Effects of Extended Pleurectomy and Decortication on Quality of Life and Pulmonary Function in Patients With Malignant Pleural Mesothelioma David Burkholder, BS, Duraid Hadi, MD, Rangesh Kunnavakkam, PhD, Hedy Kindler, MD, Kristy Todd, PA-C, Amy Durkin Celauro, PA-C, and Wickii T. Vigneswaran, MD Division of Cardiac and Thoracic Surgery, Department of Surgery, Department of Biostatistics, and Division of Hematology and Oncology, Department of Medicine, University of Chicago Medicine, Chicago, Illinois
Background. Maximal cytoreductive surgeries— extrapleural pneumonectomy and extended pleurectomy and decortication (EPD)—are effective surgical treatments in selected patients with malignant pleural mesothelioma. Extended pleurectomy and decortication results in equivalent survival yet better health-related quality of life (HRQoL). Methods. Patients with malignant pleural mesothelioma were studied for the effects of EPD on HRQoL and pulmonary function. The European Organization for Research and Treatment of Cancer Core Quality of Life Questionaire-C30 was used to evaluate HRQoL before operation, and at 4 to 5 and 7 to 8 months postoperatively. Pulmonary function tests were measured immediately before and 5 to 7 months after the operation. Patients were compared according to World Health Organization baseline performance status (PS). Results. Of the 36 patients enrolled, 17 were PS 0 and 19 were PS 1 or PS 2 at baseline. Patients in groups PS 1 and PS 2 had significantly worse global health, functional, and symptoms scores. After EPD, PS 0 patients had no change in global health or function and symptoms
scores except for emotional function, whereas PS 1 or PS 2 patients showed improvements at 4 to 5 months with further improvements at 7 to 8 months. The PS 0 patients demonstrated a significant decrease in forced vital capacity (p [ 0.001), forced expiratory volume in 1 second (p [ 0.002), total lung capacity (p [ 0.0006) and diffusing capacity of the lung for carbon monoxide (p [ 0.003) after EPD, whereas no change was observed in PS 1 and PS 2 patients. Conclusions. Extended pleurectomy and decortication did not improve overall HRQoL and had a negative impact in pulmonary function in minimally symptomatic patients. In symptomatic patients, a significant improvement in HRQoL was observed after EPD, which continued at late follow-up, although the pulmonary function was not affected. As changes in HRQoL are multidimensional, the preservation of the pulmonary function may have contributed to the net benefit observed in PS 1 and PS 2 patients.
M
Life expectancy from diagnosis of MPM is 7 to 9 months with palliative or supportive care and approximately 12 months with chemotherapy [3]. Multimodality therapy provides superior outcomes compared with other strategies [1, 3–5]. The goal of surgery is macroscopic complete resection; however, the optimal surgical therapy has been debated [6–8]. The principal cytoreductive surgical approaches for MPM are extrapleural pneumonectomy (EPP) and extended pleurectomy and decortication (EPD). Both primarily aim to resect all macroscopic tumor and control symptoms; this includes resection of all or a significant part of the ipsilateral hemidiaphragm. Extended pleurectomy and decortication is aimed additionally at restoring ipsilateral lung expansion and removing the restrictive tumor from the chest wall [8, 9]. Generally the treatment for MPM result in modest survival advantage, and therefore HRQoL is an important measurement of the net benefit achieved. There are very few studies that have focused on the effects of surgery on HRQoL after EPD surgery.
alignant mesothelioma is an aggressive malignancy, and approximately 3,000 new cases are diagnosed in the United States annually, with 85% of them affecting the pleura [1]. Patients with malignant pleural mesothelioma (MPM) invariably present with fatigue and shortness of breath as the initial symptoms. Associated pleural effusion and circumferential growth of the tumor restricting lung and chest wall expansion often is responsible for the shortness of breath in these patients. Additional symptoms include chest pain, cough, and weight loss, all of which may have a significant effect on health-related quality of life (HRQoL), which incorporates domains related to physical, mental, emotional, and social functioning [2]. Accepted for publication Jan 15, 2015. Address correspondence to Dr Vigneswaran, University of Chicago Medicine, 5841 S Maryland Ave MC 5040, Chicago, IL 60637; e-mail: [email protected].
Ó 2015 by The Society of Thoracic Surgeons Published by Elsevier
(Ann Thorac Surg 2015;-:-–-) Ó 2015 by The Society of Thoracic Surgeons
0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2015.01.058
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BURKHOLDER ET AL EXTENDED PLEURECTOMY AND DECORTICATION
Abbreviations and Acronyms = diffusing capacity of the lung for carbon monoxide EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer Core Quality of Life Questionaire-C30 EPD = extended pleurectomy and decortication EPP = extrapleural pneumonectomy FEV1 = forced expiratory volume in 1 second FRC = functional residual capacity FVC = forced vital capacity GHQoL = global health quality of life HRQoL = health-related quality of life MPM = malignant pleural mesothelioma PFTs = pulmonary function tests PS = performance status TLC = total lung capacity WHO = World Health Organization DLCO
Furthermore, few have examined pulmonary function after the treatment, and no studies have looked at both HRQoL and pulmonary function tests (PFTs) simultaneously [10–13]. The purpose of this study was to examine the effects of EPD on both HRQoL and pulmonary function and the interrelationship between the two in MPM patients.
