This population-based cohort study revealed that both a single comorbidity and multimorbidity were consistent and independent prognostic factors of short-term mortality among lung cancer patients in Spain. Six months after diagnosis, lung cancer patients with one or multiple comorbidities had a 40% higher risk of all-cause mortality than those without comorbidities, after adjusting for age, sex, histology, smoking status, province of residence, performed surgery, BMI, and tumour stage. We found high prevalence of comorbidity in lung cancer patients, especially among the elderly; men; those diagnosed with advanced-stage; smokers and obese patients.
We confirmed findings from other population-based studies that found comorbidity to be prognostically relevant and associated with lung cancer mortality, after controlling for relevant confounders, such as age, sex, or stage at diagnosis [27,28,29,30]. This association was not replicated in other, mainly smaller single-centre studies [12,13,14]. The discrepancy may be because the latter were single-centre studies that failed to take into account relevant confounders, [12,13,14] or dated population-based studies where common comorbidities, such as cardiovascular diseases, were underreported . Sandfeld-Paulsen et al.  argue that the association between comorbidity and lung cancer mortality can be detected only by using register-based data, including reliable information on all cancer patients in a defined region and time period. However, the main disadvantage of population-based studies is that they often fail to consider relevant lifestyle and behavioural factors, such as smoking status. To the best of our knowledge, our study is unique in revealing that this association remains stable after controlling for relevant lifestyle factors, such as obesity and smoking status. Furthermore, the estimated mortality risk in our study was in line with a review of studies, which concluded that mortality in lung cancer patients was between 1.1 to 1.5 times higher for patients with than those without comorbidity .
We did not find that the mortality risk was higher with an increasing number of chronic conditions, since the presence of either comorbidity or multimorbidity had comparable impact on lung cancer mortality. Results from previous studies are conflicting; while some studies found this gradient, [29, 32] others did not [14, 33]. This may be partly attributable to patients’ clinical characteristics. Studies including early stage lung cancer patients were more likely to report that multimorbidity contributed to increased mortality, while those including patients with advanced-stage cancer did not find multimorbidity had any important prognostic value . For patients with early-stage lung cancer or any potentially curable cancer, such as early-stage breast or prostate cancer, the presence and number of comorbid conditions may be more likely to predict their mortality risk [9, 10]. On the other hand, patients diagnosed with advanced-stage disease or more aggressive cancers with poor prognosis, such as lung cancer, are more likely to die from their cancer regardless of other concomitant disease.
We found that the impact of comorbidity on lung cancer mortality was independent of cancer stage or patients’ age, but these factors may be prognostically complementary to comorbidity status . Elderly patients with metastasis had a two times higher mortality risk than younger patients without metastasis, confirming findings from previous studies [27, 34]. We argue that advanced age is a prognostic factor of mortality, because the elderly tend to receive less active lung cancer treatment, including less chemotherapy, radiotherapy or surgery than younger patients .
Although surgical resection remains the main and most effective lung cancer treatment, it is only indicated in early stage tumours . Our study included 16% of patients with stage I and II tumours, with the matching 16% of performed surgeries. The probability of successful surgery is further reduced with advanced age and the presence of comorbidities, mainly due to the expected higher incidence of postoperative complications [15, 37]. Evidence suggests that between 24 and 70% of cancer patients with comorbidity are not treated according to guidelines . We did not have reliable information whether surgery was performed with curative intent. Even if a small number of patients had surgery, we found that it was highly protective of mortality risk. Therefore, we argue that in most cases surgery was performed with curative intent.
Sex did not affect the short-term mortality, when relevant confounders were considered, although women had lower mortality risk than men. Consistent with our findings, other studies found that lung cancer mortality trends were higher among women than men, but mortality rates were still higher among Spanish men [38, 39]. An increasing trend of tobacco use among women and the decreasing trend among men may contribute to this . Granada had consistently higher overall short-term mortality than the wealthier Northern region of Girona, which confirms that social inequalities may play an important role in lung cancer mortality .
