Pre-diagnosis lifestyle exposures and survival of gastric cancer patients.

Iola Ximene Guimarães Ferronha PRE-DIAGNOSIS LIFESTYLE EXPOSURES AND SURVIVAL OF GASTRIC CANCER PATIENTS Porto, 2012 1 Iola Ximene Guimarães Ferronha PRE-DIAGNOSIS LIFESTYLE EXPOSURES AND SURVIVAL OF GASTRIC CANCER PATIENTS Dissertação de candidatura ao grau de Mestre em Saúde Pública apresentada à Faculdade de Medicina da Universidade do Porto e ao Instituto de Ciências Abel Salazar. Porto, 2012 2 Investigação realizada no Departamento de Epidemiologia Clínica, Medicina Preditiva e Saúde Pública da Faculdade de Medicina da Universidade do Porto e no Instituto de Saúde Pública da Universidade do Porto (ISPUP), no âmbito de projectos financiados pela Fundação para a Ciência e a Tecnologia (PTDC/SAU-ESA/71517/2006, POCI/SAUESP/56126/2004, POCI/SAU-ESP/61685/2004) sob orientação do Professor Doutor Nuno Lunet. 3 A dissertação de Mestrado teve como base dois artigos. No primeiro colaborei activamente na definição das hipóteses em estudo, na recolha, armazenamento, análise e interpretação dos dados; no segundo artigo, colaborei activamente na definição das hipóteses em estudo, na análise e interpretação dos resultados. Elaborei as versões iniciais de ambos os artigos: - Iola Ferronha, Ana Bastos, Nuno Lunet – Pre-diagnosis lifestyle exposures and survival of gastric cancer patients: systematic review and meta-analysis. Eur J Cancer Prev. [in press] - Iola Ferronha, Clara Castro, Helena Carreira, Maria José Bento, Isabel Carvalho, Bárbara Peleteiro, Nuno Lunet – Pre-diagnosis lifestyle exposures and survival of gastric cancer patients: a cohort study from Portugal. [submetido para publicação] 4 AGRADECIMENTOS 5 Ao Professor Doutor Nuno Lunet por toda a orientação e dedicação demonstrada em todo este percurso. Aos co-autores dos trabalhos incluídos nesta dissertação, pelo seu valioso contributo. Aos meus irmãos e ao meu pai pelo incentivo. À minha mãe pelo porto de abrigo sempre constante em todas as tempestades. Ao Pinto, pelas ausências e por todo o apoio e compreensão. 6 TABLE OF CONTENTS Page 1. Gastric cancer as a public health problem 7 1.1. Gastric cancer incidence 7 1.2. Gastric cancer mortality 8 1.3. Gastric cancer in Portugal 10 2. Survival of gastric cancer patients 14 3. Objectives 16 4. Papers Paper I Pre-diagnosis lifestyle exposures and survival of gastric cancer patients: systematic review and meta-analysis 17 Paper II Pre-diagnosis lifestyle exposures and survival of gastric cancer patients: a cohort study from Portugal 34 5. General discussion and conclusions 52 6. References 53 7. Summary 60 8. Sumário 63 7 1. Gastric cancer as a public health problem Cancer is a leading cause of death in the world that has accounted for 7.6 million deaths (around 13% of all deaths) in 2008 [1] and the GLOBOCAN projections suggest that oncological diseases are likely to remain a major cause of mortality over the next couple of decades [2]. This increase will be determined for the most part by growth and aging of populations and will be largest in lowand medium-resource countries [3]. Gastric cancer is the fourth most common malignancy in the world, and it is estimated that approximately one million new cases of gastric cancer have occurred in 2008 [1]. The global burden of the gastric cancer can be measure by the economic value of disability-adjusted life years (DALY) [4]. In the year of 2008, in the world, gastric cancer is the second cancer accounting for the highest number of DALYs [5-6], with the mortality component contributing more for the burden of disease than the disability. 1.1. Gastric cancer incidence Behind lung, breast and colorectal cancer, gastric cancer represents 9.7% of all cancers (excluding skin non-melanoma) in men and 5.8% in women (Table 1) [2]. Additionally, 72.2% of cases occur in developing countries (Table 1) and half the world total occurs in Eastern Asia [1]. Gastric cancer age-standardized incidence rates are about twice as high in men than in women [1, 7]. Table 1. Gastric cancer incidence for men and women in 2008 * World standard population Source: GLOBOCAN 2008 [1] In Europe, 145,889 new cases occurred in 2008, 86,865 in men and 59,024 in women, corresponding to an age-standardized incidence rate (European standard population) of 14.5/100,000 men and 7.0/100,000 women, respectively [1]. The highest ageRegion World More developed Countries Less developed countries Men Women Men Women Men Women Number of cases 640031 348571 173014 101681 467017 246890 Percentage of all cancers (excluding skin nonmelanoma) 9.7 5.8 5.8 3.9 12.8 7.1 Crude incidence rate (/100 000) 18.8 10.4 29.0 16.1 16.6 9.1 Age-standardized * incidence rate (/100 000) 19.8 9.1 16.7 7.3 21.1 10.0 8 standardized incidence rates are observed in countries like Japan (46.8/100,000 men) or Korea (62.2/100,000 men) [1]. In Africa, the age-standardized incidence rates are the lowest (4.7/100,000 men) [1]. Despite these differences between the countries, in the last 50 years there have been widespread reductions in the gastric cancer incidence [8-9], mainly non-cardia gastric cancer [10-11]. Several studies showed an increasing [12-17] or unchanging incidence [18-21] of gastric cardia cancers. Cancers of the antrum and pylorus (non-cardia gastric cancer) tend to be most frequent in high-risk regions such as China, Japan, Eastern Europe and Central/South America [21-23], while gastric cardia cancers are more common where the overall gastric cancer incidence is lower [24]. The classification of the anatomical cardia region has changed over the years and cardia cancer was coded separately from other gastric cancers only after the 8th revision of the International Classification of Diseases (ICD-8) [25]. Difficulties in distinguishing between gastric cardia cancers and cancers of the lower third of the oesophagus are usual in the studies. In a report from the Swedish Cancer Register 15% of cardia cancer cases were classified as non-cardia gastric cancer and the observed increase in the incidence of cardia adenocarcinoma in the Swedish Cancer Register might be explained by disparities in tumour classification over time [25]. The Laurén classification [26] categorizes the gastric tumours in two major types: intestinal or diffuse. Some carcinomas may not fit into one type or another, and thus fall into 'mixed' or 'unclassified' categories [27]. The decline in incidence rates has been more pronounced in the intestinal type [28-29]. The reasons for the generalized decline in gastric cancer rates are complex and not completely know. A more varied and affluent diet and better food conservation, like a decreased reliance on salted and preserved foods; smoking decline in some parts of the developed world [9] and the decline in the frequency of Helicobacter pylori infection are potential explanations for the downward trends in gastric cancer incidence [7, 9, 30-32]. 