Worse Prognosis in the Symptomatic Patients With Lung Cancer – Czech Multicentric Study
1Department of Pulmonology, 2nd Faculty of Medicine, Charles University, University Hospital Motol, Prague, Czech Republic
2Department of Respiratory Diseases, Faculty of Medicine, Masaryk University, University Hospital, Brno, Czech Republic
3Department of Respiratory Medicine, University Hospital, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
4Department of Respiratory Medicine, Thomayer Hospital, 1st Faculty of Medicine, Charles University, Prague, Czech Republic
5Pulmonary Department, University Hospital, Charles University, Faculty of Medicine, Hradec Kralove, Czech Republic
6Department of Pneumology, Bulovka University Hospital, 3rd Faculty of Medicine, Charles University, Prague, Czech Republic
7Department of Pneumology and Phthiseology, University Hospital, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
8OAKS Consulting Praha, Prague, Czech Republic
9Institute of Biostatistics and Analyses, Ltd., Brno, Czech Republic
According to the Institute of Health Information and Statistics (IHIS), only 20% of patients were diagnosed with TNM (8th edition of the UICC TNM Classification) stage I and II between 2014 and 2018. Those in TNM stage III and IV accounted for 80% (1). These patients usually show symptomatic disease at the time of diagnosis and a worse prognosis. Some symptoms, especially hemoptysis, can also be a guide for the diagnosis of lung cancer (2). It is also known that some clinicopathological characteristics may correlate with certain symptoms or even with their severity (3). In this respect, however, we believe that it would be more appropriate to describe lung cancer as a whole, whereas the latter study dealt only with adenocarcinomas. The possible relationship of some of these lung cancer symptoms with the poorer prognosis of patients is also described (4,5). However, the Spanish study included only 267 patients, and the British study refers to patients from earlier years and a limited number of institutions. For these reasons, we performed this multicenter study with prospectively collected data that reflects patients from a recent time period and thus with modern therapies. The aim of this report was to describe the symptoms of patients with lung cancer in the Czech Republic on the basis of the (LUCAS-LUngCAncerfocuS) national registry as well as present their correlation to basic clinicopathological data and assess their possible prognostic significance.
Patients and Methods
Data from 3,322 patients in the LUCAS registry with date of diagnosis and complete data on the occurrence of symptoms were used to analyze symptoms in patients with lung cancer. The project was approved by the Ethics Committee of Palacky University in Olomouc on June 11, 2018, under reference number 63/18 MEK 13. All patients signed an informed consent to enroll in the study.
Overall survival (OS) was assessed using the Kaplan–Meier method, where all the point estimates were complemented with 95% confidence intervals. The OS was determined as the time from diagnosis to the patient’s death (for whatever reason). Patients who did not reach the OS value at the time of the set evaluation (July 2021) were censored as at the date of their last known appointment. Statistical significance for the OS was assessed using the log-rank test. The analysis of risk factors was performed using the Cox proportional hazards regression model (one-dimensional and multidimensional regression). Within the multidimensional regression, the categories of the symptoms number were adjusted by age, disease stage, performance status (PS) and tumor type.
Hypothesis testing was performed at the 5% significance level. The analysis was performed using the IBM SPSS Statistics 24 software (IBM, New York, USA).
The comparison of patients divided according to the number of symptoms into three groups (0 symptoms, 1-2 symptoms and 3 or more symptoms) showed that men had statistically significantly more symptoms than women (
The number of symptoms was very closely related to the size of the tumor (T1 through to T4), to the involvement of lymph nodes (N0 to N3), and to the existence of metastases, and therefore to the TNM stages I through to IV (
Cough (exhibited in 47.5% of patients of the entire cohort) occurred equally often in men and women, but was reported more often by younger patients (
Shortness of breath was reported by 45.6% of patients of the entire cohort. There were no differences between men and women, nor between younger or older patients. Smokers reporting higher quantity of pack-years suffered from dyspnea more often (
Weight loss (27.5% in the entire cohort) was more common in men than in women (
In the entire cohort, 9.7% of patients exhibited hemoptysis. When the case histories were collected, hemoptysis was reported significantly more frequently by men than women (11.5%
In the entire cohort, 5.6% of patients had fever before being diagnosed. Fever occurred in both sexes equally, although more frequently in younger (
The occurrence of symptoms significantly affected the probability of survival, even if adjusted according to age, TNM stage, PS, and morphological type of cancer (
Our study describes the symptoms of patients with lung cancer in a uniquely large group of individuals, since the Registry with its prospective inclusion of patients made it possible to focus on the linkage between these symptoms and clinical-anatomical data of patients and survival in the entire cohort. In addition to the usual description of symptoms, we can therefore put an emphasis on their prognostic significance.