Comorbidity remains more prevalent among patients diagnosed with lung than other cancer types [10, 17, 41, 42]. A possible explanation may be found in lifestyle factors contributing to lung cancer, especially smoking and obesity - the main risk factors for many chronic conditions [17, 29]. An estimated 26–81% of lung cancer patients have at least one other chronic medical condition i.e., comorbidity, consistent with our results . A large population-based cohort study, done in Canada, found that almost all (91%) people diagnosed with different types of cancer had other chronic medica conditions; and almost a quarter (23%) of them had five or more co-occurring conditions . They found that lung cancer patients had among the highest prevalence of multimorbidity than patients diagnosed with 15 other types of cancer, and early death most commonly occurred among the lung cancer patients. Different from Koné and Scharf, however, is that we did not find that mortality is increasing with higher number of chronic medical conditions. This may be because instead of focusing on patients diagnosed with a range of different cancers, we analysed lung cancer patients only, who have worse prognosis and higher mortality than most other cancer patients. Moreover, we adjusted our analysis for lifestyle factors, such as smoking and obesity status, and clinical factors, such as tumour histology and surgery, which may contribute to this discrepancy.
We confirmed high smoking prevalence among lung cancer patients in Spain . Smoking contributes to over 80% of lung cancers in high-income countries, and, therefore, preventive strategies require strict tobacco control . The most common comorbid conditions were age- and tobacco-related illnesses, such as respiratory (e.g., COPD) and cardiovascular (e.g., heart failure) diseases, consistent with earlier studies [15, 36]. Significant overlap occurs between symptoms of these diseases and lung cancer, including cough, dyspnea and chest tightness . Another common comorbidity, unrelated to tobacco use, was diabetes, sharing the same risk factors with lung cancer, such as age, diet and smoking [36, 45]. Our findings highlight the most prevalent comorbidities among lung cancer patients and the pattern of correlations between the most common comorbidities. This highlights the need for further research to better understand the relationships between these chronic conditions and how they might interact. For example, are patients with comorbidities more likely to be diagnosed with lung cancer early because of their frequent medical appointments, or they are more likely to have delayed diagnosis because the symptoms of their comorbid diseases are masking early signs of lung cancer? Future studies should also explore whether these common comorbidities have an additive or a multiplicative effect on lung cancer mortality.
The majority of patients in our study had advanced-stage cancer, probably because early lung cancer symptoms are hard to recognise or they overlap with other diseases, such as COPD, causing delays in diagnosis . A national lung cancer awareness campaign was introduced in England, following reports that early symptoms, such as “persistent cough or hoarseness” were least frequently recognised by the public, especially among the elderly, males and the socioeconomically disadvantaged people, who also reported most barriers to seeking medical help . The campaign achieved an increase in the number of medical appointments and diagnostic tests, as well as a shift towards an early-stage lung cancer diagnosis, when outcomes are more favourable [47, 48]. There are currently no national campaigns in Spain aimed at raising awareness about early symptoms of lung cancer and encouraging early diagnosis. Introducing such campaigns may have long-term benefits for lung cancer patients in Spain.
This is the first high-resolution study addressing the effect of comorbidity on short-term overall mortality among lung cancer patients in Spain. Accessing patients’ EHRs allowed us to enrich data from two population-based cancer registries addressing lifestyle factors, such as smoking and BMI, not often assessed in population-based studies. We used multiple imputations to address missing values, performing analyses with both observed and imputed values. We used a relatively reliable comorbidity measure, reducing the possibility to misclassify the comorbid conditions, but some residual bias is possible due to unmeasured comorbidities.
This study has limitations. First, data were collected during 2011 and 2012, because the data collection was part of the European High Resolution studies and this was the most complete population cohort available. Although this must be considered when interpreting the results, it is unlikely that the distribution of lung cancer incidence and main comorbidities would be significantly different in the more recent years. Second, we were unable to perform analysis including the malnourished patients (i.e., BMI category < 18.5 kg/m2) due to a small number of cases in this category (N = 22). Future studies should explore the role of malnutrition, especially among the elderly, as it may contribute to adverse health outcomes, such as a more advanced neoplastic disease or COPD. Third, the RCS is a simple measurement, created to compare comorbidity in patients planned for a surgical intervention. Using this score can simplify the data collection from digital medical records, but some conditions may be excluded, such as psychiatric diseases, other neoplasms, hypertension, non-COPD chronic respiratory diseases or autoimmune diseases. Therefore, the presence of different comorbidities may be underrepresented, and its impact on short-term lung cancer mortality may be even higher than we estimated in this study. Fourth, the prevalence of comorbidities might not be applicable to other regions or countries. However, the clustering of chronic conditions is likely to have a synergistic effect on health outcomes, regardless of geographical coordinates. Finally, we did not have information on other lifestyle factors, such as exercise, diet, alcohol consumption, the onset and duration of smoking or detailed socio-demographic descriptors, such as patients’ income. Future studies should investigate these factors and include data from all population-based cancer registries in Spain.