1.2. Gastric cancer mortality Worldwide, gastric cancer is the second leading cause of cancer death [33] in both sexes with 737419 deaths in 2008 [1] and a corresponding age-standardized rate (world standard population) of 10.3 deaths/100,000 inhabitants (Table 2). About fifteen percent of the gastric cancer deaths occur in the more developed countries (Table 2). 15 probability of long-term survival in patients treated in an early stage, while in patients with serosal involvement and lymph node metastasis the prognosis is extremely poor [64-68]. Efforts to increase the proportion of stage I cancers presenting for surgery can be shown to improve prognosis, by diagnosing the cancers when still surgically curable [67]. Regarding the Laurén classification of tumour, the histological type is an important independent determinant of survival, with the risk of dying being higher in the diffuse type cancers than in those of the intestinal type [69-70]. Some authors [71-72] consider that age has prognostic value because young patients with gastric cancer have a poorer prognosis than older patients. Perhaps they present with more advanced disease because the index of suspicion for malignant disease is low and so the symptoms are allowed to progress for a longer period before investigation is considered, or there may be a greater biological activity of the tumour, which is more likely to be of the Laurén diffuse type. In the USA, between 1995-2000, the 5-year relative survival for distant stage and unstaged category was worse than for the localized and regional stage [6]. In Japan, as a result of population screening and probably a greater knowledge of early symptoms and a low threshold for diagnostic evaluation, 50% of gastric cancers are diagnosed at a localized stage, and the overall 5-year survival has increased from 20% in 1962 to 40% in 1992 [73]. Gastric cardia tumours have a much poorer prognosis compared to those in the pyloric antrum, with lower 5-year survival and higher operative mortality [74]. Gastric cancer survival differences may be explained also by differences in the socioeconomic status of the patients [64, 75-78]. Patients with a higher income occupation and/or a higher educational level showed a better life expectancy. This may be associated with environmental exposures that may influence gastric cancer incidence [8] as well as prognosis [8]. The relation between behaviours before the diagnosis and the survival of gastric cancer patients remains poorly understood, and may contribute to a more comprehensive characterization of the burden associated with these exposures. It is reasonable to argue that diet could affect the progression of diet-related neoplasms and the probability of disease recurrence but only few studies address this topic. Frequent intake of fruits and vegetables appears to have a protective effect on survival [7980]. Huang et al. refer, in contrast, that other dietary items like salted fished, pickled food or red meat failed to show relationship with survival [79] and Palli et al. explain that a diet rich in animal protein may raise disease development in patients who are affected with familial gastric neoplasm [80]. 16 3. Objectives There is a large variation in gastric cancer survival across regions. The geographical and temporal differences in gastric cancer survival may be explained by a heterogeneous distribution of the access to early diagnosis and treatment across populations, as well as differences in the socioeconomic status of the patients. The latter may also be associated with environmental exposures with potential impact both in the risk of gastric cancer and the patients‟ prognosis. This dissertation addresses the association between pre-diagnosis lifestyle exposures and the survival of gastric cancer patients. It includes two studies with the following specific objectives:  To review systematically the published studies assessing the association between pre-diagnosis lifestyle exposures and the survival of gastric cancer patients (Paper I).  To quantify the association between pre-diagnosis lifestyle exposures and survival of gastric cancer patients in a Portuguese setting (Paper II). 17 Pre-diagnosis lifestyle exposures and survival of gastric cancer patients: systematic review and meta-analysis. 18 ABSTRACT The relation between lifestyles and gastric cancer has been thoroughly investigated, but few studies addressed the impact of these exposures on prognosis. Therefore, we quantified the association between pre-diagnosis smoking, alcohol intake and other dietary exposures and the survival of gastric cancer patients, through systematic review and metaanalysis. We searched Pubmed® and EMBASE® up to April 2011, and computed summary Hazard ratio (HR) estimates and respective 95% confidence intervals (95%CI) through random-effects meta-analysis (DerSimonian and Laird). Heterogeneity was quantified using the I2 statistic. Seven articles, providing data from 6856 cases evaluated in seven countries (Canada, Japan, Italy, USA, Korea, Iran and Sweden), were eligible for meta-analysis. The summary HR was 1.08 (95%CI: 0.90-1.30) for smoking (current vs. never smokers, 7 studies; I2=56.2%) and 1.13 (95%CI: 1.00-1.28) for alcohol consumption (drinkers vs. nondrinkers, 5 studies; I2=13.2%). Only two studies assessed the effect of other dietary factors. This study summarizes the best evidence available on the relation between pre-diagnosis lifestyles and survival of gastric cancer patients. Alcohol drinkers have lower survival, but results on the effect of smoking lack consistency and there is almost no information on the effects of dietary factors. Key Words: Stomach neoplasms; Survival; Smoking; Alcohol Drinking; Meta-analysis. 