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Corresponding author. Address for correspondence: Charles B. Simone II, MD, University of Maryland School of Medicine, Department of Radiation Oncology, Maryland Proton Treatment Center, 850 W. Baltimore St., Baltimore, MD 21201.
Controversy exists regarding the optimal surgical technique for malignant pleural mesothelioma (MPM). We evaluated national practice patterns and outcomes of MPM treated with extrapleural pneumonectomy (EPP) versus lung-sparing extended pleurectomy/decortication (P/D).
Methods
The National Cancer Database was queried for patients with newly diagnosed MPM undergoing EPP or P/D. Multivariable logistic regression ascertained clinical factors independently associated with P/D receipt. Kaplan-Meier analysis was used to evaluate overall survival (OS) between cohorts; multivariable Cox proportional hazards modeling was used to evaluate factors associated with OS. Survival was then evaluated between propensity-matched populations.
Results
Overall, 1307 patients (271 undergoing EPP [21%] and 1036 undergoing P/D [79%]) met the criteria. Patients receiving P/D were older (p = 0.028), whereas those undergoing EPP were more likely to live in a rural area (p = 0.044), live farther from the treating facility (p = 0.039), and receive treatment at an academic center (p = 0.050). There were no differences between cohorts in 30-day readmission or mortality (all p > 0.05). The median OS times in the EPP and P/D groups were 19 versus 16 months, respectively (p = 0.120); no differences were observed after propensity matching (p = 0.540).
Conclusions
In this largest analysis of its kind to date, findings from this contemporary cohort demonstrate that P/D comprised most surgical procedures for MPM. Procedure type was influenced by sociodemographic and geographical factors, without observed differences in survival or postoperative mortality and readmission rates between techniques.
Malignant pleural mesothelioma (MPM) is a rare but highly aggressive malignancy associated with very poor prognosis. Surgery in an attempt to achieve a gross macroscopic resection, with or without intraoperative adjuvant therapies, is considered an integral portion of multimodality therapy for most patients with operable MPM.
Pleurectomy/decortication, hyperthermic pleural lavage with povidone-iodine followed by adjuvant chemotherapy in patients with malignant pleural mesothelioma.
Whereas the historical surgical technique for MPM has been extrapleural pneumonectomy (EPP), this procedure is associated with notable perioperative and postoperative adverse events and mortality.
Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study.
In efforts to address these issues, lung-sparing surgery in the form of extended pleurectomy/decortication (P/D) has more recently been utilized and is associated with fewer complications.
outcomes compared with EPP. However, concern exists that P/D is less of an oncologic procedure and that it is more risky to deliver adjuvant radiation therapy (RT) after P/D than after EPP. Additionally, delineation of the subpopulations benefiting from either surgical approach is less clear. This controversy is exemplified by U.S. guidelines that have changed multiple times over the past several years and are currently recommending either EPP or P/D,
This investigation is the largest such study evaluating surgical practice patterns and outcomes for newly diagnosed primary MPM by using the National Cancer Database (NCDB) to determine the frequency of use of each definitive surgical procedure and determine whether one technique results in superior OS relative to the other.
Materials and Methods
The NCDB is a joint project of the Commission on Cancer (CoC) of the American College of Surgeons and the American Cancer Society that consists of information regarding tumor characteristics, patient demographics, and patient survival for approximately 70% of the United States population.
The NCDB contains information not included in the Surveillance, Epidemiology, and End Results database, including details regarding use of systemic therapy. The data used in this study were derived from a de-identified NCDB file. The American College of Surgeons and the CoC have not verified and are not responsible for either the analytic and statistical methodology used or the conclusions drawn from these data. As all patient information in the NCDB database is de-identified, this study was exempt from institutional review board evaluation.
