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Comparison of Survival by Multimodal Treatment Regimen Among Malignant Pleural Mesothelioma Patients in an Integrated Health System

Open AccessPublished:September 17, 2022DOI:https://doi.org/10.1016/j.cllc.2022.09.003

      Abstract

      Background

      Optimal therapy for malignant pleural mesothelioma (MPM) remains unclear. We compared overall survival in patients with MPM after various multimodal treatment regimens including combinations of immunotherapy, chemotherapy, and surgery.

      Patients and Methods

      We examined MPM patients treated within our integrated health system from January 1, 2009 to December 31, 2020. Patients were grouped based on treatment regimen: chemotherapy alone (CT), immunotherapy with or without chemotherapy (iCT), surgery with chemotherapy (sCT), and surgery with immunotherapy and chemotherapy (siCT). We analyzed baseline characteristics and overall patient survival among these groups and several subgroups.

      Results

      One hundred seventy-nine patients were included. Among the study groups, there was no difference in age, sex, race/ethnicity, Charlson Comorbidity Index, or Eastern Cooperative Oncology Group performance status. Patients treated with CT (N = 109), iCT (N = 35), sCT (N = 26), and siCT (N = 9) had median (95% confidence interval) survivals of 11.7 (9.9-16.3), 18.2 (14.5-29.8), 20.7 (11.6-37.2), and 22.6 (19.7-37.8) months, respectively (P < .001). Median survival among patients with and without immunotherapy was 19.7 (17.4-29.8) and 12.3 (10.6-17.3) months, respectively (P = .023). Median survival among patients with and without surgery was 21.7 (17.6-34.8) and 13.6 (11.5-17.3) months, respectively (P = .007). Patients with biphasic/sarcomatoid subtypes who received immunotherapy experienced 76.2% (55.8%-100.0%) 12 month survival vs. 13.6% (4.8%-39.0%) among those who did not (P < .001).

      Conclusion

      MPM patients receiving surgery and immunotherapy as part of multimodal treatment regimens experienced the longest survival. Surgery and immunotherapy are each associated with survival. Further investigations are warranted to assess the benefit of immunotherapy within multimodal treatment regimens for MPM.