19 Introduction Gastric cancer is worldwide the fourth most common malignancy, after lung, breast and colorectal cancers, despite the geographical differences in its frequency [1] and the widespread decline in incidence and mortality over the last decades [2]. The number of new cases and deaths continues to increase worldwide because of population growth and aging in high-risk countries. In Europe, 5-year relative survival increased from 15.0% between 1978-1980 to 21.0% in 1987-1989 [3]. Among cases diagnosed between 2000 and 2002 the 5-year relative survival estimate was 24.9%, with wide geographical differences (e.g., 16.6% in Scotland and 33.2% in Italy) [4]. Within-country variability in survival has also been observed in several settings (e.g., Italy [5], United Kingdom [6]). The geographical and temporal differences in gastric cancer survival may be explained by a heterogeneous distribution of the access to early diagnosis, and treatment across populations [7] as well as differences in the socioeconomic status of the patients [8]. The latter may also be associated with environmental exposures with potential impact both in the risk of gastric cancer [9-10] and the patients‟ prognosis [11]. The understanding of the relation between pre-diagnosis lifestyles and survival may contribute to a more accurate characterization of the burden associated with these exposures. Therefore, we conducted a systematic review and meta-analysis of the published original research. 20 Materials and methods We searched Pubmed® and EMBASE®, from inception to April 2011, with no language restrictions. Reports of cohort studies that evaluated lifestyle determinants of survival in gastric cancer patients were eligible for the systematic review whenever providing quantitative estimates of the association and respective precision estimates. Review articles and conference proceedings were not included in the present review. The search expressions and the systematic review flow-chart are presented in Annex 1. The electronic database searches, the selection of articles and the extraction of data were conducted independently by two researchers (IF, AB), following a previously defined protocol. Discrepancies were resolved by consensus or involving another researcher (NL). Hazard ratios (HR), and respective precision estimates, for the association between lifestyle exposures and survival were extracted. When a study provided more than one estimate, we selected the one adjusted for the largest set of variables. When sex or gastric cancer subtype-specific HR estimates were available, the stratum-specific HRs were considered as if were obtained from different studies. From each study we further extracted data on the following variables: country; year of publication; characteristics of the participants; sample size; study design (methods of data collection, duration of follow-up); control of potential confounding. We contacted the authors by email to obtain information on these issues when not provided or not clearly presented in the original reports; some of the authors provided complementary information that was included in Annex 2. Random-effects meta-analyses, conducted using the DerSimonian and Laird method, were conducted to obtain summary measures for the association between pre-diagnosis lifestyles (highest vs. lowest exposures) and survival of gastric cancer patients. Publication bias was examined through visual inspection of the funnel plot. The Begg adjusted rank correlation test and the Egger´s regression asymmetry test were used for further assessment of bias through hypothesis testing. All analyses were conducted using STATA® version 11.2 (StataCorp, College Station, Texas, USA). 21 Results Seven studies [11-17] were eligible for the systematic review. All of them quantified the relation between smoking and survival of gastric cancer patients and the effects of alcohol consumption were addressed in five reports; dietary exposures were evaluated in two studies (Figure 1). The studies were published between 1985 and 2008; each of them referred to an investigation conducted in a different country: two in Europe (Italy and Sweden [11, 14]); three in Asia (Japan, Korea and Iran [13, 16-17]); two in North America (Canada and USA [12, 15]). In most studies the assessment of lifestyle exposures was accomplished by trained interviewers, and referred to the period before diagnosis. In two studies the interview was done with patients or families [15, 17]. Park et al. [16] evaluated participants with a selfadministrated questionnaire. Sundelof et al. [11] estimated the alcohol intake 20 years before the interview. In the report by Bako et al. [12] the period of exposure and the method used to obtain behavioural information from cancer patients was not specified. Only three studies [11, 13-14] provided HR estimates adjusted for the stage of the disease at diagnosis and one [15] provided the crude HR estimates (Annex 2). The summary HR for the relation between smoking (current vs. never smokers) and survival of gastric cancer patients was 1.08 (95%CI: 0.90-1.30), with a high heterogeneity across the HR estimates from each individual report (I2=56.2%). Alcohol consumption was significantly associated with a poorer survival (current vs. never drinkers – summary HR=1.13, 95%CI: 1.00-1.28), and results were homogeneous (I2=13.2%) (Figure 1). Only one study presented results for cardia and