Material and Methods All patients with malignant pleural mesothelioma with epithelioid or biphasic histology with unilateral disease and World Health Organization (WHO) performance status (PS) 0 through 2 were considered for maximal cytoreductive surgery. Informed consent was obtained that was approved by the institutional review board. Patients who underwent an EPD for MPM, and enrolled in the HRQoL study with pulmonary function that was measured preoperatively and 6 months postoperatively formed the basis of this report. The HRQoL was assessed using the European Organization for Research and Treatment of Cancer Core Quality of Life QuestionaireC30 toll (EORTC QLQ-C30). This instrument had been validated in patients with MPM undergoing surgery as a useful tool in evaluating HRQoL [11, 12]. All patients underwent histologic confirmation of the disease and initial drainage of pleural effusion according to the care provider’s preference before EPD. Thirty-six patients undergoing EPD also had their PFTs performed immediately before the operation and at 6 (1) months postoperatively and participated in the HRQoL evaluation before surgery and at 4 to 5 months and 7 to 8 months after surgery. All patients received clinical and radiologic computed tomographic scan of the chest and abdomen examinations within 6 weeks of the operation and as part
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of standard follow-up at 1 month and every 3 months thereafter. Patient HRQoL was recorded immediately before surgery (0) and at 1, 4 to 5, 7 to 8, 10 to 11, and 13 to 14 months postoperatively according to the protocol. Preoperative data were entered prospectively and recorded as in the data collection for The Society of Thoracic Surgeons General Thoracic Surgery Database based on the completion of Major Procedure Data Collection Form Version 2.2 for each patient. Additional information was obtained from the initial clinical appointment forms and laboratory results. For the purpose of this study, we analyzed these 36 patients who had preoperative and 5 to 7 months postoperative PFTs and who had completed 4 to 5 and 7 to 8 months HRQoL questionnaires. Each patient underwent EPD surgery exclusively at the University of Chicago Hospital performed by the same surgeon (W.T.V.). The EPD operation consisted of removal of the parietal and visceral pleura with dissection and excision of tumor in the fissures and partial or complete resection of the hemidiaphragm with Gore-Tex (W.L. Gore and Associates, Inc, Newark, DE) prosthetic reconstruction. Pathologic tumor staging was done according to the TNM staging system [14]. The EORTC QLQ-C30 was incorporated into five functional scales (physical, role, cognitive, emotional, and social), three symptom scales (fatigue, pain, and nausea and vomiting), a global health quality of life (GHQoL) scale, and a number of single items assessing additional symptoms. Raw scores were converted to a linear scale ranging from 0 to 100, with a high score for a functional scale or GHQoL scale representing a high or healthy level of functioning, whereas a high score for a symptom scale represents a high level of symptomatology or problems. All scoring and scaling was performed according to the EORTC QLQ-C30 Scoring Manual, Third Edition. Baseline performance status (PS) was determined at the preoperative visit according to the World Health Organization criteria; PS 0 ¼ asymptomatic, able to carry on all predisease activities without restriction; PS 1 ¼ symptomatic but completely ambulatory (restricted in physically strenuous activity but able to carry out work of a light or sedentary nature); and PS 2 ¼ less than 50% in bed during the day (ambulatory and capable of all selfcare but unable to carry out any work activities; patients are up and about more than 50% of their waking hours). Patients completed their baseline HRQoL questionnaire during this visit. To determine the change in HRQoL scores for each PS group, mean scores for each functional and symptom domain of the EORTC QLQ-C30 were determined at every time point and subtracted from the baseline. In case of a change in sample size at each time point owing to death or withdrawal, mean baseline scores were recalculated for those patients remaining and used as reference to eliminate the chance that missing data may bias the results. We examined PS 0 and PS 1, 2 groups for a significant change in PFT values using the independent Student’s t test, and the change in PFT values were measured against change in QoL for both PS groups using the paired
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Student’s t test. To measure the change of PFT values, overall averages of the baseline values were subtracted from the postoperative values. Data from the following PFTs—forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), functional residual capacity (FRC), diffusing capacity of the lung for carbon monoxide (DLCO), and total lung capacity (TLC; %)—were recorded by their percent predicted and prebronchodilator level to determine lung function relative to 100%. Preoperative factors and TNM staging were tested against change in QoL from preoperative to 4 to 5 or 7 to 8 months postoperative for both PS 0 and PS 1, 2 patient groups using the paired Student’s t test. Further mixed regression models were performed to study the outcomes of QoL functional and physical domain as a longitudinal measure with each of the PFT data as predictors. Data were statistically analyzed using STATA statistical software version 12.0 (StataCorp LP, College Station, TX). To compare paired data with continuous measures, a paired Student’s t test was performed, whereas for unpaired data independent Student’s t test was used. To compare categorical variables, a c2 test was used. A probability value of less than 0.05 is considered significant.
Results The study consisted of 27 males and 9 females (Table 1). Their median age was 70 5.96 years (range, 56 to 89 years). Of these 36 patients enrolled, 17 were in WHO PS 0, 17 were in WHO PS 1, and 2 were in WHO PS 2 at the time of operation. Sixteen patients had undergone a prior talc pleurodesis operation, 9 with prior PleurX catheter (CareFusion Corp, San Diego, CA) placement, and the remaining had a thoracostomy or thoracentesis for the treatment of their pleural effusion before EPD. All patients underwent either partial or near total resection of the ipsilateral hemidiaphragm. Twenty-two patients also underwent additional pericardial resection. Pathologic stages of the patients after surgery were as follows: 2 (5%)
stage I, 11 (30.5%) stage II, 16 (44%) stage III, and 11 (30.5%) stage IV. Three patients (8%) received neoadjuvant chemotherapy and 30 patients (78%) received adjuvant chemotherapy consisting of Pemetrexed and Carboplatin or Premetrexed and Cisplatin, 13 in the PS 0 group and 10 in the PS 1, 2 group. No adjuvant radiotherapy was used in any of these patients. Patients who are PS 0 report a significantly better baseline GHQoL, functional scales, and symptom scales than those in the PS 1 or 2 group (Fig 1). From this baseline disparity, the PS 0 group was shown to have a decrease in the GHQoL scale, and among the physical and role functioning but not in emotional, cognitive, and social functioning. Similarly among symptom domain, in pain and dyspnea, at both 4 to 5 months and 7 to 8 months after EPD. The PS 1 and 2 groups showed a modest but significant improvement in GHQoL, in all functional domains, and in symptom domains at 4 to 5 months and continued to improve at 7 to 8 months evaluation after EPD (Fig 2). The PS 0 patients had a significant decrease in FEV1, FVC, TLC, FRC, and DLCO values (Table 2). There was no significant change in the PFTs in the PS 1 and PS 2 patients after EPD (Fig 3). The postoperative PFTs at 5 to 7 months were similar in all patients regardless of preoperative PS (Table 2). We did not observe any correlation between the changes in FEV1, FVC, TLC, FRC, and DLCO values and
Table 1. Demographics and Pathologic Findings in Performance Status 0 and Performance Status 1 and 2 Groups Demography and Pathology Age (y) Males Females Histology Epithelioid Biphasic Sarcomatoid T Stage T1 T2 T3 T4 Nodal stage positive PS ¼ performance status;
WHO PS 0
WHO PS 1 and 2
67.8 8.7 12 5
72.2 5.6 15 4
15 2 0
14 3 1
1 5 7 4 9
1 3 7 8 6
p Value 0.09 0.5
0.2
0.45 0.33
WHO ¼ World Health Organization.