Statistically significantly more symptoms occurred in men compared to women, in younger patients, in patients with more pack-years and with lower body weight. Similarly, more symptoms were observed in patients with small cell cancer and in higher TNM stages. These results are in agreement with those of the Spanish study published in 2021 (4). In this study among the group of 267 patients, 33% were asymptomatic, had higher TNM stages patients and exhibited more symptoms; hemoptysis occurred in 11.5% patients. The entire surveyed cohort comprised 16% of asymptomatic patients and hemoptysis was observed in 9.7% of all patients.
When analyzing the individual symptoms within the entire cohort, we found that cough occurred significantly more frequently in younger patients with squamous and small cell lung cancer. Similarly, study performed in the United Kingdom demonstrated the link between the squamous (though not small cell) type of lung cancer and cough (5).
More men than women experienced weight loss. The majority of cases were patients with the squamous type of tumor; patients with adenocarcinoma had lost weight significantly less often before the diagnosis of lung cancer. On the contrary, patients with metastases reported weight loss significantly more frequently than those who had no metastases. The same results (more frequent weight loss in men compared to women, in patients with squamous cell carcinoma and in patients with metastases) have been described in a study from Brazil where a group of 552 patients with stage IV lung cancer was evaluated. They demonstrated a statistically significantly shorter survival of patients suffering anorexia and weight loss compared to patients devoid of these symptoms (6).
More men than women suffered from hemoptysis, which was more common in heavy smokers. Interestingly, we demonstrated a higher incidence of hemoptysis in taller and heavier patients. We were also surprised by the fact that hemoptysis occurred most frequently in patients with middle lobe cancer (14.1%). On the contrary, the fact that hemoptysis was most common in patients with squamous cell carcinoma and that its frequency increased with the size of the tumor confirmed our previous experience and the findings presented in a British study (5).
As far as fevers are concerned, which were reported by 5.6% of all evaluated patients, we were not surprised that they were more common in younger patients. On the other hand, we cannot explain why fevers occurred statistically significantly more often in taller patients. We were also surprised to find out a statistically significantly higher frequency of febrile episodes in patients with involvement of mediastinal lymph nodes (N2). To the best of our knowledge, the scientific literature does not mention any such linkage. The phenomenon could probably be explained by greater pressure on the surrounding bronchi and more frequent pneumonia due to the stenosis.
The survival analysis showed that the symptoms have an unexpected high predictive capacity. We demonstrated that the groups of alive versus deceased patients differed according to the number of symptoms, and that the three groups of patients classified according to the occurrence of symptoms (asymptomatic, 1-2 symptoms, 3 more symptoms) differed significantly in the time of survival, even after adjustment for age. The same conclusions were drawn by Athey
On the contrary, the evaluation of 1,546 patients who underwent lung resection for lung cancer at a thoracic surgery center in the north-west England was concluded without evidence of a better prognosis for asymptomatic
The shorter follow-up of patients (the first subjects were included on June 1, 2018) and the subsequent lower maturity of data for OS evaluation are the limitations of this study.
In conclusion, our study points to the negative predictive significance of symptoms in patients with lung cancer, even after adjustment for age, TNM, PS and morphological type of the carcinoma. This association was further accentuated by the number of symptoms reported by the patients.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this article.
MM and M Svaton conceived the presented idea. MM, ZCH, LFCM, OV, JS, OF, AM, LH, ZG, MH, MJ, JK, DK, MB, JA, M Svovoda and M Svaton conceived and planned the experiments and collected the data. MM, M Svaton and M Svoboda analyzed the data. MM wrote the article with support from M Svaton. JA helped supervise the project. All Authors read and approved the final manuscript.
This work was supported by the project (Ministry of Health) of the conceptual development of the research organization 00064203 (FN Motol), the Czech Pneumological and Phthisiological Society and a grant of Ministry of Health of the Czech Republic - Conceptual Development of Research Organization (Faculty Hospital in Pilsen - FNPl, 00669806).