京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21016号 / 医博第4362号 / 新制||医||1028(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 小西 靖彦, 教授 福田 和彦, 教授 松村 由美 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

O câncer colorretal é a terceira neoplasia mais freqüente no mundo ocidental. No reto encontram-se 30 a 57% dos casos, sendo 80% destes passíveis de alcançar pelo exame digital do reto. Apesar de inúmeros avanços diagnósticos e terapêuticos, ainda são detectados tardiamente. A sobrevida em 5 anos mantém-se em torno de 50%, e os aspectos clínicopatológicos são os critérios prognósticos disponíveis. O presente estudo objetiva avaliar a sobrevida e os fatores clínico-patológicos relacionados aos tumores de reto em nosso meio. Os prontuários de 112 pacientes com adenocarcinoma primário e único de reto submetidos a cirurgia eletiva, num período de 7 anos (1988 a 1995), foram revisados retrospectivamente quanto a: idade, sexo, CEA pré-operatório, tipo e curabilidade da cirurgia, recidiva, seguimento, sobrevida e histopatologia do tumor. Para análise da sobrevida utilizou-se o método de Kaplan-Meyer. Nas análises bivariada e estratificada, um valor de P <0,05 foi considerado significativo. O coeficiente de correlação de Kendall foi utilizado para comparação dos sistemas de estadiamento. No modelo multivariado, utilizou-se um IC de 90%. A média de idade foi de 62,03±14,37 anos, com 52% dos casos do sexo feminino.Sessenta e dois por cento dos tumores encontravam-se no reto distal. Foram submetidos a amputação do reto 56,3% dos casos, e os demais, a retossigmoidectomia, sendo 25 procedimentos não-curativos. Sessenta e quatro pacientes (57%) apresentaram recidiva tumoral (14,3% locorregional, 32,1% à distância, e 10,7% ambas). Quarenta e cinco pacientes (40%) faleceram da neoplasia. O tempo mediano de seguimento foi de 35,27 meses (14,5 – 57,63). A sobrevida em 5 anos foi de 51%, tendo reduzido proporcionalmente ao avanço dos estágios histopatológicos da doença (P<0,001). O sistema de estadiamento de Dukes/Astler- Coller se correlacionou significativamente com o sistema TNM (τ=0,91). O adenocarcinoma 6 moderadamente diferenciado foi o mais freqüente (73,2%). A maioria dos tumores (68,2%) estendia-se até os tecidos perirretais; apenas 3,8% eram restritos à mucosa. Sessenta e sete pacientes tinham linfonodos positivos (29,4%, N1; e 30,3%, N2). Na classificação de Dukes/Astler-Coller, 14 eram estágio D; 55, C1 e C2; 15, B2; e 28, B1 e A. A localização do tumor no reto médio ou distal não influenciou a ocorrência dos óbitos, as recidivas, nem a curabilidade da cirurgia. Os tumores menos diferenciados (P=0,009), com maior penetração na parede (P=0,013), com envolvimento linfonodal (N2>N1, P<0,001), com cirurgia nãocurativa (P=0,002) e os que apresentaram recidiva (P<0,001) influenciaram significativamente a mortalidade. A classificação de Dukes/Astler-Coller e a diferenciação tumoral (P=0,089) foram fatores prognósticos independentes, bem como a penetração do tumor na parede retal (P=0,091) e o comprometimento linfonodal (P<0,001), quando excluída a classificação histopatológica. Os achados deste estudo estão de acordo com a literatura. Além da diferenciação tumoral, os fatores prognósticos identificados correspondem aos níveis de classificação dos sistemas de estadiamento vigentes, concordando com a observação de que estes ainda são os critérios prognósticos disponíveis. Este relato corrobora a predominância dos tumores em estágios avançados ao diagnóstico e a ausência de valor prognóstico da localização do tumor no reto. / Colorectal cancer is the third most common neoplasia in the Western world. About 30 to 57% of cases occur in the rectum, and, among these, 80% can be reached by digital rectal examination. However, most of them are diagnosed in advanced stages. Five-year survival rate is maintained at about 50% and clinicopathological features are still the prognostic criteria available. To evaluate survival and clinicopathological factors, the records of 112 patients submitted to elective resection of adenocarcinoma of the rectum from 1988 to 1995 were reviewed. Data were analysed as for: age, gender, preoperative serum level of CEA, type and curability of surgery, recurrence, follow-up, survival and