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Eur J Cardiothorac Surg 2005;28:759-762
© 2005 Elsevier Science NL

Charlson comorbidity index as a predictor of long-term outcome after surgery for nonsmall cell lung cancer{star}

Özcan Birim, A. Pieter Kappetein * , Ad J.J.C. Bogers

Department of Cardio-Thoracic Surgery, Erasmus MC Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands

Received 23 March 2005; received in revised form 14 June 2005; accepted 29 June 2005.

* Corresponding author. Tel.: +31 10 4635412; fax: +31 10 4633993. (Email: a.kappetein{at}erasmusmc.nl).


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
Objective: To evaluate the impact of the Charlson comorbidity index on long-term survival in nonsmall cell lung cancer surgery and determine whether this index is a better predictor of long-term survival than individual comorbid conditions. Methods: From January 1989 to December 2001, 433 (340 men, 93 women) consecutive curative resections for nonsmall cell lung cancer were performed. Each patient was preoperatively assessed according to the Charlson comorbidity index. Survival curves were estimated by the Kaplan–Meier method. Risk factors for overall and disease free survival were determined by univariate and multivariate Cox regression analysis. Results: The patients ranged in age from 37 to 82 years, with a mean age of 65 years. Hospital mortality was 3.7%. Five-year overall and disease free survival was 45 and 43%, respectively. Among patients with Charlson comorbidity grade 0, 5-year overall survival was 52%, among patients with Charlson comorbidity grade 1–2 it was 48%, and among patients with Charlson comorbidity grade ≥3 it was 28%. Univariate analysis showed that male gender, age, congestive heart failure, chronic pulmonary disease, Charlson comorbidity index, clinical stage, pathological stage, and type of resection were significantly associated with an impaired survival. Multivariate analysis showed that age (relative risk, 1.02; 95% confidence interval, 1.01–1.03), Charlson comorbidity grade 1–2 (relative risk, 1.4; 95% confidence interval, 1.0–1.8), Charlson comorbidity grade ≥3 (relative risk, 2.2; 95% confidence interval, 1.5–3.1), bilobectomy (relative risk, 1.7; 95% confidence interval, 1.2–2.5), pneumonectomy (relative risk, 1.5; 95% confidence interval, 1.1–2.0), pathological stage IB (relative risk, 1.5; 95% confidence interval, 1.1–2.2), IIB (relative risk, 1.9; 95% confidence interval, 1.2–3.0), IIIA (relative risk, 1.9; 95% confidence interval, 1.1–3.1), IIIB (relative risk, 2.8; 95% confidence interval, 1.2–6.8), and IV (relative risk, 12.4; 95% confidence interval, 3.2–48.2), were associated with an impaired survival. Conclusions: The Charlson comorbidity index is a better predictor of survival than individual comorbid conditions in nonsmall cell lung cancer surgery. We recommend the use of a validated comorbidity index in the selection of patients for NSCLC surgery.

Key Words: Charlson comorbidity index • Comorbidity • Lung cancer • Surgery • Survival


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 References
 
Although pulmonary resection is recognized as the treatment of choice for early-stage nonsmall cell lung cancer (NSCLC), actuarial 5-year survival following curative resection is disappointing, ranging from 67 to 38% in pathological stages IA–IIB [1]. Survival is not only dependent on pathological stage but also on other factors, such as comorbidity. The presence of comorbidity has been evaluated repeatedly as an important prognostic factor for survival in patients with NSCLC [2–4]. As the mean age in patients with NSCLC increases due to the increased life expectancy, the proportion of patients with serious comorbidity who are considered for surgical resection also increases [5,6]. For major postoperative complications the Charlson comorbidity index (CCI) proved to be a prognostic marker as was previously validated by us in patients operated on for primary NSCLC [7]. However, this comorbidity index has not been validated yet for prognostic impact on long-term survival in NSCLC surgery.

Therefore, the objective of this retrospective study was to evaluate the impact of the CCI on long-term survival in NSCLC surgery and determine whether this index is a better predictor of long-term survival than individual comorbid conditions.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 References
 
The medical records of 433 consecutive patients who underwent curative resection for primary NSCLC at the Department of Cardio-Thoracic Surgery of the Erasmus MC Rotterdam between January 1, 1989, and December 31, 2001 were reviewed. Patients were followed with regular visits to the outpatient clinic. Civil administrations were consulted to assess late mortality. Follow-up was completed in all patients through August 2004. Median follow-up time was 4.3 years (range, 0.0–14.9 years). Overall survival time was defined as the difference between the date of surgery and the date of last follow-up. Disease free survival time was defined as the difference between the date of surgery and the date of local or distant recurrence of disease or the date of last follow-up in case of no recurrence. Hospital mortality was defined as death occurring within 30 days of surgery or any death later during the same postoperative hospital stay.

In all patients preoperative diagnostic workup included a complete medical history, physical examination, plain chest radiography, electrocardiography, routine laboratory tests, lung function tests and computed tomography of the chest and upper abdomen. Additional staging procedures, i.e. mediastinoscopy, liver, bone and brain scans were selectively performed to aid in treatment planning according to best clinical practice at the time of presentation. Each patient was assessed preoperatively according to the CCI, and was categorized in one of the four comorbidity grades: 0, 1–2, 3–4 and 5 or more [7,8].

