Medical Oncology Unit, LluísAlcanyís Hospital, 46800 Xàtiva, Spain.
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Aim: The aim was to describe, in a prospective manner, the clinical, histopathological and epidemiological characteristics of lung cancer patients who attended as outpatients at the Lluís Alcanyís, Xàtiva Medical Oncology Hospital, València, Spain from January 2004 to July 2014. We also analyzed survival and compared our data with that reported in the literature.
Methods: Clinical and demographic characteristics were analyzed for the entire series and trends were compared by year of diagnosis. Changes in epidemiology were examined and compared.
Results: There were 701 patients (91.4% were men, mean age 67.6). Main histology was squamous cell carcinoma (41.5%). Squamous cell carcinoma prevailed in men (45.5%) and adenocarcinoma (ADC) in women (60.3%). The percentage of men with lung cancer and of patients with squamous cell carcinoma was higher than in the reported worldwide data and remained throughout the 10 years period. Mean survival was low, with < 10% survivors at 5 years. Stage of disease remained the main prognostic factor for survival.
Conclusion: Squamous cell carcinoma continues to be the most frequent histological type in our area. Male and smoking is associated with lung carcinoma while ADC more often occurs in females. Over the time, our epidemiological and histological patterns have not changed, possibly in relation to maintenance of smoking habits.
Epidemiology, histology, lung cancer, smoking, survival
Epidemiological changes in smoking habits are affecting the pattern of lung cancer patients, with perhaps an increasing number of non-smokers, women involved, and variation in the occurrence of adenocarcinoma (ADC).[1-3] Despite treatment advances in lung cancer, it continues to be one of the most lethal cancers worldwide.
Lung cancer still ranks as the leading cause of tumor-related death in the world. Some important epidemiological factors are age, gender and histology, and these have markedly changed in the past few years. Reasons could be non-smoking policies, population aging, women now smoking, improvement in histological and imaging diagnosis, etc.[2-6] The patterns of change vary, mainly given the heterogeneity of smoking habits in different countries. There is scattered information available concerning the various epidemiological and clinical aspects of lung cancer today, especially in Spain and in daily clinical practice. In order to describe how lung cancer patients are managed at our regional hospital, since 2004, all such patients who were seen at our outpatient oncology unit were prospectively registered into a hospital-based cancer registry. The aim of the present review is to describe their epidemiologic characteristics, focusing on gender, histology and stage. Trends through years were also analyzed.
The primary objective was to describe the lung cancer characteristics of patients followed for up to 10 years, from 2004 to 2014, and to study the evolution of the disease over these years. In addition, we herein describe their epidemiologic characteristics, correlations, and prognostic factors through these years.
This was a single-center study, prospectively performed at the Medical Oncology Unit of our hospital. All patients seen by our medical consultation (not all with a diagnosis of lung cancer) were prospectively included in our database registry. During the study period, our hospital served a predominantly rural community, with a population of about 210,000 in which geographic mobility was low. Our lung cancer medical unit treated and monitored patients by the same oncologist. Candidates for surgery and radiotherapy were referred to other hospitals for treatment, as our hospital does not offer this specialty.
From the records of patients who attended during the study period (2004-2014), the following information was gathered: date of diagnosis, age at appointment, gender and tumor histology (2004 WHO classification). Immunohistochemical markers (CK7, CK20, TTF-1 and p63) have been used at our hospital since 2007.[9-11] Tumor-node-metastasis (TNM) stage by American Joint Committee on Cancer, Seventh Edition, was also utilized. Patients with non-small cell lung cancer (NSCLC) were classified by clinical parameters (clinical TNM), with small cell lung cancer (SCLC) also being classified by TNM system. Dates of death were included, although when the date was undefined based on records, family was contacted. We reported the cause of death (death without disease; death with disease). For patients still alive, the last follow up was recorded as 15th July, 2014. Survival time was calculated from the time of histological/radiological diagnosis. Patients had to have at least one month of follow up.
Genetic testing, when performed, was for epidermal growth factor receptor (EGFR) and other NSCLC-driving mutations. Screening for drug-sensitive EGFR mutations was conducted as part of a clinical assistance program, since June 2010, by peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp-based testing. Those not analysed have been recorded as “not determined”. Anaplastic lymphoma kinase (ALK) translocations were determined via fluorescence in situ hybridization since June 2012. We did not study K-RAS mutations as part of standard of care. Other aspects relevant to prognosis, such as the Eastern Cooperative Oncology Group score, treatment type, weight loss, smoking habits were not recorded.
