FACTORS ASSOCIATED WITH MORTALITY IN PATIENTS WITH GASTRIC CANCER AT A REFERENCE HOSPITAL

Background:Gastric cancer (GC) is the second cause of death by tumor in the world. In Brazil, the survival rate of patients with GC is only five years, due to the low rates of early diagnosis, with about 10 to 15% of the cases. Thus, this study aims to evaluate the factors associated with mortality in CG patients treated at a reference hospital. Method: The study was carried out based on the survey of 96 medical records of patients diagnosed with GC, whose analyzed data were: sex, age, educational level, occupation (socioeconomic level), and risk factors, such as smoking, alcohol consumption, family history of cancer, staging and type of treatment adopted, among other variables. Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS-PC) and Kaplan-Meier for survival analysis. Absolute and relative frequencies were calculated for all variables. Results: The sample consisted mainly of male patients with stable union, brown-colored, who lived in the metropolitan region and presented low schooling. In addition, risk factors such as smoking and alcoholism presented a high prevalence in the sample. Regarding mortality, factors such as arterial hypertension (p = 0.1581), diabetes (p = 0.3212), and alcohol consumption (p = 0.6704) were not associated with increased mortality in this study. Conclusion: The clinical and epidemiological profile of patients with GC presented a low degree of tumor differentiation, with predominance of the mixed or unclassifiable subtype. In addition, the majority of the sample was composed of patients living in the metropolitan region and the main form of treatment adopted was surgical intervention in combination with chemotherapy.

 Introduction

Gastric cancer (GC) is the second most common reason for death due to tumor in the world, being more frequent in individuals over 50 years of age (approximately 65% of occurrences) [1][2].

In Brazil, where health systems and policies aimed at prevention are lacking, this category of cancer accounted for 14,182 deaths in 2013 [3]. The survival rate of Brazilian patients for gastric cancer is only five years and less than 30%, which is contrary to the rate of countries such as Japan and South Korea, of 60%. This low survival is directly related to the low rates of early diagnosis (10 to 15% of cases), which is essential to increase the chances of cure [4].

According to data from the (Brazilian) National Cancer Institute, the gastric tumor is among the most deadly in Brazil, with the third highest occurrence in men and fifth in women [5]. The incidence of individuals with this disease varies in different Brazilian regions, and its high incidence is related to poor eating habits and poor basic sanitation [6]. In the state of Maranhão, for example, a total of 370 new cases of gastric cancer per 100,000 inhabitants were estimated in 2016. In the city of São Luís, the estimate is around 130 new cases per 100 thousand inhabitants in 2016 [7].

The factors for developing stomach cancer are multivariate and are not fully understood. Some of them may be infection with Helicobacter pylori (considered the main cause of GC); diets with excess processed meat (source of nitrite and nitrate), salt and carbohydrate; high consumption of drugs such as alcohol and tobacco; family members with this category of cancer; presence of other diseases such as intestinal metaplasia and chronic gastritis; advanced age; being male; and low socioeconomic status. On this latter, the lack of basic sanitation and houses very close to each other are disseminating factors of H. pylori [8].

The clinical manifestations of GC depend on the stage at which the disease is diagnosed. In the early stage, 80% of patients may be asymptomatic; and in other stages, the symptoms may be non-specific [9][10]. About 90% of GC cases are diagnosed late, leading to poor prognosis [11][12].

The GC prognosis is based mainly on the pathological aspects of staging at diagnosis and is related to the depth of tumor invasion and the presence of metastatic lymph nodes. Thus, the most important indicators of the prognosis of the disease are: the damage to the lymph node groups; the age at diagnosis; and the histological type [13][14].

These characteristics will define the course of treatment. Therefore, the surgical approach for healing purposes, involving gastrectomy and lymphadenectomy, is considered the only intervention capable of prolonging survival [15]. However, surgery is also recommended in the palliation of symptoms in cases of advanced disease that, although having exceeded the possibility of cure, present a formal surgical indication due to hemorrhage or tumor obstruction [16][17].