tumor histopathology. Kaplan- Meyer method was used to analyse survival. Statistical significance on bivariate and stratified analysis was considered for a P value less than 0,05. Kendall correlation coefficient was used to compare histopathologic classifications. In the multivariate model, a 90% confidence interval was considered significant. Mean (SD) age was 62 (14) years and 52% of patients were female. Sixty-two percent of rectal tumors were distally located. Abdominoperineal resection was performed in 56% of cases and the remaining patients underwent low anterior resection. Twenty-five (22%) of these were non-curative procedures.Overall, recurrence was observed in 64 (57%) patients: local in 14%, distant in 32% and both in 10%. Forty-five patients (40%) died from disease. Median (range) follow-up was 35 (14 - 57) months. Fiveyear survival rate was 51% and reduced significantly by tumor progression (histopathologic stages; P<0,001). Both stage systems were well correlated (τ=0,91). Moderately differentiated adenocarcinoma was the most frequent tumor grade (73%). Most tumors (68%) extended to perirectal tissues, only 4% were confined to the mucosa. Positive lymph nodes were observed in 67 patients (30% each, N1 and N2). Fourteen patients were Dukes/Astler-Coller D stage; 55 were C1 or C2; 15 were B2; and 28 were B1 or A. Tumor location had no influence on deaths, recurrences or curability. On bivariate analysis, tumor grade (P=0,009), depth (P=0,013) or recurrence (P<0,001), lymph node involvement (N2>N1, P<0,001), noncurative procedure (P=0,002) related with poorer outcome. On multivariate analyses, Dukes/Astler-Coller stages and tumor grade (P=0,089) were found to be independent prognostic factors, as well as depth of invasion and lymph node involvement, when excluding Dukes staging (P=0,091 and <0,001, respectively). These findings are similar to those reported in the literature. Besides tumor grade, prognostic factors identified meet classification levels on current staging systems. Accordingly, these criteria are still the prognostic factors available. The present report corroborates the predominance of advanced stage tumours at diagnosis and the lack of prognostic value of tumor location in the rectum.

O câncer colorretal é a terceira neoplasia mais freqüente no mundo ocidental. No reto encontram-se 30 a 57% dos casos, sendo 80% destes passíveis de alcançar pelo exame digital do reto. Apesar de inúmeros avanços diagnósticos e terapêuticos, ainda são detectados tardiamente. A sobrevida em 5 anos mantém-se em torno de 50%, e os aspectos clínicopatológicos são os critérios prognósticos disponíveis. O presente estudo objetiva avaliar a sobrevida e os fatores clínico-patológicos relacionados aos tumores de reto em nosso meio. Os prontuários de 112 pacientes com adenocarcinoma primário e único de reto submetidos a cirurgia eletiva, num período de 7 anos (1988 a 1995), foram revisados retrospectivamente quanto a: idade, sexo, CEA pré-operatório, tipo e curabilidade da cirurgia, recidiva, seguimento, sobrevida e histopatologia do tumor. Para análise da sobrevida utilizou-se o método de Kaplan-Meyer. Nas análises bivariada e estratificada, um valor de P <0,05 foi considerado significativo. O coeficiente de correlação de Kendall foi utilizado para comparação dos sistemas de estadiamento. No modelo multivariado, utilizou-se um IC de 90%. A média de idade foi de 62,03±14,37 anos, com 52% dos casos do sexo feminino.Sessenta e dois por cento dos tumores encontravam-se no reto distal. Foram submetidos a amputação do reto 56,3% dos casos, e os demais, a retossigmoidectomia, sendo 25 procedimentos não-curativos. Sessenta e quatro pacientes (57%) apresentaram recidiva tumoral (14,3% locorregional, 32,1% à distância, e 10,7% ambas). Quarenta e cinco pacientes (40%) faleceram da neoplasia. O tempo mediano de seguimento foi de 35,27 meses (14,5 – 57,63). A sobrevida em 5 anos foi de 51%, tendo reduzido proporcionalmente ao avanço dos estágios histopatológicos da doença (P<0,001). O sistema de estadiamento de Dukes/Astler- Coller se correlacionou significativamente com o sistema TNM (τ=0,91). O adenocarcinoma 6 moderadamente diferenciado foi o mais freqüente (73,2%). A maioria dos tumores (68,2%) estendia-se até os