Individualized prediction of survival benefit from postoperative radiotherapy for patients with malignant pleural mesothelioma.

OBJECTIVES: The role of postoperative radiotherapy (PORT) in malignant pleural mesothelioma (MPM) remains controversial and the eighth edition TNM staging scheme for MPM has not been fully verified. We aimed to develop an individualized prediction model for identifying optimal candidates for PORT among MPM patients who received surgery plus chemotherapy and externally validate the performance of the new TNM staging scheme. MATERIALS AND METHODS: Detailed characteristics of MPM patients during 2004-2015 were retrieved from SEER registries. Propensity score matching (PSM) was conducted to reduce disparities of baseline characteristics (age, sex, histologic type, stage, and type of surgery) between the PORT group and no-PORT group. A novel nomogram was constructed based on independent prognosticators identified by multivariate Cox regression model. The discriminatory performance and degree of calibration were evaluated. We stratified patients into different risk groups according to nomogram total scores and estimated the survival benefit of PORT in different subgroups in order to identify the optimal candidates. RESULTS: We identified 596 MPM patients, among which 190 patients (31.9%) received PORT. PORT conferred significant survival benefit in the unmatched population, while there was no significant survival difference favoring PORT in the matched population. The C-index of the new TNM staging scheme was closed to 0.5, which represented a poor discriminatory ability. A novel nomogram was constructed based on clinicopathological factors, including age, sex, histology, and N stage. We stratified patients into three risk groups. Subgroup analyses indicated that PORT was beneficial for high-risk group (p = 0.003) rather than low-risk group (p = 0.965) and intermediate-risk group (p = 0.661). CONCLUSION: We established a novel predictive model, which could make individualized prediction of survival benefit of PORT for MPM and could compensate for weakness in TNM staging system.

The Impact of Adjuvant Hemithoracic Radiation on Outcomes in Patients With Stage I-III Malignant Pleural Mesothelioma: A Dual Registry Analysis.

BACKGROUND: The outcomes associated with receipt of adjuvant radiation in patients after surgery for MPM are poorly understood. OBJECTIVE: The objective of this study was to use 2 registries to compare the outcomes of patients receiving adjuvant radiation or no radiation after definitive surgery for pathologic stage I-III MPM. METHODS: Patients with resected pathologic stage I-III MPM were identified from the Duke University registry (1996-2016) and National Cancer Database (NCDB) (2004-2015). The primary outcome was overall survival. Propensity score-matched and landmark subgroup analyses were performed. RESULTS: A total of 212 institutional and 1615 NCDB patients met criteria. In both cohorts, patients who underwent radiation were more likely to have margin-negative resection and more advanced pathologic stage. At a landmark time of 4.4 and 4.7 months from surgery, Duke [hazard ratio (HR) 1.14; 95% confidence interval (CI) 0.62-2.11] and NCDB patients (HR 0.97; 95% CI 0.81-1.17) who received adjuvant radiation did not experience improved survival compared to those who did not receive radiation in multivariable analysis. Duke patients who received radiation had similar incidence of recurrence and time to both overall recurrence and ipsilateral recurrence (HR 0.87; 95% CI 0.43-1.77) compared to those who did not. Duke patients experienced 100 grade 1/2, 21 grade 3/4, and one grade 5 toxicity events during radiation. CONCLUSIONS: In this dual registry analysis of patients with resected stage I-III MPM, the receipt of adjuvant hemithoracic radiation was not associated with improved survival compared to no radiation.

Survey of malignant pleural mesothelioma treatment in Japan: Patterns of practice and clinical outcomes in tomotherapy facilities.