      Keywords

      Introduction

      Though malignant pleural mesothelioma (MPM) is associated with poor prognosis, therapeutic strategies are evolving.
      • Milano MT
      • Zhang H
      Malignant pleural mesothelioma: a population-based study of survival.
      ,
      • Taioli E
      • Wolf AS
      • Camacho-Rivera M
      • et al.
      Determinants of survival in malignant pleural mesothelioma: a surveillance, epidemiology, and end results (SEER) study of 14,228 patients.
      Several studies have reported improvements in survival with the use of multimodal treatment regimens utilizing various combinations of chemotherapy, surgery, and radiotherapy.
      • Weder W
      • Stahel RA
      • Bernhard J
      • et al.
      Multicenter trial of neo-adjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma.
      • de Perrot M
      • Feld R
      • Cho BCJ
      • et al.
      Trimodality therapy with induction chemotherapy followed by extrapleural pneumonectomy and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma.
      • Enewold L
      • Sharon E
      • Thomas A
      Patterns of care and survival among patients with malignant mesothelioma in the United States.
      • Lococo F
      • Torricelli F
      • Lang-Lazdunski L
      • et al.
      Survival results in biphasic malignant pleural mesothelioma patients: a multicentric analysis.
      • Thompson AB
      • Quinn TJ
      • Siddiqui ZA
      • Almahariq MF
      • Grills IS
      • Stevens CW
      Addition of radiotherapy to surgery and chemotherapy improves survival in localized malignant pleural mesothelioma: a surveillance, epidemiology, and end results (SEER) study.
      • Shaikh F
      • Zauderer MG
      • von Reibnitz D
      • et al.
      Improved outcomes with modern lung-sparing trimodality therapy in patients with malignant pleural mesothelioma.
      • Rimner A
      • Hu C
      • Zauderer M
      • et al.
      A phase III randomized trial of pleurectomy/decortication plus chemotherapy with or without adjuvant hemithoracic intensity-modulated pleural radiation therapy (IMPRINT) for malignant pleural mesothelioma (MPM) (NRG-LU006).
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      • Gill RR
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      • et al.
      Pleurectomy decortication in the treatment of malignant pleural mesothelioma: encouraging results and novel prognostic implications based on experience in 355 consecutive patients.
      • Lapidot M
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      Outcomes of pleurectomy decortication in patients with biphasic mesothelioma.
      Experience may also play an important role in delivering treatment to MPM patients. Our institution has found that multidisciplinary team evaluation as well as regionalization of care of MPM patients can increase availability of treatment to eligible patients (in press). Another study found that surgeon experience likely improves outcomes among MPM patients.
      • Yan TD
      • Cao CQ
      • Boyer M
      • et al.
      Improving survival results after surgical management of malignant pleural mesothelioma: an australian institution experience.
      Mesothelioma systemic treatments have evolved to include immunotherapy options such as nivolumab, ipilimumab, and pembrolizumab for patients with unresectable mesothelioma.
      • Fennell DA
      • Ewings S
      • Ottensmeier C
      • et al.
      Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trial.
      • Alley EW
      • Lopez J
      • Santoro A
      • et al.
      Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial.
      • Štrbac D
      • Dolžan V.
      Novel and future treatment options in mesothelioma: a systematic review.
      More recently, the CheckMate 743 trial demonstrated promise of first line nivolumab/ipilimumab therapy, and the FDA has since approved this combination as a first line treatment for unresectable MPM patients.
      • Baas P
      • Scherpereel A
      • Nowak AK
      • et al.
      First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial.
      • Nakajima EC
      • Vellanki PJ
      • Larkins E
      • et al.
      FDA approval summary: nivolumab in combination with ipilimumab for the treatment of unresectable malignant pleural mesothelioma.
      • Peters S
      • Scherpereel A
      • Cornelissen R
      • et al.
      First-line nivolumab plus ipilimumab versus chemotherapy in patients with unresectable malignant pleural mesothelioma: 3-year outcomes from CheckMate 743.
      Limited evidence exists, however, evaluating the effect of immunotherapy as part of multimodal therapy regimens for MPM. Similarly, limited evidence exists analyzing outcomes of MPM patients receiving immunotherapy outside of randomized controlled trials.
      Our institution has incorporated immunotherapy as an option within our multimodal treatment strategy for MPM patients, so we aimed to compare the efficacy of various multimodal regimens in terms of overall patient survival. We hypothesized that patients receiving multimodal regimens incorporating immunotherapy, chemotherapy, and surgery would have the longest overall survival compared to those receiving only components of this regimen.

