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Eur J Cardiothorac Surg 2005;27:8-13
© 2005 Elsevier Science NL
Pneumology Service, Hospital Universitario 12 de Octubre, Crrta. Andalucia 5.4, 28041 Madrid, Spain
Received 16 June 2004; received in revised form 30 August 2004; accepted 6 September 2004.
* Corresponding author. Tel./fax: +34 91 390 8492. (E-mail: lencuent{at}h12o.es).
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Abstract |
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 Top Abstract 1. Introduction2. Material and methods3. Results4. DiscussionAppendix A. Bronchogenic...References |
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Key Words: Lung cancer • Chronic obstructive pulmonary disease • Prognosis • Conditional survival analysis • Comorbidity • Surgery
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1. Introduction |
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TopAbstract1. Introduction2. Material and methods3. Results4. DiscussionAppendix A. Bronchogenic...References |
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In some cases, the functional impairment caused by COPD renders the patient inoperable [4] or makes it necessary for the surgeon to perform smaller resections, with a lower cure rate [5]. Comorbidity as a possible independent prognostic factor in surgically treated LC (SLC) [6–9] has not been analysed as frequently.
The aim of this paper is to analyse patient characteristics with and without COPD and the possible prognostic value of this comorbidity using a sample of 2994 cases of SLC.
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2. Material and methods |
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TopAbstract1. Introduction2. Material and methods3. Results4. DiscussionAppendix A. Bronchogenic...References |
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Operative mortality was understood to include all deaths directly related with the surgical procedure, regardless of when they occurred. The final number of cases included in this study was 2994.
For the objectives of this paper in terms of analysing the characteristics of surgically treated LC cases with and without COPD, the entire population was selected (n=2994). The prognostic analysis excluded cases presenting the most potent prognostic factors (microcytic type, no resection or incomplete resection) or factors that might confound the prognostic study (operative mortality, induction therapy). In line with several other studies on the prognosis of non-small cell lung cancer (NSCLC) that excluded these characteristics from analysis [10], our study also excluded cases with operative mortality. The number of cases for this prognostic analysis is 2051.
2.2. Methods
The same criteria for the functional operability of the patients and the oncological operability of the tumour were used in all the GCCB-S hospitals [11].
The degree of certainty of the TNM-stages classification depends on the diagnostic methods used; according to some international organizations, post-mortem study yields the maximum certainty factor and the clinical findings yield the minimum certainty factor [12]. By consensus among the members of the GCCB-S coordinating group (two thoracic surgeons and a pneumologist), we established the methods for affirming maximum classificatory certainty for each component (maximum possible clinical certainty adjusted for each problem) [13,14]. Lymph node categories (N) were evaluated using different diagnostic criteria of classificatory certainty. To confirm a cN0 classification, there had to be no lymph node enlargement at all or lymph node enlargement of less than 1cm in diameter as confirmed by computed tomography in lymph node areas 4, 7 and 10 [15]. Furthermore, there had to be no lymph node enlargement in the aorto-pulmonary window or in the anterior mediastinal area (areas 5 and 6), if the LC was left-sized (superior lobule or main left bronchus). If these criteria were not met, negative mediastinoscopy–mediastinotomy or negative fine-needle aspiration biopsy (transbronchial, transthoracic or transesophageal) of these areas was required. The cN1 classification was confirmed by cytohistological evidence (transbronchial fine-needle biopsy, hilioscopy). To confirm a cN2 classification, cytohistological evidence was required (mediastinoscopy, mediastinotomy, fine-needle aspiration biopsy using any approach).
Surgical–pathological N0 was classified by radical mediastinal lymph node dissection or sampling of at least four lymph node areas (2 [only in right LC], 4, 7 and 10 on the same side as the tumour), especially in pT3 [14]. This criterion is similar to that defended in recently proposed guidelines, such as the six hilarmediastinal enlarged lymph nodes in the international tumoral classification [12].