non-cardia cancers [15], with no differences according to cancer subsite, and Sundelof et al. [11] only evaluated cases of cancer of the cardia. In one of the reports [14] that assessed the effect of dietary exposure on survival, no significant associations were observed for any specific food or food group, except for αtocopherol (HR=0.75; 95%CI: 0.56-0.99). In the other study [13] the consumption of raw vegetables (HR 0.74; 95%CI: 0.56-0.99), bean curd (HR=0.65; 95%CI: 0.42-0.98) and chicken meat (HR=0.61; 95%CI: 0.39-0.94) were associated with a significantly higher survival. For alcohol consumption there was no evidence of publication bias by the visual inspection of the funnel plot (Figure 2), in accordance with the results from the Begg adjusted rank correlation test (P=0.851) and the Egger´s regression asymmetry test (P=0.840). For smoking the funnel plot suggests that small studies with a negative association may be 22 underrepresented (Begg adjusted rank correlation test, P=0.297; Egger´s regression asymmetry test, P=0.003). 23 Discussion This systematic review and meta-analysis summarizes the best evidence available on the relation between the lifestyles before diagnosis and survival of gastric cancer patients. Only 7 eligible studies, published over more that 20 years, were identified despite the comprehensiveness of the search strategy. We searched the two most important electronic databases – Pubmed® and EMBASE® – with no language restrictions, and using highly sensitive and unspecific search expressions, including the main terms referring to smoking, alcohol drinking and other dietary exposures. The “number-needed-to-read” was 277, which confirms the low specificity and high sensitivity of the searches. Furthermore, there was no evidence of publication bias for alcohol drinking, and the conclusions regarding the effects of smoking on gastric cancer survival are not likely to be influenced by a potential bias. The main findings of the present quantitative synthesis are naturally influenced by intrinsic limitations of the primary sources of information. In addition to the heterogeneous methods used in the different studies, all addressed the effects of pre-diagnosis exposures without taking into account possible behavioural changes occurring after the baseline evaluation. Previous investigations showed lifestyle modifications in cancer patients after diagnosis or treatment [18-19] and healthier lifestyles than the subjects at higher risk of developing a cancer [20-21]. However, despite the potential impact of post-diagnosis lifestyles in the survival of gastric cancer patients, the disease duration is relatively low and we may hypothesise that the cumulative exposures throughout life are more relevant as a potential determinant of survival. The conclusions of our meta-analyses apply only to prediagnosis exposures, and further research is needed to address the impact of behavioural changes occurring after cancer diagnosis. Lifestyle predictors of survival have been studied for other cancers, namely breast [22-23], lung [24-25] and laryngeal carcinoma [26-28]. The results suggest that patients with a higher intake of fruits and vegetables before diagnosis have a better survival, and that smoking and drinking may be detrimental for prognosis, which is compatible with our observations for gastric cancer. The relatively small number of reports addressing this subject precludes more robust conclusions. However, our study provides a transparent and reproducible assessment of the published evidence on this topic. The potential effects of pre-diagnosis lifestyle exposures in the prognosis of gastric cancer patients seem relatively modest and well designed epidemiologic studies with large samples are needed for a more robust assessment of these determinants of survival. 24 Acknowledgments Grants from Fundação para a Ciência e Tecnologia are gratefully acknowledged (PTDC/SAU-ESA/71517/2006, POCI/SAU-ESP/56126/2004, POCI/SAU-ESP/61685/2004). Conflicts of interest There are no conflicts of interest. 31 References 1. Ferlay, J., Shin H., Bray F., Forman D., Mathers C., and Parkin D. GLOBOCAN 2008, Cancer Incidence and Mortality Worldwide. IARC CancerBase No. 10. 2010. Available from: http://globocan.iarc.fr. 2. Bertuccio, P., Chatenoud L., Levi F., Praud D., Ferlay J., Negri E., et al. Recent patterns in gastric cancer: a global overview. Int J Cancer 2009. 125(3): 666-73. 3. Sant, M., Capocaccia R., Coleman M.P., Berrino F., Gatta G., Micheli A., et al. 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Malignant epithelial tumours in the upper digestive tract: a dietary and socio-medical casecontrol and survival study. Eur J Clin Nutr 1998. 52(4): 271-8. 28. Crosignani, P., Russo A., Tagliabue G., and Berrino F. Tobacco and diet as determinants of survival in male laryngeal cancer patients. Int J Cancer 1996. 65(3): 308-13. 34 Pre-diagnosis lifestyle exposures and survival of gastric cancer patients: a cohort study from Portugal 35 Abstract Dietary habits and smoking are recognized as important gastric cancer determinants. However, their impact on prognosis remains poorly understood. We aimed to quantify the association between lifestyles and the survival of gastric cancer patients in a large sample of gastric cancer cases with a long follow-up. The study included 568 patients recruited in the two major public hospitals in the north of Portugal (2001-2006). Participants were inquired about pre-diagnosis smoking and dietary habits regarding the year preceding the diagnosis. The latter were recorded using a validated semi-quantitative food frequency questionnaire and data were analysed by food group and dietary pattern. The vital status of all participants, up to 2011 (maximum follow-up: 10 years), was assessed through the North Region Cancer Registry. Survival curves were estimated by the Kaplan-Meier method. Cox proportional hazards regression models were used to estimate age-, sex-, educationand extent of disease-adjusted hazard ratios (HRs) and 