      Patients and Methods

      We conducted a review of Electronic Medical Records (EMRs) of all adult patients with histologically confirmed MPM from January 1, 2009 through December 31, 2020.
      The study was approved by the Kaiser Permanente Northern California Institutional Review Board with a waiver of the requirement for informed consent. The study's funding source had no involvement in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
      Baseline characteristics including age, sex, and race/ethnicity as well as clinical characteristics such as Charlson Comorbidity index (CCI), Eastern Cooperative Oncology Group (ECOG) performance status, stage, and histology were extracted from EMRs. The primary outcome of interest was overall survival which was determined as the time from cancer diagnosis until death, date of disenrollment, or study end date (May 31, 2021), whichever occurred first. Patients were divided and compared based on the type of treatment regimen they received. The 4 comparison groups were: chemotherapy alone (CT), immunotherapy with or without chemotherapy (iCT), surgery with chemotherapy (sCT), and surgery with immunotherapy and chemotherapy (siCT). Those who underwent surgery in addition to chemotherapy, immunotherapy, or both were considered to have undergone multimodal therapy. Additionally, several subgroup comparisons were performed. Treatment regimen groups were compared among patients with only stage I or II disease, those with only epithelial histology, those with only biphasic histology, and those with only sarcomatoid histology. Comparisons were also made between patients receiving immunotherapy vs. those who did not receive immunotherapy. Similarly, patients were compared based on whether or not they underwent multimodal therapy.
      Of patients receiving surgery, either extra pleural pneumonectomy (EPP) or extended pleurectomy with decortication (PD) was performed. EPP was performed in standard fashion with open thoracotomy, complete extra pleural pneumonectomy, pericardial resection with mesh reconstruction, diaphragmatic resection with mesh reconstruction, and complete mediastinal lymph node dissection. PD consisted of open thoracotomy, extended radical parietal and visceral pleurectomy, complete lung decortication, pericardial resection with mesh reconstruction, diaphragm resection with mesh reconstruction, and complete mediastinal lymph node dissection. All operations were performed with curative intent. Patients with complete macroscopic resections (R1) as well as those with partial resections (R2) were included.
      Given limited data examining immunotherapy as a first line option for MPM during our study period, the patients who received immunotherapy in our study typically received it as a second or third line option for presumed recurrence or new metastatic disease. These patients were those who were deemed to require further treatment but who were also healthy enough to undergo the treatment.
      We used the Kaplan-Meier method and log-rank test to compare survival rates by treatment group. Comparisons of patient characteristics were assessed in bivariate analyses using Chi-square or Fisher exact tests for categorical variables and Kruskal-Wallis test for continuous variables. All analyses were performed using SAS v.9.4 (Cary, NC, USA).