Internal and external audits were made to survey the ratio between the number of patients undergoing surgery and the cases included in the registry (standard over 95%) as well as to determine the presence and validity of the data recorded for each case (standard over 70%), including the consistency of tumoral staging [13]. The criterion used to assess the validity of the survival data was the existence of a known follow-up for 85%, or more, of the cases registered in each hospital. In the hospitals that did not meet these conditions, the cases corresponding to the period of at issue were excluded. Finally, correct data transmission by a single central office from the paper record to the computer database was verified. These procedures were designed to control the selection biases of surgical cases, of registered cases out of the total number of surgical cases, sample size, type of hospital, prognostic migration due to the prolonged period of case recruitment, classification with low or deficient degrees of certainty, contamination by data from incomplete series or erroneous data and loss of long-term follow-up.
COPD is defined when a compatible clinical picture exists, when there is a chronic obstruction to the air flow and when other conditions with similar symptoms are ruled out. Obstruction to the air flow was confirmed when the post-bronchodilator FEV1/FVC was <0.7 [16]. All functional data were subjected to quality control audits conducted at the GCCB-S between 1993 and 1997.
The performance status (PS) scale (ECOG) was: 0, normal activity or asymptomatic; 1 symptomatic, completely ambulatory; 2 symptomatic, restrained to bed less than 50% of day time; 3 symptomatic restrained to bed more than 50%; 4 restrained to bed 24h (100% of the time).
2.3. Analysis
To compare the frequency of presentation of the characteristics amongst the different populations, we used either the Pearson 
2 technique or the Fisher's exact test for qualitative variables and the T student test and the Levene test, when required, for quantitative variables. The difference is considered significant when P<0.05.
In this study, overall survival was used to evaluate the prognosis, considering exitus from any cause as an event. We hypothesised that with this comorbidity (COPD), and in the presence of a disease as severe as NSCLC, we could only ascertain its prognostic value after the annual death load due to NSCLC had been reduced after the 2nd or 3rd year of progress following therapeutic treatment. Because of this, besides calculating the actuarial survival (Kaplan–Meir test) in the presence or in the absence of COPD and its comparison (Log-rank test), the conditional survival at 2, 3 or 5 years from surgery was also calculated. Data were obtained by determining the accumulated probability to be alive at 5 years, with the condition to be alive at 2 or 3 years, or survival at 8 years, if alive after 5 years.
Lastly, using the most widely accepted test (post-bronchodilator FEV1%) and a comparison of its most extreme quartiles, the functional severity of COPD was considered as a logical prognostic factor.
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3. Results |
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TopAbstract1. Introduction2. Material and methods3. Results4. DiscussionAppendix A. Bronchogenic...References |
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In 2928 cases (98%), primary data on FEV1 and FVC were available and, thus, the FEV1/FVC relation known; of these 2928 cases, 1370 patients (46%) had COPD. The FEV1% values were: mean 70.6 (SD 16.2); median 70.6. The FEV1/FVC values were: mean 0.61 (SD 0.8); median 0.62. Classification, according to the severity of COPD [16], was: stage I, 371; stage IIA, 836; stage IIB, 137; stage III, 5. In 21 cases the FEV1 value was not available in a percentage of the theoretical value.
3.1. Characteristics of the patients with and without COPD
No statistically significant differences were found between both groups when assessing the presence of previous tumor, ischemic cardiopathy, systemic arterial hypertension or diabetes mellitus. Likewise, no differences were found in the peripheral or central localization of the SLC, or in the presence of weight loss 
10%, as compared to baseline figures. In relation to the extension of the resection, no differences were found in the frequency of pneumonectomy between the group with COPD (389; 28%) and the group without COPD (465; 30%), or in the frequency of lobectomy—bilobectomy (49 and 50%, respectively). Lesser resections were more frequent in the COPD group (8.8 vs 5%). No differences were found in the values of haemoglobin, total leukocyte count, percentage of polynuclear cells or in the tumoral pathological size. However, differences were found in relation to FEV1 (%), FEV1 (liters) and FEV1/FVC. Obviously, by definition, the values were lower in the COPD group. Table 1 shows the variables that presented significant differences. There are also significant differences (P=0.001) in smoking between patients with COPD (mean, 54.5 pack-years) and the group without COPD (46 pack-years).
