Association between Charlson comorbidity index score and outcome in patients with stage IIIB-IV non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is a common malignant tumour worldwide [1]. Because there are few valid diagnoses of early-onset NSCLC, most patients have late stage cancer at the time of diagnosis [2, 3], and systemic chemotherapy or precision therapy with several targeted drugs are the only treatment options. According to a number of studies, the primary prognostic factors for NSCLC patients are pathological stage, performance status, gender, age, histology, and weight [4‐7]. Because many patients are elderly at the time of diagnosis and because the prevalence of previous or current smokers is high, medical comorbidities are often present. Asmis et al. suggested that the presence of comorbidity, rather than being older than65 years, was associated with worse survival of NSCLC patients [8].

The use of comorbidities for prognostic assessment has been extensively studied in many fields [9, 10], including oncology [11‐13]. A common model of comorbidity is the Charlson comorbidity index (CCI) [14]. The CCI is based on 19 underlying diseases with variously assigned weights that are combined into a composite score. The CCI was originally derived for hospitalized patients in general (internal) medicine, but revised versions have since been validated in multiple patient populations, including patients with NSCLC [15‐18].

The CCI score has been positively associated with increased risk of death in patients with inoperable NSCLC treated with radiofrequency ablation (hazard ratio [HR] = 1.3, 95% confidence interval [CI; 25.5–58.2]) [16]. In patients with stages I-III NSCLC, the CCI score, gender, ethnicity, tumour stage, histology, and insurance type have been associated with overall survival; patients with higher CCI scores were found to have worse clinical outcomes [19]. The CCI score has also been found to be a better predictor of comorbidity than are individual risk factors in patients who have undergone resection for NSCLC [20].

The effects of treatment selection on outcome in both surgical and nonsurgical patients with early-stage NSCLC have been assessed [21]. However, to the best of our knowledge, there has been no study of a correlation between the CCI score and chemotherapy benefit or survival of patients with unresectable advanced NSCLC.

Elderly patients are often excluded from clinical trials because it is believed that they are unable to tolerate aggressive chemotherapy and are more likely to suffer increased toxicity, resulting in poorer quality of life. However, it has been demonstrated that age alone is not an independent prognostic factor, and the tolerance to treatment, its toxicity and the benefits experienced by elderly patients with good performance status are similar to those of the nonelderly [22].

The present study retrospectively investigated whether CCI scores can predict the long-term survival of patients with unresectable advanced NSCLC.

The Research Ethics Board of Beijing Friendship Hospital approved this retrospective study. The study complied with the Declaration of Helsinki. All subjects gave written informed consent.

From 1 May 2010 to 1 October 2014, 297 patients received a new diagnosis of stage IIIB-IV NSCLC. Of these, 132 patients were excluded for being positive for EGFR or ALK gene mutations, having received radiotherapy in the lung area, having a performance status level of ≥3, or being lost early during follow-up. Therefore, 165 patients were included in the analysis (Table 1).

The median follow-up duration for the surviving patients was 28 months; the last follow-up assessment was 1 May 2015. The median age of the patients was 61 years; 58% of the patients were smokers, and 56% and 44% had non-squamous or squamous carcinoma, respectively. The most prevalent comorbid illnesses (present in > 5% of the population each) were metastatic solid tumours (82%), chronic pulmonary disease (37%), mild liver disease (29%), cerebrovascular disease (23%), diabetes with end-organ damage (21%), congestive heart failure (21%), peptic ulcer disease (19%), and peripheral vascular disease (16%).

Using ROC analysis, a CCI score of ≥9 was significantly associated with the decreased survival of patients in palliative care (P < 0.05). The result of ROC analysis showed that a CCI score of 9 was the cut-off (Fig. 1). Hence, for further analyses, we divided CCI scores as follows: CCI < 9 (moderate), indicating that patients have metastatic cancer or other complications; and CCI ≥ 9 (severe), indicating that patients have more complications.

Using modified CCI categories, CCI scores of <9 were classified as low, and CCI scores of ≥9 were considered high (90 and 75 subjects, respectively). The median survival time was 19.3 months (95% CI 17.00–23.30). The median survival rates at 1, 2, and 3 years were 78.31%, 41.56%, and 11.53%, respectively. The survival rates of patients in the low CCI score group at 1, 2, and 3 years (81.23%, 43.46%, and 16.45%, respectively) were better than those of patients with high CCI scores (62.48%, 38.79%, and 7.48%, respectively). The median survival time of patients in the low CCI score group (20.84 months [95% CI, 19.52–22.17]) exceeded that of patients in the high CCI score group (17.80 months [95% CI, 16.61–18.96]) (Fig. 2).

The logistic regression analyses showed that smoking status and performance status were independent prognostic factors for CCI scores (Table 2). Smoking and a higher performance status were associated with an increased risk of mortality, with smokers having an odds ratio (OR) of 4.12 (95% CI, 1.92–8.84), and patients with a performance status of 2 having an OR of 2.22 (95% CI, 1.14–4.33). Other factors (age, gender, histology, and tumour staging) were not significant (P > 0.05). The Cox regression analysis revealed that there were significant differences (P < 0.05) between stage, CCI score, smoking status, gender, and the probability of surviving.

Higher stages (stage IV), high CCI scores (CCI ≥ 9), smoking, and male gender were associated with higher HRs than were lower stages, lower CCI scores, not smoking, and female gender (Table 3). Patients with higher stages had an HR of 1.73 (1.18–2.52), patients with high CCI scores had an HR of 1.14 (1.07–1.21), smokers had an HR of 2.07 (1.46–2.95) and male patients had an HR of 1.41 (1.01–1.96). However, age and histology were not significantly associated with prognosis (P > 0.05).