      Results

      Of the 179 patients that met inclusion criteria, 109 were in the CT group, 35 were in the iCT group, 26 were in the sCT group, and 9 were in the siCT group. Of the 4 groups, baseline characteristics did not vary except for stage and histology (Table 1). Among patients with only stage I/II disease, baseline characteristics did not vary (Table 2). Among those with only epithelial histology, baseline characteristics did not vary other than by stage (Table 3).
      Table 1Patient Characteristics by Treatment Type
      VariablesiCT (n = 9)sCT (n = 26)iCT (n = 35)CT (n = 109)P-value
      Mean Age ± SD67.1 ± 10.669.1 ± 6.772.0 ± 9.772.1 ± 8.3.14
      Kruskal-Wallis test
      Female4 (44.4)4 (15.4)9 (25.7)25 (22.9).35
      Chi-square test
      CCI.76
      Fisher's exact test
       0-35 (55.6)12 (46.2)16 (45.7)61 (56.0)
       4-62 (22.2)6 (23.1)10 (28.6)29 (26.6)
       7+2 (22.2)8 (30.8)9 (25.7)19 (17.4)
      ECOG performance status (if available)
      ECOG missing for 30 subjects.
      .86
      Fisher's exact test
      02 (33.3)13 (56.5)18 (53.0)38 (44.2)
      14 (66.7)8 (34.5)13 (38.2)40 (46.5)
      20 (0)2 (8.7)2 (5.9)7 (8.1)
      30 (0)0 (0)1 (2.9)1 (1.2)
      Race/Ethnicity.21
      Fisher's exact test
       White3 (33.3)19 (73.1)26 (74.3)79 (72.5)
       Black0 (0)1 (3.9)1 (2.9)4 (3.7)
       Hispanic3 (33.3)3 (11.5)4 (11.4)15 (13.8)
       Asian/Pacific Islander2 (22.2)2 (7.7)4 (11.4)3 (2.8)
       Other1 (11.1)1 (3.9)0 (0)8 (7.3)
      Stage<.01
      Fisher's exact test
       I1 (11.1)7 (26.9)6 (17.1)35 (32.1)
       II5 (55.6)6 (23.1)6 (17.1)12 (11.0)
       III2 (22.2)11 (42.3)12 (34.3)26 (23.9)
       IV1 (11.1)2 (7.7)11 (31.4)36 (33.0)
      Histology<.01
      Fisher's exact test
       Epithelial8 (88.9)23 (88.5)19 (54.3)56 (51.4)
       Mesothelioma NOS0 (0)1 (3.9)3 (8.6)31 (28.4)
       Biphasic1 (11.1)2 (7.7)7 (20.0)9 (8.3)
       Sarcomatoid006 (17.1)13 (11.9)
      Abbreviations: CCI = charlson comorbidity index; CT = chemotherapy alone; ECOG = eastern cooperative oncology group; iCT = immunotherapy with or without chemotherapy; NOS = not otherwise specified; sCT = surgery with chemotherapy; SD = standard deviation; siCT = surgery with immunotherapy and chemotherapy.
      a Kruskal-Wallis test
      b Chi-square test
      c Fisher's exact test
      d ECOG missing for 30 subjects.
      Table 2Stage I/II Subgroup Patient Characteristics by Treatment Type
      Variable, N (%)siCT (N = 6)sCT (N = 13)iCT (N = 12)CT (N = 47)P Value
      Mean Age ± SD70.0 ± 5.168.0 ± 9.073.3 ± 11.372.1 ± 7.8.42
      Kruskal-Wallis test
      Female2 (33.3)3 (23.1)2 (16.7)9 (19.1).85
      Fisher's exact test
      CCI.78
      Fisher's exact test
       0-32 (33.3)5 (38.5)7 (58.3)25 (53.2)
       4-62 (33.3)3 (23.1)3 (25.0)13 (27.7)
       7+2 (33.3)5 (38.5)2 (16.7)9 (19.1)
      Race/Ethnicity.41
      Fisher's exact test
       White3 (50.0)10 (76.9)9 (75.0)36 (76.6)
       Black0 (0)0 (0)0 (0)1 (2.0)
       Hispanic1 (16.7)2 (15.4)1 (8.3)4 (8.5)
       Asian/Pacific Islander1 (16.7)0 (0)2 (16.7)1 (2.1)
       Other1 (16.7)1 (7.7)0 (0)5 (10.6)
      Histology.49
      Fisher's exact test
       Epithelial6 (100)11 (84.6)9 (75.0)30 (63.8)
       Mesothelioma NOS0 (0)0 (0)1 (8.3)10 (21.3)
       Biphasic0 (0)2 (15.4)1 (8.3)3 (6.4)
       Sarcomatoid001 (8.3)4 (8.5)
      Abbreviations: CCI = charlson comorbidity index; CT = chemotherapy alone; iCT= immunotherapy with or without chemotherapy; sCT = surgery with chemotherapy; SD = standard deviation; siCT = surgery with immunotherapy and chemotherapy; NOS = not otherwise specified.
      a Kruskal-Wallis test
      b Fisher's exact test
      Table 3Epithelial Subgroup Patient Characteristics by Treatment Type
      VariablessiCT (N = 8)sCT (N = 23)iCT (N = 19)CT (N = 56)P Value
      Mean Age ± SD67.6±11.268.6±6.770.4±10.571.9±7.4.24
      Kruskal-Wallis test
      Female3 (37.5)4 (17.4)5 (26.3)12 (21.4).6
      Fisher's exact test
      CCI.93
      Fisher's exact test
       0-34 (50.0)10 (43.5)9 (47.4)27 (48.2)
       4-62 (25.0)5 (21.7)6 (31.6)17 (30.4)
       7+2 (25.0)8 (34.8)4 (21.1)12 (21.4)
      Race/Ethnicity.22
      Fisher's exact test
       White3 (37.5)17 (73.9)16 (84.2)43 (76.8)
       Black0 (0)1 (4.4)0 (0)0 (0)
       Hispanic2 (25.0)2 (8.7)1 (5.3)7 (12.5)
       Asian/Pacific Islander2 (25.0)2 (8.7)2 (10.5)2 (3.6)
       Other1 (12.5)1 (4.3)0 (0)1 (1.8)
      Stage<.01
      Fisher's exact test
       I1 (12.5)6 (26.1)4 (21.1)23 (41.1)
       II5 (62.5)5 (21.7)5 (26.3)7 (12.5)