95% confidence intervals (95%CI). Only a dietary pattern characterized by high consumptions of most food groups and low vegetable soup intake was significantly associated with a better prognosis among patients with the extent of disease classified as regional spread (HR=0.45; 95%CI, 0.22-0.93). No significant associations were observed for other variables (alcohol, smoking, consumption of fruits and vegetables, red and processed meat or foods with the highest contribution for sodium intake). This study shows that pre-diagnosis lifestyles have a small impact in the survival of gastric cancer patients. Key Words: Stomach neoplasms; Survival; Smoking; Alcohol Drinking; Diet. 36 Introduction Gastric cancer is the fourth most common malignancy in the world [1]. Although its frequency has been declining for decades it remains the second leading cause of cancer mortality [2] and ranks second among the cancers accounting for the highest number of disability-adjusted life years (DALYs) (9.6%) [3-4]. In Europe, the average 5-year relative survival rate of patients diagnosed between 2000 and 2002 was estimated in 24.9%, however varying widely across countries [5]. The prognosis of gastric cancer patients varies with the tumour‟s characteristics, namely location and histological type, and it is also likely to be related with the socioeconomic status of the patients [6].The latter, in addition to its relation with access to health care and stage at diagnosis [7], may also be associated with environmental exposures with potential impact both in the risk of gastric cancer and in the survival of cancer patients [8-9]. The understanding of the relation between pre-diagnosis lifestyles and survival may contribute to a more accurate characterization of the burden associated with these exposures. However, the effect of behavioural factors, such as alcohol drinking, tobacco smoking and dietary habits, on the survival of gastric cancer patients has seldom been addressed and available evidence showed inconsistent results [10]. Therefore, we aimed to quantify the association between pre-diagnosis lifestyles and the survival of gastric cancer patients, in a large sample followed prospectively for up to 10 years, with special emphasis on the potential modification of the effects according to the time of survival. 37 Methods Setting and selection of participants As part of a case-control study previously described in detail [11-13] we evaluated incident cases of gastric cancer selected among those admitted to the surgery wards of the two major public hospitals for cancer patients in the north of Portugal (Hospital de S. João and Instituto Português de Oncologia Francisco Gentil, both in Porto), between June 2001 and December 2006. Eligible patients were incident gastric cancer cases that had not been previously diagnosed with cancer (except skin non-melanoma), nor had been subjected to subtotal gastrectomy for benign conditions; they also had to be able to provide informed consent. To evaluate cognitive function, all individuals older than 64 years took a Mini-Mental State Examination [14] and we restricted the analysis to participants without serious cognitive impairment at baseline (score ≥18 points) [15]. Evaluation of environmental exposures The participants completed a comprehensive structured questionnaire providing information on demographic, social, behavioural and medical characteristics, applied by trained interviewers during in-hospital stay, shortly after admission, mostly before surgical treatment. Since illness duration is related with changes in food intake, the assessment of the dietary intake referred to the previous year or the year before onset of symptoms, as applicable. We excluded from the analyses the patients declaring to have changed dietary habits more than one year before the interview. Dietary exposures were quantified using a semi-quantitative food frequency questionnaire (FFQ) comprising 82 food/beverage items or categories, designed according to Willett [16] and adapted by inclusion of a variety of typical Portuguese food items. Foods with a similar nutrient composition were grouped together as a single item. The FFQ was validated with a 7-day food record and, regarding the fatty acid composition, with the composition of subcutaneous adipose tissue [17-18]. For each FFQ item, subjects were asked the average frequency of consumption (nine possible responses ranging from never to six or more times per day), the portion size usually consumed (based on a photograph manual with small, medium, and large portion sizes), and the number of months during which it had been consumed in the previous year. Also, for each item, this information was used to estimate the frequency of consumption of medium servings, corrected for seasonality by multiplying the reported consumption by the ratio between the number of months during which the food item was reported to be consumed and 12 months. For analysis, the 38 frequency of consumption of each food group was categorized using the tertiles of the overall distribution as cut-offs. The overall intake of fruits and vegetables, red and processed meat and foods with a high contribution to salt intake was established by adding up the amounts of single items or groups consumed per day, as follows: fruits and vegetables (apple or pear, orange or mandarin, banana, kiwi, strawberry, cherry, peach or plum, melon or watermelon, persimmon, fig or loquat or apricot, grapes, natural fruit juices, lettuce, watercress, tomato, cucumber, green and white cabbages, broccoli, cauliflower or Brussels sprout, spinach or spring greens or turnip greens, spinach, bean pod, carrot, turnip, green beans, green pepper, onion, beans and peas); red and processed meat (beef, pork, liver, tongue, ham, sausage, bacon, hamburger); food items with the highest contribution to sodium intake (namely grains, cereals, rice, pasta, potatoes, bread, meat, meat products, offal, vegetable soup, fish and cheese). The latter were defined according