The role of heredity in the etiology of large bowel cancer: Data from the Melbourne colorectal cancer study

Family history data of colorectal cancer, heart disease, and stroke were obtained on near relatives (parents, siblings, and children) in 702 colorectal cancer cases and 710 age-/sex-matched community controls as part of a large, comprehensive, population-based epidemiological and clinicopathological study of colorectal cancer conducted in Melbourne (the Melbourne Colorectal Cancer Study). There was a statistically significant higher family history rate of colorectal cancer in cases than in controls (relative risk=2.13; 95% confidence interval=1.53–2.96; p < 0.001). This family history effect was more pronounced for colon cancer than for rectal cancer and there was an earlier age of detection of colorectal cancer in those with a family history of this cancer when compared with those without such a history. Dietary risk factors for colorectal cancer, which were previously described in the Melbourne study, were separate and independent from the family history effects. It is concluded that a family history of colorectal cancer is an important indication to screen individuals for this cancer, and also that while heredity has a definite role in the etiology of colorectal cancer, this hereditary effect is either likely to be small, or else likely to be important in only a proportion (perhaps 20%) of cases.

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Resumen La predisposición hereditaria y la dieta representan las 2 principales hipótesis sobre etiología del cáncer colorrectal. La información contenida en este artículo proviene de un amplio estudio comprensivo, clinicopatológico, y epidemiológico sobre la incidencia, etiología, y sobrevida (el Estudio de Melbourne sobre Cáncer Colorrectal), y los datos de historia familiar provienen de casos controlados del estudio. Los datos de historia familiar de cáncer colorrectal, enfermedad cardiaca, y accidente cerebrovascular fueron obtenidos en familiares cercanos (padres, hermanos, e hijos) de 702 pacientes con cáncer colorrectal y de 710 personas control de similar edad y sexo, en la misma comunidad de Melbourne. Se encontró una estadísticamente significativa mayor tasa de historia familiar de cáncer colorrectal en los pacientes que en los controles (riesgo relativo=2.13; 95%, intervalo confidencial=1.53–2.96;p<0.001). Tal efecto de historia familiar apareció más pronunciado en el cáncer del colon que en el cáncer del recto, y se observó una edad de detección más temprana del cáncer colorrectal en los pacientes con historia familiar de este tipo de cáncer, en comparación con aquellos sin la historia familiar. Los factores dietéticos en el cáncer colorrectal, los cuales fueron previamente descritos en el estudio de Melbourne, aparecieron aislados e independientes de los efectos de la historia familiar. Se présenta la conclusión de que la historia familiar de cáncer colorrectal es una importante indicación para el tamizaje individual, y también de que si bien es cierto que la herencia posee una influencia definitiva en la etiología del cáncer colorrectal, este efecto hereditario aparentemente es menor o sólo llegar a ser de importancia en apenas una parte (tal vez 20%) de los casos.

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Résumé Les antécédents de cancers familiaux colorectaux, maladie cardiaque, et accidents vasculaires cérébraux ont été recueillis des proches parents (parents, fratrie, et enfants) chez 702 patients ayant présenté un cancer colorectal et chez 710 sujets témoins comparables en ce qui concerne l'âge et le sexe, dans une étude à grande échelle, épidémiologique, et anatomoclinique sur le cancer colorectal, menée à Melbourne, Australie (Melbourne Colorectal Cancer Study). Il y avait plus d'antécédents familiaux de cancer colorectal chez ceux qui avaient un cancer que chez les témoins (risque relatif=2.13; intervalle de confiance à 95%=1.53–2.96;p<0.001). Ceci était plus net pour les patients ayant un cancer colique que pour ceux qui avaient un cancer rectal. Le cancer était détecté plus tôt chez les patients ayant des antécédents familiaux de cancer que chez ceux qui n'en avaient pas. Les risques alimentaires du cancer colorectal déjà décrits n'étaient pas liés aux antécédents familiaux. Les antécédents familiaux de cancer colorectal sont un facteur important dans le dépistage de ces cancers. L'hérédité joue un rôle important dans l'édologie du cancer colorectal chez 20% des patients.

     

Postoperative adjuvant chemotherapy and radiotherapy for cancer of the large bowel and rectum

Forty patients with invasive regional-stage adenocarcinoma of the large bowel and rectum received adjuvant postoperative chemotherapy combined with doses of radiation below the maximal tissue tolerance level. This treatment was reserved for patients with stage B2, C1, and C2 lesions, with only two exceptions. The treatment was well tolerated. It appeared to result in a longer disease-free interval when compared with population-based results for patients with sigmoid cancer who had surgery alone. Our results paralleled those of the Gastrointestinal Tumor Study Group (GITSG) for combined adjuvant therapy of rectal cancer, who also indicated an advantage for long-term survival. Patients who received additional extended chemotherapy had at least the same percentage of favorable outcomes. Tumors above the peritoneal reflection also appeared to share the same improved results. We believe a multicenter randomized study should be performed to evaluate this group of patients.     

