This is a prospective study designed following the World Medical Association guidelines (Seventh revision of the Declaration of Helsinki, Fortaleza, Brazil, 2013)20 for research on human beings and approved by the institutional Ethics Committee on Human Investigation (Hospital del Mar–IMIM, Barcelona, Spain). All patients invited to participate in the study signed the written informed consent.

Patients were prospectively recruited from the Lung Cancer Clinic of the Respiratory Medicine Department at Hospital del Mar (Barcelona, Spain). All the patients were part of the Lung Cancer Mar Cohort that started in 2008. For this observational study, 125 patients with LC were recruited. Patients were further subdivided post hoc into two groups on the basis of underlying COPD: (1) 87 patients with LC and COPD (LC-COPD group) and (2) 38 patients with LC without COPD (LC group). These patients were simultaneously participating in another investigation aimed to explore the associations between the immune microenvironment (B cells and tertiary lymphoid structures) in the lung tumor specimens and OS of the patients (submitted to another journal).

LC diagnosis and staging were established by histological confirmation and classified according to currently available guidelines for the diagnosis and management of LC.21,22 TNM (tumor, node, and metastasis) staging was defined as stated in the 8th edition Lung Cancer Stage Classification.23 In all cases, pre-operative staging was performed using chest and upper abdomen Computed Tomography (CT) scan and Fluoro-deoxy-glucose positron emission tomography/computed tomography (PET) body-scan. When suspected mediastinal lymph-node involvement, a fiberoptic bronchoscopy with endo-bronchial ultra-sound (EBUS) and trans-tracheal biopsy of the suspected nodes were performed. In case of negative results, a surgical exploration of the mediastinum: cervical video-assisted mediastinal lymphadenectomy (VAMLA) and/or anterior mediastinotomy were performed, the latter depending on the location of the suspected nodes. Notwithstanding, in all surgical cases, intra-operative systematic hilar and mediastinal lymphadenectomy (at least, ipsilateral paratracheal, subcarinal, and ipsilateral pulmonary ligament) was performed as previously recommended.24,25 Standard clinical guidelines were used to establish the selection of patients and contraindications for thoracic surgery as previously described.26 Decisions on the best therapeutic approach were always made during the weekly meetings of the Multidisciplinary Lung Cancer Committee. Lung tumor resections were applied using classical thoracotomy for all the patients in this study.

In the current investigation, exclusion criteria for the participants were established as follows: small cell lung cancer (SCLC), severe malnutrition status, chronic cardiovascular disease, metabolic or clot system disorders, signs of severe inflammation and/or bronchial infection (bronchoscopy), current or recent invasive mechanical ventilation, or long-term oxygen therapy. The presence/absence of these diseases was confirmed using standard clinical tests: exercise capacity electrocardiogram, clinical examination, blood tests, bronchoscopy and echocardiography.

In all patients, lung function parameters were assessed following standard procedures. Diagnosis and severity of patients with COPD were determined according to current guidelines.10 Preoperative nutritional evaluation included the assessment of body mass index (BMI) and nutritional blood parameters from all patients. All the parameters were quantified prior to thoracotomy for their lung neoplasm. Moreover, body weight loss over the previous year to study entry was also quantified in all the study patients. Body weight loss during follow-up was not quantified routinely in patients of this study.

The normality of the study variables was examined using the Shapiro–Wilk test. Accepting an alpha risk of 0.05 and a beta risk of 0.2 in a two-sided test, 33 subjects were necessary in the LC group and 66 in the LC-COPD group to identify a statistically significant difference greater than or equal to 3 units in mean of BMI variable. The common standard deviation was assumed as 5. The number of patients in each group was calculated using GRANMO (IMIM, Barcelona). Moreover, taking each variable categorized into two groups, estimated power for two-sample comparisons of survivor functions Log-rank test was applied using the Freedman method. Accepting an alpha risk of 0.05 in a two-sided test with 87 and 38 patients in each group (post hoc subdivision), the statistical power was 85% (albumin), BMI (76%), and 100% (FEV1).

For the descriptive analysis of clinical parameters, qualitative variables were described as frequencies (number and percentage) and quantitative variables as mean and standard deviation. Differences in clinical parameters between LC and LC-COPD were assessed using Student's T-test or Mann–Whitney U tests for parametric and non-parametric variables, respectively. Chi-square test was used to assess differences between the two groups for the categorical variables.

OS was defined as the time from the date of diagnosis of LC to the date of death from this disease or the last follow-up which was completed in December 2018. The median follow-up duration was 37.7 months (P25=20.4 months, P75=60.5 months). Patients were followed for a minimum of one year and up to maximum period of 10 years. Patients who did not died of lung cancer were excluded in the investigation. Two patients who were lost during follow-up were not included in the OS analyses. Threshold analysis was carried out for each continuous variable to determine the best cut-off point as predictor of OS, which was the endpoint in the study. The cut-off point was defined using the web-based software Cutoff Finder,27 which has also been previously used in other studies.28,29 For each variable, we identified the threshold level at which a log-rank test allowed segregation of patients into groups with better and worse survival. Kaplan–Meier survival curves were performed for each dichotomized variable (below versus above cutoff values, described as Lo and Hi) and log-rank test p-value was estimated.