We conducted a nationwide survey of tomotherapy for malignant pleural mesothelioma (MPM) in Japan. Fifty-six facilities were surveyed and data on 31 patients treated curatively between 2008 and 2017 were collected from 14 facilities. Twenty patients received hemithorax irradiation after extrapleural pneumonectomy (EPP) (first group). Five patients received irradiation without EPP (second group), while six received salvage radiotherapy for local recurrence (salvage group). Among the seven patients not undergoing EPP, five (four in the second group and one in the salvage group) were treated with lung sparing pleural irradiation (LSPI) and two with irradiation to visible tumors. Two-year overall survival (OS) rates in the first and second groups were 33% and 60%, respectively (median, 13 vs 30 months, P = 0.82). In the first and second groups, 2-year local control (LC) rates were 53 and 67%, respectively (P = 0.54) and 2-year progression-free survival (PFS) rates were 16% and 60%, respectively (P = 0.07). Distant metastases occurred in 15 patients in the first group and three in the second group. In the salvage group, the median OS was 18 months. Recurrence was observed in the irradiated volume in four patients. The contralateral lung dose was higher in LSPI than in hemithorax irradiation plans (mean, 11.0 ± 2.2 vs 6.1 ± 3.1 Gy, P = 0.002). Grade 3 or 5 lung toxicity was observed in two patients receiving EPP and hemithorax irradiation, but not in those undergoing LSPI. In conclusion, outcomes of EPP and hemithorax irradiation were not satisfactory, whereas LSPI appeared promising and encouraging.

Anticancer agent α-sulfoquinovosyl-acylpropanediol enhances the radiosensitivity of human malignant mesothelioma in nude mouse models.

Malignant pleural mesothelioma (MPM) is a highly malignant disease that develops after asbestos exposure. Although the number of MPM cases is predicted to increase, no effective standard therapies have been established. The novel radiosensitizer α-sulfoquinovosyl-acylpropanediol (SQAP) enhances the effects of γ-radiation in human lung and prostate cancer cell lines and in animal models. In this study, we explored the radiosensitizing effect of SQAP and its mechanisms in MPM. The human MPM cell lines MSTO-211H and MESO-4 were implanted subcutaneously into the backs and thoracic cavities of immunodeficient KSN/Slc mice, then 2 mg/kg SQAP was intravenously administered with or without irradiation with a total body dose of 8 Gy. In both the orthotopic and ectopic xenograft murine models, the combination of irradiation plus SQAP delayed the implanted human MSTO-211H tumor growth. The analysis of the changes in the relative tumor volume of the MSTO-211H indicated a statistically significant difference after 8 Gy total body combined with 2 mg/kg SQAP, compared to both the untreated control (P = 0.0127) and the radiation treatment alone (P = 0.0171). After the treatment in each case, immunostaining of the harvested tumors revealed decreased cell proliferation, increased apoptosis and normalization of tumor blood vessels in the SQAP- and irradiation-treated group. Furthermore, hypoxia-inducible factor (HIF) 1 mRNA and protein expression were decreased, indicating reoxygenation in this group. In conclusion, SQAP improved hypoxic conditions in tumor tissue and may elicit a radiosensitizing effect in malignant mesothelioma models.

Local radiotherapy for pleural dissemination of thymic tumors after initial treatment.

Pleural dissemination is a common pattern of failure after initial treatment of thymoma and thymic carcinoma, but there is no standardized treatment. As these tumors are relatively radiosensitive, we investigated the effectiveness of radiotherapy. Twenty patients underwent 33 series of local radiotherapy for 96 pleural dissemination lesions after initial treatment. Conventional radiotherapy (CRT), tomotherapy, and combination of the two were employed in 19, 13, and 1 series, respectively. The median follow-up period after the first irradiation for pleural dissemination was 46 months (range, 14-161). For all 20 patients, overall survival (OS) rates from initial radiotherapy for pleural dissemination were 100% at three years and 86% at five years. Progression-free survival (PFS) rates after 33 series of radiotherapy were 30% at three years and 16% at five years. Local control (LC) rates for 96 lesions were 98% at three years and 96% at five years. In-field recurrence was observed in only two among the 96 lesions. One patient (5%) developed grade 3 radiation pneumonitis and another (5%) developed grade 3 pericardial effusion. No other serious adverse events were observed. When disseminated nodules can be covered within localized fields, local radiotherapy may be a treatment option. Using tomotherapy, multiple lesions can be treated safely.

Prophylactic irradiation of tracts in patients with malignant pleural mesothelioma: A systematic review and meta-analysis of randomized trials.

