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Eur J Cardiothorac Surg 2007;31:779-782. doi:10.1016/j.ejcts.2007.01.036
Copyright © 2007, European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved

The risk of pneumonectomy over the age of 70.

A case–control study

Francesco Leoa,*, Paolo Scanagattaa, Pierangelo Baglioa, Davide Radiceb, Giulia Veronesia, Piergiorgio Sollia, Francesco Petrellaa, Lorenzo Spaggiaria,c

a Thoracic Surgery Department, European Institute of Oncology, Milan, Italy
b Epidemiology and Biostatistics Department, European Institute of Oncology, Milan, Italy
c University of Milan School of Medicine, Milan, Italy

Received 13 September 2006; received in revised form 27 December 2006; accepted 15 January 2007.

* Corresponding author. Address: Thoracic Surgery Department, European Institute of Oncology, Via Ripamonti 435 20141 Milan, Italy. Tel.: +39 02 57489665; fax: +39 02 57489698. (Email: francesco.leo{at}ieo.it).


   Abstract
Top
 Abstract
1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 Appendix A
 References
 
Objective: A higher mortality has been reported after pneumonectomy over the age of 70. The aim of the study was to quantify the additional risk due to age after standard pneumonectomy for lung cancer by a case–control study. Methods: Our clinical database was reviewed to search for patients aged 70 years or more who underwent standard pneumonectomy for lung cancer between 1998 and 2005. A control group of patients younger than 70 (one case/two controls) was matched for sex, cardiovascular disease, American Association of Anaesthetists score, respiratory function, side of pneumonectomy, induction chemotherapy and stage. Overall mortality and morbidity were compared. Long-term survival data were also analysed. Results: During the considered period, 35 patients aged 70 years or more underwent pneumonectomy (30 males, median age 73 years, 15 right-sided procedures). The control group was composed of 70 patients. The two groups were homogeneous in the variables used for matching. Overall mortality and morbidity were 11.4 and 54.2% in the elderly group as compared to 4.3 and 41.6% in controls (p-value not significant). Elderly patients experienced a higher rate of respiratory complications (25.7%) as compared to controls (8.3%, p = 0.01). At univariate analysis, the only risk factor for death was the occurrence of respiratory complications (OR 6.5, CI 1.8–18.2). At multivariate analysis, age ≥70 years (OR 5.36, CI 1.48–19.3) and preoperative chemotherapy (OR 7.65, CI 2.04–28.6) were confirmed as predictors of respiratory complications. Five-year survival was 17.5% in the elderly group and 53.6% in the control group (p = 0.003). Elderly patients with a better respiratory function (FEV1 > 70%) had a 5-year survival of 45.4%. Conclusions: In the elderly patients, the risk of respiratory complications after pneumonectomy is increased as compared to younger patients with equivalent respiratory function. Age and preoperative chemotherapy are independent risk factors for respiratory complications. A lower mortality and a better long-term survival are obtained in elderly patients with a better respiratory function (FEV1 ≥ 70%).

Key Words: Pneumonectomy • Elderly • Lung cancer


   1. Introduction
Top
 Abstract
 1. Introduction
2. Material and methods
 3. Results
 4. Discussion
 Appendix A
 References
 
Lung cancer remains a fatal disease even in the subset of elderly patients, for which surgery represents the most effective treatment [1]. Life expectancy in untreated lung cancer patients or patients receiving only palliative care is in the order of 1.5 years [2], while people of 80 years have a life expectancy of 5–9 years in 50% of the cases [3].

Given the increased risk of postoperative morbidity in the elderly [4], all technical efforts are made in order to avoid pneumonectomy by the use of parenchyma sparing procedures as bronchoplasty. Nevertheless, there is a proportion of older patients that require pneumonectomy for the cure of cancer. The risk of pneumonectomy over the age of 70 is still a matter of debate. The Lung Cancer Study Group reported a postoperative mortality rate over the age of 70 after pneumonectomy lower (5.9%) than after lobectomy (7.3%), probably due to strict preoperative selection [4]. More recently, several authors have reported postoperative mortality after pneumonectomy over the age of 70 as being well above 10% [5,6], probably due to the use of less restrictive indications. The main limitation of these reports is that a selected elderly population is usually compared to an unselected population of younger patients, making the assessment of the additional risk, purely due to chronological age, unreliable. The purpose of this study was to overcome this problem by a case–control study.


