Is pleurectomy and decortication superior to palliative care in the treatment of malignant pleural mesothelioma?

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1 doi: /icvts Interactive CardioVascular and Thoracic Surgery 12 (2011) Best evidence topic - Thoracic oncologic Is pleurectomy and decortication superior to palliative care in the treatment of malignant pleural mesothelioma? a a b b, Imran Zahid, Sumera Sharif, Tom Routledge, Marco Scarci * a Imperial College London, South Kensington Campus, London SW7 2AZ, UK b Department of Thoracic Surgery, Guy s Hospital, Great Maze Pond, London SE1 9RT, UK Received 18 September 2010; received in revised form 25 January 2011; accepted 27 January 2011 Summary A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was whether pleurectomyy decortication (PyD) is superior to palliative care in the treatment of patients with malignant pleural mesothelioma (MPM). Overall 80 papers were found using the reported search, of which 11 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results are tabulated. We conclude that PyD may lead to superior survival rates but at the expense of higher morbidity rates to palliative treatment. Six studies reported patient outcomes after use of radical PyD to treat patients with MPM. Radical PyD leads to a higher median survival than supportive care (14.5 vs. 4.5 months) and non-radical decortication (15.3 vs. 7.1 months, P-0.000). However, radical PyD had a complication rate of 30%, hospital stay of 12 days with an operative mortality rate of 9.1%. One-year survival rate was 65% but this fell to 0 24% at three years. Three studies highlighted the use of palliative chemotherapy to manage patients with MPM. Median survival (14 vs. 10 months) was higher in patients who received chemotherapy early compared to those on a delayed protocol. Early chemotherapy had a longer time to disease progression (25 vs. 11 weeks, Ps0.1) and greater one-year survival (66% vs. 36%) than the delayed group. Active symptom control (ASC) alone had lower symptom control rates than the combination of ASC plus MVP (mitomycinqvinblastineqcisplatin) (7% vs. 11%, Ps0.0017) and ASC plus vinorelbine (4% vs. 7%, Ps0.047). Three studies reported results of palliative surgery in patients with known MPM. Median survival period was 213 days with a 30-day mortality rate of 7.8%. Survival rates reduced from 70.6% at three months to 25.5% at one-year post-surgery. Prolonged air-leak and postoperative empyema complicated 9.8% and 4% of patients, respectively. PyD is a morbid operation that is associated with significant perioperative mortality and complication rates. Although a number of retrospective studies have shown a small benefit in survival with PyD, the heavily documented similarity in patient outcomes between PyD and extrapleural pneumonectomy along with the results of the Mesothelioma and Radical Surgery trial, should induce the surgical community to consider the use of PyD only in patients with malignant mesothelioma enrolled in prospective trials Published by European Association for Cardio-Thoracic Surgery. All rights reserved. Keywords: Pleurectomyydecortication; Malignant mesothelioma; Supportive care 1. Introduction A best evidence topic was constructed according to a structured protocol. This is fully described in the ICVTS w1x. 2. Three-part question In wpatients with malignant pleural mesotheliomax is wpleurectomyydecortication (PyD)x superior to wpalliative carex in terms of wmorbidity, symptom control and survivalx. 3. Clinical scenario You review a 63-year-old retired miner, with a known diagnosis of malignant pleural mesothelioma (MPM), complaining of chest pain and worsening cough. CT chest and abdomen evaluated the tumour to be International Meso- *Corresponding author. Tel.: q ; fax: q address: marco.scarci@mac.com (M. Scarci) Published by European Association for Cardio-Thoracic Surgery thelioma Interest Group (IMIG) stage III disease with no chest wall involvement. You are unsure as to whether undergoing radical pleurectomyydecortication (P/D) would be superior to palliative care. You resolve to check the literature. 4. Search strategy Medline search 1950 to August 2010 was performed using the OVID interface wpleurectomyydecortication.mp OR PyD.mpx OR wexp Mesotheliomayor mesothelioma.mp.x 5. Search outcome Eighty papers were found using the reported search. From these, 11 papers were identified that provided the best evidence to answer the question. These are presented in Table 1. In addition, the reference list of each paper was searched.