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Fig 1. European Organization for Research and Treatment of Cancer Core Quality of Life Questionaire-C30 mean scores of (A) functional scales and (B) symptom scales in performance status (PS) 0 (striped bars) and PS 1 (solid bars) patients at baseline. *Indicates two-sample Student’s t test shows a significant difference (p < 0.05) between baseline means of PS 0 and PS 1 groups. (QoL ¼ quality of life.)
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Fig 3. Mean change in pulmonary function testing (% predicted). *p < 0.05. (DLCO ¼ diffusing capacity of the lung for carbon monoxide; FEV1 ¼ forced expiratory volume in 1 second; FRC ¼ functional residual capacity; FVC ¼ forced vital capacity; PS ¼ performance status; RV ¼ residual volume; TLC ¼ total lung capacity.)
Fig 2. European Organization for Research and Treatment of Cancer Core Quality of Life Questionaire-C30 domain changes from baseline at 4 to 5 (solid bars) and 7 to 8 months (striped bars) for performance status (PS) 0 and PS 1 groups. (A) PS 1 and 2 quality of life (QoL) changes; (B) PS 0 quality of life changes. *Indicates significant change (p < 0.05), probability value acquired from Student’s t test: paired two sample for means.
the HRQoL in GHQoL or functional domain and symptom domains as a whole group or analyzed separately according to the WHO PS score. Table 3 shows the results of the mixed regression model for each of the PFT data measured as a univariate analysis.
Comment By definition, EPD is performed in patients with MPM to remove all macroscopic tumor that is feasible, which
involves resection of the tumor off the chest wall, diaphragm, mediastinum, and lung, freeing the trapped lung and restoring lung reexpansion. The maximal removal of tumor often involves resection and reconstruction of the hemidiaphragm and pericardium [9, 10]. Although resection of the restricting tumor from the parietal and visceral pleura improves lung and chest wall mechanics, resection of the diaphragm compromises pulmonary function. Although there is no clear evidence, singlecenter studies and large database analysis suggest EPD leads to a higher median survival than supportive care or palliative intervention, and best survival is observed among those patients who received adjuvant therapy [5, 7, 15, 16]. Extrapleural pneumonectomy when performed for MPM is offered only to patients with good pulmonary reserve. It is necessary to have good baseline pulmonary function for consideration of this surgery as the remaining contralateral lung need to support the patient. In contrast, one of the goals of EPD is recruitment of the ipsilateral lung that is restricted by MPM. Ploenes and colleagues [17] showed significant reduction in pulmonary function after EPP as compared with EPD. This is not unexpected when considering the loss of lung in patients
Table 2. Pulmonary Function Testing Preoperatively and 5 to 7 Months Postoperatively in Performance Status 0 and Performance Status Groups
Pulmonary Function Test FEV1 FVC TLC FRC DLCO
PS 0 Pre 84.11 80.2 88.2 92.9 88.4
(16.9) (4.12) (16.0) (17.3) (22.3)
5–7 months Postoperative PFTs in PS 0 and PS 1 and 2 Patients
PS 1 Post 72.4 67.1 75.0 82.8 77.3
(17.3) (3.7) (2.3) (15.8) (16.9)
Pre 65.6 61.7 77 84.3 69
(14.9) (14.0) (11.9) (17.0) (18.7)
Post 72.8 64.8 74.9 86.3 72.3
(17.5) (14.4) (9.1) (14.4) (18.8)
Post (PS 0) 72.4 67.1 75.0 82.8 77.3
(17.3) (3.7) (2.3) (15.8) (16.9)
Post (PS 1 and 2) 72.8 64.8 74.9 86.3 72.3
(17.5) (14.4) (9.1) (14.4) (18.8)
DLCO ¼ diffusing capacity of the lung for carbon monoxide; FEV1 ¼ forced expiratory volume in 1 second; FRC ¼ functional residual capacity; FVC ¼ forced vital capacity; PFTs ¼ pulmonary function tests; PS ¼ performance status; TLC ¼ total lung capacity.