Results were expressed as means (standard deviation) and percentages. The relationships between different variables were evaluated. Statistics of contrasts, such as Chi-square, Mann-Whitney U, or Kruskal-Wallis H test, were used for comparisons of two variables. Estimations are accompanied by 95% confidence intervals. Statistical significance was set at a value of P < 0.05. Survival time was defined as the period from the date of first visit to date of mortality or last follow-up. Survival date was updated on July 15, 2014. In addition to the estimation of the survival rates by Kaplan-Meier method, patients were classified into groups for comparison of their demographic and clinical characteristics as follows: gender, stage, and histology. The same classification was made for comparison of survival by year of diagnosis.Statistical analysis was performed using SPSS 12.
The institution’s ethical reviewboard approved the study, and all patients provided writteninformed consent and gave permission before study entryto collect their clinical data for scientific purposes and publication.
From January 1, 2004 to June 15, 2014, 701 patients were included at our series. Patients’ characteristics are shown in [Table 1]. We found an aged and male-predominant population (mean age: 67.6; 91.4% were male).
Patient characteristics (n = 701)
|Mean, range||67.6 (34-94)|
|Small cell||120 (17.1)|
|Non-small cell||556 (79.4)|
|Large cell carcinoma||43 (6.1)|
|Carcinoma not typed||15 (2.1)|
|Sarcoma-squamous (carcinosarcoma)||3 (0.4)|
|Neuroendocrine tumors||11 (1.6)|
|Stage at diagnosis|
|Mean, range||25.58 (22.1-29)|
|Situation at last follow-up (July 15, 2014)|
|Alive without disease||42 (6)|
|Alive with disease||115 (16.4)|
|Death without disease||23 (3.3)|
|Death with disease||521 (74.3)|
|Situation at last follow-up (July 15, 2014)|
Only 59 (8.4%) patients were women [Figure 1]. This low incidence maintained across the years. We found a slightincrease of women from 2010 to 2014 (P = 0.045). A ratio of almost 9:1 was maintained across the years. Female was related to younger age (P = 0.001), histology (adenocarcinoma and small cell: P = 0.001), stage IV (P = 0.02) [Table 2].
Comparison between men and women
|Male n (%): 633 (90.3%)||Female: n (%): 68 (9.7%)||Chi-square Pearson|
|Mean (range)||68 (34-94)||63.3 (34-88)||P = 0.000|
|Histology, n (%)|
|Unconfirmed||23 (3.6)||1 (1.5)||P = 0.000|
|Small cell||109 (17.2)||10 (14.7)|
|Squamous||288 (45.5)||4 (5.9)|
|Adenocarcinoma||146 (23.1)||41 (60.3)|
|Large cell carcinoma||39 (6.2)||4 (5.9)|
|Carcinoma not typed||9 (1.4)||6 (8.8)|
|Sarcoma-squamous (carcinosarcoma)||3 (0.5)||0|
|Neuroendocrine tumors||10 (1.6)||1 (1.5)|
|Stage at diagnosis|
|0||0||1 (0.6)||P = 0.02|
|I||66 (10.4)||7 (10.3)|
|II||48 (7.6)||4 (5.9)|
|III||162 (25.6)||8 (11.8)|
|IV||357 (56.4)||49 (71.4)|
Histology related to smoking habit (SCLC and squamous cell lung cancer (SQCLC)) predominated (121, 17.2% SCLC and 291, 41.5% SQCLC) [Table 1].
Trends through years showed a decline in SQCLC. Although it was the main histology (incidence 37-45%), in later years, we found a significant increase in adenocarcinoma (ADC) (32-40%) and a significant and relevant increase in SCLC (last date near 20-25%) (P = 0.0001) [Figure 2].