tecidos perirretais; apenas 3,8% eram restritos à mucosa. Sessenta e sete pacientes tinham linfonodos positivos (29,4%, N1; e 30,3%, N2). Na classificação de Dukes/Astler-Coller, 14 eram estágio D; 55, C1 e C2; 15, B2; e 28, B1 e A. A localização do tumor no reto médio ou distal não influenciou a ocorrência dos óbitos, as recidivas, nem a curabilidade da cirurgia. Os tumores menos diferenciados (P=0,009), com maior penetração na parede (P=0,013), com envolvimento linfonodal (N2>N1, P<0,001), com cirurgia nãocurativa (P=0,002) e os que apresentaram recidiva (P<0,001) influenciaram significativamente a mortalidade. A classificação de Dukes/Astler-Coller e a diferenciação tumoral (P=0,089) foram fatores prognósticos independentes, bem como a penetração do tumor na parede retal (P=0,091) e o comprometimento linfonodal (P<0,001), quando excluída a classificação histopatológica. Os achados deste estudo estão de acordo com a literatura. Além da diferenciação tumoral, os fatores prognósticos identificados correspondem aos níveis de classificação dos sistemas de estadiamento vigentes, concordando com a observação de que estes ainda são os critérios prognósticos disponíveis. Este relato corrobora a predominância dos tumores em estágios avançados ao diagnóstico e a ausência de valor prognóstico da localização do tumor no reto. / Colorectal cancer is the third most common neoplasia in the Western world. About 30 to 57% of cases occur in the rectum, and, among these, 80% can be reached by digital rectal examination. However, most of them are diagnosed in advanced stages. Five-year survival rate is maintained at about 50% and clinicopathological features are still the prognostic criteria available. To evaluate survival and clinicopathological factors, the records of 112 patients submitted to elective resection of adenocarcinoma of the rectum from 1988 to 1995 were reviewed. Data were analysed as for: age, gender, preoperative serum level of CEA, type and curability of surgery, recurrence, follow-up, survival and tumor histopathology. Kaplan- Meyer method was used to analyse survival. Statistical significance on bivariate and stratified analysis was considered for a P value less than 0,05. Kendall correlation coefficient was used to compare histopathologic classifications. In the multivariate model, a 90% confidence interval was considered significant. Mean (SD) age was 62 (14) years and 52% of patients were female. Sixty-two percent of rectal tumors were distally located. Abdominoperineal resection was performed in 56% of cases and the remaining patients underwent low anterior resection. Twenty-five (22%) of these were non-curative procedures.Overall, recurrence was observed in 64 (57%) patients: local in 14%, distant in 32% and both in 10%. Forty-five patients (40%) died from disease. Median (range) follow-up was 35 (14 - 57) months. Fiveyear survival rate was 51% and reduced significantly by tumor progression (histopathologic stages; P<0,001). Both stage systems were well correlated (τ=0,91). Moderately differentiated adenocarcinoma was the most frequent tumor grade (73%). Most tumors (68%) extended to perirectal tissues, only 4% were confined to the mucosa. Positive lymph nodes were observed in 67 patients (30% each, N1 and N2). Fourteen patients were Dukes/Astler-Coller D stage; 55 were C1 or C2; 15 were B2; and 28 were B1 or A. Tumor location had no influence on deaths, recurrences or curability. On bivariate analysis, tumor grade (P=0,009), depth (P=0,013) or recurrence (P<0,001), lymph node involvement (N2>N1, P<0,001), noncurative procedure (P=0,002) related with poorer outcome. On multivariate analyses, Dukes/Astler-Coller stages and tumor grade (P=0,089) were found to be independent prognostic factors, as well as depth of invasion and lymph node involvement, when excluding Dukes staging (P=0,091 and <0,001, respectively). These findings are similar to those reported in the literature. Besides tumor grade, prognostic factors identified meet classification levels on current staging systems. Accordingly, these criteria are still the prognostic factors available. The present report corroborates the predominance of advanced stage tumours at diagnosis and the lack of prognostic value of tumor location in the rectum.