   2. Material and methods
Top
 Abstract
 1. Introduction
 2. Material and methods
3. Results
 4. Discussion
 Appendix A
 References
 
2.1 Population
The database of the Thoracic Surgery Department of the European Institute of Oncology was reviewed to identify all patients who underwent standard pneumonectomy (defined as intrapericardial or extrapericardial removal of the entire lung, associated with radical mediastinal lymph node dissection without any resection of mediastinal, chest wall or diaphragmatic structure) for lung cancer between January 1998 and August 2005.

The study population was composed of all patients who underwent pneumonectomy at the age of 70 or more (group A) during the considered period.

For each case of group A, two controls were matched for sex, cardiovascular disease, American Association of Anaesthetists (ASA) score [7], respiratory function (FEV1%), induction chemotherapy (three or four courses of cisplatinum 80 mg/m2 days 1 and 21 and gemcitabine 1250 mg/m2 days 1, 8 and 21), side of pneumonectomy and pathological stage. These patients comprised the control group (group B).

2.2 Patient management
Preoperative respiratory function assessment was performed routinely by blood gas analysis, spirometry and lung perfusion scan. A predicted postoperative FEV1 less than 30% was considered a contraindication for pneumonectomy, independently of age. In elderly patients, the presence of ischaemic heart disease was considered an absolute contraindication to pneumonectomy over the age of 75. In all the other cases, surgical indication was discussed during the weekly multidisciplinary meeting.

Intraoperative management was focused on maximally reducing risk of damage to the controlateral lung; fluid administration was in the order of 5–7 ml/kg/h cristalloids infusion, not exceeding a total amount of 1500 cc in all cases. Ventilation was managed using a protective-ventilation strategy (a tidal volume ≤6 ml/kg, driving pressure <20 cm H2O above the PEEP value, permissive hypercapnia, and the preferential use of pressure-limited ventilatory modes) [8]. Postoperatively, patients had two assisted sessions of chest physiotherapy daily starting on the first postoperative day and were asked to repeat physiotherapy program six times during the day until discharge. Amoxicillin-clavulanic acid was administered for the first five postoperative days in non-allergic patients.

2.3 Postoperative complications
Postoperative death was defined as any death occurring during postoperative hospital stay or during the first month after surgery; 90-day death was defined as any death occurring within 3 months from the day of pneumonectomy.

Complications were classed as respiratory (acute respiratory failure, ARDS and ALI — as defined by the American European Consensus Conference on ARDS in 1994 [9] — pneumonia, atelectasis requiring bronchoscopy, pulmonary embolism, pulmonary edema, chronic respiratory failure), cardiac (cardiac rhythm problems, angina, myocardial infarction, cardiogenic shock), surgical (haemothorax, bronchial fistula, empyema, chylothorax, cardiac dislocation) and others.

2.4 Statistical analysis
Group A and group B were compared for all relevant variables, including demographics and all possible risk factors for postoperative complications, using Student's t-test (paired values) for continuous variables and the Fisher's Exact Test for categorical variables.

Postoperative mortality and postoperative complications were considered as the outcome in a logistic regression model, using the following covariates (risk factors): age (<70 years vs ≥70 years), sex, preoperative FEV1%, induction chemotherapy, operating time, side of pneumonectomy. Odds ratio and the corresponding 95% CIs were reported for covariates that were considered clinically relevant or statistically significant at the 0.05 significance level (Wald chi-square test).

Survival curves were obtained via the Kaplan–Meier method and were compared between groups by the log-rank test.


   3. Results
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
4. Discussion
 Appendix A
 References
 
There were 35 patients in the elderly group and 70 patients in the control group, and they were homogeneous for all the matching variables (Table 1 ).


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  		Table 1 The two groups were homogeneous in terms of matching variables
 
Thirty-day postoperative mortality was 11.4% (4/35) in the elderly group and 4.3% (3/70) in the control group (p 0.17). Ninety days after surgery, one additional death was recorded in both groups (p 0.13).

Compared to the control group, elderly patients experienced an increased incidence of cardiac (28.5% vs 11.4%, p 0.03) and respiratory complications (25.7% vs 8.3%, p 0.01). No other significant difference was recorded between groups in term of overall morbidity, surgical and other complications (Table 2 ). In the elderly, a reduced preoperative respiratory function (<70%) translated into higher respiratory morbidity (43.7% vs 11.5%) and mortality (12.5% as compared to 3.8%).