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Table 3. Quality of Life and Physical Functioning Outcome GHQoL Change in FVC Change in FEV1 Change in DLCO Change in TLC Change in FRC Physical functioning Change in FVC Change in FEV1 Change in DLCO Change in TLC Change in FRC
Coefficient (CI) 0.001 0.09 0.09 0.011 0.04 0.06 0.07 0.12 0.09 0.05
p Value
(0.35 to 0.36) (0.24 to 0.44) (0.4 to 0.20) (0.48 to 0.47) (0.43 to 0.50)
0.99 0.57 0.54 0.96 0.88
(0.40 (0.26 (0.16 (0.46 (0.41
0.74 0.68 0.4 0.6 0.8
to to to to to
2.8) 0.4) 0.40) 0.27) 0.32)
CI ¼ confidence interval; DLCO ¼ diffusing capacity of the lung for carbon monoxide; FEV1 ¼ forced expiratory volume in 1 second; FRC ¼ functional residual capacity; FVC ¼ forced vital capacity; GHQoL ¼ global health quality of life; TLC ¼ total lung capacity.
undergoing EPP. In our study we observed reduction in pulmonary function in minimally symptomatic patients after EPD. Nevertheless the postoperative PFTs were similar regardless of the preoperative PS; perhaps this could be accounted for by loss of diaphragmatic function. There are various adjuvant therapies that have been used after maximal cytoreductive surgery, often chemotherapy or radiation therapy alone or in combination. It is difficult to determine what effects the adjuvant therapy have in the HRQoL in this setting. Different adjuvant therapies may have an impact in the HRQoL and pulmonary function in different ways. Radiation therapy can compromise pulmonary function in the neoadjuvant or adjuvant setting. None of the patients in this cohort received radiation therapy. It is difficult to separate the effects of adjuvant chemotherapy on the HRQoL among those patients who received the adjuvant therapy in our study. Extended pleural decortication, like many other major thoracic procedures, is associated with impaired HRQoL in the postoperative period until the patient recovers from the surgical insult [18, 19]. This recovery is expected to be accomplished in the majority of patients within 3 months, but in some proportion of them it may persist beyond that period. For any procedure that has modest improvement in length of survival, it is important to evaluate how it affects the quality of the extended life and therefore the net benefit. We originally set to examine how EPD affects HRQoL, and hypothesized that the change in PFTs may have a direct impact. The results show the difference in HRQoL outcomes based on baseline physical performance status of patients undergoing EPD for MPM. The PS 0 patients have little room to improve when starting from an asymptomatic baseline (74.1 score, with 0 ¼ very poor to 100 ¼ excellent) versus the symptomatic group (53.8 score). The HRQoL is a multidimensional concept and goes beyond the direct measures of health and focuses on the quality of life consequences of health status. As far as we can observe,
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there are few differences between the PS 0 and PS 1, 2 groups except for their functional status and pulmonary function changes. We have shown that symptomatic patients (PS 1, 2) improve in HRQoL after EPD [11]. There was no significant impact noted in PFTs in these patients after EPD. This observation is important considering that all these patients had their ipsilateral diaphragm removed with prosthetic reconstruction, compromising respiratory mechanics. The PS 0 patients did not show a decrease in HRQoL after EPD in either functional domain or symptoms domain except for emotional function compared with PS 1 and PS 2 patients, who showed a significant improvement in all aspects from baseline. When comparing the change in PFT values to the change in QoL domains, there is no statistical correlation observed; however, we are limited by the sample size. One would suspect that an improvement in pulmonary function will lead to an improvement in the scores of physical functioning and vice versa. Considering that HRQoL is multidimensional, we believe preservation of pulmonary function after EPD is an important contributor in the overall net benefit.
Limitations There are some limitations in this study: a relatively small sample size and the study examined only patients who were able to complete the EORTC QLQ-C30 questionnaire at 4 to 5 months and 7 to 8 months after the EPD and patients who were able to perform the PFTs before and 6 to 7 months after EPD. This has the inherent bias that the patients who participated were those who were doing well during this period. Additionally, all patients had only one PFT measurement after the surgical resection and not serial measurements to evaluate the trend. Other limitations were that it was also not possible to separate the effects of adjuvant therapy or the psychological effects of having a diagnosis of cancer on HRQoL measurements.
Conclusions At intermediate follow-up, EPD for MPM had a negative impact on PFTs in minimally symptomatic patients without any improvement in HRQoL measurements. In patients who were symptomatic at presentation, EPD had no impact on PFTs but a significant improvement on global health, symptom, and functional domains. The preservation of pulmonary function in this group of patients may be partially responsible for the improvement in HRQoL after EPD.