O câncer colorretal é a terceira neoplasia mais freqüente no mundo ocidental. No reto encontram-se 30 a 57% dos casos, sendo 80% destes passíveis de alcançar pelo exame digital do reto. Apesar de inúmeros avanços diagnósticos e terapêuticos, ainda são detectados tardiamente. A sobrevida em 5 anos mantém-se em torno de 50%, e os aspectos clínicopatológicos são os critérios prognósticos disponíveis. O presente estudo objetiva avaliar a sobrevida e os fatores clínico-patológicos relacionados aos tumores de reto em nosso meio. Os prontuários de 112 pacientes com adenocarcinoma primário e único de reto submetidos a cirurgia eletiva, num período de 7 anos (1988 a 1995), foram revisados retrospectivamente quanto a: idade, sexo, CEA pré-operatório, tipo e curabilidade da cirurgia, recidiva, seguimento, sobrevida e histopatologia do tumor. Para análise da sobrevida utilizou-se o método de Kaplan-Meyer. Nas análises bivariada e estratificada, um valor de P <0,05 foi considerado significativo. O coeficiente de correlação de Kendall foi utilizado para comparação dos sistemas de estadiamento. No modelo multivariado, utilizou-se um IC de 90%. A média de idade foi de 62,03±14,37 anos, com 52% dos casos do sexo feminino.Sessenta e dois por cento dos tumores encontravam-se no reto distal. Foram submetidos a amputação do reto 56,3% dos casos, e os demais, a retossigmoidectomia, sendo 25 procedimentos não-curativos. Sessenta e quatro pacientes (57%) apresentaram recidiva tumoral (14,3% locorregional, 32,1% à distância, e 10,7% ambas). Quarenta e cinco pacientes (40%) faleceram da neoplasia. O tempo mediano de seguimento foi de 35,27 meses (14,5 – 57,63). A sobrevida em 5 anos foi de 51%, tendo reduzido proporcionalmente ao avanço dos estágios histopatológicos da doença (P<0,001). O sistema de estadiamento de Dukes/Astler- Coller se correlacionou significativamente com o sistema TNM (τ=0,91). O adenocarcinoma 6 moderadamente diferenciado foi o mais freqüente (73,2%). A maioria dos tumores (68,2%) estendia-se até os tecidos perirretais; apenas 3,8% eram restritos à mucosa. Sessenta e sete pacientes tinham linfonodos positivos (29,4%, N1; e 30,3%, N2). Na classificação de Dukes/Astler-Coller, 14 eram estágio D; 55, C1 e C2; 15, B2; e 28, B1 e A. A localização do tumor no reto médio ou distal não influenciou a ocorrência dos óbitos, as recidivas, nem a curabilidade da cirurgia. Os tumores menos diferenciados (P=0,009), com maior penetração na parede (P=0,013), com envolvimento linfonodal (N2>N1, P<0,001), com cirurgia nãocurativa (P=0,002) e os que apresentaram recidiva (P<0,001) influenciaram significativamente a mortalidade. A classificação de Dukes/Astler-Coller e a diferenciação tumoral (P=0,089) foram fatores prognósticos independentes, bem como a penetração do tumor na parede retal (P=0,091) e o comprometimento linfonodal (P<0,001), quando excluída a classificação histopatológica. Os achados deste estudo estão de acordo com a literatura. Além da diferenciação tumoral, os fatores prognósticos identificados correspondem aos níveis de classificação dos sistemas de estadiamento vigentes, concordando com a observação de que estes ainda são os critérios prognósticos disponíveis. Este relato corrobora a predominância dos tumores em estágios avançados ao diagnóstico e a ausência de valor prognóstico da localização do tumor no reto. / Colorectal cancer is the third most common neoplasia in the Western world. About 30 to 57% of cases occur in the rectum, and, among these, 80% can be reached by digital rectal examination. However, most of them are diagnosed in advanced stages. Five-year survival rate is maintained at about 50% and clinicopathological features are still the prognostic criteria available. To evaluate survival and clinicopathological factors, the records of 112 patients submitted to elective resection of adenocarcinoma of the rectum from 1988 to 1995 were reviewed. Data were analysed as for: age, gender, preoperative serum level of CEA, type and curability of surgery, recurrence, follow-up, survival and tumor histopathology. Kaplan- Meyer