Histological typing occurred according to The World Health Organization Histological Typing of Lung Tumours [9]. Clinical and pathologic staging of the patients occurred according to the international TNM classification for lung cancer [1].

The following risk factors for overall and disease free survival were evaluated: sex, age, smoking, type of resection, histological cell type, forced expiratory volume in 1 s (FEV1; unknown in 21 patients), clinical stage, pathological stage, and the CCI as well as the most common comorbidities of the CCI.

2.1 Statistical analysis
Discrete variables are displayed as proportions, continuous variables as means ± standard deviations unless specified otherwise. The {chi} 2 or Fisher exact test was used to analyze the categorical data. Continuous variables were analyzed using the unpaired Student t-test. Survival curves were estimated by the Kaplan–Meier method. Univariate and multivariate Cox proportional hazard analysis within different time intervals determined risk factors for survival. The Cox proportional multivariate analyses were performed with a stepwise forward regression model in which each variable with a p-value of less than 0.20 in the univariate analysis was entered in the model. Relative risks are reported with 95% confidence intervals. All data analysis was performed with SPSS for Windows (release 12.0; SPSS Inc., Chicago, IL).


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 References
 
Of the 433 patients included in this analysis, 340 (79%) were men and 93 (21%) women. The mean age at time of diagnosis was 65 ± 9 years (range, 37–82 years). The patient's preoperative characteristics are outlined in Table 1 . The CCI and the comorbid conditions are presented in Table 2 . The types of procedures performed consisted of a wedge resection in 14 (3%) patients, a lobectomy in 244 (56%) patients, a bilobectomy in 45 (10%) patients, and a pneumonectomy in 130 (30%) patients. Tumours were classified histologically as squamous cell carcinoma (215; 50%), adenocarcinoma (143; 33%), large cell carcinoma (55; 13%), and bronchoalveolar cell carcinoma (20; 5%). The patient's operative demographics are listed in Table 3 . Surgical-pathologic upstaging was observed in 31% (133/433) of the patients.


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  		Table 1. Patient characteristics
 

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  		Table 2. Charlson comorbidity index and prevalence of comorbid conditions
 

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  		Table 3. Operative characteristics
 
Hospital mortality was 3.7% (16/433). Operations in these patients were wedge resection (1), lobectomy (4), bilobectomy (3), and pneumonectomy (8). Hospital mortality rate was significantly (p = 0.03) higher after pneumonectomy compared with lesser resections. One, 2 and 5-year overall survival was 81% (95% confidence interval 77–85), 66% (95% confidence interval 62–71), and 45% (95% confidence interval 40–50), respectively. One, 2, and 5-year disease free survival was 74% (95% confidence interval 70–78), 61% (95% confidence interval 56–65), and 43% (95% confidence interval 38–48), respectively. Among patients with Charlson comorbidity grade 0, 5-year overall survival was 52% (95% confidence interval 43–61), among patients with Charlson comorbidity grade 1–2 it was 48% (95% confidence interval 39–57), and among patients with Charlson comorbidity grade ≥3 it was 28% (95% confidence interval 18–38) (Fig. 1 ). When evaluating risk factors for overall survival with the Cox proportional hazards analysis, in univariate analysis male gender, age, congestive heart failure, chronic pulmonary disease, CCI, clinical stage, pathological stage, and type of resection were significantly associated with an impaired survival (Table 4 ). In multivariate analysis, age (relative risk, 1.02; 95% confidence interval, 1.01–1.03), Charlson comorbidity grade 1–2 (relative risk, 1.4; 95% confidence interval, 1.0–1.8), Charlson comorbidity grade ≥3 (relative risk, 2.2; 95% confidence interval, 1.5–3.1), bilobectomy (relative risk, 1.7; 95% confidence interval, 1.2–2.5), pneumonectomy (relative risk, 1.5; 95% confidence interval, 1.1–2.0), pathological stage IB (relative risk, 1.5; 95% confidence interval, 1.1–2.2), IIB (relative risk, 1.9; 95% confidence interval, 1.2–3.0), IIIA (relative risk, 1.9; 95% confidence interval, 1.1–3.1), IIIB (relative risk, 2.8; 95% confidence interval, 1.2–6.8), and IV (relative risk, 12.4; 95% confidence interval, 3.2–48.2), were associated with an impaired overall survival (Table 4). For disease free survival the same risk factors were identified in the multivariate analysis.


Figure 1
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  		Fig. 1. Overall survival curves after curative resection for nonsmall cell lung cancer according to the Charlson comorbidity index (CCI).