to the results of a previous nutrition survey conducted in same setting [19]. Dietary patterns were defined by principal components and cluster analyses, as previously described in detail [20]. Three dietary patterns were identified (Pattern I – high consumption of fruits and dairy products, and low consumption of alcoholic beverages; Pattern II – low consumption of fruit, salads, vegetables, dairy products, fish and meat; Pattern III – high consumptions of most food groups and low vegetable soup intake). Pattern II was shown previously to be associated with a higher risk of gastric cancer when compared with patterns I or III [20]. Smoking and alcohol consumption status were assessed. Individuals smoking regularly at least one cigarette per day were classified as current smokers and those who stopped smoking at least 6 months before the interview as former smokers [21]. Individuals drinking regularly at least one alcoholic drink per day were classified as current drinkers and those who stopped drinking at least 6 months before the interview as former drinkers. Clinical characteristics The anatomic site (cardia/non-cardia/not defined) and histological type of the tumours (intestinal/diffused/mixed) were classified according to the routine procedures of both institutions, based on gastrectomy specimens or endoscopic biopsy material. To guarantee a standard pathologic classification according to the Laurén criteria, a single experienced pathologist reviewed all pathology reports and slides were reassessed whenever necessary. For a more accurate classification of the tumour histological type [22-23] only those cases from whom a surgical specimen was available were considered for the analyses including information on the tumours‟ histological type (78% of the patients eligible for data analysis). 39 The information on the extent of disease, according to the European Network of Cancer Registries criteria [24], was obtained from the North Region Cancer Registry (RORENO). Follow-up The vital status of the participants was assessed by the RORENO. The event of interest was death by all causes. Patients were followed until the end of July, 2011, or date of death, whichever occurred first. No follow-up information could be obtained for 10 patients. The median duration of follow-up was 6.6 years for patients alive at the end of study and 1.2 years for those reported dead, with a maximum follow-up of 10 years. Statistical analysis A total of 568 gastric cancer patients with follow-up information were available for data analysis. We used the Kaplan-Meier survival function to estimate the observed survival at 1, 3 and 5 years of follow-up, and Cox proportional hazard regression analysis to compute adjusted hazard ratios (HR) with the corresponding 95% confidence intervals (95%CI). Differences in survival estimates between groups were tested using the Log-rank test. All analyses were conducted using STATA®, version 11.2 (StataCorp, College Station, Texas, USA). Ethics The study was approved by the ethics committees of the involved hospitals and the participants provided written informed consent. 40 Results Characteristics of the participants Incident gastric cancer patients were mostly men (62.1%) and nearly one-quarter were aged 50 years or less (median age of 63 years). Approximately three-quarters of the participants had 4 or less schooling years. Most cancers were located in the non-cardia region (78.6%), and 55% of those from whom a surgical specimen was available were of the Laurén‟s intestinal histological type. No information was available to classify 16.9% of the cases according to the extent of disease, and one-quarter were advanced cancers (Table 1). At baseline, approximately one-fifth of the patients were smokers and one-quarter exsmokers, while 72.9% reported being current drinkers. The median daily consumption of fruits and vegetables, red and processed meat and foods accounting for high salt intake was 3.4, 0.7 and 2.0 servings, respectively (Table 2). Observed survival Survival decreased significantly with age (P=0.001). Patients aged 24-50 years and 51-60 years had a similar survival until the third year of follow-up, diverging only after that (Figure 1). Only 32.0% and 7.0% of the patients with an advanced cancer were alive at one and three years after diagnosis, respectively. The patients with unknown stage had a survival in-between the observed for the regional spread and advanced cancers until the 5 years of follow-up, and thereafter closer to the observed for cases with regional spread (Figure 2). Women presented a significantly lower survival than men (35.8% vs. 44.2% at 5 years, P=0.016). Cardia cancers had worse survival than the non-cardia (29.0 vs. 46.3 at 5 years), as well as those of the Laurén‟s diffuse type compared with the intestinal (36.2 vs. 56.6 at 5 years) (Table 1). Regarding the relation with lifestyle characteristics, significant differences were observed only according to the smoking status (P=0.039), with never smokers having a poorer survival than current smokers (36.8 vs. 43.7 at 5 years) (Table 2). There were virtually no changes in the results when excluding the patients who died up to one week after the surgery that could be considered due to postoperative complications (data not shown). Multivariate analysis No independent meaningful or statistical significant associations were observed between the pre-diagnosis lifestyles and gastric cancer survival, overall or across strata defined by cancer subsite, histological type or stage, except for a significantly lower hazard 47 Figure 1. Survival probability according to age of gastric cancer patients using KaplanMeier method 48 Figure 2. Survival probability according to extent of disease of gastric cancer patients using Kaplan-Meier method 49 References 1. Ferlay, J., Shin H., Bray F., Forman D., Mathers C., and Parkin D. GLOBOCAN 2008, Cancer Incidence and Mortality Worldwide. IARC CancerBase No. 10. 