In view of the above, the present study aims to evaluate the factors associated with mortality in patients with GC living in a region with a high index of this type of neoplasia.

Materials and Methods

This is a cross-sectional, descriptive and retrospective study based on the medical records of patients diagnosed with GC, attended at the Tarquínio Lopes Filho General Hospital (Cancer Hospital) in São Luís - MA. All procedures and protocols were approved by the Ethics Committee (Protocol No. 1,756,464).

The present study requested the exemption of the Informed Consent Form (ICF) because it is a post-factum research and does not involve contact with the subjects in any stage of the research, following the ethical aspects contained in Resolution 196/96 of the National Health Council [18].

The inclusion criteria were patients of any age and sex, attended at the Cancer Hospital with a diagnosis of GC and who had undergone oncological (curative or palliative) treatment between the year 2011 and 2016. Patients without the surveyed information available and patients who were undergoing treatment were not included in the study. A total of 96 medical records of GC patients attended at Cancer Hospital between 2011 and 2016 were randomly selected. Data analyzed were sex, age, educational level, occupation (socioeconomic level) and risk factors such as smoking, ethnicity, family history of cancer, and type of treatment adopted, among other variables.

The data was tabulated in spreadsheet using the Microsoft Office Excel 2007 for Windows program. The Statistical Package for the Social Sciences (SPSS-PC) and the Kaplan-Meier method for survival analysis were used for the statistical analysis. The absolute and relative frequencies (%) were calculated for all variables.

Results

In the study, 96 medical records of patients diagnosed with GC in the years 2011 to 2016, attended at the Tarquínio Lopes Filho General Hospital (Cancer Hospital) in São Luís – MA, were analyzed. Data on socioeconomic, demographic and risk factors are shown in Table 1, with the absolute and relative frequency of clinical variables.

Variable n %
Sex
Male 61 59.5
Female 35 40.5
Age at diagnosis (years)
Up to 25 1 1.1
26-40 7 7.5
41-60 43 46.2
Above 60 42 45.2
Marital status
Single 14 15.4
Married/Stable Union 72 79.1
Separated/Divorced 1 1.1
Widowed 4 4.4
Ethnicity
White 13 21.7
Brown 40 66.7
Black 6 10
Yellow 1 1.7
Origin
Metropolitan region 53 55.2
Interior of Maranhão 43 44.8
Schooling
Illiterate 8 10.7
Elementary School 45 60.0
High school 19 25.3
Higher education 3 4.0
Risk factors
Smoking 36 40.0
Alcoholism 38 42.2
Positive H. pylori 17 18.9
Family history of cancer 29 48.3

In relation to sex, the present study presented a higher prevalence of males, with 61 (59.5%), while females were represented by 35 (40.5%) individuals. The mean age of GC diagnosis ranged from 25 to 60 years, with a higher incidence among people aged 41 to 60 years (46.2%). Regarding the patient's age in the hospitalization period for treatment, there was prevalence of people aged 41 to 60 years (46.9%).

We observed the predominance of married people/in stable union, represented by 72 (79.1%) patients. In relation to ethnicity, the brown color was the most prevalent, with 40 (66.7%) patients, followed by the white color, with 13 (21.7%), black color, with 6 (10%), and yellow color, with 1 (1.7%) patient.

Of the analyzed patients, 53 (55.2%) came from the metropolitan region, and 43 (44.8%) lived in the interior of the state of Maranhão. In addition, there was a low level of schooling in this sample. Among the 96 charts analyzed, 45 (60%) were patients who studied until elementary school, 19 (25.3%) studied until high school, only 3 (4%) were patients with higher education and 8 (10.7%) patients were illiterate.

The use of tobacco is a factor closely associated with the presence of GC, being characterized as a risk factor. In the present study, 36 (40%) of the patients reported smoking. Regarding alcohol consumption, 38 (42.2%) patients reported consuming alcoholic beverages. H. pylori infection was confirmed in 17 (18.9%) patients, however this information was not available in 79 (81.1%) medical records. On the family history of cancer, 29 (48.3) patients report that there are cases of GC among family members.