 

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  		Table 4. Univariate and multivariate Cox proportional hazard analysis of overall survival
 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
References
 
Not unexpectedly, pathological stage proved to be an important determinant of long-term survival in this study. Surgical-pathological upstaging was seen in 31% of the patients. Obviously, clinical staging with current imaging techniques has its shortcomings indicating the need for further improvement of preoperative staging techniques. Besides tumor stage, in patients with NSCLC comorbid conditions also play a significant role in clinical practice treatment decisions and patients whose outcomes are judged unfavourable because of serious comorbidity are usually selected for non-surgical management. Many reports in the literature have shown the prognostic impact of comorbidity on survival in NSCLC surgery [2,4,10,11]. Summarizing a multidimensional phenomenon such as comorbidity is not an easy matter, and currently no standard method exists for assessing comorbidities collectively in NSCLC surgery patients. In this study the CCI was used to assess comorbidity. This comorbidity index has been used in several clinical studies [12–14] and has previously been validated by us for prediction of major postoperative complications after NSCLC surgery [7]. In this analysis comorbidity severity had a significant negative impact on long-term survival when comorbidity was assessed according to the CCI. After controlling for age, gender, type of resection, clinical stage, pathological stage, and individual comorbid conditions in a multivariate analysis, the relative risk of impaired survival as a function of the CCI was 1.4 times higher among patients with Charlson comorbidity grade 1–2, and 2.2 times higher among patients with Charlson comorbidity grade ≥3 compared with patients with no comorbidity. This indicates that the CCI is a better predictor of survival than individual comorbid conditions and validates the ability of the CCI to stratify comorbidity severity in NSCLC surgery patients.

The management of patients with NSCLC remains a significant challenge. Comorbidity is common in NSCLC patients and has a major impact on their survival, independent of other factors. Our study shows the importance of the CCI as an independent prognostic factor for impaired survival. This comorbidity index is a better predictor of long-term survival than individual comorbid conditions. We recommend the use of a validated comorbidity index in the selection of patients for NSCLC surgery.


   Footnotes
 
{star} Presented at the joint 19th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 13th Annual Meeting of the European Society of Thoracic Surgeons, Barcelona, Spain, September 25–28, 2005. Back


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 

  1. Mountain CF. Revisions in the international system for staging lung cancer. Chest 1997;111:1710-1717.[Abstract/Free Full Text]
  2. Ambrogi V, Pompeo E, Elia S, Pistolese GR, Mineo TC. The impact of cardiovascular comorbidity on the outcome of surgery for stage I and II non-small-cell lung cancer. Eur J Cardiothorac Surg 2003;23:811-817.[Abstract/Free Full Text]
  3. Firat S, Bousamra M, Gore E, Byhardt RW. Comorbidity and KPS are independent prognostic factors in stage I non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2002;52:1047-1057.[CrossRef][Medline]
  4. Battafarano RJ, Piccirillo JF, Meyers BF, Hsu HS, Guthrie TJ, Cooper JD, Patterson GA. Impact of comorbidity on survival after surgical resection in patients with stage I non-small cell lung cancer. J Thorac Cardiovasc Surg 2002;123:280-287.[Abstract/Free Full Text]
  5. Janssen-Heijnen ML, Smulders S, Lemmens VE, Smeenk FW, van Geffen HJ, Coebergh JW. Effect of comorbidity on the treatment and prognosis of elderly patients with non-small cell lung cancer. Thorax 2004;59:602-607.[Abstract/Free Full Text]
  6. Janssen-Heijnen ML, Schipper RM, Razenberg PP, Crommelin MA, Coebergh JW. Prevalence of co-morbidity in lung cancer patients and its relationship with treatment: a population-based study. Lung Cancer 1998;21:105-113.[CrossRef][Medline]
  7. Birim O, Maat AP, Kappetein AP, van Meerbeeck JP, Damhuis RA, Bogers AJ. Validation of the charlson comorbidity index in patients with operated primary non-small cell lung cancer. Eur J Cardiothorac Surg 2003;23:30-34.[Abstract/Free Full Text]
  8. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373-383.[CrossRef][Medline]
  9. The world health organization histological typing of lung tumours. second ed. Am J Clin Pathol 1982;77:123-136.[Medline]
  10. Lopez-Encuentra A, Astudillo J, Cerezal J, Gonzalez-Aragoneses F, Novoa N, Sanchez-Palencia A. Prognostic value of chronic obstructive pulmonary disease in 2994 cases of lung cancer. Eur J Cardiothorac Surg 2005;27:8-13.[Abstract/Free Full Text]
  11. Lopez-Encuentra A. Comorbidity in operable lung cancer: a multicenter descriptive study on 2992 patients. Lung Cancer 2002;35:263-269.[CrossRef][Medline]
  12. Beddhu S, Bruns FJ, Saul M, Seddon P, Zeidel ML. A simple comorbidity scale predicts clinical outcomes and costs in dialysis patients. Am J Med 2000;108:609-613.[CrossRef][Medline]
  13. Fried L, Bernardini J, Piraino B. Charlson comorbidity index as a predictor of outcomes in incident peritoneal dialysis patients. Am J Kidney Dis 2001;37:337-342.[Medline]
  14. Singh B, Bhaya M, Stern J, Roland JT, Zimbler M, Rosenfeld RM, Har-El G, Lucente FE. Validation of the Charlson comorbidity index in patients with head and neck cancer: a multi-institutional study. Laryngoscope 1997;107:1469-1475.[CrossRef][Medline]



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