The multivariate analysis showed that higher CCI scores (CCI ≥ 9), smoking, and male gender were associated with higher HRs (P < 0.05; Table 3). Performance status was included in the multivariate analysis to assess whether there was an association with survival that was not captured by the CCI score. It was found that the HR for CCI score decreased from 1.10 to 1.07 when performance status was included in the analysis, but the association of survival with the CCI score remained significant (P < 0.05).

This study found a comprehensive prognostic factor for predicting whether NSCLC patients can benefit from chemotherapy. To rule out possible interference from other factors, we chose only patients with stage IIIB-IV (advanced, non-resectable) NSCLC without gene mutations in EGFR or ALK. The results showed that higher CCI scores (CCI ≥ 9), smoking, and male gender were associated with higher HRs.

Currently, the prognostic determinants of NSCLC are disease stage, performance status, male gender, age greater than 60 years, non-squamous histology, and weight loss. Grosso et al. demonstrated that intraoperative complications did not differ between young and old patients who underwent surgery for stage I-III colorectal cancer, whereas some differences were found in postoperative complications and late complications [26]. In another study, Grosso et al. found a significant association between a greater adherence to the Mediterranean diet (MD) and lower odds of having cancer (odds ratio = 0.46, 95% confidence interval: 0.28–0.75) [27]. Marventano et al. found that symptoms, surgical procedures and the number of comorbidities significantly affected health-related quality of life (QoL) [28]. However, recent studies suggest that these prognostic factors should be reassessed. Multicentre studies with large sample sizes have indicated that compared with age, the CCI score is a better predictor of survival for patients with advanced NSCLC [22]. Brock et al. demonstrated that comorbidities, tumour stage, and gender have a greatest influencer upon survival than age in patients with resectable NSCLC [29]. However, Janssen-Heijnen et al. concluded that comorbidity had no independent prognostic effect in elderly patients with NSCLC [30]. A study conducted by Gironés et al. showed that, although there was a high prevalence of comorbidity in untreated lung cancer patients older than 70 years, comorbidity was not related to survival [31].

In the present study, we evaluated whether the CCI score can be used to predict chemotherapy benefit and survival in patients with unresectable stage IIIB-IV NSCLC. As cancer metastasis is very common in these patients, the CCI score is usually >6. We adjusted the CCI groups using ROC analysis to determine the best cut-off (CCI = 9). We found that the CCI score, gender, and smoking status were prognostic factors for patients with unresectable stage IIIB-IV NSCLC without EGFR or ALK gene mutations. In the clinical setting, we usually choose cancer stage and performance status to determine the treatment strategy. Although these factors are easy to determine, their prognostic accuracy is questionable. Rather, the present study found that the CCI score, smoking status, and gender are potential prognostic factors for patients with unresectable stage IIIB-IV NSCLC. Although there is evidence that comorbidities may influence the progression of aggressive cancers, patients often die of the cancer before the comorbidity can affect survival [32, 33]. Our present study showed that comorbidity can indeed significantly affect survival in patients with unresectable stage IIIB-IV NSCLC without EGFR and ALK genetic mutations.

TNM staging is an important factor in the prognosis of NSCLC patients. However, for advanced NSCLC patients, such as patients with stage IIIB or stage IV NSCLC, whose tumours have similar biological behaviours, the main treatment and prognosis (unresectable tumours, mainly treatment with chemotherapy and radiotherapy) are very similar. In our study, tumour staging was significant in the univariate analysis of OS but not in the multivariate analysis, indicating that tumour staging is not an independent predictor of OS. For example, most of the chemotherapy drugs are hepatotoxic and nephrotoxic; the most commonly used chemotherapy drug, paclitaxel, isneurotoxic, and the new targeted drug bevacizumab has the side effect of arterial embolization. When IIIB patients cannot be effectively treated because of liver and kidney dysfunction, diabetes, peripheral neuropathy, cardiovascular and cerebrovascular events, and other comorbidities, the OS of these patients may lower than that of stage IV patients without these comorbidities or with less comorbidity. We found that the CCI score was more significantly associated with the prognosis of NSCLC patients than was tumour staging. This finding also shows that the presence of complications may have a certain impact on the treatment of the NSCLC patients, which may affect the prognosis of patients. Comorbidities in patients with aggressive cancers should not be ignored. Further research is needed to determine whether the CCI score is a strong prognostic factor in patients with other cancers and whether it is useful in choosing chemotherapeutics.

This study is limited, first, by the relatively small sample size, as more cases would increase the statistical power of the results. Second, the CCI was not designed specifically for patients with cancer, and some common comorbidities (such as hypertension) have not been incorporated into the CCI. A CCI score that is applicable specifically for cancer patients should be established. Finally, we defined the cut-off CCI score as9 to predict whether patients can benefit from chemotherapy, and this should be confirmed in the future.

The CCI score can be considered an independent prognostic factor for stage IIIB-IV NSCLC patients that do not have EGFR or ALK genetic mutations. Performance status attenuates the strength of the association with the CCI score, but the CCI score is still significantly associated with survival after adjusting for performance status. Smoking status and gender were also found to be independent prognostic factors in this study. More large-scale research is required to further verify whether the CCI score is an independent prognostic factor for the overall survival of patients with NSCLC and other solid tumours.