Regarding the histopathological characteristics, 29 (30.2%) patients presented initial degree of tumor differentiation, 17 (17.7%) presented the tumor in a moderate state of differentiation, 12 (12.5%) presented the tumor in a well differentiated state and 38 (39.6) patients did not present this information available in their medical records (Table 2).

Variable N %
Degree of differentiation of tumor cells
Well differentiated 12 12.5
Moderately differentiated 17 17.7
Poorly differentiated 29 30.2
Undifferentiated 38 39.6
Subtype
Diffuse 25 26.0
Intestinal 20 20.8
Mixed or Unclassifiable 37 38.5
Other types of cancer 14 14.6
Treatment
Exclusive surgery 28 29.4
Surgery + adjuvant CT 33 34.5
Surgery + adjuvant CTRT 9 9.6
Exclusive CT 15 15.7
CTRT 2 2.3
Ignored 8 8.5
TOTAL 96 100

CT, chemotherapy; CTRT, chemotherapy and radiotherapy.

The most common subtype was mixed or unclassifiable, present in 37 (38.6%) patients; followed by the diffuse subtype present in 25 (26%) patients; and the intestinal subtype present in 20 (20.8%) patients. Other cancer subtypes were found in 14 (14.6%) of the medical records.

Regarding the type of treatment performed for GC, according to the analyzed records, 70 (73.5%) patients had undergone surgery, of whom 33 (34.5%) received adjuvant chemotherapy and 9.6% chemotherapy and adjuvant radiotherapy. In addition, 15 (15.7%) patients received exclusive chemotherapy, 2 (2.3%) received only chemotherapy and radiotherapy, and 8 (8.5%) patients did not present this information on the medical records (Table 2).

In relation to the survival rate of GC patients in the period evaluated, factors such as arterial hypertension (p = 0.1581), diabetes (p = 0.3212), and alcoholism (p = 0.6704) were not associated with increased mortality in this study (Fig 1, Fig 2 and Fig 3).

<fig id="figure-5e1898e9920c2e64c22c5b091a30c297"> <label>Figure 3. Stratified survival curve for alcoholism</label> <caption id="caption-a8270390526b4401ceaf9aa5b4485481"> <title>

</sec> <sec id="heading-8b7cb42658ca092049d4b2eee6b80ca3"> <title> Discussion

The objective of this study was to evaluate the factors associated with mortality in GC patients treated at a reference hospital in São Luís, Maranhão. The analysis of the information contained in the medical records showed that the sample consisted mainly of male patients, in stable union, brown, living in the metropolitan region and with low educational level. In addition, risk factors such as smoking and alcoholism were found to be highly prevalent in the sample; H. pylori infection was confirmed; and patients report that there are cases of GC among family members.

With regard to age, it was observed that, as in other studies [19][20], the incidence of gastric cancer increases markedly with age. Other studies [21][22], suggest that the individual risk of stomach cancer is established near or below 40 years and that the increase in its incidence occurs predictably after this age.

According to a study [23], the incidence increases progressively with age, with peak incidence between 50 and 70 years. Only 2% to 9% of all gastric cancer patients are under 40 years of age. In this way, the incidence of GC increases in adulthood because aging impairs the efficiency of physiological processes and causes the reduction of mechanisms of protection and reparation of the gastric mucosa. Also, the harmful effects of the environmental risk factors become more evident, and one’s unfavorable lifestyle changes the cellular processes, resulting in the development and progression of cancer [10].

These results corroborate with the existing scientific literature regarding the predominance of this type of cancer among males [24], consumers of alcohol and tobacco and with low educational level. This aspects are associated with delay of more than 30 days until the first treatment, demonstrating that not only clinical aspects, but also socio-cultural patterns interfere in the search for treatment [25].