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3.2. COPD as a prognostic factor
To evaluate the possible prognostic value of COPD in NSCLC, a sequence of the results obtained is presented. Two analyses were performed on the selected population to study the prognostic value of COPD: an initial analysis on the overall survival and then a second analysis studying temporary conditional survival at 2, 3 and 5 years (Table 2). The analysis of conditional survival at 2, 3 or 5 years from surgery was performed determining the accumulated probability to be alive at 5 years, with the condition to be alive at 2 or 3 years, or survival at 8 years, if alive after 5 years. The overall survival at 5 years is not different between the groups under analysis (COPD/no COPD). However, the overall survival is in fact different when the conditional survival at 36 months is considered.
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For the populations analysed in Table 2, and based on the last conditional survival (over 60 months), no differences were found between both groups (COPD vs no COPD) in the frequency of peripheral vascular disease, perioperative transfusion, PS2, body mass index or age. The difference (P=0.05) between histological types was maintained (P=0.05) with a higher frequency of squamous tumors in the COPD group (66 vs 57%). Slightly decreased values of serum albumin were found in the COPD group (4 vs 4'15) (P=0.02).
For the same population, but in stage pI (Table 3), only the age was higher in the group with COPD (65 vs 63'5) (P=0.05).
Lastly, when the patients in the COPD group were divided according to the extreme values of FEV1% (Table 4), no differences were noted between the two groups in any of the mentioned variables.
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4. Discussion |
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TopAbstract1. Introduction2. Material and methods3. Results4. DiscussionAppendix A. Bronchogenic...References |
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The results of the study show that LC cases with COPD occur most frequently in males and the tumour is of a squamous type. This higher rate in gender and type has also been reported in other studies [7]. None of the other various variables analysed presented any differences with regard to frequency in the group with COPD, and when they did, their clinical significance was low. In terms of prognosis, COPD comorbidity can present a possible prognostic value in stage pI NSCLC when it is analyzed using conditional survival. The functional severity of COPD (FEV1%) has its own prognostic gradient within the COPD group.
The functional criteria for the diagnosis of COPD obviates, to a large extent, the problem raised by the use of clinical criteria or by the use of the administrative date on the discharge form. With these last procedures, cases of COPD could be underdiagnosed in the presence of a severe disease such as LC [17,18]. In our study, a database was initially designed (1993) for the prospective compilation of the preoperative value of FEV1 (liters) and FVC (liters). These two values were retrieved in 98% of the total 2994 number of cases and were also the subject of external audits. The definition of COPD used in this paper is different to that published in other studies, which can in turn lead to a different measurement of disease frequency [19].
The number of probable or possible prognostic factors in LC is very high [20]. Unfortunately comorbidity has not been studied in depth in LC [21,22] and even less in surgical LC [7–9]. The majority of prognostic studies that focus on comorbidity in LC take into account ratios that change various diseases, such as the so-called Charlson index [9] or the Kaplan–Feinstein index [8]. The deleterious effect of this comorbidity was identified through the use of different definitions, methods of analysis and LC populations [7,9]. Moreover, this type of prognostic factor analysis can be of even greater relevance in the light of the increased rate of LC seen in ex-smokers—who do not die of other diseases earlier in life—and thus have a higher probability to present other comorbidities later in life [3].
In this paper, conditional survival analysis was used for the prognostic analysis of COPD, given the important annual rate of deaths caused by LC in the first 2 years after surgery [10]. This type of survival analysis has been used in LC [23], having been defended as a highly reliable method in demonstrating survival in LC [24]. In our study this type of analysis has been shown to be very useful in determining the value of COPD as a ‘differed’ prognostic value after the second year of survival.
In the population selected by the GCCB-S for this prognostic study, the most important and best known factors in LC were controlled: NSCLC type, complete surgical resection. In a second phase of the analysis, another important factor was controlled, the pathological stage. It is in this latter population (NSCLC, stage pI with complete resection), where the deleterious prognostic value of COPD was best appreciated after 2 years survival (Table 3).
Other prognostic studies on this specific comorbidity (COPD) have also shown its prognostic value to determine overall survival [6] and the mortality caused by other late intercurrent conditions after 3 years of follow-up [7].
