Age, comorbidity, treatment decision and prognosis in lung cancer
SIR—Lung cancer is now the leading cause of cancer-related death in most developed countries. Approximately 80–85% of lung cancer subtypes are of non-small cell (NSCLC), two-thirds of which are at advanced stages on diagnosis.
Like other solid tumours, lung cancer is predominantly a disease of the elderly and 
30–50% of all patients are older than 70 years when the disease is diagnosed [1, 2]. Despite the high incidence of lung cancer and its high mortality rate in elderly patients, the likelihood of receiving active treatment appears to decrease with increasing age [3, 4]. The presence of comorbid conditions is regarded as an important factor influencing treatment decisions [5]. In spite of the fact that comorbid conditions are very common in the elderly [6], the prognostic impact of age and comorbidity remains controversial.
With these aspects in mind, we performed an observational study to analyse the influence of age and comorbidity on choice of treatment and prognosis in advanced NSCLC.
Patients
Patients with cyto-histological diagnosis of NSCLC stages III-B or IV according to the TNM system [7], between January 1997 and June 2006, were analysed retrospectively.
Exclusion criteria were as follows: performance status (PS) >2 according to the Eastern Cooperative Oncology Group (ECOG) or death before treatment due to causes unrelated to neoplastic disease.
The oncological committee of our hospital (comprising physicians from the oncology, radiotherapeutic oncology, thoracic surgery and clinical pneumology departments) assessed all patients to decide on the most appropriate treatment. Patients received purely palliative treatment if they themselves refused other treatment proposed or if the committee so decided.
The following definitions were established: comorbidity as any disease present 12 months before the date of cancer diagnosis, active treatment as chemotherapy with or without radiotherapy or radical radiotherapy alone, weight loss as a decrease of >5% of habitual weight in the previous 6 months, best supportive care (BSC) as pharmacotherapy or palliative radiotherapy as well as endobronchial recanalization with laser resection or stent insertion and survival as the number of weeks from the time of diagnosis until the last examination or death (survival cut-off date was 31 December 2006).
This evaluation was approved by our investigational review board, and patient consent was not deemed necessary when the study started.
Variables
The following variables were analysed: age, sex, comorbidity (type and number) according to an adapted version of the index developed by Charlson et al. [8], weight loss, PS on the ECOG scale, TNM staging, treatment (active or BSC) and survival.
Statistical analysis
Quantitative variables were expressed as means and qualitative variables as percentages. Student's t-test was used to compare quantitative variables and chi-square distribution for qualitative variables.
We used a logistic regression model with forward stepwise conditional methods to identify factors that could have influenced the choice of treatment. Independent variables were age, sex, comorbidity, performance status and stage at diagnosis.
Survival estimates were derived by the Kaplan–Meier analysis, and the log-rank test was used to assess differences of survival between groups. For evaluation of the independent prognostic effects a multivariate Cox proportional hazard model was built and was stratified by performance status. With respect to comorbidities, the prognostic effects of the specific diseases/combinations were evaluated.
A P value of <0.05 was considered to be statistically significant.
Overall results
During the study period, 320 patients were diagnosed, 26 of whom met at least one of the exclusion criteria. The final study sample consisted of 294 patients with mean age 62.7 years (range: 33–85; SD: 11.83), 74 being older than 70 years.
One hundred and sixty-nine patients had concomitant diseases and the most frequent were chronic obstructive pulmonary disease and cardiovascular disease. Of these patients, 72 had two or more comorbidities.
General characteristics of the patients are shown in Table 1.
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Treatment
Of those patients aged 70 years or less, 14.1% received best supportive care compared with 40.5% in the age group >70 years (Table 1).
The proportion of patients with comorbid conditions who underwent BSC was 27.2% compared with 11.2% in patients without comorbidity; for patients with 
2 comorbidities, this proportion was 65 and 38% of those aged >70 and 70 or younger, respectively (P = 0.001).
In the logistic regression analysis, the likelihood of not receiving active treatment was correlated with age >70 years [OR: 3.38 (1.74–6.57) P = 0.0001], 2 comorbidities [OR: 2.4 (1.22–4.71) P = 0.01] or PS 2 [OR: 5.71 (2.61–12.5) P = 0.0001].
Survival analysis
Median survival was 32 weeks (range: 26–38).