References 1. Merritt N, Blewett CJ, Miller JD, Bennett WF, Young JE, Urschel JD. Survival after conservative (palliative) management of pleural malignant mesothelioma. J Surg Oncol 2001;78:171–4. 2. Ferrans CE. Definitions and conceptual models of quality of life. In: Lipscomb J, Gotay CC, Snyder C (eds). Outcomes assessment in cancer. Cambridge, England: Cambridge University; 2005:14–30. 3. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus
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cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003;21:2636–44. Rusch V, Baldini EH, Bueno R, et al, participants in 2012 International Mesothelioma Interest Group Congress. The role of surgical cytoreduction in the treatment of malignant pleural mesothelioma: meeting summary of the International Mesothelioma Interest Group Congress, September 11–14, 2012, Boston, MA. J Thorac Cardiovasc Surg 2013;145:909–10. Flores RM, Pass HI, Seshan VE, et al. Extrapleural pneumonectomy versus pleurectomy/decortication in the surgical management of malignant pleural mesothelioma: results in 663 patients. J Thorac Cardiovasc Surg 2008;135:620–6; e1–3. Hasani A, Alvarez JM, Wyatt JM, et al. Outcome for patients with malignant pleural mesothelioma referred for trimodality therapy in Western Australia. J Thorac Oncol 2009;4: 1010–6. Rusch VW, Giroux D, Kennedy C, et al, IASLC Staging Committee. Initial analysis of the international association for the study of lung cancer mesothelioma database. J Thorac Oncol 2012;7:1631–9. B€ ol€ ukbas S, Eberlein M, Schirren J. Prospective study on functional results after lung-sparing radical pleurectomy in the management of malignant pleural mesothelioma. J Thorac Oncol 2012;7:900–5. Rice D, Rusch V, Pass H, et al, International Association for the Study of Lung Cancer International Staging Committee and the International Mesothelioma Interest Group. 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. J Thorac Oncol 2011;6:1304–12. Rusch VW. Extrapleural pneumonectomy and extended pleurectomy/decortication for malignant pleural mesothelioma:
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the Memorial Sloan-Kettering Cancer Center approach. Ann Cardiothorac Surg 2012;1:523–31. Mollberg NM, Vigneswaran Y, Kindler HL, et al. Quality of life after radical pleurectomy decortication for malignant pleural mesothelioma. Ann Thorac Surg 2012;94:1086–92. Rena O, Casadio C. Extrapleural pneumonectomy for early stage malignant pleural mesothelioma: a harmful procedure. Lung Cancer 2012;77:151–5. Kao SC, Vardy J, Harvie R, et al. Health-related quality of life and inflammatory markers in malignant pleural mesothelioma. Support Care Cancer 2013;21:697–705. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A III, eds. Pleural mesothelioma. In: AJCC cancer staging manual. 7th ed. New York, NY: Springer-Verlag; 2010:271–78. Sugarbaker DJ, Flores RM, Jaklitsch MT, et al. Resection margins, extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma: results in 183 patients. J Thorac Cardiovasc Surg 1999;117:54–63. Weder W, Stahel RA, Bernhard J, et al, Swiss Group for Clinical Cancer Research. Multicenter trial of neo-adjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma. Ann Oncol 2007;18: 1196–202. Ploenes T, Osei-Agyemang T, Krohn A, et al. Changes in lung function after surgery for mesothelioma. Asian Cardiovasc Thorac Ann 2012;21:48–55. Sabanathan, Eng J, Mearns AJ. Alterations in respiratory mechanics following thoracotomy. J R Coll Surg Edinb 1990;35:144–50. Agostini P, Naidu B, Cieslik H, et al. Effectiveness of incentive spirometry in patients following thoracotomy and lung resection including those at high risk for developing pulmonary complications. Thorax 2013;68:580–5.
Background. Maximal cytoreductive surgeries— extrapleural pneumonectomy and extended pleurectomy and decortication (EPD)—are effective surgical treatments in selected patients with malignant pleural mesothelioma. Extended pleurectomy and decortication results in equivalent survival yet better health-related quality of life (HRQoL). Methods. Patients with malignant pleural mesothelioma were studied for the effects of EPD on HRQoL and pulmonary function. The European Organization for Research and Treatment of Cancer Core Quality of Life Questionaire-C30 was used to evaluate HRQoL before operation, and at 4 to 5 and 7 to 8 months postoperatively. Pulmonary function tests were measured immediately before and 5 to 7 months after the operation. Patients were compared according to World Health Organization baseline performance status (PS). Results. Of the 36 patients enrolled, 17 were PS 0 and 19 were PS 1 or PS 2 at baseline. Patients in groups PS 1 and PS 2 had significantly worse global health, functional, and symptoms scores. After EPD, PS 0 patients had no change in global health or function and symptoms
scores except for emotional function, whereas PS 1 or PS 2 patients showed improvements at 4 to 5 months with further improvements at 7 to 8 months. The PS 0 patients demonstrated a significant decrease in forced vital capacity (p [ 0.001), forced expiratory volume in 1 second (p [ 0.002), total lung capacity (p [ 0.0006) and diffusing capacity of the lung for carbon monoxide (p [ 0.003) after EPD, whereas no change was observed in PS 1 and PS 2 patients. Conclusions. Extended pleurectomy and decortication did not improve overall HRQoL and had a negative impact in pulmonary function in minimally symptomatic patients. In symptomatic patients, a significant improvement in HRQoL was observed after EPD, which continued at late follow-up, although the pulmonary function was not affected. As changes in HRQoL are multidimensional, the preservation of the pulmonary function may have contributed to the net benefit observed in PS 1 and PS 2 patients.
M
Life expectancy from diagnosis of MPM is 7 to 9 months with palliative or supportive care and approximately 12 months with chemotherapy [3]. Multimodality therapy provides superior outcomes compared with other strategies [1, 3–5]. The goal of surgery is macroscopic complete resection; however, the optimal surgical therapy has been debated [6–8]. The principal cytoreductive surgical approaches for MPM are extrapleural pneumonectomy (EPP) and extended pleurectomy and decortication (EPD). Both primarily aim to resect all macroscopic tumor and control symptoms; this includes resection of all or a significant part of the ipsilateral hemidiaphragm. Extended pleurectomy and decortication is aimed additionally at restoring ipsilateral lung expansion and removing the restrictive tumor from the chest wall [8, 9]. Generally the treatment for MPM result in modest survival advantage, and therefore HRQoL is an important measurement of the net benefit achieved. There are very few studies that have focused on the effects of surgery on HRQoL after EPD surgery.
alignant mesothelioma is an aggressive malignancy, and approximately 3,000 new cases are diagnosed in the United States annually, with 85% of them affecting the pleura [1]. Patients with malignant pleural mesothelioma (MPM) invariably present with fatigue and shortness of breath as the initial symptoms. Associated pleural effusion and circumferential growth of the tumor restricting lung and chest wall expansion often is responsible for the shortness of breath in these patients. Additional symptoms include chest pain, cough, and weight loss, all of which may have a significant effect on health-related quality of life (HRQoL), which incorporates domains related to physical, mental, emotional, and social functioning [2]. Accepted for publication Jan 15, 2015. Address correspondence to Dr Vigneswaran, University of Chicago Medicine, 5841 S Maryland Ave MC 5040, Chicago, IL 60637; e-mail: [email protected].