In the present study, 38% of patients diagnosed with GC confirmed to be both alcoholics and smokers. According to a study [2], smoking is an important risk factor for developing GC. Since 2002, the IARC has said there is sufficient evidence of causality between smoking and GC. Other epidemiological studies [25][26], suggest that alcohol plays a key role in carcinogenesis, especially for cancers of the mouth, pharynx, larynx, esophagus and stomach, due to its greater effect on directly exposed tissues during consumption and for having a synergic action with tobacco. The duration of smoking time is also a factor that influences carcinogenesis. Even after interrupting it, the reduction of risk does not seem to be immediate, and ex-smokers are usually at increased risk [27]. In this way, there is evidence that alcohol and tobacco are important risk factors for developing GC.

Most patients in the present study were brown-colored and, in general, those with lower levels of education and low income were the most affected. A study [28], demonstrated that the low socioeconomic level strongly points to a greater risk of developing GC. Disadvantaged social groups tend to have less access to health services. Helicobacter pylori infection was confirmed in 18.9% of the patients, however, in 60% the information was not available in the medical record, and it was impossible to conclude whether no survey was done or if the result was negative.

According to the histopathological analyzes and the treatment adopted by the patients, the classification of malignant tumors of the evaluated sample was found to be more prevalently in stage IV (34%), followed by stages IIA, IB and IA with 11, 9 and 8%, respectively. This result is partly explained by the precarious public health practices practiced in relation to gastric cancer in Brazil, where the patients arrive at the hospital with a late diagnosis of the disease and are treated lately, obtaining little chance of cure when compared to the international centers of excellence, such as those located in Japan [28][29]. Another possible explanation is that patients in the early stages are often asymptomatic and therefore the diagnosis is made late in the vast majority of Western countries [30][31].

Regarding the treatment, in the findings of the present study, surgery was mandatory in most patients, of whom about 73.5% were submitted to some type of procedure. As demonstrated in a study [32], depending on staging of the disease, the main treatment is the surgical one. This is because the main treatment of gastric adenocarcinoma is tumor resection [33], and the type of gastrectomy to be performed will basically depend on the location of the tumor and the desired surgical margin. In proximal tumors, total gastrectomy is performed, whereas in the distal tumors, especially when well differentiated, subtotal gastrectomy can be performed [34][35].

Another treatment option is the use of chemotherapy as a neo-adjuvant or adjuvant therapy. In addition to tumor resection, the use of chemotherapeutic agents in T3/T4 or N1/N2/N3 tumors is currently recommended [35]. In the present study, chemotherapy was present in the treatment of 62.1% of patients, distributed as adjuvant treatment associated with surgery in 35.5%; as adjuvant treatment associated with surgery and radiotherapy in 9.6% and as exclusive chemotherapy in 15.7%.

The time of hospitalization to perform the treatment was an average of 26.6 days (± 52.6) for all the patients analyzed. In addition, in the present study, 82 patients had been discharged from hospital and 13 died during this period. Some studies [26][36][37], state that in many parts of the world, more than 90% of GC cases are detected in advanced stage. It is worth noting that the present study presented limitations in relation to some variables due to the absence of the information in the selected medical record and/or because the patient was hospitalization. The patients who were being treated for GC were excluded from the analysis.

In conclusion, we conclude that the clinical and epidemiological profile of patients with GC presented, in the majority of cases, a low degree of tumor differentiation, with a predominance of the mixed or unclassifiable subtype, and factors such as hypertension, diabetes and alcoholism did not present association with increased mortality in the present study. In addition, the majority of the sample was composed of patients living in the metropolitan area, and the main form of treatment adopted was the surgical intervention in combination with chemotherapy.

Acknowledgements

We thank all the medical and administrative staff of Tarquínio Lopes Filho General Hospital for the support and availability during the period of this research.

Funding

The study was not funded.