2 I. Zahid et al. / Interactive CardioVascular and Thoracic Surgery 12 (2011) Table 1. Best evidence papers Author, date and country, Patient group Outcomes Key results Comments Study type (level of evidence) Schipper et al., (2008), Single centre experience Median survival Total PyD: 17.2 Total PyD leads to superior Ann Thorac Surg, UK, over 18 years (ns285) (months) Subtotal PyD: 8.1 patient outcomes than w2x Exploration without subtotal PyD and Total PyD (ns10) resection: 6.8 exploration without Retrospective Subtotal PyD (ns34) resection cohort study Exploration without Survival )31 days Total PyD: 0.74 resection (ns22) postoperative Subtotal PyD: 1.62 (Hazard ratio) Exploration without resection: 1.97 Hospital stay (days) Total PyD: 6.5 Subtotal PyD: 6.5 Exploration without resection: 6 Complications Total PyD: 20% Luckraz et al., (2010), Single centre experience Thirty-day mortality 1.1% Multimodality therapy Eur J Cardiothorac Surg, over 30 years ns85 provides leads to lower UK, w3x Complications (%) PyD: 18 complication and higher PyD (ns34) PyDqCTqRT: 13 survival rates Retrospective cohort PyDqCTqRT (ns24) (P-0.02) (90% 95% tumour excision) Median survival PyD: 8.3 (months) PyDqCTqRT: 26 (P-0.001) Flores et al., (2008), Retrospective Operative mortality 4% PyD can manage malignant J Thorac Cardiovasc Surg, multicentre experience mesothelioma but leads to USA, w4x over 16 years Respiratory 6.4% high respiratory complications complications Retrospective PyD (ns278) cohort study Survival (months) 16 Okada et al., (2008), Single centre experience Median survival PyD: 17 months Pleurectomyydecortication Interact CardioVasc over 20 years EPP: 13 months results in equivalent Thorac Surg, Japan, survival rates to EPP w5x PyD (ns34) Three-year survival PyD: 24% EPP (ns31) rate EPP: 33% Retrospective cohort study Operative mortality PyD: 0 Major complication PyD: 15% rate postoperative Nakas et al., (2008), Single centre study Mortality: There was a significantly Eur J Cardiothorac Surg, over 10 years ns days 5.9 vs. 9.8% (Ps0.36) higher 90-day mortality in UK, w6x 90 days 9.8 vs. 29.4% (Ps0.012) patients with radical Group R: surgery Cohort study Radical PyD (ns51) Morbidity 55 vs. 28% (Ps0.023) Major complications Group NR: Hospital stay 12 vs. 10 (Ps0.99) included chylothorax, Non-radical (days) oesophageal rupture, decortication (ns51) bleeding and diaphragmatic Median survival 15.3 vs. 7.1 (P-0.000) patch disruption (months) When patients were split into subgroups according to cell type, radical surgery had longer survival only for epithelioid cell type Best Evidence Topic Maziak et al., (2005), Thirty-two studies were Median survival PyD: 14.5 Three out of eight Lung Cancer, Canada, identified involving (months) Supportive: 4.5 prospective studies w7x 3152 patients reported increased survival Operative mortality 9.1% for PyD compared to Systematic review All patients had a supportive care (level 2a) known diagnosis of MPM Complications 30% (Continued on next page)

3 814 I. Zahid et al. / Interactive CardioVascular and Thoracic Surgery 12 (2011) Table 1. (Continued) Author, date and country, Patient group Outcomes Key results Comments Study type (level of evidence) PyD leads to very high complication rates O Brien et al., (2006), Multicentre Time to commence Early: 0 weeks Early introduction of Ann Oncol, UK, w8x randomised control trial chemotherapy Delayed: 17 weeks chemotherapy produces over four years (range 3 96) greater symptom Randomised control trial improvement and survival (level 1b) Early chemotherapy Median time to Early: 25 weeks rates in patients with (ns21) symptom progression Delayed: 11 weeks malignant mesothelioma (Ps0.1) Delayed chemotherapy (ns17) Patients requiring Early: ns4 second line Delayed: ns0 All patients had WHO chemotherapy