INTRODUCTION: The role of prophylactic irradiation of tracts (PIT) to prevent tumor seeding at the site of a diagnostic or therapeutic intervention in patients with malignant pleural mesothelioma (MPM) is controversial. This study aimed to determine the efficacy of PITs in preventing procedure tract metastases (PTM) after a chest wall procedure in MPM. MATERIALS AND METHODS: We searched various databases from inception date to April 2020 for randomized controlled trials (RCTs) comparing PIT with no PIT in patients who had a chest wall procedure for MPM. We assessed the risk of bias of individual RCT using the RoB2 tool. The primary outcome was the occurrence of PTM. Meta-analysis was performed using random-effects model. We employed the GRADE approach to assess the certainty of the evidence. RESULTS: We identified five RCTs including 737 patients. Two RCTs had a low risk of bias. PIT was associated with a significant reduction in the odds of PTM (odd ratio, 0.55; 95 % confidence interval, 0.32 to 0.95; P-value = 0.03; I2 = 13 %; GRADE: moderate certainty). One RCT reported no difference in overall survival outcome with the use of PIT. None of the RCTs performed subgroup analyses. Sensitivity analyses showed similar results when limited to RCTs with low risk of bias. CONCLUSION: PIT significantly reduces the occurrence of PTM in patients with MPM who had a diagnostic or therapeutic chest wall procedure.

RapidPlan for Knowledge-Based Planning of Malignant Pleural Mesothelioma.

PURPOSE: Treatment planning for malignant pleural mesothelioma is a challenging task due to the relatively large size of the target and the need to spare critical organs that overlap with or are within the target volume. We aimed to develop a knowledge-based model using RapidPlan (RP) for patients with 2 intact lungs. METHODS AND MATERIALS: Data from 57 patients treated with volumetric modulated arc therapy were chosen for training the dose estimation model at a single dose level. The prescription dose was 50.4 Gy in 1.8 Gy fractions. The model was validated on 23 new patients by comparing the clinical plan to the RP. Time taken to plan the RP was compared with that for the clinical plan. RESULTS: For similar target coverage and plan inhomogeneity, RP significantly improved the sparing of the contralateral lung, heart, stomach, esophagus, and ipsilateral kidney. On average, the contralateral lung V5 Gy and V10 Gy were reduced by 13.9% (P < .001) and 7.9% (P < .001), respectively. The mean heart dose was reduced by 5 Gy (P < .001) and V30 Gy by 9.1% (P < .001). Mean dose to the stomach and esophagus were both reduced by 5 Gy (P < .001), and the ipsilateral kidney V18 Gy by 4.1% (P < .001). Mean total lung dose was reduced by 0.8 Gy with RP, which enabled an increase in prescription dose by 1 fraction Absolute volume of ipsilateral lung was adequately spared by both techniques, while sparing of all other organs, namely the cord, liver, and bowel, was not compromised with RP. Time taken with RP was 20 minutes, 45 seconds versus at least 4 hours for an experienced treatment planner. CONCLUSIONS: The RP model for malignant pleural mesothelioma showed improved sparing of critical organs with a reduced treatment planning time and increased prescription dose.

Intensity Modulated Radiation Therapy for Pleural Recurrence of Thymoma: A Prospective Phase 2 Study.

PURPOSE: This study aimed to evaluate the efficacy and safety of intensity modulated radiation therapy (IMRT) for pleural recurrence of thymoma that was not suitable for surgery and had progressed after chemotherapy. MATERIALS AND METHODS: From February 2012, consecutive patients with pleural recurrence of thymoma were prospectively enrolled. Due to dose restrictions to normal tissue (lung, liver, and kidney), 3 different levels of radiation doses (30 Gy, 40 Gy, and 50 Gy) were prescribed for pleural lesions of different sizes and locations, with a daily fraction dose of 2 Gy. The objective response rate, local control time (LCT), overall survival time, and toxicity were recorded, respectively. RESULTS: By August 2016, 31 patients had completed the IMRT treatment. There were 21 male and 10 female patients, with a median age of 49 (range, 22-70) years. B3 thymoma was the major (62%) tumor subtype observed. During the median follow-up of 48 (24-70) months, the objective response rate was 97%, and the median LCT was 49 (95% confidence interval, 40.4-58.1) months. However, 29 (93.5%) patients developed out-of-field recurrence, among whom 10 (32%; 30 Gy, n = 7; 40 Gy, n = 3) developed both out-of-field and in-field recurrence. The median progression-free survival was 19 months, and no in-field recurrence occurred in the 50 Gy group. Moreover, a higher dose was related to a longer LCT. No toxicities higher than a grade 4 occurred after IMRT within the normal-tissue dose limitation. The 5-year overall survival of the patients was 81%. CONCLUSIONS: IMRT for pleural recurrence may act as an alternative treatment when surgery is not feasible, with a higher dose resulting in a longer LCT. In this study, out-of-field recurrence was considerably common, but repeated IMRT for new recurrence should be cautiously carried out due to the high risk of radiation-induced pneumonitis.

