Addition of radiotherapy to surgery and chemotherapy improves survival in localized malignant pleural mesothelioma: A Surveillance, Epidemiology, and End Results (SEER) study
Introduction
Malignant pleural mesothelioma (MPM) is a highly aggressive cancer of the visceral or parietal pleura, with greater than 90% of cases occurring in the setting of asbestos exposure. It is a relatively rare cancer, with an incidence of approximately 10 per 1 million person-years in the United States. It has a long latency period, up to 20 years after asbestos exposure, and the median age of diagnosis is 75 years old. [1,2]
The optimal treatment of mesothelioma remains controversial, with heterogeneous data regarding all major treatment modalities and their impact on survival and other disease-related parameters. While patterns of care have changed over the years, survival improvements have been modest. Progress in understanding the optimal treatment of mesothelioma has been hampered by a lack of high-quality randomized trials for this rare malignancy.
Chemotherapy has level I evidence supporting its use in non-surgical patients, with first-line cisplatin/pemetrexed (cis/pem) showing a clear benefit to median OS over cisplatin alone (12.3 vs 9.3months). [3] The more recent phase III MAPS trial demonstrated a significantly improved median OS (18.8 vs. 16.1 months) and PFS (9.2 vs. 7.3 months) with the addition of bevacizumab to cis/pem compared to cis/pem alone [4]. However, for patients who are eligible for surgical resection, the data are less clear.
No phase III data exists for the use of chemotherapy in surgical MPM patients, but population database studies support the use of chemotherapy in all patients with MPM. An analysis of Surveillance, Epidemiology, and End Results (SEER) Medicare data in 2016 demonstrated improvements in 1- and 2-year OS for patients who received chemotherapy, regardless of surgical intervention. Survival was further improved in those patients undergoing surgery, with 1-year OS of 61% for patients undergoing dual-modality therapy, which dropped to 42% for patients who did not undergo surgery. [5]
The role of surgery similarly lacks high-quality phase III data. There has only been a single randomized surgical trial in MPM, the trimodality MARS I trial, in which all patients received induction chemotherapy followed by extrapleural pneumonectomy (EPP) and postoperative radiation vs no EPP or adjuvant radiotherapy. Overall survival and median survival were not statistically different between the two arms. [6] Significant criticism has been leveled at these conclusions, however, noting the small sample size, high cross-over rate between arms, and inconsistent adjuvant therapy [7]. Other series [8,9] and reviews [10] have generally indicated a survival benefit with surgical resection (either EPP or Pleurectomy/Decortication [P/D]), which has been supported by recent national database studies.
A recent National Cancer Database (NCDB) propensity matched analysis evaluated 20,561 patients and showed an improvement in survival with cancer-directed surgery (HR 0.77) with 30 and 90 day mortality rates of 6.3 and 15.5%. [11] A SEER database analysis of > 15,000 patients showed that patients who did not receive surgery or RT had a median survival of only 6.5 months, while patients receiving surgery alone had a median survival of 14.5 months. [12]. While both analyses used propensity matching to reduce the impact of selection bias, as with all database studies it cannot be completely eliminated.
The role of radiotherapy remains controversial. Patterns of failure analyses consistently demonstrate that local and locoregional recurrence are persistently high even after surgical resection, and that local progression is a frequent cause of death. [[13], [14], [15], [16]] The benefit of adding radiotherapy for patients receiving surgery and chemotherapy is an open question and data regarding the benefit of trimodality therapy have been heterogeneous. While the underpowered MARS I and SAKK 17/04 trials failed to show a locoregional survival benefit to trimodality therapy, other series have shown a benefit, with median OS ranges from 13 to 25.5 months and 40–70% of patients completing trimodality therapy [12,[17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27]].
Given the heterogeneity of available data regarding the potential benefit of trimodality therapy for patients with MPM, the purpose of this analysis was to evaluate the SEER database to assess whether trimodality therapy showed a survival benefit compared to surgery and chemotherapy alone.
Section snippets
Data source
The SEER database captures approximately 34% of cancer incidence in the United States. During the study period of 1976–2016, 16,396 patients with mesothelioma were diagnosed. SEER survival analysis requires that only patients with known follow-up and single primary cancer be analyzed, leaving 11,347 patients. From this, we limited analysis to patients that underwent surgery (N = 2,182) and also received chemotherapy (N = 1,015). The specialized Radiation/Chemotherapy Database (SEER 18 Custom
Results
A total of 1015 patients were identified meeting our inclusion criteria, with 678 patients (66.8%) receiving dual-modality treatment with surgery and chemotherapy, and 337 patients (33.2%) receiving trimodality therapy. Without IPTW adjustment, patients receiving trimodality therapy were younger (p < 0.0001), diagnosed more recently (p = 0.003), and more likely to undergo pneumonectomy (p < 0.001) (Supplementary Table S1). With IPTW adjustment, these differences became non-significant and there
Discussion
Using a large, population-based, national cancer registry, we have demonstrated that incorporating radiotherapy as a component of trimodality therapy for patients with localized MPM yields a significant and meaningful improvement to overall survival. This benefit remains significant for this cohort of patients after IPTW adjustment and conditional landmark analysis, reducing the likelihood that this conclusion suffers from indication bias and immortality bias, respectively.
The role of
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors
Transparency document
CRediT authorship contribution statement
Andrew B. Thompson: Conceptualization, Writing - original draft, Writing - review & editing, Project administration. Thomas J. Quinn: Writing - original draft, Writing - review & editing, Methodology, Formal analysis, Investigation, Visualization. Zaid A. Siddiqui: Writing - original draft, Writing - review & editing, Conceptualization. Muayad F. Almahariq: Writing - original draft, Writing - review & editing, Conceptualization. Inga S. Grills: Writing - original draft, Writing - review &
Declaration of Competing Interest
None.
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2022, Clinical Lung CancerCitation Excerpt :Though malignant pleural mesothelioma (MPM) is associated with poor prognosis, therapeutic strategies are evolving.1,2 Several studies have reported improvements in survival with the use of multimodal treatment regimens utilizing various combinations of chemotherapy, surgery, and radiotherapy.3–11 Experience may also play an important role in delivering treatment to MPM patients.
Pericardial dual mesh uptake on PET scan mimicking residual mesothelioma; a case report
2022, International Journal of Surgery OpenCitation Excerpt :Yet, increase in survival rate has been rather small [18]. According to a study by Thomas and colleagues in 2020, the addition of radiotherapy to the combination of chemotherapy plus resection might improve clinical outcome of these cases, however sufficient data regarding this trimodal therapy is currently lacking [3]. In this study, the patient underwent 3 sessions of cisplatin and pemetrexed chemotherapy induction followed by resection of the tumor and the implantation of a dual pericardial surgical mesh proceeded by a final session of cisplatin and pemetrexed chemotherapy.