Table 2 shows the univariate and multivariate analysis of survival. In univariate analysis, survival decreased with age, number of comorbidities, diabetes mellitus, weight loss and BSC. Multivariate analyses identify comorbidities 2, BSC and weight loss as independent poor prognostic factors. With respect to specific diseases, only the combination of COPD and cardiovascular disease had a negative influence on survival in univariate analysis (P = 0.006). However, this effect disappeared in multivariate analysis.
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Discussion
In this study, age and comorbidity played an important role in treatment decisions in advanced NSCLC. Two population studies [9, 10] found that in advanced stages, in the age group of 60–79 years, treatment was symptomatic in 34–40% of patients increasing to 52–65% in those aged 80 years or older as compared with 19–20% in patients aged <60 years. In these series, comorbidity also influenced therapeutic choice but was less important than age. In our case both variables were correlated with the likelihood of receiving only BSC although the association was stronger with age.
Given these considerations an interesting finding of our analysis is that treatment and comorbidity are prognostic factors independent of age. This is in agreement with the observations of other authors [5, 11] that age and comorbidity influenced treatment selection, but only comorbidity was associated with prognosis. Similarly, in a study involving 966 patients, the presence of cardiovascular and cerebrovascular diseases adversely affected survival outcome in advanced stages, independently of age and performance status [12]. In our study, the number of comorbidities but not the specific diseases had prognostic significance. We think that it could be explained because the effect of more conditions may be multiplicative rather than additive.
Nowadays, the prognostic significance of comorbidity remains controversial. Read et al. [13] found that comorbidities had no relevant prognostic impact in groups of patients with lowest survival rates, including patients with advanced lung cancer. Similarly, in a prospective study of stage III-b and IV patients older than 70 years, previous quality of life but not concurrent health conditions was the main determinant of survival [14], but the authors explained this by the fact that eligibility criteria excluded patients with high comorbidity; an important point in their study was that performance status was correlated with quality of life and this with comorbidity. So it seems that future efforts should be directed at analysing whether the reasons for compromised performance status are tumour burden, comorbidity or both.
Given our results, not treating with chemotherapy only according to ‘chronological’ age does not seem justified, especially considering that cytostatic treatment has demonstrated its efficiency in terms of survival both in clinical trials [15, 16] and in usual health care [17, 18], even in elderly people just as in their younger counterparts. Nevertheless, it seems necessary to perform a careful comorbidity evaluation in older people with PS 2 to decide on the best therapeutic option, and this will acquire more importance because chemotherapy has proven its utility in certain subgroups of these patients with acceptable toxicity rates [19].
The present study has certain limitations. We did analyse the association between specific comorbidities and survival but the number of cases was low in certain subgroups, so our results must be interpreted with caution in this point. Similarly, we used the Charlson index with a qualitative yes/no checklist which does not provide information about the severity of concomitant disease and thus probably underestimated the prognostic impact of comorbidity in some cases. Due to the retrospective design, we did not analyse quality of life which has an important prognostic value [20, 21], but we want to emphasize that this variable could be related to comorbidity as it has been mentioned above.
Elderly people were defined with a cut-off age of 70 years because evidence shows an increased incidence of age-related changes after this age [17]. We only included patients with PS 
2 because it is in this group in which cytotoxic treatment is recommended [22, 23].
In conclusion, we found that in advanced-stage non-small cell lung cancer, age and comorbidity have a significant impact on treatment choice, but only the presence of more than one comorbid condition worsens prognosis. This means that physicians should make therapy decisions on the basis of ‘biological’ age, and to define it more precisely a thorough evaluation of comorbidities would be very important.
- Not treating with chemotherapy only according to "chronological" age is not justified.
- It is necessary to perform a careful comorbidity evaluation in older people to decide the best therapeutic option.
- Chemotherapy is as effective in elderly people as in their younger counterparts.
The authors have no conflicts to disclose.
1 C/La Marina n° 49-4° izquierda, 38001, Santa Cruz de Tenerife, Spain
2 C/Ramón y Cajal n° 31-5° izquierda, 38001, Santa Cruz de Tenerife, Spain
3 C/S. Juan Bautista n° 19 portal A 1° dcha, 38009, Santa Cruz de Tenerife, Spain
4 C/Sabino Berthelot n° 16-5° izquierda, 38003, Santa Cruz de Tenerife, Spain
5 C/Real Orotava 164 A, 38360 Ravelo-El Sauzal, Santa Cruz de Tenerife, Spain
* To whom correspondence should be addressed Email: jagb965{at}yahoo.es
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