The NCDB Participant User File corresponding to mesothelioma (2004–2012) was utilized for this study. The inclusion criterion for this investigation was being a patient with newly diagnosed MPM who underwent EPP or P/D. Surgery type was defined by a thoracic surgeon with notable experience in mesothelioma surgery (J. S. F.) as surgery of the primary intrathoracic site with codes 20 to 23, 30, 33, 40, 45 to 48, and 50 for P/D and 55 to 56, 60, 66, and 70 for EPP. Patients who underwent all other types of surgical procedures (including with the following ambiguous surgical codes/labels: 12–13, 15, 19, and 24 [local tumor destruction or excision, laser]; 80 [resection, not otherwise specified]; 90 [surgery, not otherwise specified]) and those undergoing a surgical procedure to the nonprimary tumor site or unknown type of surgical procedure were excluded. Patients without proper TNM staging were also removed, as were patients with metastases (stage M1) and/or receiving palliative care. In accordance with the variables in NCDB files, information collected on each patient broadly included demographic, clinical, and treatment data.
R Core Team (2017). R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. https://www.R-project.org/. Accessed May 23, 2017.
Tests were two sided, with a threshold of p less than 0.05 for statistical significance. First, Kaplan-Meier curves were calculated to evaluate OS, defined as the interval between the date of diagnosis and the date of death or last contact. Second, the univariate association of each covariate with OS was assessed by using a Cox proportional hazards model. Covariates that were significantly associated with OS (p < 0.05) were included in a multivariable model, and backward stepwise selection was performed with an α value of 0.20. Third, to estimate the propensity score for each patient, the univariate association of each covariate with treatment type was assessed by using a simple regression model. Covariates that were significantly associated with treatment type (p < 0.05) were included in a multivariable regression model, and backward stepwise selection was performed with an α value of 0.20. Propensity score matching was performed with approximately two patients undergoing P/D being matched to every patient undergoing EPP by using a “greedy” nearest neighbor algorithm with a caliper 0.2 times the standard deviation of the logit propensity score.
Validating recommendations for coronary angiography following an acute myocardial infarction in the elderly: a matched analysis using propensity scores.
Kaplan-Meier curves were calculated on the propensity-matched patients, and a multivariable Cox model was fit on the propensity-matched data set by the same method described earlier.
Results
A complete flow diagram of patient selection is provided in Figure 1. In total, 1307 patients met the study analysis criteria; this included 271 patients who underwent EPP (21%) and 1036 who underwent lung-sparing extended P/D (79%). Figure 2 demonstrates that the overall number of definitive surgical procedures performed is increasing over time but the proportion of lung-sparing and lung-sacrificing surgical procedures has remained relatively constant.
Figure 2(A) Temporal trends in number of extrapleural pneumonectomies versus lung-sparing extended pleurectomy/decortication procedures. (B) Temporal trends in proportion of lung-sparing procedures. EPP, extrapleural pleurectomy; P/D, pleurectomy/decortication.
Table 1 displays notable clinical characteristics of both cohorts. Patients were predominantly male (79%) and white (94%), had a median age of 68 years (range, 58–76), and were clinically node negative (cN0 79%). Multivariable logistic regression analysis revealed several noteworthy sociodemographic factors that were independently associated with the type of surgery performed. Specifically, older patients were more likely to undergo lung-sparing P/D (p = 0.028), as were patients living in urban areas (p = 0.036). EPP was more likely to be performed on patients living in rural areas (p = 0.044), those living farther from the facility (p = 0.039), and those treated at academic centers (p = 0.050) and at institutions located in the Pacific (AK, CA, HI, OR, or WA) and West North Central (IA, KS, MN, MO, ND, NE, or SD) regions of the United States (p < 0.05).
Table 1Characteristics of the Overall Cohort and Significant Factors Associated with Receiving a Lung-Sparing Operation in the Final Multivariable Logistic Regression Model
Median follow-up was 15 months (range 0–125 months). Kaplan-Meier estimates comparing OS in the EPP and P/D groups are illustrated in Figure 3A. The 3- and 5-year OS rates in the respective groups were 26.5% (95% confidence interval [CI]: 21.4%–32.7%) versus 19.9% (95% CI: 17.5%–22.7%) and 9.9% (95% CI: 6.2%–15.9%) versus 11.1% (95% CI: 9.1%–13.7%). This corresponded to a median OS of 19 and 16 months, respectively (p = 0.120).
Figure 3(A) Overall survival with 95% confidence intervals (shaded) between populations on the basis of surgery type. (B) Overall survival between groups in the propensity score–matched populations. EPP, extrapleural pleurectomy; P/D, pleurectomy/decortication.