Ó 2015 by The Society of Thoracic Surgeons Published by Elsevier
(Ann Thorac Surg 2015;-:-–-) Ó 2015 by The Society of Thoracic Surgeons
0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2015.01.058
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BURKHOLDER ET AL EXTENDED PLEURECTOMY AND DECORTICATION
Abbreviations and Acronyms = diffusing capacity of the lung for carbon monoxide EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer Core Quality of Life Questionaire-C30 EPD = extended pleurectomy and decortication EPP = extrapleural pneumonectomy FEV1 = forced expiratory volume in 1 second FRC = functional residual capacity FVC = forced vital capacity GHQoL = global health quality of life HRQoL = health-related quality of life MPM = malignant pleural mesothelioma PFTs = pulmonary function tests PS = performance status TLC = total lung capacity WHO = World Health Organization DLCO
Furthermore, few have examined pulmonary function after the treatment, and no studies have looked at both HRQoL and pulmonary function tests (PFTs) simultaneously [10–13]. The purpose of this study was to examine the effects of EPD on both HRQoL and pulmonary function and the interrelationship between the two in MPM patients.
Material and Methods All patients with malignant pleural mesothelioma with epithelioid or biphasic histology with unilateral disease and World Health Organization (WHO) performance status (PS) 0 through 2 were considered for maximal cytoreductive surgery. Informed consent was obtained that was approved by the institutional review board. Patients who underwent an EPD for MPM, and enrolled in the HRQoL study with pulmonary function that was measured preoperatively and 6 months postoperatively formed the basis of this report. The HRQoL was assessed using the European Organization for Research and Treatment of Cancer Core Quality of Life QuestionaireC30 toll (EORTC QLQ-C30). This instrument had been validated in patients with MPM undergoing surgery as a useful tool in evaluating HRQoL [11, 12]. All patients underwent histologic confirmation of the disease and initial drainage of pleural effusion according to the care provider’s preference before EPD. Thirty-six patients undergoing EPD also had their PFTs performed immediately before the operation and at 6 (1) months postoperatively and participated in the HRQoL evaluation before surgery and at 4 to 5 months and 7 to 8 months after surgery. All patients received clinical and radiologic computed tomographic scan of the chest and abdomen examinations within 6 weeks of the operation and as part
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of standard follow-up at 1 month and every 3 months thereafter. Patient HRQoL was recorded immediately before surgery (0) and at 1, 4 to 5, 7 to 8, 10 to 11, and 13 to 14 months postoperatively according to the protocol. Preoperative data were entered prospectively and recorded as in the data collection for The Society of Thoracic Surgeons General Thoracic Surgery Database based on the completion of Major Procedure Data Collection Form Version 2.2 for each patient. Additional information was obtained from the initial clinical appointment forms and laboratory results. For the purpose of this study, we analyzed these 36 patients who had preoperative and 5 to 7 months postoperative PFTs and who had completed 4 to 5 and 7 to 8 months HRQoL questionnaires. Each patient underwent EPD surgery exclusively at the University of Chicago Hospital performed by the same surgeon (W.T.V.). The EPD operation consisted of removal of the parietal and visceral pleura with dissection and excision of tumor in the fissures and partial or complete resection of the hemidiaphragm with Gore-Tex (W.L. Gore and Associates, Inc, Newark, DE) prosthetic reconstruction. Pathologic tumor staging was done according to the TNM staging system [14]. The EORTC QLQ-C30 was incorporated into five functional scales (physical, role, cognitive, emotional, and social), three symptom scales (fatigue, pain, and nausea and vomiting), a global health quality of life (GHQoL) scale, and a number of single items assessing additional symptoms. Raw scores were converted to a linear scale ranging from 0 to 100, with a high score for a functional scale or GHQoL scale representing a high or healthy level of functioning, whereas a high score for a symptom scale represents a high level of symptomatology or problems. All scoring and scaling was performed according to the EORTC QLQ-C30 Scoring Manual, Third Edition. Baseline performance status (PS) was determined at the preoperative visit according to the World Health Organization criteria; PS 0 ¼ asymptomatic, able to carry on all predisease activities without restriction; PS 1 ¼ symptomatic but completely ambulatory (restricted in physically strenuous activity but able to carry out work of a light or sedentary nature); and PS 2 ¼ less than 50% in bed during the day (ambulatory and capable of all selfcare but unable to carry out any work activities; patients are up and about more than 50% of their waking hours). Patients completed their baseline HRQoL questionnaire during this visit. To determine the change in HRQoL scores for each PS group, mean scores for each functional and symptom domain of the EORTC QLQ-C30 were determined at every time point and subtracted from the baseline. In case of a change in sample size at each time point owing to death or withdrawal, mean baseline scores were recalculated for those patients remaining and used as reference to eliminate the chance that missing data may bias the results. We examined PS 0 and PS 1, 2 groups for a significant change in PFT values using the independent Student’s t test, and the change in PFT values were measured against change in QoL for both PS groups using the paired
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Student’s t test. To measure the change of PFT values, overall averages of the baseline values were subtracted from the postoperative values. Data from the following PFTs—forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), functional residual capacity (FRC), diffusing capacity of the lung for carbon monoxide (DLCO), and total lung capacity (TLC; %)—were recorded by their percent predicted and prebronchodilator level to determine lung function relative to 100%. Preoperative factors and TNM staging were tested against change in QoL from preoperative to 4 to 5 or 7 to 8 months postoperative for both PS 0 and PS 1, 2 patient groups using the paired Student’s t test. Further mixed regression models were performed to study the outcomes of QoL functional and physical domain as a longitudinal measure with each of the PFT data as predictors. Data were statistically analyzed using STATA statistical software version 12.0 (StataCorp LP, College Station, TX). To compare paired data with continuous measures, a paired Student’s t test was performed, whereas for unpaired data independent Student’s t test was used. To compare categorical variables, a c2 test was used. A probability value of less than 0.05 is considered significant.