       III1 (12.5)10 (43.5)6 (31.6)9 (16.1)
       IV1 (12.5)2 (8.7)4 (21.1)17 (30.4)
      Abbreviations: CCI =, charlson comorbidity index; CT =, chemotherapy alone; iCT = immunotherapy with or without chemotherapy; sCT = surgery with chemotherapy; SD = standard deviation; siCT = surgery with immunotherapy and chemotherapy.
      a Kruskal-Wallis test
      b Fisher's exact test
      Median (95% confidence interval (95% CI)) survival was 22.6 (19.7-37.8) months in the siCT group, 20.7 (11.6-37.2) months in the sCT group, 18.2 (14.5-29.8) months in the iCT group, and 11.7 (9.9-16.3) months in the CT group (P < .001, Figure 1). Among patients with stage I/II disease (N = 78), 24-month (95% CI) survival was 53.3% (21.4%-100%) in the siCT group, 51.3% (28.0%-93.9%) in the sCT group, 55.0% (29.4%-100%) in the iCT group, and 30.6% (19.5%-48.1%) in the CT group (log rank test P = P =.007). Among patients with epithelial histology (N = 106), 24-month survival was 51.4% (23.6-100%) in the siCT group, 43.6% (26.8%-71.0%) in the sCT group, 52.6 (31.9%-86.5%) in the iCT group, and 29.7% (19.4%-45.6%) in the CT group (log rank test P = P =.03; Table 4).
      Figure 1
      Figure 1Overall survival among malignant pleural mesothelioma patients by treatment regimen log-rank test P-value. CI = confidence interval; HR = hazard ratio; siCT = surgery with immunotherapy and chemotherapy; sCT = surgery with chemotherapy; iCT = immunotherapy with or without chemotherapy; CT = chemotherapy alone
      Table 4Survival by Subgroup
      SubgroupsiCTsCTiCTCTLog-rank test P Value
      Stage I/II (N = 78)N = 6N = 13N = 12N = 47.007
      12 mo Survival, % (95% CI)100.0 (100.0-100.0)82.1 (62.1-100.0)82.5 (63.1-100.0)56.4 (43.7-72.8)
      24 moh Survival, % (95% CI)53.3 (21.4-100.0)51.3 (28.0-93.9)55.0 (29.4-100.0)30.6 (19.5-48.1)
      Epithelial (N = 106)N = 8N = 23N = 19N = 56.03
      12 mo Survival, % (95% CI)100.0 (100.0-100.0)67.8 (50.7-90.8)82.6 (66.3-100.0)60.0 (48.3-74.5)
      24 mo Survival, % (95% CI)51.4 (23.6-100.0)43.6 (26.8-71.0)52.6 (31.9-86.5)29.7 (19.4-45.6)
      Biphasic (N = 19)N = 1
      Excluded from analysis given small number.
      N = 2
      Excluded from analysis given small number.
      N = 7N = 9.06
      12 mo Survival, % (95% CI)--68.6 (40.3-100.0)33.3 (13.2-84.0)
      24 mo Survival, % (95% CI)--34.3 (11.2-100.0)0 (NE)
      Sarcomatoid (N = 19)N = 0
      Excluded from analysis given small number.
      N = 0
      Excluded from analysis given small number.
      N = 6N = 13.003
      12 mo Survival, % (95% CI)--83.3 (58.3-100.0)0 (NE)
      24 mo Survival, % (95% CI)--20.8 (3.7-100.0)0 (NE)
      Abbreviations: CI =, confidence interval; CT =, chemotherapy alone; iCT = immunotherapy with or without chemotherapy; NE = non-estimable; sCT = surgery with chemotherapy; siCT = surgery with immunotherapy and chemotherapy.
      a Excluded from analysis given small number.
      When only patients with biphasic subtypes were examined (N = 19), the numbers of patients in the siCT (N = 1) and sCT (N = 2) groups were too small to report survival. iCT patients with biphasic histology had higher 12-month survival (68.6% (40.3%-100%)) and 24-month survival (34.3% (11.2%-100.0%)) compared to CT patients (33.3% (13.2%-84.0%) and 0% (NE), respectively), however, the differences were not significant (log rank test P =.06; Table 4). Among patients with only sarcomatoid histology (N = 19), no patients underwent surgery. iCT patients with sarcomatoid histology had significantly higher 12-month survival (83.3% (58.3%-100.0%)) and 24-month survival (20.8% (3.7%-100.0%)) compared to CT patients (0% (NE) and 0% (NE), respectively; log rank test P =.003; Table 4).
      Among the immunotherapy vs. non-immunotherapy groups, overall median survivals (95% CI) were 19.7 (17.4-29.8) months and 12.3 (10.6-17.3) months, respectively (P =.02; Figure 2). When similarly broken down into multimodal vs systemic only therapy, overall median survivals (95% CI) were 21.7 (17.6-34.8) months and 13.6 (11.5-17.3) months, respectively (P = .007; Figure 3).
      Figure 2
      Figure 2overall survival among malignant pleural mesothelioma patients receiving immunotherapy vs. no immunotherapy. Log-Rank Test P-value. CI = confidence interval; HR = hazard ratio; Immuno = Immunotherapy
      Figure 3
      Figure 3Overall survival among malignant pleural mesothelioma patients receiving multimodal vs. systemic only therapy. Log Rank Test P-value. CI = confidence interval; HR = hazard ratio