In an attempt to minimize bias based on available clinical and demographic features, patients in both cohorts (241 who underwent EPP and 441 who underwent P/D) underwent propensity matching and subsequent Kaplan-Meier survival analysis (Fig. 3B). Again, there were no statistically significant differences in OS between groups (median 19 versus 19 months [p = 0.540]).
In the overall cohort, after adjustment for potential confounders, there were several predictors of OS on multivariable analysis (Table 2). Factors independently predictive of worse OS were advanced age (p < 0.001), male sex (p = 0.002), urban residence (p = 0.018), treatment at a community center (p = 0.018), and nonmetastatic stage IV disease (p < 0.001). Improved OS was associated with receipt of chemotherapy (p = 0.029) and increased total radiation dose (p = 0.001). Of note, year/era of treatment and type of surgery were not statistically significant and were removed from the multivariable model during stepwise selection.
Table 2Multivariate Cox Proportional Hazards Model for Overall Survival
Lastly, the NCDB tabulates postoperative mortality and readmission rates, which were analyzed between groups. The respective 30-day readmission rates in the EPP and P/D groups were 7% and 5% (p = 0.292). The respective 30-day mortality rates were 5% and 5% (p = 0.999). In the propensity-matched population, the respective 30-day readmission and 30-day mortality rates were 8% versus 5% (p = 0.370) and 5% versus 3% (p = 0.322).
Discussion
This investigation of a large national database that evaluated practice patterns of surgery for MPM demonstrates that the predominant surgical procedure utilized in this population is a lung-sparing P/D. We identified sociodemographic and geographical factors that were independently related to receipt of a particular surgical approach. We also did not find any apparent differences between EPP and P/D in terms of OS or perioperative mortality and readmission rates.
In the absence of randomized data comparing the surgical procedures, the fact that this population (2004–2012) largely underwent lung-sparing procedures (without change in temporal trends) is noteworthy, especially in light of the current and former guideline recommendations.
This highlights the impact of existing retrospective and phase I and II data demonstrating that lung-sparing approaches provide satisfactory oncologic outcomes and low rates of complications and adverse events, which is also supported by the finding that older persons were more likely to receive P/D. However, surgical management is clearly individualized by institution: whereas some centers perform P/D whenever technically possible,
from these data, EPP was identified to be more often performed in facilities in certain regions of the western/midwestern United States and at academic centers. Whether this geographical correlation relates to practice patterns of a few specific high-volume tertiary care institutions is unknown, although it is possible that EPP was more commonly performed in academic centers, potentially because these centers are more likely to have more experienced surgeons who specialize in thoracic surgery and are willing to perform the potentially more risky procedure.
Although it is of great importance from a health disparities standpoint that no racial or socioeconomic differences independently predicted for receipt of a particular type of surgery, access to care on the basis of location was readily identified. On multivariable analysis, urban-dwelling patients living closer to the treating institution were more likely to receive P/D, whereas EPP was more often performed on rural patients who lived farther from the treating facility. These differences are important for clinicians, patients, and mesothelioma support groups when considering geographical barriers to treatment of patients with MPM.
Next, although the precise reasons for choice of surgical procedure (or receipt of a particular technique) are not tabulated by the NCDB, few patients in this cohort with T4 and/or node-positive disease underwent surgery. Although these patients with more advanced disease are often not recommended for definitive surgery, they may still have extended survival with resection as part of multimodality therapy.
Although this cohort included few patients with biphasic MPM, and even fewer with the sarcomatoid histologic type, the large number of unknown values precludes further conclusions. Although RT administration was numerically more common in the EPP cohort (consistent with national guidelines
), this was not correlative after multivariable adjustment for potential confounders. Furthermore, a recent randomized phase II trial did not find an appreciable benefit to post-EPP RT,
Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma with or without hemithoracic radiotherapy (SAKK 17/04): a randomised, international, multicentre phase 2 trial.
Although concern for radiation pneumonitis is heightened during delivery of adjuvant RT after a lung-sparing surgical procedure because of the near-uniform volume of ipsilateral lung receiving clinically significant doses of irradiation, recent data demonstrate that use of intensity-modulated RT has substantial utility and promise as part of multidisciplinary lung-sparing management.
