitabine, vinorelbine.
• Gemcitabine + ramucirumab (RAMES): mOS 13.8 vs 7.5 mo, HR 0.71. Epithelioid 13.8 vs 8.8 mo; non-epithelioid 13 vs 3.4 mo.
• Pembrolizumab as 2L monotherapy: ORR ~20% in phase 2; phase 3 (PROMISE-meso) failed to improve PFS/OS over single-agent chemo (gemcitabine or vinorelbine). NOT preferred in 2L if IO-naive.
• PARP inhibitors (olaparib, niraparib) in BAP1-mutant disease: investigational, modest activity.

Peritoneal mesothelioma

• Subtypes: epithelioid (most common) vs biphasic vs sarcomatoid.
• Workup: CT abdomen, diagnostic laparoscopy with biopsy.
• Standard of care for resectable: cytoreductive surgery (CRS) + HIPEC.
• CRS: aim for completeness of cytoreduction (CCR-0/1).
• HIPEC agents: cisplatin (preferred over mitomycin C in mesothelioma).
• Survival post CRS+HIPEC: mOS often 30 to 60+ mo in well-selected pts (varies by series); historical mOS without surgery <12 mo.
• Predictors of better OS: younger age (<60), low-grade epithelioid histology, complete CCR, cisplatin HIPEC.
• Unresectable peritoneal mesothelioma: systemic therapy similar to pleural, cis/peme +/- bev; ipi/nivo and pembro+chemo extrapolated from pleural data (NCCN supports).

High-yield mesothelioma pearls

• Asbestos latency 20 to 40 yrs; smoking does NOT add to mesothelioma risk.
• Tract seeding, minimize biopsy procedures.
• Subtype matters: sarcomatoid → ipi/nivo; epithelioid → pembro+chemo or ipi/nivo or cis/peme +/- bev.
• CheckMate 743: ipi/nivo 1L → 5-yr OS 14% vs 6% (HR 0.74).
• IND.227 (KEYNOTE-483): pembro + cis/peme 1L → mOS 17.3 vs 16.1 mo (HR 0.79). FDA-approved Sep 2024.
• MARS-2: P/D + chemo NOT better than chemo alone, surgical role being re-examined; EPP abandoned (MARS, P/D vs EPP).
• BAP1: germline → tumor predisposition syndrome. Loss by IHC supports mesothelioma dx.
• Peritoneal: CRS + HIPEC (cisplatin) is curative-intent option; mOS 29 to 98 mo.
• Adjuncts: TTFields (NovoTTF) HDE approved; not RCT-proven.
• Pleural fluid cytology alone is INADEQUATE for diagnosis, get tissue (VATS biopsy).