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  		Table 2 In terms of postoperative morbidity and mortality, elderly patients had an increased rate of cardiac and respiratory complications as compared to controls, despite being matched for preoperative cardiac comorbidity and respiratory status
 
Postoperative mortality did not increase with age until the age of 80, remaining in the order of 10%. Over the age of 80, the risk increased. Out of the three patients who underwent pneumonectomy over the age of 80, one died due to respiratory failure. Between the age of 70 and 79, morbidity increased with age, with an evident higher risk of cardiac complications over the age of 75 without an evident effect of postoperative mortality.

Univariate analysis showed that the occurrence of pulmonary complication was the only predictor of postoperative death (OR 6.5, CI 1.8–18.2, p 0.02).

In the elderly group, patients who developed respiratory complications had lower Dlco (p 0.05), longer operating time (p 0.04) and received preoperative chemotherapy more often (p 0.02; Table 3 ). In the control group, respiratory complications occurred in patients with a lower FEV1% (p 0.04) and were more frequent after induction treatment (p 0.01). Logistic regression confirmed the roles of age ≥70 years (OR 5.36, CI 1.48–19.3, p 0.01) and preoperative chemotherapy (OR 7.65, CI 2.04–28.6, p 0.002) as independent risk factors for respiratory complications.


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  		Table 3 The univariate analysis of respiratory complications in elderly and controls
 
Survival information was obtained for the entire population of the study. With a median follow-up time of 554 days, overall 5-year survival was 17.5% in elderly patients and 53.6% in group B (p 0.003) (Fig. 1 ). In the elderly group, 9 of the 24 deaths recorded (37.5%) were unrelated to cancer, compared to 5 out of the 36 death recorded in the younger group. The only factor affecting long-term survival in the elderly was preoperative respiratory function. Patients with a preoperative FEV1 ≥ 70% had a 5-year survival of 45.4%, meanwhile none of the patients having a FEV1 < 70% was alive 3 years after surgery (log-rank 0.04) (Fig. 2 ).


Figure 1
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  		Fig. 1. Overall actuarial survival in the elderly group (17.5%) and in the control group (53.6%, log-rank 0.003).

 

Figure 2
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  		Fig. 2. Five-year survival of elderly patients with a preoperative FEV1 ≥ 70% was significantly better (45.4%) compared to patients with a preoperative FEV1 < 70% (0, p 0.04).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
Appendix A
 References
 
Restriction of potentially curative surgery on the basis of age alone is no longer an appropriate option [10]. On the other hand, elderly patients are more likely to develop toxicity from treatment [11]. In the last 20 years, several studies have shown that the surgical treatment of lung cancer is feasible and safe in selected cases, except in the case when the removal of the whole lung is required. In fact, mortality after pneumonectomy is equivalent to mortality in younger patients only when very selective criteria of selection are adopted [4]. When less restrictive criteria are used, mortality dramatically increases well above 10% [5,6,12,13].

During this study, we adopted the same selection criteria for older and younger patients. By this approach, postoperative mortality was 11%. Surprisingly, the case–control design of the study showed that age per se increases mortality by the increase in respiratory complications, even when compared to controls with the same respiratory function. The consequence is that 30% as the cut-off value of postoperative predicted FEV1% is probably too low, and it should be increased in order to reduce postoperative risk. Additionally, the selection of higher cut-off values in the elderly may improve long-term results, given the fact that functional parameters are predictors of life expectancy in COPD patients [14].

Elderly and younger patients did not share all risk factors for respiratory complications. Apart from preoperative chemotherapy, which was already reported as increasing respiratory morbidity in our hospital [15], Dlco and duration of surgery resulted as being additional risk factors in the univariate analysis. Multivariate analysis did not confirm their role, probably due to the link between them. In fact, patients receiving preoperative chemotherapy usually have an impaired Dlco [16] and often require more lengthy surgery. Nevertheless, it is possible that Dlco can express additional information on the ageing status of the alveolo-capillary membrane, and Dlco should be routinely inserted in the preoperative respiratory function assessment.

In conclusion, pneumonectomy in the elderly is a feasible option of cure with increased risk of respiratory complications as compared to younger patients with equivalent respiratory function. Therefore, redefining selective respiratory criteria specifically for elderly patients could improve surgical results. This process may also improve overall long-term results, which are, at present, disappointing (17.5% at 5 year), but consistently higher than those obtained by chemo-radiotherapy with curative intent [17]. In fact, patients with a preoperative FEV1 ≥ 70% had a postoperative mortality (5.2%) and a long-term survival (45.4% at 5 year) which are comparable to those of younger patients. Moreover, a better functional selection would probably reduce late deaths occurring for causes unrelated to cancer, which was represented in the elderly as 37.5% of all recorded deaths. Given the fact that the main risk factor in this cohort is represented by the occurrence of respiratory complications, the redefinition of the functional cut-off values of operability for elderly patients could provide an optimal solution for increasing the safety of pneumonectomy for this highly vulnerable age group.


