Addition of radiotherapy to surgery and chemotherapy improves survival in localized malignant pleural mesothelioma: A Surveillance, Epidemiology, and End Results (SEER) study

Highlights

• Radiotherapy provides survival benefit for localized malignant mesothelioma.

• This survival benefit is independent of surgery and chemotherapy.

• This is the first population level analysis to demonstrate this finding.

• No additional survival benefit was seen with regional or metastatic disease.

Abstract

Introduction

Malignant pleural mesothelioma (MPM) is a devastating disease with poor survival outcomes for most patients. Optimizing therapeutic approaches is thus vital, but has been hampered by a dearth of randomized trials to guide decision making. We used a population-level database to evaluate the impact of radiotherapy as a component of trimodality therapy on overall survival (OS) in MPM.

Methods

We retrospectively reviewed the SEER Radiation/Chemotherapy database for patients with MPM who received surgery and chemotherapy, with or without radiotherapy. A propensity score-matched analysis with inverse probability of treatment weighting (IPTW) was performed. Weight-adjusted univariate KM analysis was performed and doubly robust, IPTW-adjusted multivariable cox proportional hazards regression modeling was also performed to quantify the effect of radiotherapy on OS in trimodality therapy for MPM.

Results

1015 patients were identified. 678 patients received surgery and chemotherapy, and 337 patients received trimodality therapy. For patients with localized disease, OS was significantly improved with trimodality therapy (HR 0.56, CI 0.4 – 0.8, p = 0.001), which persisted with IPTW adjustment (HR 0.65, CI 0.49 – 0.95, p = 0.0248). No significant benefit was seen for patients with regional or distant disease. On multivariate analysis, positive predictors of survival after IPTW adjustment were female sex, diagnosis after 2005, and left-sided disease.

Conclusions

These findings support a significant benefit to OS by incorporating radiotherapy as a component of trimodality therapy for patients with localized MPM compared to only surgery and chemotherapy. It does not provide a significant overall survival benefit for patients with regional or metastatic disease.

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.