Phase II study of hemithoracic intensity-modulated pleural radiation therapy (IMPRINT) as part of lung-sparing multimodality therapy in patients with malignant pleural mesothelioma.
Similarly, another advanced RT technique, proton therapy, may also allow for safe delivery of adjuvant treatment in the setting of a lung-sparing surgery
given the dosimetric benefit of protons in reducing doses to lungs and other organs at risk compared with photons when administered for thoracic malignancies.
Establishing the feasibility of the dosimetric compliance criteria of RTOG 1308: phase III randomized trial comparing overall survival after photon versus proton radiochemotherapy for inoperable stage II-IIIB NSCLC.
Intensity-modulated proton therapy for elective nodal irradiation and involved-field radiation in the definitive treatment of locally advanced non-small-cell lung cancer: a dosimetric study.
Total RT dose, when analyzed as a continuous variable, independently predicted for higher OS when a multivariable Cox proportional hazards model was used, indicating the potential of dose escalation when feasible. This is in keeping with prior reports suggesting superior local control with higher adjuvant RT doses for MPM.
The survival figures herein are comparable to those in the existing literature (although contemporary series at high-volume centers display markedly higher survival
Direct comparisons with these data are difficult because less than two-thirds of those patients underwent an operation, which is consistent with Surveillance, Epidemiology, and End Results–Medicare data.
Mesothelioma in the United States: a Surveillance, Epidemiology, and End Results (SEER)-Medicare investigation of treatment patterns and overall survival.
(consisting mostly of patients from outside the United States) were EPP. Largely in keeping with our findings, those authors found no difference in outcomes between EPP and P/D except for stage I disease, which was associated with higher survival after EPP.
The postoperative readmission and mortality figures herein are most likely higher than those of high-volume centers with experienced clinicians
because they represent a general cohort with likely a wide range of surgeon experience and hospital volume. A publication using the Society of Thoracic Surgeons database showed similar findings: of 225 patients (58% of whom underwent P/D), 5% experienced 30-day mortality.
Although our postoperative outcomes were not significantly different even after propensity matching, we observed equivalent survival; in light of this, previous studies have shown fewer postoperative complications in the P/D cohort, which may explain the relatively lower proportion of EPP patients from this national data set. Additionally, as patients in the current study who underwent P/D were older and generally had higher comorbidity scores compared with patients undergoing EPP, this may also explain why morbidity and mortality rates were not lower with P/D.
Propensity matching is an important tool with which to potentially decrease indication biases. However, it is inherently limited by availability of a finite set of variables, as well as by the completeness of reporting those variables. In our study, no changes were found in terms of survival or postoperative outcomes after propensity matching. Herein, factors utilized for propensity matching included variables significant on multivariate logistic regression analysis as well as salient factors known to be associated with outcomes: facility location and type, age, histologic type, stage, and receipt of chemotherapy and RT. Notably, this did not include other important items such as socioeconomic parameters. Despite the large number of unknown/unspecified values, histologic type was still utilized given its clear impact on prognosis; we found a trend (p = 0.065) toward improved OS with epithelioid tumors that likely did not reach statistical significance because of the very limited number of patients with nonepithelial tumors who underwent a surgical procedure. This approach is analogous to those in other studies that have also performed similar measures of propensity matching for variables with relatively high unreported values.
Taken together, a salient point is that no propensity-matched procedure can account for all possible confounders (both reported and unreported), and thus, not even propensity matching can substitute for a prospective randomized trial on this subjection, which unfortunately is not likely to occur.
Although the NCDB provides a unique platform with which to study this important clinical question, our investigation is not without limitations. First, the major caveat herein is that any retrospective study can never control for biases in receipt of a particular treatment or paradigm. Second, because many of the conclusions made herein rely on definitions of P/D and EPP that were based on NCDB surgical codes, another shortcoming is that there is a lack of universal standardization of either surgical approach, particularly for extended P/D.
Recommendations for uniform definitions of surgical techniques for malignant pleural mesothelioma: a consensus report of the International Association for the Study of Lung Cancer International Staging Committee and the International Mesothelioma Interest Group.