Univariate and multivariate Cox regression models were used to study OS among all LC patients. Those variables with p-value smaller than 0.1 were entered into the multivariate analyses. The proportional hazard assumption, checked by examining Schoenfeld residuals (for overall model and variable by variable), was not violated. Statistical significance was established at p≤0.05. All statistical analyses were carried out using the software Stata/MP 15 (StataCorp LLC, Texas, USA).

No significant differences were seen in age between the two study groups (Table 1). In this prospective study, the number of LC-COPD patients was greater than patients in the LC group (Table 1). BMI, although within normal ranges, was significantly lower in LC-COPD than in LC patients (Table 1). The number of male patients among the LC-COPD group was significantly higher than in LC group (Table 1). Smoking history including packs-year was significantly worse in the LC-COPD patients than in LC group (Table 1). In LC-COPD patients, the lung functional parameters FEV1, FEV1/FVC, DLCO and KCO were significantly reduced compared to LC patients (Table 1). COPD patients were mostly in GOLD I and II stages (91%). TNM staging or histological subtypes did not significantly differ between the two groups. The proportions of patients that received adjuvant therapy did not significantly differ between the two study groups (Table 1).

Total leukocyte, neutrophil and lymphocyte counts were significantly greater in LC-COPD patients (Table 1). However, albumin levels were significantly reduced in LC-COPD patients (Table 1). No significant differences were shown in levels of total proteins, fibrinogen, C-reactive protein (CRP), globular sedimentation velocity (GSV) between LC-COPD and LC patients (Table 1). Body weight loss did not significantly differ between the study groups (Table 1). In LC-COPD group of patients, only four patients (2 current smokers and 2 ex-smokers) experienced the greatest weight loss range (6–10kg) within the previous 12 months before study entry (Table 1). In LC group, only one smoker patient exhibited a great range of weight loss (Table 1).

When all patients were analyzed together, a lower level of BMI (cut-off: 21.5kg/m2) was associated with a poorer 10-year survival (Fig. 1A). When patients were subdivided according to the presence of COPD, a significant worse ten-year survival was observed in LC-COPD patients with a lower degree of BMI (Fig. 1B). Similar results were observed when only ex-smokers and never-smokers were analyzed independently (Fig. S1A and S1B). As to the levels of albumin, when all patients were analyzed together, a lower level of albumin (cut-off: 3.55g/dL) was associated with a poorer 10-year survival (Fig. 2A). When patients were subdivided according to the presence of COPD, a significant worse survival was observed in LC-COPD patients with lower levels of albumin (Fig. 2B). Similar findings were also obtained when non-smokers (never smokers and ex-smokers) were analyzed separately (Fig. S2A and S2B). The patients’ 10-year survival was almost significantly reduced in patients with lower levels of total proteins (cut-off: 5.65/dL) when patients were analyzed altogether (p=0.055) and in the group of LC-COPD (p=0.075, Fig. 3A and B, respectively). Non-significant differences were observed in OS when non-smokers (never-smokers and ex-smokers) were analyzed independently (Fig. S3A and S3B). Cigarette smoking was also analyzed in the study. When all patients were analyzed together higher levels of cigarette smoking burden (cut-off: 48 packs-year) were associated with a poorer 10-year survival (Fig. 4A). Moreover, when patients were subdivided according to the presence of COPD, an almost significant worse survival (p=0.090) was observed in LC-COPD patients with a greater cigarette smoking burden (Fig. 4B). Interestingly, no significant differences were seen in OS when non-smoker patients were analyzed separately (Fig. S4A and S4B). In the study cohort, the presence of underlying COPD per se was also significantly associated with a lower 10-year survival as shown in Fig. 5. Consistently, no significant differences were seen when non-smokers were analyzed independently (Fig. S5).

Fig. 1.

(A) Kaplan–Meier survival curves for OS in all patients based on the cut-off value of the BMI (above and below the cut-off value: 21.5kg/m2). (B) Kaplan–Meier survival curves for OS in LC patients with and without COPD based on the cut-off value of the BMI (above and below the cut-off value: 21.5kg/m2). This information was not available in two patients. Definition of abbreviations: BMI, body mass index; LC, lung cancer; COPD, chronic obstructive pulmonary disease; Hi, high level (above cut-off value); Lo, low level (below cut-off value).

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Fig. 2.

(A) Kaplan–Meier survival curves for OS in all patients based on the cut-off value of the albumin level (above and below the cut-off value: 3.55g/dL) in blood. (B) Kaplan–Meier survival curves for OS in LC patients with and without COPD based on the cut-off value of the albumin level (above and below the cut-off value: 3.55g/dL) in blood. This information was not available in three patients. Definition of abbreviations: LC, lung cancer; COPD, chronic obstructive pulmonary disease; Hi, high level (above cut-off value); Lo, low level (below cut-off value).

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Fig. 3.