Results The study consisted of 27 males and 9 females (Table 1). Their median age was 70 5.96 years (range, 56 to 89 years). Of these 36 patients enrolled, 17 were in WHO PS 0, 17 were in WHO PS 1, and 2 were in WHO PS 2 at the time of operation. Sixteen patients had undergone a prior talc pleurodesis operation, 9 with prior PleurX catheter (CareFusion Corp, San Diego, CA) placement, and the remaining had a thoracostomy or thoracentesis for the treatment of their pleural effusion before EPD. All patients underwent either partial or near total resection of the ipsilateral hemidiaphragm. Twenty-two patients also underwent additional pericardial resection. Pathologic stages of the patients after surgery were as follows: 2 (5%)
stage I, 11 (30.5%) stage II, 16 (44%) stage III, and 11 (30.5%) stage IV. Three patients (8%) received neoadjuvant chemotherapy and 30 patients (78%) received adjuvant chemotherapy consisting of Pemetrexed and Carboplatin or Premetrexed and Cisplatin, 13 in the PS 0 group and 10 in the PS 1, 2 group. No adjuvant radiotherapy was used in any of these patients. Patients who are PS 0 report a significantly better baseline GHQoL, functional scales, and symptom scales than those in the PS 1 or 2 group (Fig 1). From this baseline disparity, the PS 0 group was shown to have a decrease in the GHQoL scale, and among the physical and role functioning but not in emotional, cognitive, and social functioning. Similarly among symptom domain, in pain and dyspnea, at both 4 to 5 months and 7 to 8 months after EPD. The PS 1 and 2 groups showed a modest but significant improvement in GHQoL, in all functional domains, and in symptom domains at 4 to 5 months and continued to improve at 7 to 8 months evaluation after EPD (Fig 2). The PS 0 patients had a significant decrease in FEV1, FVC, TLC, FRC, and DLCO values (Table 2). There was no significant change in the PFTs in the PS 1 and PS 2 patients after EPD (Fig 3). The postoperative PFTs at 5 to 7 months were similar in all patients regardless of preoperative PS (Table 2). We did not observe any correlation between the changes in FEV1, FVC, TLC, FRC, and DLCO values and
Table 1. Demographics and Pathologic Findings in Performance Status 0 and Performance Status 1 and 2 Groups Demography and Pathology Age (y) Males Females Histology Epithelioid Biphasic Sarcomatoid T Stage T1 T2 T3 T4 Nodal stage positive PS ¼ performance status;
WHO PS 0
WHO PS 1 and 2
67.8 8.7 12 5
72.2 5.6 15 4
15 2 0
14 3 1
1 5 7 4 9
1 3 7 8 6
p Value 0.09 0.5
0.2
0.45 0.33
WHO ¼ World Health Organization.
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Fig 1. European Organization for Research and Treatment of Cancer Core Quality of Life Questionaire-C30 mean scores of (A) functional scales and (B) symptom scales in performance status (PS) 0 (striped bars) and PS 1 (solid bars) patients at baseline. *Indicates two-sample Student’s t test shows a significant difference (p < 0.05) between baseline means of PS 0 and PS 1 groups. (QoL ¼ quality of life.)
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Fig 3. Mean change in pulmonary function testing (% predicted). *p < 0.05. (DLCO ¼ diffusing capacity of the lung for carbon monoxide; FEV1 ¼ forced expiratory volume in 1 second; FRC ¼ functional residual capacity; FVC ¼ forced vital capacity; PS ¼ performance status; RV ¼ residual volume; TLC ¼ total lung capacity.)
Fig 2. European Organization for Research and Treatment of Cancer Core Quality of Life Questionaire-C30 domain changes from baseline at 4 to 5 (solid bars) and 7 to 8 months (striped bars) for performance status (PS) 0 and PS 1 groups. (A) PS 1 and 2 quality of life (QoL) changes; (B) PS 0 quality of life changes. *Indicates significant change (p < 0.05), probability value acquired from Student’s t test: paired two sample for means.
the HRQoL in GHQoL or functional domain and symptom domains as a whole group or analyzed separately according to the WHO PS score. Table 3 shows the results of the mixed regression model for each of the PFT data measured as a univariate analysis.
Comment By definition, EPD is performed in patients with MPM to remove all macroscopic tumor that is feasible, which
involves resection of the tumor off the chest wall, diaphragm, mediastinum, and lung, freeing the trapped lung and restoring lung reexpansion. The maximal removal of tumor often involves resection and reconstruction of the hemidiaphragm and pericardium [9, 10]. Although resection of the restricting tumor from the parietal and visceral pleura improves lung and chest wall mechanics, resection of the diaphragm compromises pulmonary function. Although there is no clear evidence, singlecenter studies and large database analysis suggest EPD leads to a higher median survival than supportive care or palliative intervention, and best survival is observed among those patients who received adjuvant therapy [5, 7, 15, 16]. Extrapleural pneumonectomy when performed for MPM is offered only to patients with good pulmonary reserve. It is necessary to have good baseline pulmonary function for consideration of this surgery as the remaining contralateral lung need to support the patient. In contrast, one of the goals of EPD is recruitment of the ipsilateral lung that is restricted by MPM. Ploenes and colleagues [17] showed significant reduction in pulmonary function after EPP as compared with EPD. This is not unexpected when considering the loss of lung in patients
Table 2. Pulmonary Function Testing Preoperatively and 5 to 7 Months Postoperatively in Performance Status 0 and Performance Status Groups
Pulmonary Function Test FEV1 FVC TLC FRC DLCO
PS 0 Pre 84.11 80.2 88.2 92.9 88.4
(16.9) (4.12) (16.0) (17.3) (22.3)
5–7 months Postoperative PFTs in PS 0 and PS 1 and 2 Patients
PS 1 Post 72.4 67.1 75.0 82.8 77.3
(17.3) (3.7) (2.3) (15.8) (16.9)
Pre 65.6 61.7 77 84.3 69
(14.9) (14.0) (11.9) (17.0) (18.7)
Post 72.8 64.8 74.9 86.3 72.3
(17.5) (14.4) (9.1) (14.4) (18.8)
Post (PS 0) 72.4 67.1 75.0 82.8 77.3
(17.3) (3.7) (2.3) (15.8) (16.9)
Post (PS 1 and 2) 72.8 64.8 74.9 86.3 72.3
(17.5) (14.4) (9.1) (14.4) (18.8)
DLCO ¼ diffusing capacity of the lung for carbon monoxide; FEV1 ¼ forced expiratory volume in 1 second; FRC ¼ functional residual capacity; FVC ¼ forced vital capacity; PFTs ¼ pulmonary function tests; PS ¼ performance status; TLC ¼ total lung capacity.