      Discussion

      Overall, our findings support our hypothesis that multimodal regimens, and particularly those including immunotherapy and surgery, were associated with improved survival among MPM patients. While prior studies have demonstrated benefit of multimodal therapy, our study is unique in its inclusion of immunotherapy. Also, our subgroup analyses provide several insights into MPM patient outcomes after multimodal regimens among various stages and histology types. Our results are likely generalizable to the population at large given that our integrated health system cares for nearly 40% of the insured population in Northern California, and our patient demographic breakdown is quite similar to the region at large.
      • Gordon NP.
      How does the adult kaiser permanente membership in Northern California compare with the larger community?.
      Not surprisingly, stage I/II MPM was associated with improved survival, and our findings of >50% 24-month survival among each of the siCT, sCT, and iCT cohorts compare quite favorably to previously reported survival rates by stage.
      • Rusch VW
      • Giroux D
      • Kennedy C
      • et al.
      Initial analysis of the international association for the study of lung cancer mesothelioma database.
      Similarly, while epithelial histology is known to be associated with improved prognosis, our findings within this subgroup compare favorably to prior studies.
      • Milano MT
      • Zhang H
      Malignant pleural mesothelioma: a population-based study of survival.
      ,
      • Taioli E
      • Wolf AS
      • Camacho-Rivera M
      • et al.
      Determinants of survival in malignant pleural mesothelioma: a surveillance, epidemiology, and end results (SEER) study of 14,228 patients.
      ,
      • de Perrot M
      • Feld R
      • Cho BCJ
      • et al.
      Trimodality therapy with induction chemotherapy followed by extrapleural pneumonectomy and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma.
      Biphasic and sarcomatoid subtypes are associated with worse outcomes.
      • Weder W
      • Stahel RA
      • Bernhard J
      • et al.
      Multicenter trial of neo-adjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma.
      ,
      • Lococo F
      • Torricelli F
      • Lang-Lazdunski L
      • et al.
      Survival results in biphasic malignant pleural mesothelioma patients: a multicentric analysis.
      ,
      • Rusch VW
      • Giroux D
      • Kennedy C
      • et al.
      Initial analysis of the international association for the study of lung cancer mesothelioma database.
      However, in the 3 year outcome report from the CheckMate 743 randomized controlled trial, there was significantly longer survival among patients with non-epithelioid subtypes receiving immunotherapy compared to those receiving chemotherapy (18.1 vs. 8.8 months).
      • Peters S
      • Scherpereel A
      • Cornelissen R
      • et al.
      First-line nivolumab plus ipilimumab versus chemotherapy in patients with unresectable malignant pleural mesothelioma: 3-year outcomes from CheckMate 743.
      When examining only sarcomatoid subtypes, we found a similarly stark increase in associated survival among those patients who received immunotherapy. This is the first real world retrospective dataset reported to our knowledge that supports the CheckMate 743 findings that immunotherapy improves survival over standard chemotherapy regimens in MPM patients with non-epithelioid histologies.
      National Comprehensive Cancer Network guidelines now recommend either observation or a Nivolumab/Ipilimumab regimen for first-line treatment of non-epithelioid disease with results from the CheckMate 743 trial supporting the use of first-line Nivolumab/Ipilimumab for these subtypes.
      • Štrbac D
      • Dolžan V.
      Novel and future treatment options in mesothelioma: a systematic review.
      ,
      • Peters S
      • Scherpereel A
      • Cornelissen R
      • et al.
      First-line nivolumab plus ipilimumab versus chemotherapy in patients with unresectable malignant pleural mesothelioma: 3-year outcomes from CheckMate 743.
      ,