In addition to the potential for miscoding in any large database study, the potential for “interpretation bias” between institutions and clinicians in defining the types of surgery is acknowledged and is likely present in any retrospective work. Given that there likely is more variability in the operative approach of an extended P/D than of an EPP,
Recommendations for uniform definitions of surgical techniques for malignant pleural mesothelioma: a consensus report of the International Association for the Study of Lung Cancer International Staging Committee and the International Mesothelioma Interest Group.
it is possible that a higher proportion of lung-sparing cases included in this analysis were more palliative than definitive in intent despite our excluding all cases coded in the NCDB as palliative. This effect might have served to artificially lower the survival of P/D relative to EPP. Additionally, the retrospective nature of this investigation makes it difficult to draw firm conclusions regarding the safety and efficacy of P/D versus EPP, although the findings herein recapitulate other findings.
Third, although receipt of chemotherapy was independently predictive of higher OS, it is possible that chemotherapy was less commonly administered to patients with poorer performance status, a variable not coded by the NCDB. Despite this caveat, we propose careful patient selection for trimodality therapy. Fourth, although the NCDB includes data for 70% of the U.S. population, only CoC-accredited facilities contribute data. Therefore, these findings may not necessarily be representative of the entire U.S. population. Fifth, the NCDB does not keep track of several noteworthy variables, such as surgical margin status, pulmonary function tests, and salvage therapies, all of which could affect OS and confound conclusions of the current study. It also does not record other end points such as tolerance of therapy (including premature cessation of chemotherapy and/or RT), cancer-specific survival, and local/regional control. Lastly, there may also be suboptimal coding for several variables, such as the large number of unknown or not otherwise specified values for histologic type, which may affect the integrity of propensity matching, survival outcomes, and factors associated with such. The definitions of not otherwise specified may arise from several potential causes, including pathologic ambiguity (with or without subsequent resolution) and/or pathologic diagnosis and treatment at different facilities. Further investigation to corroborate our survival conclusions and investigate these other variables is warranted.
Conclusion
This contemporary NCDB data set, the largest of its kind to date, illustrates that most operative cases were treated with a lung-sparing extended P/D approaches. There were noteworthy sociodemographic and geographical factors associated with receipt of EPP and P/D. There were no apparent differences in survival, postoperative mortality, or readmission between the different surgical techniques, thus supporting either surgical technique as a viable treatment option for this disease.
References
Bovolato P.
Casadio C.
Bille A.
et al.
Does surgery improve survival of patients with malignant pleural mesothelioma? A multicenter retrospective analysis of 1365 consecutive patients.
Pleurectomy/decortication, hyperthermic pleural lavage with povidone-iodine followed by adjuvant chemotherapy in patients with malignant pleural mesothelioma.
Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study.
R Core Team (2017). R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. https://www.R-project.org/. Accessed May 23, 2017.
Validating recommendations for coronary angiography following an acute myocardial infarction in the elderly: a matched analysis using propensity scores.
Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma with or without hemithoracic radiotherapy (SAKK 17/04): a randomised, international, multicentre phase 2 trial.
Phase II study of hemithoracic intensity-modulated pleural radiation therapy (IMPRINT) as part of lung-sparing multimodality therapy in patients with malignant pleural mesothelioma.
Establishing the feasibility of the dosimetric compliance criteria of RTOG 1308: phase III randomized trial comparing overall survival after photon versus proton radiochemotherapy for inoperable stage II-IIIB NSCLC.
Intensity-modulated proton therapy for elective nodal irradiation and involved-field radiation in the definitive treatment of locally advanced non-small-cell lung cancer: a dosimetric study.
Mesothelioma in the United States: a Surveillance, Epidemiology, and End Results (SEER)-Medicare investigation of treatment patterns and overall survival.
Recommendations for uniform definitions of surgical techniques for malignant pleural mesothelioma: a consensus report of the International Association for the Study of Lung Cancer International Staging Committee and the International Mesothelioma Interest Group.
We read with great interest the report on pneumonectomy versus pleurectomy/decortication that was published in the Journal of Thoracic Oncology by Verma et al.1 Malignant pleural mesothelioma is a rare malignancy with a very poor prognosis. Surgery is considered part of multimodality therapy for select patients. Historically, extrapleural pneumonectomy has been the procedure of choice, but it is associated with substantial morbidity and mortality.
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