2010. Available from: http://globocan.iarc.fr. 2. Boyle, P. and Levin B., eds. World Cancer Report 2008. ed. World Health Organization. 2008: Lyon, France. 3. John, R.M. and Ross H. Economic value of disability-adjusted life years lost to cancers. American Cancer Society 2008. 4. 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Association between enviromental factors and CDX2 expression in gastric cancer patients. European Journal of Cancer Prevention [in press] 2011. 14. Folstein, M.F., Folstein S.E., and McHugh P.R. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975. 12(3): 189-98. 15. Murden, R.A., McRae T.D., Kaner S., and Bucknam M.E. Mini-Mental State exam scores vary with education in blacks and whites. J Am Geriatr Soc 1991. 39(2): 149-55. 16. Willett, W. Nutritional Epidemiology (2nd ed). 1998, New York: Oxford University Press. 17. Lopes C, Reproducibility and validation of a semi-quantitative food-frequency questionnaire. Diet and Acute Myocardial Infarction: A Population-Based CaseControl Study. PhD Thesis [in Portuguese]. 2000, University of Porto, : Porto. 18. Lopes, C., Aro A., Azevedo A., Ramos E., and Barros H. Intake and adipose tissue composition of fatty acids and risk of myocardial infarction in a male Portuguese community sample. J Am Diet Assoc 2007. 107(2): 276-86. 19. Lopes C, Oliveira A, Santos AC, Ramos E, Gaio AR, Severo M, et al., Consumo alimentar no Porto, Faculdade de Medicina do Porto, Editor. 2006: Porto. 20. Bastos, J., Lunet N., Peleteiro B., Lopes C., and Barros H. Dietary patterns and gastric cancer in a Portuguese urban population. Int J Cancer 2010. 127(2): 433-41. 21. World Health Organization, Definition, diagnosis and classification of diabetes mellitus and its complications Part I: diagnosis and classification of diabetes mellitus. , Department of Noncomunicable Disease Surveillance, Editor. 1999: Geneva. 22. Palli, D., Bianchi S., Cipriani F., Duca P., Amorosi A., Avellini C., et al. Reproducibility of histologic classification of gastric cancer. Br J Cancer 1991. 63(5): 765-8. 23. Flucke, U., Monig S.P., Baldus S.E., Zirbes T.K., Bollschweiler E., Thiele J., et al. Differences between biopsyor specimen-related Lauren and World Health Organization classification in gastric cancer. World J Surg 2002. 26(2): 137-40. 24. Berrino, F., Brown C., Möller T., Sobin L., and Faivre J., ENCR Recomendations Condensed TNM for Coding the Extent of Disease., European Network of Cancer Registries, Editor. 2002: Lyon, France. 51 25. Blanchard, C.M., Denniston M.M., Baker F., Ainsworth S.R., Courneya K.S., Hann D.M., et al. Do adults change their lifestyle behaviors after a cancer diagnosis? Am J Health Behav 2003. 27(3): 246-56. 26. Patterson, R.E., Neuhouser M.L., Hedderson M.M., Schwartz S.M., Standish L.J., and Bowen D.J. Changes in diet, physical activity, and supplement use among adults diagnosed with cancer. J Am Diet Assoc 2003. 103(3): 323-8. 27. Pacheco-Figueiredo, L., Antunes L., Bento M.J., and Lunet N. Health-related behaviours in the EpiPorto study: cancer survivors versus participants with no cancer history. Eur J Cancer Prev 2011. 20(4): 348-54. 28. Palli, D., Russo A., Saieva C., Salvini S., Amorosi A., and Decarli A. Dietary and familial determinants of 10-year survival among patients with gastric carcinoma. Cancer 2000. 89(6): 1205-13. 29. Huang, X.E., Tajima K., Hamajima N., Kodera Y., Yamamura Y., Xiang J., et al. Effects of dietary, drinking, and smoking habits on the prognosis of gastric cancer. Nutr Cancer 2000. 38(1): 30-6. 52 5. General discussion and conclusions The present dissertation contributes to the understanding of the relationship between pre-diagnosis lifestyles and the survival of gastric cancer patients, taking into account the systematic review of the published articles addressing this topic and a large study with a long follow-up conducted in a high-risk Portuguese population. The meta-analysis is based in the most comprehensive systematic review on this topic, and provides a summary of the best available evidence on the relation between pre-diagnosis lifestyles and gastric cancer survival. The results from the cohort study are similar with the conclusions from the systematic review and meta-analysis. Most of the previous research [79-80] has addressed the relationship between foods or nutrients separately without taking into account the effect of dietary patterns. Our study adds the analysis also by dietary patterns. The present study also adds to previous investigations [79-85] the analysis of the pre-diagnosis determinants in relation with the extent of disease, which is an important factor for survival. Our findings suggest that only dietary pattern III, related with high consumptions of most food groups and low vegetable soup intake, was significantly associated with a better relative survival, but only for patients identified with an extent of disease as regional spread. The dietary patterns are population-dependent and therefore these results may not be generalizable to other settings, particularly to populations with different dietary habits. In conclusion, this dissertation showed no consistent effects of pre-diagnosis behaviours in the survival of gastric cancer patients, even among the subjects with clinical characteristics at diagnosis that are associated with a better prognosis. 53 6. References 1. Ferlay, J., Shin H., Bray F., Forman D., Mathers C., and Parkin D. GLOBOCAN 2008, Cancer Incidence and Mortality Worldwide. IARC CancerBase No. 10. 2010. Available from: http://globocan.iarc.fr. 2. Ferlay, J., Shin H.R., Bray F., Forman D., Mathers C., and Parkin D.M. 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Evolução da Tx de Incidência Padronizada. 2010. Available from: http://www.roreno.com.pt/pt/estatisticas/graficos/evolucao-10-anos.html. 42. ROR Centro, Registo Oncológico Regional Região Centro 1997, Instituto Português de Oncologia de Coimbra Francisco Gentil, Editor. 2003: Coimbra. 43. ROR Centro, Registo Oncológico Regional Região Centro 1998, Instituto Português de Oncologia de Coimbra Francisco Gentil, Editor. 