Radical Hemithoracic Radiotherapy Versus Palliative Radiotherapy in Non-metastatic Malignant Pleural Mesothelioma: Results from a Phase 3 Randomized Clinical Trial.

PURPOSE: We conducted a phase 3 randomized clinical trial to assess whether radical hemithoracic radiation therapy (RHR) compared with palliative radiation therapy (PR) can achieve overall survival (OS) advantages in patients with malignant pleural mesothelioma (MPM). METHODS AND MATERIALS: From August 2014 to May 2018, patients with histologically diagnosed nonmetastatic MPM, who underwent nonradical lung-sparing surgery and chemotherapy (CHT), were randomly assigned (1:1) to receive RHR or PR. RHR total dose to the involved pleural cavity was 50 Gy in 25 fractions, and the gross residual disease received a simultaneous integrated boost of 60 Gy. The primary endpoint was OS. Secondary endpoints were local control, distant metastasis-free survival, progression-free survival, and acute and late toxicity rates. A sample size of 108 patients considering a type I error (α) of 0.05 and a statistical power of 80% was calculated to prove that RHR could improve the 2-year OS. OS was estimated with the Kaplan-Meier method and the log-rank test (2-sided) tested differences between arms. The univariate and multivariate analyses were performed using Cox proportional hazard model. Possible prognostic factors investigated: age, sex, performance status, lung surgery, gross residual disease, and histology. RESULTS: One hundred eight patients were randomized: 53 to the PR arm and 55 to the RHR arm. Median follow-up was 14.6 months. The 2-year OS rate was 58% in the RHR arm versus 28% in the PR arm (hazard ratio, 0.54; 95% confidence interval, 0.31-0.95; P = .031). In the RHR arm: 11 patients experienced acute toxicity grade ≥3, 17 patients had grade 3 to 4 late toxicity. Nine patients experience a grade ≥2 pneumonitis, including 1 patient with grade 5. CONCLUSIONS: RHR significantly improves survival in patients with MPM treated with nonradical lung-sparing surgery and CHT compared with palliative treatments, although it is associated with a nonnegligible toxicity profile.

Salvage radiotherapy for oligo-progressive malignant pleural mesothelioma.

OBJECTIVES: No standard treatment option is available for patients with unresectable malignant pleural mesothelioma (MPM) progressing after upfront chemotherapy. We aimed to explore the role of focal radiotherapy (FRT) as a treatment modality for oligo-progressive MPM. MATERIALS AND METHODS: In this retrospective study, consecutive patients pretreated with ≥1 lines of chemotherapy were included. Oligo-progressive MPM was defined as an unresectable disease with radiological progression at ≤3 sites according to a chest-abdominal contrast-enhanced computed tomography. Patients were treated with either stereotactic body radiotherapy (SBRT, ≥5 Gy per fraction) or hypo-fractionated radiotherapy (hypoRT, <5 Gy per fraction). Time to further systemic therapy (TFST) and local control (LC) after FRT were the primary endpoints. Biologically effective dose (BED) was calculated using three different alpha/beta models (1.5 Gy, 3 Gy and 10 Gy). RESULTS: From April 2006 to March 2019, 37 patients were treated on 43 pleural lesions; 16/37 (43 %) had undergone upfront multimodality treatment (MMT) including surgery. FRT was given in 22/37 (59.5 %) after one line of chemotherapy. SBRT was delivered for 26/43 lesions (60.5 %), hypoRT for 17/43 (39.5 %). Median TFST was 6 months (95 % CI 4.9-7.1). LC at 6 months and 1 year was 84 % and 76 %, respectively. Median TFST was longer in patients treated after 1 vs >1 line of chemotherapy (9 vs 4 months, p = 0.001) and in patients pretreated with MMT (6 vs 3 months, p = 0.021). Six-month LC was better in patients treated with a BED > 100 using alpha/beta 1.5 and 3. No ≥ G3 acute or late toxicities were reported. CONCLUSION: FRT was feasible in selected patients with oligo-progressive MPM, allowing delay of further systemic therapies, with no severe toxicity. FRT was more effective when performed at progression after one line of systemic therapy. Our results suggest a radio-resistant behavior of MPM.