   Appendix A
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 Appendix A
References
 
Conference discussion

Dr A. Turna (Istanbul, Turkey): Did you make any adjustment according to the age in your survival data? The expected age of the patients with an age more than 70 years is lower than the other control patients. In other words, did you categorize the causes of death of the patients in the elderly group?

Dr Leo: As I showed you, the risk of death from causes unrelated to cancer is three times higher in the elderly. We did not adjust for the age because it was a case–control study, so we didn’t need to do it, but it was shown in the slides showing survival.

Dr Turna: So all the deaths are cancer-specific deaths?

Dr Leo: We have analysed both cancer and cancer-related deaths, and the differences are in the deaths unrelated to cancer, which were three times higher in the elderly group.


   Footnotes
 
\#9734; Presented at the joint 20th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 14th Annual Meeting of the European Society of Thoracic Surgeons, Stockholm, Sweden, September 10–13, 2006.


   References
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 Appendix A
 References
 

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  5. Mizushima Y, Noto H, Sugiyama S, Kusajima Y, Yamashita R, Kashii T, Kobayashi M. Survival and prognosis after pneumonectomy for lung cancer in the elderly. Ann Thorac Surg 1997;64:193-198.[Abstract/Free Full Text]
  6. Dyszkiewicz W, Pawlak K, Gasiorowski L. Early post-pneumonectomy complications in the elderly. Eur J Cardiothorac Surg 2000;17:246-250.[Abstract/Free Full Text]
  7. Owens W, Felts J, Spitznagel E. ASA physical status classifications: a study of consistency of ratings. Anesthesiology 1978;49:239-243.[Medline]
  8. Amato MB, Barbas CS, Medeiros DM, Magaldi RB, Schettino GP, Lorenzi-Filho G, Kairalla RA, Deheinzelin D, Munoz C, Oliveira R, Takagaki TY, Carvalho CR. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998;5:338347–354.
  9. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, LeGall JR, Morris A, Spragg R. The American European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994;149:818-824.[Abstract]
  10. Jaklitsch MT, Mery CM, Audisio RA. The use of surgery to treat lung cancer in elderly patients. Lancet Oncol 2003;4:463-471.[CrossRef][Medline]
  11. Cerfolio RJ, Bryant AS. Survival and outcomes of pulmonary resection for non-small cell lung cancer in the elderly: a nested case–control study. Ann Thorac Surg 2006;82:424-430.[Abstract/Free Full Text]
  12. Pagni S, McKelvey A, Riordan C, Federico JA, Ponn RB. Pulmonary resection for malignancy in the elderly: is age still a risk factor?. Eur J Cardiothor Surg 1998;14:40-45.[CrossRef][Medline]
  13. Licker M, Spiliopoulos A, Frey JG, Robert J, Hohn L, de Perrot M, Tschopp JM. Risk factors for early mortality and major complications following pneumonectomy for non-small cell carcinoma of the lung. Chest 2002;121:1890-1897.[CrossRef][Medline]
  14. Mannino DM, Reichert MM, Davis KJ. Lung function decline and outcomes in an adult population. Am J Respir Crit Care Med 2006;173:985-990.[Abstract/Free Full Text]
  15. Leo F, Solli P, Veronesi G, Radice D, Floridi A, Gasparri R, Petrella F, Borri A, Galetta D, Spaggiari L. Does chemotherapy increase the risk of respiratory complications after pneumonectomy?. J Thorac Cardiovasc Surg 2006;132:519-523.[Abstract/Free Full Text]
  16. Leo F, Solli P, Spaggiari L, Veronesi G, de Braud F, Leon ME, Pastorino U. Respiratory function changes after chemotherapy: an additional risk for postoperative respiratory complications?. Ann Thorac Surg 2004;77:260-265.[Abstract/Free Full Text]
  17. Okamoto T, Maruyama R, Shoji F, Ikeda J, Miyamoto T, Nakamura T, Asoh H, Ichinose Y. Clinical patterns and treatment outcome of elderly patients in clinical stage IB/II non-small cell lung cancer. J Surg Oncol 2004;87(3):134-138.[CrossRef][Medline]



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