performance score F2, GFR G35 mlyh, no Median survival Early: 14 months rapid change on CXR Delayed: 10 months over four weeks preoperative One-year survival Early: 66% rate Delayed: 36% Mean change in quality of life scores at follow-up Physical functioning: Early: (Ps0.6) Delayed: (Ps0.008) Dyspnoea: Early: (Ps0.7) Delayed: (Ps0.025) Muers et al., (2008), Multicentre Completion of ASCqMVP: 64% Addition of chemotherapy Lancet, UK, w9x randomised control trial treatment schedule ASCqV: 50% to ASC leads to greater involving 409 patients tumour response rate and Randomised control trial over five years Tumour response rate Formally assessed: symptomatic improvement (level 1b) ASCqMVP: 10% in patients with MPM Active symptom ASCqV: 16% control (ASC) alone (ns136) Clinician opinion at 15 weeks: ASC: 14% ASCqMVP ASCqMVP: 29% chemotherapy (ns137) ASCqV: 31% ASCqvinorelbine Symptom Chest pain: chemotherapy (ns136) improvement ASC: 7% ASCqMVP: 11% (Ps0.0017) Median time from ASCqV: 10% (Ps0.051) diagnosis to randomisations60 days Lethargy: Patients were mainly ASC: 4% IMIG disease stage III ASCqMVP: 9% (Ps0.54) (31%) or IV (45%) ASCqV: 7% (Ps0.047) Sweating: ASC: 5% ASCqMVP: 9% (Ps0.012) ASCqV: 6% (Ps0.48) Side effect profile Haematological: ASC: 0% ASCqMVP: 13.3% ASCqV: 36% Quality of life Physical functioning: EORTC questionnaire ASC: 66 score at three months ASCqMVP: 70 ASCqV: 70 Global quality of life: ASC: 56 (Continued on next page)

4 I. Zahid et al. / Interactive CardioVascular and Thoracic Surgery 12 (2011) Table 1. (Continued) Author, date and country, Patient group Outcomes Key results Comments Study type (level of evidence) ASCqMVP: 56 ASCqV: 57 Survival Hazard ratio ASC: 1 ASCqMVP: 0.99 (Ps0.95) ASCqV: 0.77 (Ps0.04) ASCqchemotherapy: 0.89 (Ps0.29) % Alive at one year: ASC: 29 ASCqchemotherapy: 32 Median survival (months): ASC: 7.6 ASCqV: 9.5 ASCqchemotherapy: 8.5 Merritt et al., (2001), Single centre Treatment types Talc pleurodesis: ns70 Palliative treatment for J Surg Oncol, retrospective study Radiotherapy: ns30 MPM leads to a short Canada, w10x over 12 years Chemotherapy: ns9 overall survival period which was not affected by Retrospective Palliative treatment Median survival 213 days (95% CI: the type of palliative cohort study (ns101) ) treatment option (Ps0.59) MPM was confirmed Mortality at 89.1% using surgical follow-up biopsy and immunohistochemistry Aziz et al., (2002), Single centre experience Median survival PyD: 14 PyD leads to equivalent Eur J Cardiothorac Surg, over nine years (months) Supportive care: 7 survival rates to EPP UK, w11x (range 1 19) PyD (ns47) EPP: 13 Retrospective EPP (ns64) cohort study Thirty-day operative PyD: 0 mortality Major complication rate PyD: 4% incl. bleeding Survival rate for PyD One year: 65% Three years: 0% Martin-Ucar et al., (2001), Single centre Treatment types VATS pleurectomy: ns17 Surgical debulking with Eur J Cardiothorac Surg prospective study over VATS decortication: ns3 palliative intent produces UK, w12x four years Open decortication: ns31 poor survival rates Prospective cohort study Palliative surgical Median hospital stay Seven days (range 2 17) It leads to high morbidity debulking (ns51) postoperative rates and low symptom improvement rates in MPM was confirmed Thirty-day mortality 7.8% patients with MPM using surgical biopsy and Morbidity Prolonged air-leak (9.8%) immunohistochemistry Postoperative empyema (4%) Best Evidence Topic Median survival 215 days (95% CI: ) Survival rate Three months: 70.6% Six months: 47.1% One-year: 25.5% Symptom Three months: 78.4% improvement Six months: 41.2% One-year: 25.5% EPP, extrapleural pneumonectomy; MPM, malignant pleural mesothelioma; RT, radiotherapy; GFR, glomerular filtration rate; CXR, chest X-ray; VATS, videoassisted thoracoscopic surgery.

5 816 I. Zahid et al. / Interactive CardioVascular and Thoracic Surgery 12 (2011) Results Palliative management of MPM includes the use of chemotherapy or surgery to reduce patient symptoms or prolong survival without the prospect of a cure. We define the operative technique of radicalytotal PyD as complete parietal, visceral and mediastinal pleurectomy, with or without removal of the pericardium or ipsilateral hemi-diaphragm with curative intent. Any study that deviates from this definition of PyD is highlighted. Diagnosis of MPM was confirmed by histopathology in all studies unless stated otherwise. Six studies reported patient outcomes after use of PyD to treat patients with MPM. Schipper et al. w2x managed MPM using total PyD (ns10), subtotal PyD (ns34) or exploration without resection (ns22). Subtotal PyD is a non-radical decortication that involves removal of up to 70% of the parietal pleura. Total PyD had greater median survival period (17.2 vs. 8.1 vs. 6.8 months) than subtotal PyD and exploration without resection, respectively. Luckraz et al. w3x reported patient outcomes after PyD with chemoradiotherapy (ns24) and PyD alone (ns34). Multimodality therapy produced higher median survival rates (26 vs. 8.3 months, P-0.001) and lower complication rates (13% vs. 18%, P-0.02) than PyD alone. Flores et al. w4x reported longer median survival (16 vs. 12 months, P-0.001) with PyD compared to extrapleural pneumonectomy (EPP). Patients with epithelial MPM or American Joint Committee on Cancer (AJCC) stage I disease had greater survival than non-epithelial or higher stage disease (P-0.001). In contrast, Okada et al. w5x reported equivalent median (17 vs. 13 months, Ps0.922) and three-year survival rates (24% vs. 33%, Ps0.922) with PyD compared to EPP. However, they also found greater survival with epithelial MPM (Ps0.0048) and stage I disease (Ps0.8927) compared to non-epithelial and stage II disease, respectively. Pivotally, Treasure w13x is aiming to follow-up his Mesothelioma and Radical Surgery (MARS) trial, with a multicentre randomised control trial, provisionally called MARS-2, to determine whether radical PyD is superior to best continued care. Interestingly, initial results of the MARS trial wtreasure T, Waller D, Tan C, Entwisle J, O Brien M, O Bryne K, Thomas G, Snee M, Spicer J, Landau D, Lang-Lazdunski L, Bliss J, Peckitt C, Rogers S, Marriage E, Coombes G, Webster-smith M and Peto J. Principal results of the feasibility phase of the Mesothelioma and Radical Surgery trial (MARS-feasibility) 2010 Available from have demonstrated a clear disadvantage of conducting radical EPP surgery (ns24) compared to no-epp (ns26) with lower 12- month survival rates (52.2% vs. 73.1%) with a hazard ratio of 2.75 (95% CI: , Ps0.02) in favour of no EPP. Although the MARS trial analysed patient outcomes after EPP, radical PyD is a morbid operation that leads to similar survival rates as EPP. Nakas et al. w6x compared outcomes of radical PyD (ns51) to palliative non-radical decortication (ns51), which spared the diaphragm and pericardium. Although a pathological diagnosis of MPM was established in only 65% of patients, the remainder were treated on the basis of highly suspicious pleural biopsies. Radical PyD led to higher morbidity rates (55% vs. 28%, Ps0.023) and equivalent hospital stay (12 vs. 10 days, Ps0.99) compared to non-radical decortication. Maziak et al. w7x systematically reviewed 32 studies and found PyD had a longer median survival (14.5 vs. 4.5 months) than supportive care but led to an operative mortality rate of 9.1% with a complication rate of 30%. Two studies highlighted patient outcomes after palliative use of chemotherapy to manage unresectable MPM. O Brien et al. w8x randomised patients to receive chemotherapy either early (ns21) or after a delay (ns17) of 17 weeks. Early chemotherapy produced a longer median survival period (14 vs. 10 months) and greater one-year survival rates (66% vs. 36%) than delayed chemotherapy. Muers et al. w9x reported significant improvements in chest pain (11% vs. 7%, Ps0.0017) and sweating (9% vs. 5%, Ps0.012) in patients with adjunctive chemotherapy to active symptom control (ASC) alone. Adjunctive chemotherapy conferred a marginal survival advantage (8.5 vs. 7.6 months) compared to ASC alone. Three studies reported results of palliative surgery in patients with known MPM. Merritt et al. w10x carried out talc pleurodesis (ns70), chemotherapy (ns30) and radiotherapy (ns9) with palliative intent. Median survival was 213 days with a high mortality rate of 89.1% at four-year follow-up. Aziz et al. w11x found that palliative PyD had a longer median survival period (14 vs. 7 vs. 13 months) than supportive care but equivalent to EPP, respectively. PyD led to major complications in 4% of cases with no mortalities at 30 days postoperative. Survival rates were 65% at one-year but fell to 0% by three years postoperative. Martin-Ucar et al. w12x performed thoracoscopic (ns3) and open (ns31) decortications and thoracoscopic pleurectomies (ns17), to debulk disease with palliative intent. The median survival period was 215 days. Survival rates fell from 70.6% at three months to 25.5% at one-year postoperative. The optimal approach for decortication is currently debated. Srivastava et al. w14x reported effective symptoms palliation using VATS decortication in patients with MPM. 7. Clinical bottom line PyD is a morbid operation that is associated with significant perioperative mortality and complication rates. Although a number of retrospective studies have shown a small benefit in survival with PyD, the heavily documented similarity in patient outcomes between PyD and EPP along with the results of the MARS trial, should induce the surgical community to consider the use of PyD only in patients with malignant mesothelioma enrolled in prospective trials. References w1x Dunning J, Prendergast B, Mackway-Jones K. Towards evidence-based medicine in cardiothoracic surgery: best BETS. Interact CardioVasc Thorac Surg 2003;2: w2x Schipper PH, Nichols FC, Thomse KM, Deschamps C, Cassivi SD, Allen MS, Pairolero PC. Malignant pleural mesothelioma: surgical management in 285 patients. Ann Thorac Surg 2008;85: ; discussion 264. w3x Luckraz H, Rahman M, Patel N, Szafranek A, Gibbs AR, Butchart EG. Three decades of experience in the surgical multi-modality management of pleural mesothelioma. Eur J Cardiothorac Surg 2010;37:

6 I. Zahid et al. / Interactive CardioVascular and Thoracic Surgery 12 (2011) w4x Flores RM, Pass HI, Seshan VE, Dycoco J, Zakowski M, Carbone M, Bains MS, Rusch VW. Extrapleural pneumonectomy versus pleurectomyydecortication in the surgical management of malignant pleural mesothelioma: results in 663 patients. J Thorac Cardiovasc Surg 2008;135: , 626.e1 626.e3. w5x Okada M, Mimura T, Ohbayashi C, Sakuma T, Soejima T, Tsubota N. Radical surgery for malignant pleural mesothelioma: results and prognosis. Interact CardioVasc Thorac Surg 2008;7: w6x Nakas A, Trousse DS, Martin-Ucar AE, Waller DA. Open lung-sparing surgery for malignant pleural mesothelioma: the benefits of a radical approach within multimodality therapy. Eur J Cardiothorac Surg 2008; 34: w7x Maziak DE, Gagliardi A, Haynes AE, Mackay JA, Evans WK, Cancer Care Ontario Program in Evidence-based Care Lung Cancer Disease Site Group. Surgical management of malignant pleural mesothelioma: a systematic review and evidence summary. Lung Cancer 2005;48: w8x O Brien ME, Watkins D, Ryan C, Priest K, Corbishley C, Norton A, Ashley S, Rowell N, Sayer R. A randomised trial in malignant mesothelioma (M) of early (E) versus delayed (D) chemotherapy in symptomatically stable patients: the MED trial. Ann Oncol 2006;17: w9x Muers MF, Stephens RJ, Fisher P, Darlison L, Higgs CM, Lowry E, Nicholson AG, O Brien M, Peake M, Rudd R, Snee M, Steele J, Girling DJ, Nankivell M, Pugh C, Parmar MK, MS01 Trial Management Group. Active symptom control with or without chemotherapy in the treatment of patients with malignant pleural mesothelioma (MS01): a multicentre randomised trial. Lancet 2008;371: w10x Merritt N, Blewett CJ, Miller JD, Bennett WF, Young JEM, Urschel JD. Survival after conservative (palliative) management of pleural malignant mesothelioma. J Surg Oncol 2001;78: w11x Aziz T, Jilaihawi A, Prakash D. The management of malignant pleural mesothelioma; single centre experience in 10 years. Eur J Cardiothorac Surg 2002;22: w12x Martin-Ucar AE, Edwards JG, Rengajaran A, Muller S, Waller DA. Palliative surgical debulking in malignant mesothelioma. Predictors of survival and symptom control. Eur J Cardiothorac Surg 2001;20: w13x Treasure T. Surgery for mesothelioma: MARS landing and future missions. Eur J Cardiothorac Surg 2010;3: w14x Srivastava V, Dunning J, Au J. Does video-assisted thoracoscopic decortication in advanced malignant mesothelioma improve prognosis? Interact CardioVasc Thorac Surg 2009;8: Work in Editorial New Ideas Progress Report Protocol Institutional Report ESCVS Article Proposal for Bailout Procedure Negative Results Follow-up Paper State-of-the-art Best Evidence Topic Nomenclature Historical Pages Brief Case Report Communication