A tendency ofan increaseof earlier stages in the last years is shown in Figure 3 (P = 0.063). There was also a decrease in stage IV and an increase of stage III patients. Stage was related to gender (female and stage IV, P = 0.024). For histology and stage, we found a relationship (P = 0.03) between squamous cell and stage III and between ADC and stage IV. When we studied correlations between stages and histology, we found more early stage patients with NSCLC (P = 0.015). SCLC was related to advanced stage. Genetic testing for EGFR and other NSCLC-driving mutations was performed only for stage IV patients, with only EGFR and ALK being analysed. Only ADC had EGFR-activating mutations (4% of all ADC, 3.2% all NSCLC, stage IV). Female ADC was related to EGFR mutation (11 patients, 36% of women). Only 1.7% of ADC in men had EGFR mutations. No patients in our series had ALK rearrangement.
Survival time was ascertained for all patients. Median overall survival (OS) for the entire series was 25.5 months (22-29) [Figure 4]. At last follow-up, 22.4% of patients were alive and 77.6% were deceased. There were 6.1% (43) alive without disease, 16.5% (115) alive with disease, 3.3% (23) were dead without disease, and 74.1% (520) were dead from lung cancer. The only significant prognostic factor for OS was stage (P = 0.000). Stage was a predictive factor for better survival and remained significant through all years. It shows OS by stage. [Figure 5] Histology was unrelated to survival by stages, except for stage IV (P = 0.003). Through the years, survival for stages I and II decreased, it maintained for stage III, and had an increase of 2 months for stage IV [Figure 6]. As death by other cause is important for OS, we analysed causes of death. Only for stages I (26.8%) and II (5.8%) were there deaths without disease. For stages III and IV, lung cancer was the main cause of dead for all patients. Gender and histology were only related to survival for stage IV. Women with ADC and neuroendocrine differentiation had better survival (P = 0.021), while men with squamous cell carcinoma had better survival (P = 0.044), both groups in stage IV. Also, molecular prognostic factors, in particular mutated EGFR was related to better survival for stage IV [17.3 (10.3-24.3) months vs. 10.4 (9-11) months; P = 0.02] but when weanalyzed females, there was no difference in survival with women with EGFR-mutated vs. wild type or unknown ADC (EGFR-mutated (16.7 months) vs. wild type or unknown (14.8 months, P = 0.54).
Median OS for stage IV patients was nearly 12 months and there were 100 patients with median OS of 12 months or more in this stage (24.6%). Median OS for those with less than 12 months was only 5 months (4.6-5.3). For those surviving more than one year, OS was 26.5 months (23-30 range) (P = 0.0000). Prognostic factors related to longer survival with stage IV were: female (P = 0.000), histology (ADC and neuroendocrine), and EGFR mutation for men only. Longer survival was statistically significant related to year of diagnosis (2011 and 2012, P = 0.006).
After the analysis of our ten years data base, we have found that lung cancer in our region remains a disease of smoker men. The predominant cause oflung cancerin men is active cigarette smoking. From our date, we cannot check the hypothesis that women are more susceptible than men to smoking-inducedlung cancer. What we have found is that young women are smokers and elderly are non-smoker lung cancer patients. However, aspects of lung cancer in men and women continue to indicate potential male and female differences in the etiology of lung cancer, which based on several observations. Among never smokers, women have higherlung cancerincidence rates than men. There are different clinical characteristics oflung cancerin women compared with men, such as the higher percentage of ADC in never smokers, the greater prevalence of EGFR gene mutations in adenocarcinomas among never smokers, and better prognosis. Our study reports on the variation in lung cancer patterns and trends across 10 years in a single center registry.[13-16] Special attention has been given to gender, histology, stage, and survival. We found a high incidence of lung cancer in men that maintained across the years. The majority of patients were diagnosed at advanced stage and overall survival remained poor for all the series. Stage was the main prognostic factor for survival.
The predominance of lung men in our series has been reported yet in Spain[17-20]. The current male-to-female ratio in the USA is close to one.[21,22] In Spain, the ratio of males to females with lung cancer is still high,[23-25] especially for rural areas, such as the ours. In any case, the male-to-female ratio is still substantially higher in Spain (8.5 in 2003)[26,27] than in other western countries, where it varies between 1.3 and 4.5likely due to the much more rare habit of smoking in women than in men.[2,4,28] It’s known that over 95% of Spanish male lung cancer patients smoke. Anti-tobacco policies had been introduced in Spain only in recent years.[20,28] So the reason for the predominance of male patients in our area could be explained by tobacco use. We have not specified tobacco habits of our series, but almost 90% were likely current or former smokers. There is a popular type of manufactured cigar, named “caliqueño”, without filter, and not low-tar so that smokers maintained the profile of tobacco users (not inhaling deeper, so generating central tumors, as squamous and small cell cancers).