method was used to analyse survival. Statistical significance on bivariate and stratified analysis was considered for a P value less than 0,05. Kendall correlation coefficient was used to compare histopathologic classifications. In the multivariate model, a 90% confidence interval was considered significant. Mean (SD) age was 62 (14) years and 52% of patients were female. Sixty-two percent of rectal tumors were distally located. Abdominoperineal resection was performed in 56% of cases and the remaining patients underwent low anterior resection. Twenty-five (22%) of these were non-curative procedures.Overall, recurrence was observed in 64 (57%) patients: local in 14%, distant in 32% and both in 10%. Forty-five patients (40%) died from disease. Median (range) follow-up was 35 (14 - 57) months. Fiveyear survival rate was 51% and reduced significantly by tumor progression (histopathologic stages; P<0,001). Both stage systems were well correlated (τ=0,91). Moderately differentiated adenocarcinoma was the most frequent tumor grade (73%). Most tumors (68%) extended to perirectal tissues, only 4% were confined to the mucosa. Positive lymph nodes were observed in 67 patients (30% each, N1 and N2). Fourteen patients were Dukes/Astler-Coller D stage; 55 were C1 or C2; 15 were B2; and 28 were B1 or A. Tumor location had no influence on deaths, recurrences or curability. On bivariate analysis, tumor grade (P=0,009), depth (P=0,013) or recurrence (P<0,001), lymph node involvement (N2>N1, P<0,001), noncurative procedure (P=0,002) related with poorer outcome. On multivariate analyses, Dukes/Astler-Coller stages and tumor grade (P=0,089) were found to be independent prognostic factors, as well as depth of invasion and lymph node involvement, when excluding Dukes staging (P=0,091 and <0,001, respectively). These findings are similar to those reported in the literature. Besides tumor grade, prognostic factors identified meet classification levels on current staging systems. Accordingly, these criteria are still the prognostic factors available. The present report corroborates the predominance of advanced stage tumours at diagnosis and the lack of prognostic value of tumor location in the rectum.

Rectal cancer is a common malignancy treated with surgical resection and curative intent in the majority of cases. One treatment option is low anterior resection (LAR) with preserved bowel continuity, often involving the formation of a temporary defunctioning stoma (DS). The general aim of this thesis was to improve understanding of the role of DS in rectal cancer surgery with regard to timing of stoma reversal and development of anastomotic leakage (AL), impact on long-term anorectal function (AF), as well as aspects of cost-effectiveness. Study I addressed the timing of stoma reversal following LAR. We found that 19% of reversed patients were reversed within 4 months of LAR, while 81% of reversals were delayed. In 58% of delayed reversals the delay was due to low priority on surgical waiting lists. Studies II-IV were based on 234 patients randomized to receive a DS or no DS following LAR. Study II compared patients with AL following LAR diagnosed during the initial hospital stay (early leakage, EL) with patients diagnosed after hospital discharge (late leakage, LL). LL was more common in females, and originated more frequently from the transverse stapler line. EL was more common in males, and originated more frequently from the circular stapler line. Study III assessed AF 5 years after LAR with regard to whether patients initially had a DS or no DS. We found no difference in AF between the two randomized groups. When comparing with a 1-year follow-up in the same patient cohort, there were no further changes in AF over time. Study III assessed necessary healthcare resources and cost within 5 years of LAR, depending on whether patients initially had a DS or no DS. The overall cost analysis revealed a higher cost for patients randomized to DS, regardless of the cost-savings associated with a reduced frequency of anastomotic leakage.