2006: Coimbra. 44. ROR Centro, Registo Oncológico Regional Região Centro 1999, Instituto Português de Oncologia de Coimbra Francisco Gentil, Editor. 2006: Coimbra. 45. ROR Centro, Registo Oncológico Regional Região Centro 2000, Instituto Português de Oncologia de Coimbra Francisco Gentil, Editor. 2007: Coimbra. 46. ROR Centro, Registo Oncológico Regional Região Centro 2001, Instituto Português de Oncologia de Coimbra Francisco Gentil, Editor. 2007: Coimbra. 47. 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RORENO, Análise de Sobrevivência, Principais Cancros da Região Norte 2000/2001, Instituto Português de Oncologia do Porto Francisco Gentil, Editor. 2010: Porto. 54. ROR-Sul, Top 10. Os 10 tumores mais frequentes na população portuguesa adulta na região sul de Portugal, no período 2000/01, Instituto Português de Oncologia de Lisboa Francisco Gentil, Editor. 2008, : Lisboa 63 8. Sumário Estilos de vida antes do diagnóstico e sobrevivência dos doentes com cancro gástrico O cancro gástrico é a quarta neoplasia maligna mais frequente e embora a sua incidência tenha vindo a diminuir ao longo de décadas, continua a ser a segunda principal causa de mortalidade por cancro e ocupa a segunda posição entre os cancros que contabilizam o maior número de anos de vida potencialmente perdidos (AVPP). Na Europa, a sobrevivência relativa média nos doentes diagnosticados entre 2000 e 2002 foi estimada em 24,9%, variando largamente entre os países. As diferenças geográficas e temporais na sobrevivência de doentes com cancro gástrico pode ser explicada por uma distribuição heterogénea do acesso ao diagnóstico precoce e tratamento entre as populações, bem como diferenças no estatuto socioeconómico dos doentes. Também pode ser associada com as exposições ambientais com impacto potencial tanto no risco de cancro gástrico como no prognóstico dos doentes. A compreensão da relação entre os estilos de vida antes do diagnóstico e sobrevivência podem contribuir para uma caracterização mais precisa da carga associada a estas exposições. O objectivo desta dissertação foi estudar a relação entre estilos de vida antes do diagnóstico e a sobrevivência dos doentes com cancro gástrico, através consecução dos seguintes objectivos específicos:  Revisão sistemática dos estudos publicados que avaliam a associação entre a exposição pré-diagnóstica e a sobrevivência de doentes com cancro gástrico (Manuscrito I).  Quantificar a associação entre estilos de vida antes do diagnóstico e a sobrevivência dos doentes com cancro gástrico numa população portuguesa (Manuscrito II). Manuscrito I – Estilos de vida antes do diagnóstico e sobrevivência dos doentes com cancro gástrico: revisão sistemática e meta-análise Os estudos publicados que quantificavam a associação entre a história pré diagnostica do consumo de tabaco e de bebidas alcoólicas e a sobrevivência de doentes com cancro gástrico foram sistematicamente revistos na Pubmed® e 64 EMBASE® até Abril de 2011. Foi usado um modelo de efeitos aleatórios (DerSimonian e Laird) para calcular estimativas conjuntas de Hazard Ratio (HR) e respectivos intervalos de confiança de 95% (IC 95%) referentes à comparação dos níveis de exposição mais elevados com os mais baixos (fumadores versus não fumadores para o tabaco e para o consumo de álcool, consumidores de álcool versus não consumidores de álcool). A heterogeneidade foi quantificada através da estatística I2. Sete artigos foram elegíveis para meta-análise, fornecendo dados a partir de 6856 casos avaliados em sete países (Canadá, Japão, Itália, EUA, Coreia, Irão e Suécia). O HR foi 1,08 (IC 95%: 0,90-1,30) para fumadores (fumadores versus não fumadores; 9 estimativas de 7 estudos; I2 = 56,2%) e 1,13 (IC 95%: 1,00-1,28) para o consumo de álcool (consumidores de álcool versus não consumidores de álcool, 6 estimativas de cinco estudos, I2 = 13,2%). Apenas dois estudos avaliaram o efeito de outros factores dietéticos. Manuscripto II – Estilos de vida antes do diagnóstico e a sobrevivência dos doentes com cancro gástrico: um estudo de coorte de Portugal Foram avaliados casos incidentes de cancro gástrico internados nos serviços de cirurgia de dois hospitais, entre Junho de 2001 e Dezembro de 2006. Os doentes foram entrevistados sobre as suas características demográficas, sociais, comportamentais e médicas. O consumo de tabaco foi avaliado, assim como ingestão habitual de alimentos por um questionário de frequência alimentar (QFA) validado, com base em informação relativa ao ano anterior ao diagnóstico. As curvas de sobrevivência foram estimadas pelo método de Kaplan-Meier. Foram utilizados modelos de regressão de Cox para calcular Hazard Ratio ajustados para a idade, sexo, educação, extensão da doença, com os respectivos intervalos de confiança de 95% (IC 95%). O tempo máximo de seguimento foi de 10 anos. Três padrões alimentares foram identificados: (I) alto consumo de frutas e produtos lácteos, e baixo consumo de bebidas alcoólicas; (II) baixo consumo de frutas, saladas, legumes, lacticínios, peixe e carne; (III) consumos elevados da maioria dos grupos alimentares e baixa ingestão de sopa. Somente o padrão alimentar III foi correlacionado significativamente com uma melhor sobrevivência relativa a 5 anos, mas apenas para uma extensão da doença caracterizada por disseminação regional (HR, 0,45, 95% IC, 0,22-0,93). Os resultados não foram significativos para as outras variáveis (álcool, tabaco, consumo de frutas e 65 verduras, ingestão de carnes vermelhas e processadas e ingestão de alimentos com a elevada contribuição de sódio). Conclusões  De acordo com a revisão sistemática e meta-análise, o consumo de álcool está associado a uma menor sobrevivência dos doentes com cancro gástrico, não se observou uma relação significativa com o tabaco e a informação sobre os efeitos das exposições alimentares é escassa.  Os resultados de um estudo de coorte realizado em Portugal confirmam que os estilos de vida pré-diagnósticos têm um pequeno impacto na sobrevivência dos doentes com cancro gástrico.