References 1-6. p 2012 IARC Cancer Bases Globocan 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012 228 34. p 2017 Silva RD DM Incidência do carcinoma basocelular e espinocelular em usuários atendidos em um hospital de câncer I. I Estimativa de cancer no Brasil 2014:p. 2016 1 24.P 2017 Sales ML GA Fatores de risco no desenvolvimento de câncer gástrico 2015 PP S Instituto Nacional de Câncer 5 05 963-972 85 2017 10.1016/j.gie.2016.10.013 Sekiguchi Masau Oda Ichiro Suzuki Haruhisa Abe Seiichiro Nonaka Satoru Yoshinaga Shigetaka Taniguchi Hirokazu Sekine Shigeki Saito Yutaka Gastrointestinal Endoscopy Clinical outcomes and prognostic factors in gastric cancer patients aged ≥85 years undergoing endoscopic submucosal dissection 400 411.p 2011 Subirat Esquivel L GID Algunas consideraciones actuales sobre el Cáncer Gástrico 04 1 07 33-42 18 2014 10.1007/s10120-014-0397-4 Park Do Joong Thomas Nicholas J. Yoon Changhwan Yoon Sam S. Gastric Cancer Vascular Endothelial Growth Factor A Inhibition in Gastric Cancer I. I Estimativa de cancer no Brasil 2016, :p. 2016 1 5 2017 Sales ML Guimarães AVS Revista Brasileira de Ciências da Vida FATORES DE RISCO NO DESENVOLVIMENTO DE CÂNCER GÁSTRICO 09 6 06 e98581 9 2014 10.1371/journal.pone.0098581 Hur Hoon Paik Man Jeong Xuan Yi Nguyen Duc-Toan Ham In-Hye Yun Jisoo Cho Yong Kwan Lee Gwang Han Sang-Uk Castresana Javier S. PLoS ONE Quantitative Measurement of Organic Acids in Tissues from Gastric Cancer Patients Indicates Increased Glucose Metabolism in Gastric Cancer 4 178-182 34 2011 10.1159/000327007 Khedmat Hossein Panahian Mohammad Mashahdian Mehrdad Rajabpour Mojtaba Vand Zendehdel Kazem Onkologie Prognostic Factors and Survival in Stomach Cancer – Analysis of 15 Years of Data from a Referral Hospital in Iran and Evaluation of International Variation 455 485. p 2017 Chen S RH Liu J et al Lymph nodes ratio based nomogram predicts survival of resectable gastric cancer regardless of the number of examined lymph nodes Ajani J BJ Bekaii-Saab T NCCN Clinical practice guidelines in oncology. 2010 445 451 50 2014 Sousa MTDd S-RP Cabral MMDÁ Jornal Bras Pat Med Labor Impact of using a lymph node revealing solution in surgical specimens for pathological staging of gastric cancer Network NCC Clinical Practice Guidelines in Oncology: Gastric Cancer Version 3. 2015. suppl_5 09 v38-v49 27 2016 10.1093/annonc/mdw350 Smyth E. C. Verheij M. Allum W. Cunningham D. Cervantes A. Arnold D. Annals of Oncology Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up† Brasil Saúde BMd Diretrizes e Normas Regulamentadoras de Pesquisas Envolvendo Seres Humanos: Diário Oficial da União.1996 Conselho Nacional de Saúde. Resolução nº. 196 de 10 de outubro de 1996 1 14 13 2014 10.4103/1477-3163.146506 Carcas LaurenPeirce Journal of Carcinogenesis Gastric cancer review 71 79. p 2016 Aguiar Jr P SG Barão K Forones N Chemotherapy for elderly patients with gastric cancer: experience of a Brazilian center 93 100. p 2012 Pereira APdS CC Martins MRI Pinto MH Netinho JG Associations among socio-demographic and clinical factors and the quality of life of ostomized patients 15 1 03 6 2006 10.1186/1471-2407-6-65 Wachtel Mitchell S Zhang Yan Chiriva-Internati Maurizio Frezza Eldo E BMC Cancer Different regression equations relate age to the incidence of Lauren types 1 and 2 