      Guidelines Detail. NCCN. Available at: https://www.nccn.org/guidelines/guidelines-detail. Accessed: April 2, 2022.

      Several randomized controlled trials have begun to shed light on the potential for immunotherapy in MPM while others are ongoing. In addition to the CheckMate 743 trial results which demonstrated benefit of a first line nivolumab/ipilimumab regimen compared to chemotherapy, Scherpereel et al found promising quality of life metrics among the patients in this trial who received first-line immunotherapy.
      • Peters S
      • Scherpereel A
      • Cornelissen R
      • et al.
      First-line nivolumab plus ipilimumab versus chemotherapy in patients with unresectable malignant pleural mesothelioma: 3-year outcomes from CheckMate 743.
      ,
      • Scherpereel A
      • Antonia S
      • Bautista Y
      • et al.
      First-line nivolumab plus ipilimumab versus chemotherapy for the treatment of unresectable malignant pleural mesothelioma: patient-reported outcomes in CheckMate 743.
      The CONFIRM phase III randomized controlled trial compared nivolumab to placebo among patients who had experienced progression on first-line chemotherapy and found improvements in both progression free survival and overall survival among those receiving nivolumab.
      • Fennell DA
      • Ewings S
      • Ottensmeier C
      • et al.
      Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trial.
      The phase III randomized controlled PROMISE-meso trial compared pembrolizumab to single agent chemotherapy and found no difference in progression free survival or overall survival, however, the KEYNOTE phase II trial showed promise for pembrolizumab in MPM patients.
      • Popat S
      • Curioni-Fontecedro A
      • Dafni U
      • et al.
      A multicentre randomised phase III trial comparing pembrolizumab versus single-agent chemotherapy for advanced pre-treated malignant pleural mesothelioma: the European thoracic oncology platform (ETOP 9-15) PROMISE-meso trial.
      ,
      • Yap TA
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      • et al.
      Efficacy and safety of pembrolizumab in patients with advanced mesothelioma in the open-label, single-arm, phase 2 KEYNOTE-158 study.
      Very little data exists, however, demonstrating the efficacy of immunotherapy in MPM outside of a clinical trial. For this reason, our findings of an associated increase in survival among patients in the immunotherapy group compared to the non-immunotherapy group are particularly interesting, especially considering that the baseline characteristics between the groups were similar. The smaller percentage of “other” histology subtypes in the immunotherapy group is likely due to the fact that these patients tended to be from later in the study period when pathologic diagnosis continued to become more accurate. It is worth noting, however, that the percentages of patients with epithelial histology were similar between the 2 groups (61.4% in the immunotherapy group and 58.5% in the non-immunotherapy group). The increased associated survival among patients receiving immunotherapy was most pronounced in the sarcomatoid subgroup. While our data suggest a possible association with improved survival among patients with epithelial histology, it is possible that some of these patients had particular characteristics such as high levels of programmed death-ligand 1 (PD-L1) expression that allowed for an improved response. While an association with improved survival among patients with biphasic subtypes was not shown in this subgroup, it is possible that this could be due to limited sample size within this subgroup.
      Nationally, the debate continues as to the role of surgery for MPM patients.
      • Scherpereel A
      • Opitz I
      • Berghmans T
      • et al.
      ERS/ESTS/EACTS/ESTRO guidelines for the management of malignant pleural mesothelioma.
      • Song KJ
      • Flores RM
      • Wolf AS.
      Taken together.
      • Janes SM
      • Alrifai D
      • Fennell DA.
      Perspectives on the treatment of malignant pleural mesothelioma.
      While our patients who underwent surgery were younger with a smaller percentage of biphasic/sarcomatoid subtypes, the substantially increased survival among the surgery group suggests that surgery may play an important role in treatment among appropriately selected patients. To further support this, among epithelial patients, the use of both surgery and chemotherapy was associated with improved 24-month survival relative to those receiving chemotherapy alone. The number of patients that underwent surgery during the 11 year period emphasizes that these patients were carefully selected and that this selection process of generally earlier stage patients with adequate performance status likely contributes to the observed increase in survival.
      In addition to its retrospective nature, our study has a few limitations. First, groupings are based upon the type of treatment regimen patients received. While all patients received treatment, it is possible that some patients in the CT group may have died prior to receiving an alternative treatment modality. The baseline characteristics between the 4 groups, however, were similar, and this was even more so the case when only stage I/II or epithelial patients were analyzed. In fact, stage I/II patients had no baseline differences across treatment groups. Another limitation is that during most of the study period, protocols were not in place to start patients on up front immunotherapy. Rather, in a majority of cases, patients who had already received surgery, chemotherapy, or both were started on immunotherapy based on evidence of recurrence on imaging. Our results, therefore, may not represent the effect of immunotherapy as a first line treatment. Instead, they are likely more reflective of the use of immunotherapy in any line of therapy for MPM patients. Also, we do not have data on pulmonary function testing. Though this may play a role in selection for surgery and even survival, we do include CCI which provides insight into the baseline health status of each group's patient population. Finally, due to sample size considerations, patients in the iCT group could have received either immunotherapy alone or sequential treatments of immunotherapy followed by chemotherapy, or vice versa. Despite the heterogeneity in this particular group, given the large differences in associated survival compared to the CT group, we suspect the immunotherapy component to be the driving force for the increased survival.