Given that the most severe form of COPD rendered some patients inoperable (4), the analysis subject of this study was performed using a selected population with mild or moderate COPD with a FEV1/FVC spectrum between the 25 percentile of 0.56 and the 75 percentile of 0.67. Despite this restrictive range of functional pulmonary alteration in COPD, the comparison between extreme percentiles of FEV1% in COPD with stage pI NSCLC still detects a significant prognostic gradient (Table 4). This value is in accordance with all the data available on COPD [25].
This paper presents some limitations, such as the functional definition of COPD, without taking into consideration other spirometric or clinical criteria [19]. It is, thus, possible that other studies with different diagnostic criteria for COPD may fail to reproduce the results yielded by this study. Moreover, the possible volume reduction effect of some resections in patients with emphysema [4] was not studied either in this paper. Lastly, only the overall survival, which takes into account death for any cause (cancer or other causes), was studied in this paper.
The future implications of the prognostic value of this frequent comorbidity relate to the manner in which this COPD variable must be used in multivariate models for the prognostic analysis of surgical LC. A more specific knowledge of its value and the way in which it impacts on patient prognosis will help us manage this comorbidity variable more efficiently. If these data were to be confirmed by independent studies, the comorbidity of NSCLC with COPD should be taken into account when elaborating multiparametric prognostic indexes.
In summary, this study on COPD comorbidity in SLC shows that this association can be of deleterious prognostic value in patients who present both diseases. The effect is observed after 2 years of resection surgery and in COPD it is directly related with the degree of functional severity (FEV1%).
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Appendix A. Bronchogenic Carcinoma Cooperative Group of the Spanish Society of Pneumology and Thoracic Surgery |
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TopAbstract1. Introduction2. Material and methods3. Results4. DiscussionAppendix A. Bronchogenic...References |
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A.2. Local representatives
Julio Astudillo, MD; Pedro López de Castro, MD (Hospital Germans Trias i Pujol, Barcelona); Emilio Canalís, MD; José Belda, MD. (Hospital Clinic, Barcelona); Antonio Cantó, MD; Antonio Arnau (Hospital Clínico, Valencia); Juan Casanova, MD; Mariñan MD (Hospital de Cruces, Bilbao); Jorge Cerezal, MD (Hospital Universitario, Valladolid); Antonio Fernández de Rota, MD; Antonio Arrabal, MD. (Hospital Carlos Haya, Málaga); Federico González Aragoneses, MD; Nicolas Moreno, MD (Hospital Gregorio Marañón, Madrid); Jorge Freixinet, MD; Pedro Rodríguez, MD. (Hospital Doctor Negrin, Las Palmas); Nicolás Llobregat, MD (Hospital Universitario del Aire, Madrid); Nuria Mañes, MD (Fundación Jiménez Díaz, Madrid); Miguel Mateu, MD; Mireia Serra, MD (Hospital Mutua de Terrassa, Barcelona); José Luis Martín de Nicolás, MD (Hospital Universitario 12 de Octubre, Madrid); Nuria Novoa (Complejo Hospitalario, Salamanca); Jesús Rodríguez, MD (Complejo Hospitalario, Oviedo); Antonio José Torres García, MD (Hospital Universitario San Carlos, Madrid); Mercedes de la Torre (Hospital Juan Canalejo, La Coruña); Abel Sanchez-Palencia, MD; Javier Ruíz Zafra, MD. (Hospital Virgen de las Nieves, Granada); Andrés Varela Ugarte, MD; Pablo Gámez, MD. (Clínica Puerta de Hierro, Madrid); Yat Wah Pun, MD; Lorenzo Fernández Fau, MD (Hospital de la Princesa, Madrid).
A.3. Data analysis
Agustín Gómez de la Cámara, MD; Francisco Pozo Rodriguez, MD (Hospital Universitario 12 de Octubre, Madrid).
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Acknowledgments |
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Footnotes |
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References |
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TopAbstract1. Introduction2. Material and methods3. Results4. DiscussionAppendix A. Bronchogenic...References |
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