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Table 3. Quality of Life and Physical Functioning Outcome GHQoL Change in FVC Change in FEV1 Change in DLCO Change in TLC Change in FRC Physical functioning Change in FVC Change in FEV1 Change in DLCO Change in TLC Change in FRC
Coefficient (CI) 0.001 0.09 0.09 0.011 0.04 0.06 0.07 0.12 0.09 0.05
p Value
(0.35 to 0.36) (0.24 to 0.44) (0.4 to 0.20) (0.48 to 0.47) (0.43 to 0.50)
0.99 0.57 0.54 0.96 0.88
(0.40 (0.26 (0.16 (0.46 (0.41
0.74 0.68 0.4 0.6 0.8
to to to to to
2.8) 0.4) 0.40) 0.27) 0.32)
CI ¼ confidence interval; DLCO ¼ diffusing capacity of the lung for carbon monoxide; FEV1 ¼ forced expiratory volume in 1 second; FRC ¼ functional residual capacity; FVC ¼ forced vital capacity; GHQoL ¼ global health quality of life; TLC ¼ total lung capacity.
undergoing EPP. In our study we observed reduction in pulmonary function in minimally symptomatic patients after EPD. Nevertheless the postoperative PFTs were similar regardless of the preoperative PS; perhaps this could be accounted for by loss of diaphragmatic function. There are various adjuvant therapies that have been used after maximal cytoreductive surgery, often chemotherapy or radiation therapy alone or in combination. It is difficult to determine what effects the adjuvant therapy have in the HRQoL in this setting. Different adjuvant therapies may have an impact in the HRQoL and pulmonary function in different ways. Radiation therapy can compromise pulmonary function in the neoadjuvant or adjuvant setting. None of the patients in this cohort received radiation therapy. It is difficult to separate the effects of adjuvant chemotherapy on the HRQoL among those patients who received the adjuvant therapy in our study. Extended pleural decortication, like many other major thoracic procedures, is associated with impaired HRQoL in the postoperative period until the patient recovers from the surgical insult [18, 19]. This recovery is expected to be accomplished in the majority of patients within 3 months, but in some proportion of them it may persist beyond that period. For any procedure that has modest improvement in length of survival, it is important to evaluate how it affects the quality of the extended life and therefore the net benefit. We originally set to examine how EPD affects HRQoL, and hypothesized that the change in PFTs may have a direct impact. The results show the difference in HRQoL outcomes based on baseline physical performance status of patients undergoing EPD for MPM. The PS 0 patients have little room to improve when starting from an asymptomatic baseline (74.1 score, with 0 ¼ very poor to 100 ¼ excellent) versus the symptomatic group (53.8 score). The HRQoL is a multidimensional concept and goes beyond the direct measures of health and focuses on the quality of life consequences of health status. As far as we can observe,
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there are few differences between the PS 0 and PS 1, 2 groups except for their functional status and pulmonary function changes. We have shown that symptomatic patients (PS 1, 2) improve in HRQoL after EPD [11]. There was no significant impact noted in PFTs in these patients after EPD. This observation is important considering that all these patients had their ipsilateral diaphragm removed with prosthetic reconstruction, compromising respiratory mechanics. The PS 0 patients did not show a decrease in HRQoL after EPD in either functional domain or symptoms domain except for emotional function compared with PS 1 and PS 2 patients, who showed a significant improvement in all aspects from baseline. When comparing the change in PFT values to the change in QoL domains, there is no statistical correlation observed; however, we are limited by the sample size. One would suspect that an improvement in pulmonary function will lead to an improvement in the scores of physical functioning and vice versa. Considering that HRQoL is multidimensional, we believe preservation of pulmonary function after EPD is an important contributor in the overall net benefit.
Limitations There are some limitations in this study: a relatively small sample size and the study examined only patients who were able to complete the EORTC QLQ-C30 questionnaire at 4 to 5 months and 7 to 8 months after the EPD and patients who were able to perform the PFTs before and 6 to 7 months after EPD. This has the inherent bias that the patients who participated were those who were doing well during this period. Additionally, all patients had only one PFT measurement after the surgical resection and not serial measurements to evaluate the trend. Other limitations were that it was also not possible to separate the effects of adjuvant therapy or the psychological effects of having a diagnosis of cancer on HRQoL measurements.
Conclusions At intermediate follow-up, EPD for MPM had a negative impact on PFTs in minimally symptomatic patients without any improvement in HRQoL measurements. In patients who were symptomatic at presentation, EPD had no impact on PFTs but a significant improvement on global health, symptom, and functional domains. The preservation of pulmonary function in this group of patients may be partially responsible for the improvement in HRQoL after EPD.
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