      Conclusion

      Overall, our data demonstrate that incorporation of immunotherapy, surgery, and chemotherapy into multimodal treatment regimens may be associated with improved survival among carefully selected MPM patients in a community setting. Future data and research from current ongoing randomized clinical trials evaluating the potential beneficial effect of adjuvant immunotherapy in mesothelioma will shed further light on the potential importance of this treatment in multimodal regimens for MPM.

      Clinical Practice Points

      • Several studies have suggested the benefit of multimodal therapies of chemotherapy and surgery for patients with malignant pleural mesothelioma, and randomized controlled trials have suggested benefit of immunotherapy for these patients.
      • Very limited evidence exists, however, analyzing the effects of immunotherapy outside of a randomized controlled trial or as part of a multimodal treatment regimen.
        We therefore, aimed to analyze multimodal treatment regimens with and without immunotherapy among patients at our large integrated healthcare system in order to determine the benefits of such regimens.
      • We found that multimodal regimens including immunotherapy and surgery were associated with the best overall survival. We also found that immunotherapy and surgery were each associated with improved survival among carefully selected patients.
      • While immunotherapy was associated with improved survival in several subgroups (early stage, epithelial, and sarcomatoid), the effect was pronounced among patients with sarcomatoid subtypes. These results support the further investigation of immunotherapy within multimodal treatment regimens for patients with malignant pleural mesothelioma.

      Acknowledgments

      This work was supported by the Kaiser Permanente Northern California Graduate Medical Education Program, Kaiser Foundation Hospitals.

      Disclosure

      The authors have stated that they have no conflicts of interest.

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