Epidemiology of large bowel cancer

Results from epidemiologic studies have provided insights into the etiology of large bowel cancer. Markedly diverse incidences of colorectal cancer exist in various parts of the world and within different regions of a given country. Studies of migrant populations have revealed a role for environmental factors, particularly dietary, in the etiology of colorectal cancers. Genetic factors and inflammatory bowel disease also place certain individuals at increased risk. Sedentary lifestyle, cholecystectomy, and ureterosigmoidostomy may also increase the risk of developing large bowel cancer.

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Resumen Los resultados de estudios epidemiológicos han provisto nuevos conocimientos sobre los factores etiológicos involucrados en el desarrollo del cáncer de colon. Marcadas variaciones en la incidencia de cáncer colorrectal se observan en diversas partes del mundo y entre diferentes regiones dentro de un mismo país. Estudios sobre poblaciones migrantes han revelado el rol de factores ambientales, en particular los de carácter dietario, en la etiología de estos cánceres. Factores genéticos y la enfermedad inflamatoria del colon también colocan a ciertos individuos en condición de riesgo aumentado. La vida sedentaria, la colecistectomía y la ureterosigmoidostomía peuden también incrementar el riesgo de desarrollar cáncer del colon.

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Résumé Un aperçu des facteurs étiologiques dans le développement du cancer colorectal a été dégagé grâce à une étude épidémiologique. L'incidence du cancer colorectal varie beaucoup dans le monde et au sein d'un même pays suivant les régions. L'étude des populations migrantes a démontré le rôle de l'environnement, et en particulier de l'alimentation, dans la génèse des cancers colorectaux. Des facteurs génétiques et l'existence d'une maladie inflammatoire de l'intestin ont également été incriminés chez certains individus. La sédentarité, la cholécystectomie et l'urétérosigmoïdostomie sont aussi de possibles facteurs favorisants.

     

Current perspectives in staging large bowel cancer

Today, a standardized method of staging that is internationally accepted is urgently needed for the management of patients with colorectal cancer. The use of a uniform, sensitive staging system would greatly improve case selection and avoid unnecessary bias when entering patients into adjuvant therapy trials. This would allow a more accurate evaluation of new treatment protocols and assist in the development of more effective follow-up programmes.     

Effect of adjuvant immunotherapy with Nocardia rubra cell-wall skeleton in lung cancer

A randomized clinical trial of intrapleural Nocardia rubra cell-wall skeleton (N-CWS) followed by intradermal N-CWS was performed against lung cancer patients from November, 1977 to June 1981. Totally, 190 patients were entered into this trial. The N-CWS treatment was effective in terms of prolongation of remission duration against not only operable but also inoperable patients. However, significant improvement of survival rate was observed only in operable patients, especially curative+relatively curative resection-group (p less than 0.05). The mode of recurrence was classified as local recurrence and distant metastasis in the curative+relatively curative resection-group. The rates of distant metastasis were 34.1 and 17.6%, respectively, in the control and the N-CWS groups. The rate of local recurrence was 13.6% in the control group, however, no local recurrence was observed in the C-NWS group. These results indicate the clinical effectiveness of the N-CWS treatment especially in curatively resectable lung cancer. No serious side effect was experienced during this trial.     

早期大肠癌诊断研究进展

大肠癌发病率有逐年上升的趋势~([1])，早期诊断和术后复发是影响其预后的两大因索，也是大肠癌临床诊治中的两大难点。因此，大肠癌的早期诊断一直是临床上迫切需要解决的重要研究课题。     

Sepsis and asepsis in large bowel cancer surgery

A patient undergoing surgery for carcinoma of the large bowel has 2 hurdles to negotiate before claiming a cure. The first is postoperative complications and the second, recurrence of the tumor. Recurrence of the tumor will occur almost always within the first 5 years. Postoperative complications are mainly related to infection. Infection on its own is rarely responsible for the death of the patient, but by damaging the vascular endothelium may predispose to arterial or venous thrombosis. More commonly, sublethal sepsis is the cause of considerable morbidity whether within the abdominal wound or the intraperitoneal cavity. One or more of 3 basically different methods are employed to control infection in large bowel surgery: (1) reduction in the number of microorganisms in the large bowel; (2) reduction in the number of microorganisms contaminating the wound, whether within or without the peritoneal cavity; and (3) destruction of microorganisms contaminating the wound. The authors have relied on reducing the number of microorganisms contaminating the wound by strict attention to wound protection and aseptic surgery, and the destruction of microorganisms that actually reach the wound. To this end, excellent results with antibiotics have been obtained by combining meticulous aseptic surgery with the use of cefazolin and metronidazole administered a short time prior to surgery.     

Current status of tumor markers in large bowel cancer

The aim of a primary screening system is to detect premalignant lesions and carcinomas when amenable to curative surgery. Although a number of classical tumor markers have acquired potential for clinical management, none is presently adequate for presymptomatic diagnosis or screening. In colorectal carcinoma, the screening potential of carcinoembryonic antigen (CEA), the gastrointestinal-related antigen, CA19-9, and other more recently characterized biochemical markers is virtually nonexistent, even in patients at high risk to develop the disease. Promising new leads are beginning to emerge from somatic cell genetic and molecular biological approaches. In common with other epithelial neoplasms, perturbations in oncogene expression have been demonstrated in colorectal cancers, and probably reflect important events in malignant transformation and progression. Studies of oncogene expression have, however, not yet yielded clinically useful information. