treatment of malignant pleural mesothelioma?

ARTICLE IN PRESS doi:10.1510/icvts.2010.256289

Interactive CardioVascular and Thoracic Surgery 12 (2011) 1040–1045 www.icvts.org

Best evidence topic - Thoracic oncologic

Extrapleural pneumonectomy or supportive care: treatment of malignant pleural mesothelioma? Sumera Sharifa, Imran Zahida, Tom Routledgeb, Marco Scarcib,* a Imperial College London, South Kensington Campus, London SW7 2AZ, UK Department of Thoracic Surgery, Guy’s Hospital, Great Maze Pond, London SE1 9RT, UK

b

Received 18 September 2010; received in revised form 3 February 2011; accepted 7 February 2011

Summary A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was whether extrapleural pneumonectomy (EPP) is superior to supportive care in the treatment of patients with malignant pleural mesothelioma (MPM). Overall, 110 papers were found using the reported search, of which 14 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 EPP confers no advantage to chemotherapy and palliative treatment in terms of survival and symptom improvement. Ten studies evaluated the role of EPP in the management of MPM. The median survival was 13 months and perioperative and 30-day mortality rates were 5.7% and 9.1%, respectively. There was a high morbidity rate of 37% including atrial fibrillation, empyema and supraventricular arrhythmias. Disease recurred in 73% of patients at a median time of 10 months. Median hospital stay was 13 days and intensive care unit stay was 1.5 days. At three months postsurgery, improvement in symptoms was achieved in 68% of patients. Significant advantages were observed in patients with epithelial MPM (19 vs. 8 months, P-0.01) compared to non-epithelial MPM and with N2 disease (19 vs. 10 months) compared to N1 or N0 disease, respectively. Two studies reported outcomes after chemotherapy in patients with MPM. The median survival was 13 months and symptoms improved in 50% of patients. Response rate of 21% was achieved and the median time to disease progression was 7.2 months. Postoperative haematological toxicity was common and included neutropenia (25%), anaemia (5%) and thrombocytopenia (7.4%). Two studies analysed palliative treatment in mesothelioma and reported a median survival of seven months and improvement in symptoms in 25% of patients at one-year post-treatment. The 30-day mortality rate was 7.8% and complications included prolonged air leak (9.8%) and empyema (4%). Median hospital stay was seven days. Overall, EPP shows no benefit in terms of survival or symptom improvement which is compounded by its high operative mortality and recurrence rate. 䊚 2011 Published by European Association for Cardio-Thoracic Surgery. All rights reserved. Keywords: Extrapleural pneumonectomy; Malignant mesothelioma; Supportive care

1. Introduction A best evidence topic was constructed according to a structured protocol. This is fully described in ICVTS w1x. 2. Three-part question In wpatients with malignant mesotheliomax is wextrapleural pneumonectomy (EPP)x superior to wsupportive carex in terms of wmorbidity, symptom control and survivalx. 3. Clinical scenario You are at a multidisciplinary meeting and review a 67year-old male with known epithelioid malignant mesothelioma. Computed tomography–Positron emission tomography (CT–PET)-scan shows that the disease is confined to the pleura space with no mediastinal nodal involvement. You are asked if this patient would be a candidate for EPP. You are worried about potential complications and are *Corresponding author. Tel.: q44-75-15542899; fax: q44-20-71881016. E-mail address: [email protected] (M. Scarci). 䊚 2011 Published by European Association for Cardio-Thoracic Surgery

uncertain about results. You resolve to check the literature yourself. 4. Search strategy Medline search 1950 to August 2010 was performed using the OVID interface wextrapleural pnuemonectomy.mp. OR EPP.mpx OR wexp Mesotheliomayor mesothelioma.mp.x 5. Search outcome One hundred and ten papers were found using the reported search. From these, 14 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. 6. Results Supportive management of malignant pleural mesothelioma (MPM) includes the use of chemotherapy or surgery

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Table 1. Best evidence papers Author, date and country Study type (level of evidence)

Patient group

Outcomes

Key results

Comments

Aziz et al., (2002), Eur J Cardiothorac Surg, UK, w2x

Single-centre experience over nine years

Median survival (months)

EPP: 13 Supportive care: 7 (range 1–19)

EPP alone (ns13) Supportive care (ns191)

Thirty-day operative mortality

EPP: 9.1%

EPP leads to longer median survival but is associated with high complication rates

Complication rate

Major: EPP: 21% incl. ARDS, empyema

Retrospective cohort study (level 2b)

Minor: EPP: 28% incl. atrial dysrhythmia

Ambrogi et al., (2009), J Surg Oncol, Italy, w3x

Median time for disease recurrence

10 months (range 8–14)

Survival rate

EPP: One year: 49% Three years: 0%

Single-centre experience over seven years

Thirty-day postoperative morbidity

31%

EPP (ns16)

Improvement of symptoms at three months

Dyspnoea 62% (ns10; P-0.01) Pain 75% (ns12; P-0.01) Cough 62% (ns10; P-0.01) Fever 68% (ns11; P-0.001)

SF-36 scores during the first three months

Physical component summary 27.8"11.2 to 36.6"10.6 (P-0.01)


13

Operative mortality

7%

Respiratory complications

10%

Survival

12 months

Cohort study (level 2b)

Retrospective multicentre experience over 16 years


EPP ns385

Nakas et al., (2008), Eur J Cardiothorac Surg, UK, w5x

Single-centre experience over nine years ns208

Thirty-day mortality

23%

Hospital stay

36.6 days


EPP ns112

Mean survival

11.5 months

Yan et al., (2009), J Thorac Cardiovasc Surg, Australia, w6x

Single-centre experience over 14 years (ns70)

Perioperative complications

Overall: 37% (ns26)


Van Sandick et al., (2008), Ann Surg Oncol, The Netherlands, w7x

EPP: Complete cytoreduction (ns63)

Haemothorax (ns7) Atrial fibrillation (ns6) Empyema (ns4) Perioperative mortality

5.7%

Residual macroscopic disease (ns7)

Median survival

20 months

Single-centre experience over three years (ns15)

Median operating time

5.3 h

Median blood loss

1900 ml

The most common complications were reported to be respiratory and cardiac in nature

EPP is associated with a high mortality rate and long hospital stay

A significant proportion of patients who were treated with EPP received neoadjuvant chemotherapy (9%), adjuvant radiotherapy (40%) and postoperative permetrexed-based chemotherapy (23%). The latter two were associated with improved survival EPP in combination with hemithoracic radiation may achieve

(Continued on next page)

Best Evidence Topic

Flores et al., (2008), J Thorac Cardiovasc Surg, USA, w4x

EPP may improve symptoms in MPM patients but has high morbidity rates postoperative

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Table 1. (Continued) Author, date and country Study type (level of evidence)

Patient group

Outcomes

Key results

Comments


EPP and postoperative hemithoracic radiation

Median ICU stay

Two days

Postoperative complications

53% (diaphragmatic herniation most common, 13%)

local control but has a high rate of postoperative complications


0%

Median survival

29 months

Disease-free survival

21 months

Local control

67% with a median follow-up of 19 months

Recurrence

73%

Operative mortality

EPP: 8.2% Exploration without resection: 9.1%

Major complications

EPP: 50.7% Exploration without resection: 9.1% (P-0.0001)

Hospital stay (days)

EPP: 9 Exploration without resection: 6


EPP: 16 Exploration without resection: 6.8

Survival )31 days postoperative (Hazard ratio)

EPP: 1 Exploration without resection: 1.97 (Ps0.01)

Single-centre experience over 11 years

Radical R0 resection achieved

80% (ns39)

EPP (ns49)

Perioperative complications

Atrial fibrillation (ns10) Transient recurrent laryngeal nerve palsy (ns3) Temporary paraplegia (ns2) Contralateral pneumonia (ns2)

Median ICU stay

One day

Median hospital stay

13 days

Median survival

12.5 months

Median survival

13 months

Three-year survival rate

33%

Operative mortality

3.2%

Major complication rate

48% Supraventricular arrhythmias (ns8) Respiratory failure (ns4)

Multicentre randomised control trial

Perioperative deaths

EPP: 3 (12.5%) No EPP: 1 (3.8%)

EPP 24

Twelve-month survival rate

EPP: 52.2% (95% CI: 30.5–70.0) No EPP: 73.1% (95% CI: 51.7–86.2)

Schipper et al., (2008), Ann Thorac Surg, UK, w8x

Single-centre experience over 18 years ns95

EPP may lead to greater survival rates but has high complication rates

EPP ns73 Retrospective cohort study (level 2b)

Aigner et al., (2008), Eur J Cardiothorac Surg, Austria, w9x

Exploration without resection ns22


Okada et al., (2008), Interact CardioVasc Thorac Surg, Japan, w10x

Single-centre experience over 20 years EPP (ns31)


Treasure et al., (2009), J Thorac Oncol, UK, w11x Randomised control trial (level 1b)

No EPP 26

EPP is a morbid operation but improves survival period compared to supportive therapy

EPP has a high complication and operative mortality rate

EPP surgery leads to a distinct disadvantage in patients with MPM



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Patient group

Outcomes

Key results

Hazard ratio

2.75 (95% CI: 1.21–6.26; Ps0.02) in favour of no EPP

Pinto et al., (2006), Lung Cancer, Italy, w12x

Multicentre experience (ns54)

Complete responses (CR)

ns3; 5.6%

Prospective cohort study (level 2b)

Cisplatinygemcitabine (CG) followed by mitoxantroneymethotrexateymitomycin (MMM) for unresectable MPM

Partial responses (PR)

ns13; 24%

Stable disease (SD)

ns33; 61.6%

Progressive disease (PD)

ns5; 9.2%

Median time to progression

9.5 months

Median overall survival

13 months

Improvement in symptoms

Dyspnoea 52.9% Pain 48.3%

Toxicity

CG vs. MMM Neutropenia: 11.1 vs. 35.2% Anaemia: 1.9 vs. 5.5% Thrombocytopenia: 7.4 vs. 7.4%

CR

4% (ns2)

PR

26% (ns14)

Median survival

16.8 months

Median time to progression

7.2 months

Toxicity

Leukopenia: ns26; 48%

Sørensen et al., (2008), Br J Cancer, UK, w13x Cohort study (level 2b)

Single-centre experience (ns54) Cisplatin and vinorelbine in inoperable patients

Single-centre prospective study over four years

Treatment types

VATS pleurectomy: ns17 VATS decortication: ns3 Open decortication: ns31


Palliative surgical debulking (ns51)

Median hospital stay postoperative

Seven days (range 2–17)

MPM was confirmed using surgical biopsy and immunohistochemistry


7.8%

Morbidity

Prolonged air-leak (9.8%) Postoperative empyema (4%)

Median survival

Seven months (95% CI: 152– 278)

Survival rate

Three months: 70.6% Six months: 47.1% One-year: 25.5%

Symptom improvement

Three months: 78.4% Six months: 41.2% One-year: 25.5%

Median survival

Lung-sparing RD: 16.9 months Palliative: 6.8 months (Ps0.001)

Shahin et al., (2011), Eur J Cardiothorac Surg, UK, w15x

Single-centre prospective study over two years


Palliative surgery (ns13)

Two active chemotherapeutic regimens showed good disease control in MPM, with improvement in symptoms and mild toxicity only

Cisplatin and intravenous vinorelbine is an effective regimen in MPM

Surgical debulking with palliative intent produces poor survival rates Its leads to high morbidity rates and low symptom improvement rates in patients with MPM

Surgical debulking with lung-sparing technique produces superior patient outcomes than surgery with palliative intent


Best Evidence Topic

Martin-Ucar et al., (2001), Eur J Cardiothorac Surg, UK, w14x

Comments

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Patient group

Outcomes

Key results

Comments

Lung-preserving radical decortication (RD) (ns13) All patients were either unsuitable or declined to take in the MARS trial EPP, extrapleural pneumonectomy; MPM, malignant pleural mesothelioma; ICU, intensive care unit; CI, confidence interval; MARS, mesothelioma and radical surgery; ARDS, adult respiratory distress syndrome; VATS, video-assisted thoracoscopic surgery.

with palliative intent. EPP with curative intent may produce different patient outcomes than chemotherapy or palliative surgery w16x. Ten studies evaluated the role of EPP in MPM. Aziz et al. w2x reported greater median survival with EPP than supportive care (13 vs. 7 months). EPP had major complication and 30-day mortality rates of 21% and 9.1%, respectively. The addition of chemotherapy to EPP improved survival rates at one year (84% vs. 49%, Ps0.001) and three years (48% vs. 0%, Ps0.0001), respectively, compared to EPP alone. Histological type of MPM had little effect on survival rates one year after EPP but there was a trend towards improved survival (48% vs. 25%, Ps0.07) at three years postEPP with epithelial MPM compared to sarcomatous MPM. Similarly, Ambrogi et al. w3x reported significant improvement in symptoms (dyspnoea 62% and pain 75%; P-0.01) at three months postEPP. Median survival was 13 months with a 30-day postoperative morbidity rate of 31%. Non-epithelial MPM (8 vs. 19 months, P-0.01) and N2 disease (10 vs. 19 months) led to shorter survival than epithelial MPM and N0yN1 disease, respectively. Flores et al. w4x reported a median survival of 12 months in patients who underwent EPP with an operative mortality rate of 7%. Respiratory problems complicated 10% of patients. In contrast, Nakas et al. w5x observed 208 patients who underwent EPP and reported high 30-day mortality rates of 23% with a mean hospital stay of 36.6 days. Yan et al. w6x evaluated outcomes of 70 patients undergoing EPP. Median survival was 20 months with high perioperative mortality and complication rates of 5.7% and 37%, respectively. In 2008, Van Sandick et al. w7x reviewed 15 patients who underwent EPP and postoperative hemithoracic radiation. Median survival was 29 months and no mortalities were observed at 30-day postoperative. However, the postoperative complication rate was 53% and disease recurred in a large majority (73%) of patients. Schipper et al. w8x surgically managed patients with either EPP (ns73) or exploration without resection (ns22). Median survival (16 vs. 6.8 months), major complications (50.7% vs. 9.1%; P-0.0001) and hospital stay (9 vs. 6 days) were greater with EPP than exploration without resection. Operative mortality rates (8.2% vs. 9.1%) were similar between the treatment options. Aigner et al. w9x reviewed their experience of 49 patients who underwent EPP. Median survival was 12.5 months and intensive care unit (ICU) and hospital stay were one and 13 days, respectively. Perioperative complications included atrial fibrilla-

tion (ns10) and temporary paraplegia (ns2). Higher survival rates were observed in patients with epithelial MPM (Ps0.01) compared to biphasic and sarcomatous MPM. Okada et al. w10x found median survival of 13 months in 31 patients who underwent EPP. Operative mortality rate was 3.2% and major complications occurred in 48% of patients. Pivotally, Treasure et al. w11x are currently conducting the mesothelioma and radical surgery (MARS) trial, which is the first multicentre randomised control trial, to determine whether EPP is superior to best continued care. Initial results of the trial wTreasure T, MARS trialists as listed. Principal results of the feasibility phase of the mesothelioma and radical surgery trial (MARS-feasibility) 2010 Available from http:yywww.ncri.org.ukyncriconferencey2010 abstractsyabstractsyLB74.htmx 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%), higher perioperative mortality (12.5% vs. 3.8%) and a hazard ratio of 2.75 w95% confidence interval (CI): 1.21–6.26, Ps0.02x in favour of no EPP. These results clearly highlight that the high morbidity associated with radical surgery may be detrimental to patients with MPM. Two studies highlighted the outcomes of chemotherapy used in the palliation of patients with MPM. Pinto et al. w12x conducted a multicentre study comparing the effectiveness of cisplatinygemcitabine (CG) and mitoxantroney methotrexateymitomycin (MMM) to treat unresectable MPM. Median survival was 13 months. Dyspnoea and pain improvement occurred in 52.9% and 48.3% of patients, respectively. Sørensen et al. w13x treated 54 patients with inoperable MPM with cisplatin and vinorelbine. Median survival was 16.8 months with complete and partial responses achieved in 4% and 26% of patients, respectively. Two studies evaluated palliative treatment in the management of MPM. In 2001, Martin-Ucar et al. w14x evaluated treatment outcomes in 51 patients undergoing palliative surgical debulking. Median survival was seven months. Symptoms improved in 78.4% of patients at three months but fell to 25.5% at one year posttreatment. Median hospital stay was seven days with a 30-day mortality rate of 7.8%. In contrast, Shahin et al. w15x recently showed that lung-sparing radical decortication produces higher median survival rates compared to palliative surgery.


w7 x

w8 x

w10x

References w12x

w15x

Negative Results

w16x

Proposal for Bailout Procedure

w14x

ESCVS Article

w13x

Institutional Report Follow-up Paper

w1x Dunning J, Prendergast B, Mackway-Jones K. Towards evidence-based medicine in cardiothoracic surgery: best BETS. Interact CardioVasc Thorac Surg 2003;2:405–409. w2x Aziz T, Jilaihawi A, Prakash D. The management of malignant pleural mesothelioma; single centre experience in 10 years. Eur J Cardiothorac Surg 2002;22:298–305. w3x Ambrogi V, Mineo D, Gatti A, Pompeo E, Mineo TC. Symptomatic and quality of life changes after extrapleural pneumonectomy for malignant pleural mesothelioma. J Surg Oncol 2009;100:199–204. 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;135:620–6, 626.e1–3. w5x 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;34:886–891. w6x Yan TD, Boyer M, Tin MM, Wong D, Kennedy C, McLean J, Bannon PG, McCaughan BC. Extrapleural pneumonectomy for malignant pleural

Protocol

w11x

Work in Progress Report

w9 x

New Ideas

EPP is a highly morbid operation with high perioperative mortality and recurrence rate. Although a number of retrospective studies have shown a small benefit in survival with EPP, there is consensual agreement that even in subgroups with the best prognostic indicators (epithelial histology and N0yN1 disease), EPP still results in high complication rates with minimal symptomatic improvement. Great weight should be given to the initial findings of the MARS trial, which has clearly demonstrated the detrimental effects of conducting radical EPP surgery compared to conservative management.

mesothelioma: outcomes of treatment and prognostic factors. J Thorac Cardiovasc Surg 2009;138:619–624. Van Sandick JW, Kappers I, Baas P, Haas RL, Klomp HM. Surgical treatment in the management of malignant pleural mesothelioma: a single institution’s experience. Ann Surg Oncol 2008;15:1757–1764. 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;85:257–264; discussion 264. Aigner C, Hoda MA, Lang G, Taghavi S, Marta G, Klepetko W. Outcome after extrapleural pneumonectomy for malignant pleural mesothelioma. Eur J Cardiothorac Surg 2008;34:204–207. 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;7:102–106. Treasure 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, Peto J. The mesothelioma and radical surgery randomised controlled trial. The Mars Feasibility Study. J Thorac Oncol 2009;4:1254–1258. Pinto C, Marino A, De Pangher Manzini V, Benedetti G, Galetta D, Mazzanti P, Del Conte G, dell’Amore D, Piana E, Giaquinta S, Lopez M, Martoni A. Sequential chemotherapy with cisplatinygemcitabine (CG) followed by mitoxantroneymethotrexateymitomycin (MMM) in patients with malignant pleural mesothelioma. A multicenter Italian Phase II Study (SITMP1). Lung Cancer 2006;52:199–206. Sørensen JB, Frank H, Palshof T. Cisplatin and vinorelbine first-line chemotherapy in non-resectable malignant pleural mesothelioma. Br J Cancer 2008;99:44–50. 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;20:1117– 1121. Shahin Y, Wellham J, Jappie R, Pointon K, Majewski A, Black E. How successful is lung-preserving radical surgery in the mesothelioma and radical surgery-trial environment? A case-controlled analysis. Eur J Cardiothorac Surg 2011;39:360–363. Stahel RA, Weder W. Improving the outcome in malignant pleural mesothelioma: non-aggressive or aggressive approach? Curr Opin Oncol 2009;21:124–130.

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