(A) Kaplan–Meier survival curves for OS in all patients based on the cut-off value of the total protein level (above and below the cut-off value: 5.65g/dL) in blood. (B) Kaplan–Meier survival curves for OS in LC patients with and without COPD based on the cut-off value of protein levels (above and below the cut-off value: 5.65g/dL) in blood. This information was not available in three patients. Definition of abbreviations: LC, lung cancer; COPD, chronic obstructive pulmonary disease; Hi, high level (above cut-off value); Lo, low level (below cut-off value).

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Fig. 4.

(A) Kaplan–Meier survival curves for OS in all patients based on the cut-off value of cigarette smoking burden (above and below the cut-off value: 48 packs-year). (B) Kaplan–Meier survival curves for OS in LC patients with and without COPD based on the cut-off value of cigarette smoking burden (above and below the cut-off value: 48 packs-year). This information was not available in six patients. Definition of abbreviations: LC, lung cancer; COPD, chronic obstructive pulmonary disease; CS, cigarette smoking; Hi, high level (above cut-off value); Lo, low level (below cut-off value).

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Fig. 5.

Kaplan–Meier survival curves for OS in LC patients according to the presence of underlying COPD. This information was not available in two patients. Definition of abbreviations: LC, lung cancer; COPD, chronic obstructive pulmonary disease.

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When all patients were analyzed together, a lower level of FEV1 (cut-off: 82.5%) was associated with a poorer 10-year survival (Fig. 6A). When patients were subdivided according to the presence of COPD, no significant differences in ten-year survival were observed in any of the subgroups (Fig. 6B). No significant differences were seen when non-smokers (never smokers and ex-smokers) were analyzed independently (Fig. S6A and S6B). When all patients were analyzed together, a lower level of DLCO (cut-off: 83.5%) was not significantly associated with a poorer 10-year survival (Fig. 7A). When patients were subdivided according to the presence of COPD, no significant differences were observed in any of the subgroups (Fig. 7B). No significant differences were seen when non-smokers (never smokers and ex-smokers) were analyzed separately (Fig. S7A and S7B).

Fig. 6.

(A) Kaplan–Meier survival curves for OS in all patients based on the cut-off value of FEV1 (above and below the cut-off value: 82.5%). (B) Kaplan–Meier survival curves for OS in LC patients with and without COPD based on the cut-off value of FEV1 (above and below the cut-off value: 82.5%). This information was not available in two patients. Definition of abbreviations: LC, lung cancer; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in one second; Hi, high level (above cut-off value); Lo, low level (below cut-off value).

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Fig. 7.

(A) Kaplan–Meier survival curves for OS in all patients based on the cut-off value of DLCO (above and below the cut-off value: 83.5%). (B) Kaplan–Meier survival curves for OS in LC patients with and without COPD based on the cut-off value of DLCO (above and below the cut-off value: 83.5%). This information was not available in three patients. Definition of abbreviations: LC, lung cancer; COPD, chronic obstructive pulmonary disease; DLCO, transfer factor of the lung for carbon monoxide; Hi, high level (above cut-off value); Lo, low level (below cut-off value).

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Administration of adjuvant therapy did not significantly influence the 10-year survival in any of the study groups of patients (Fig. 8). Consistently, no significant differences were seen when non-smokers (never-smokers and ex-smokers) were analyzed separately (Fig. S8).

Fig. 8.

Kaplan–Meier survival curves for OS in all patients based on the presence or absence of administration of adjuvant therapy to all patients together (LC and LC-COPD). This information was not available in two patients. Definition of abbreviations: LC, lung cancer; COPD, chronic obstructive pulmonary disease.

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The univariate analysis showed that smoking history (HR=1.01, p=0.02), and COPD (HR=2.41, p=0.04) predicted a higher mortality risk, while BMI (HR=0.92, p=0.05), FEV1 (HR=0.98, p=0.06), albumin (HR=0.51, p=0.02), and total protein levels (HR=0.68, p=0.04) were associated with a lower mortality risk among all the LC patients (Table 2). Furthermore, the multivariate Cox proportional hazard regression analysis showed that BMI (HR=0.89, p=0.03) was an independent prognostic factor for OS among all the LC patients (Table 2).

In this cohort of LC patients with relatively well-preserved nutritional status, international nutritional classifications have not been used as only very few patients would have fell into the most severe categories. Furthermore, several parameters indispensable for the classification of the patients into several groups of nutritional abnormalities were not available for all of them.36,37

Another limitation might be the surgical procedure (thoracotomy versus VATS) used to resecting the lung tumors in the study patients. Nevertheless, we believe that this has had no significant effect on either BMI or albumin prior to surgery or on the long-term survival of the patients as also demonstrated previously.38,39

In the present investigation, no specific scales of comorbidity were used prior to patient recruitment.40 Nonetheless, very selective inclusion and exclusion criteria were established before patient recruitment. As described in methods, despite these limitations, we believe that the current investigation sheds light into the relevance of preoperative nutritional status, even if relatively well-preserved, in patients with resectable lung tumors and in particular in those with underlying COPD. The current results will serve as the basis for the design of multicenter studies to analyze the prognosis value of other variables using similar approaches in the near-future.