stomach cancer in the SEER database: these equations are unaffected by sex or race 3 03 S7-S15 46 2014 10.1016/j.amepre.2013.10.029 White Mary C. Holman Dawn M. Boehm Jennifer E. Peipins Lucy A. Grossman Melissa Jane Henley S. American Journal of Preventive Medicine Age and Cancer Risk 9 03 e2873 95 2016 10.1097/md.0000000000002873 Zhou Fan Shi Jiong Fang Cheng Zou Xiaoping Huang Qin Medicine Gastric Carcinomas in Young (Younger than 40 Years) Chinese Patients 09 5 10 E359-E386 136 2014 10.1002/ijc.29210 Ferlay Jacques Soerjomataram Isabelle Dikshit Rajesh Eser Sultan Mathers Colin Rebelo Marise Parkin Donald Maxwell Forman David Bray Freddie International Journal of Cancer Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012 1 9. p 2017 Dalla Valle T TR de Brito Poveda V Fatores intervenientes para o início do tratamento de pacientes com câncer de estômago e colorretal 0 25 2017 10.1590/1518-8345.1493.2879 Valle Thaína Dalla Turrini Ruth Natalia Teresa Poveda Vanessa de Brito Revista Latino-Americana de Enfermagem Intervening factors for the initiation of treatment of patients with stomach and colorectal cancer 251. p 2012 Hu B El Hajj N Sittler S Lammert N Barnes R Meloni-Ehrig A Gastric cancer: Classification, histology and application of molecular pathology 26 33. p 2013 Araújo Júnior ON AA Barboza DRMM Meireles MS Pinheiro MV Pinheiro ATM Perfil epidemiológico e histopatológico do câncer gástrico 6405 6415 34 2014 Seabra AD AT Mello FAR et al Antican resear High-density array comparative genomic hybridization detects novel copy number alterations in gastric adenocarcinoma 29 24 03 8 2017 10.18632/oncotarget.16258 Pirini Francesca Noazin Sassan Jahuira-Arias Martha H. Rodriguez-Torres Sebastian Friess Leah Michailidi Christina Cok Jaime Combe Juan Vargas Gloria Prado William Soudry Ethan Pérez Jimena Yudin Tikki Mancinelli Andrea Unger Helen Ili-Gangas Carmen Brebi-Mieville Priscilla Berg Douglas E. Hayashi Masamichi Sidransky David Gilman Robert H. Guerrero-Preston Rafael Oncotarget Early detection of gastric cancer using global, genome-wide and <i>IRF4, ELMO1, CLIP4</i> and <i>MSC</i> DNA methylation in endoscopic biopsies 2 06 126-130 24 2011 10.1590/s0102-67202011000200007 Andreollo Nelson Adami Lopes Luiz Roberto Coelho Neto João de Souza ABCD. Arquivos Brasileiros de Cirurgia Digestiva (São Paulo) Complicações pós-operatórias após gastrectomia total no câncer gástrico: análise de 300 doentes 161 3 164 25 2012 Zilberstein B Mucerino DR Yagi OK Ribeiro-Junior U Lopasso FP Bresciani C et al Results of D2 gastrectomy for gastric cancer: lymph node chain dissection or multiple node resection? Arquivos brasileiros de cirurgia digestiva : ABCD = Brazilian archives of digestive surgery 145 149.p 2011 Cóvos FHG FF Navarro PF Magalhães P David WRdF J Malheiros CA Câncer gástrico avançado: complicação pós operatória–discussão de caso 355 364 55 2009 C. M Rev Bras Cancerol Estratégias de enfrentamento utilizadas pelos pacientes oncológicos submetidos a cirurgias mutiladoras 28 32 3 2016 Cabral PG MK Teixeira MCA dos Santos Fernandes G Rev Sau Faciplac Resposta completa e duradoura em câncer gástrico metastático HER2-positivo 986 990 18 2015 Colombi S Baia RdSM Nursin Sistematização da assistência de enfermagem a um paciente de gastrectomia total: relato de experiência