The Association between Malignant Pleural Mesothelioma and Thoracic Radiation Therapy for Hodgkin's Lymphoma: The First Case Report in Japan.

Malignant pleural mesothelioma (MPM) is mostly observed in patients with a history of asbestos exposure. Although other causes are rare, there are several reports of MPM induced by therapeutic radiation, mainly in Europe and North America. However, no such case has been reported in Japan. We herein report a 50-year-old Japanese woman who developed MPM 25 years after thoracic radiation therapy for Hodgkin's lymphoma. The patient had no history of exposure to asbestos; therefore, her history of radiation therapy was considered to be the cause of MPM. Clinicians should consider secondary MPM in patients with a history of thoracic radiation therapy.

Locoregional control and toxicity after pleurectomy/decortication and intensity-modulated pleural radiation therapy in patients with malignant pleural mesothelioma.

BACKGROUND: Treatment of malignant pleural mesothelioma (MPM) represents a major challenge for oncologists. Multimodality treatment, which generally involves induction chemotherapy, surgery and radiotherapy have recently shown promising results. The aim of this study was to evaluate the locoregional control and toxicity of intensity modulated radiotherapy (IMRT) after pleurectomy and decortication (P/D) as part of trimodality therapy for patients with locally advanced MPM. METHODS: We prospectively analyzed data from 20 patients with MPM treated at a single tertiary-care institution. Initially every patient received induction chemotherapy with platinum-based chemotherapy. After chemotherapy, patients without progression underwent P/D, and if feasible, hemi-thoracic IMRT was administered at a planned dose of 50.4-54 Gy in 28-30 fractions and treated with 9-11 noncoplanar fields. RESULTS: A total of 15 of the 20 enrolled patients underwent P/D followed by IMRT to the hemi-thoracic cavity. The median total radiotherapy dose was 48.7 Gy (23.4-54 Gy). Radiation pneumonitis (RP) developed in nine patients (60%), and of these, two patients (13.3%) experienced G3 or G4 RP. The estimated locoregional-relapse-free survival at two years was 75.9%, and the main pattern of recurrence was distant (72.7%). For the entire cohort median follow-up was 22.7 months, median progression-free survival was 18.9 months and median overall survival 23.6 months. CONCLUSIONS: Platinum-based chemotherapy followed by lung-sparing surgery (P/D) and IMRT is a feasible and safe treatment modality that yields acceptable locoregional control in patients with locally advanced MPM; however, these results should be corroborated in larger studies.

The Role of Extrapleural Pneumonectomy in Malignant Pleural Mesothelioma.

Extrapleural pneumonectomy (EPP) is the most extensive form of surgery for mesothelioma, involving en bloc resection of visceral and parietal pleura, lung, diaphragm and pericardium, with reconstruction of the pericardium and diaphragm. It can be performed safely in carefully selected patients. It should be performed in experienced centers as part of a multimodality treatment plan. The SMART approach, with a short course of induction hemithoracic radiation followed by EPP has demonstrated safety and value of hypofractionated hemithoracic radiation combined with complete macroscopic resection. We are conducting a clinical trial with oligofractionated hemithoracic radiation in early-stage mesothelioma.

Radiation Therapy for Malignant Pleural Mesothelioma.

The treatment of malignant pleural mesothelioma with radiation therapy has always been a technical challenge. For many years, radiation therapy was delivered after extrapleural pneumonectomy with acceptable results. As the utilization of pleurectomy/decortication increased, techniques, such as pleural intensity-modulated radiation therapy (IMRT) have been introduced. The experience with these techniques have grown and multiple trials using IMRT, both in the setting of extrapleural pneumonectomy or pleurectomy, are being conducted to assess its effectiveness.