In our rural area, in the non-smoking population, the incidence of lung cancer is higher among women. For women, we found a dual distribution: those aged developed ADC and never were smokers while younger ones developed cancer type related to smoke, as SCLC. Recent findings also suggest that women may be somewhat more susceptible to the carcinogenic effect of tobacco,[31,32] although this remains a matter of debate.
Respect to histology, in our area we found a predominance of squamous and small cell cancer through the years. This distribution is different from those worldwide. Worldwide, the trend is towards an increase in the proportion of adeno- and a decrease in squamous cell carcinomas, although the rate of change varies across different geographical areas. This change has mainly been attributed to the decline in the number of smokers and the more widespread consumption of filtered cigarettes in USA. In spite of the proportional decline over the last 20 to 30 years, squamous cell carcinoma is still the most common histological subtype among males in several European countries (37% in France, 44% in Poland and 45% in Holland). In Spain, squamous cell carcinoma is the most common subtype with percentages varying between 24% and 50% in local and regional registries and SCLC still accounts for some 20% of cases in most Spanish registries. In United States, ADC (40%) is the most common subtype, followed by squamous cell carcinoma (25%) and large cell carcinoma (10%). Incorporation of women into tobacco use worldwide and smoking filtered cigarettes that are low in nicotine could partiallyexplain the rise in the rate of ADC worldwide.[28,33] We found a relationship between histology and gender as squamous and small cell cancers prevailed in males, and ADC in females. In our series as in most series, stage IV remained the most common stage. However, our series distribution by stage has changed through the years, with a decrease in stage IV and increase in stage III. We have not implemented yet the lung cancer screening. We cannot explain this tendency change on stage across years.
OS for our entire series remained low. Overall 5-year survival rate for all stages of lung cancer, worldwide, is 17%. Our 5-year OS for all series was 15% and the only factor related to survival was stage. For stage IV, a median increase of 2 months was seen through years with a better prognosis in the latest years. When we analysed stage IV patients, we found a double distribution. Those that did not survive more than 12 months had a median OS of only 5 months. Although long survival in lung cancer has been described and is a matter of interest, shorter survival patients are still more common and should be a matter of study to know why there are so many patients with this discouraging overall survival. For long survival at our data base, the main factor was a molecular prognostic factor (EGFR mutation). There was an interaction between female gender, ADC histology, and EGFR mutation, as women with adenocarcinoma were near all mutated. Our series had a low percentage of patients with EGFR activating mutations. However, most patients hadn’t been tested for EGFR status. Probably, the low rate of men with ADC EGFR mutations (only 1.7%) could be explained by the high rate of smoking habit in this population.
Our work has some weak points. Despite the importance of a long follow-up time, our work is not as accurate as it could have been. In fact, first we presented a hospital-based cancer registry of outpatient service; therefore a selection bias could not be excluded. Population-based cancer registries should be preferred. However, in Spain, in spite the many efforts[17-20] no more than 26% of the Spanish population (28% in the case of childhood cancer) is covered by cancer registries and the distribution of them is not random. Second, we have not considered other prognostic factors, such as performance status or treatment. Thus, we must be cautious with conclusions. Treatment could be one of the explanations of why women with ADC had no differences on survival depending on EGFR status. In our country, lung cancer patients have access to EGFR TKI on second and third line, regardless on EGFR status. and most of these patients may have received EGFR TKI. Despite this bias and weaknesses, we believe on the value of having own clinical real date, if all admit that cancer is an individual disease, and probably, lung cancer is different according to epidemiology characteristics.
In conclusion, this single centre analysis suggests that at least at our region, lung cancer remains a men disease and tobacco related cancer. Advances and improvements on overall survival seemed to have been achieved only in those tumors unrelated to smoking (non-smoker women EGFR mutated patients). Efforts to reduce tobacco use and carry on with improvement in treatment could modify this disappointing survival for our patients.
There are no conﬂicts of interest.
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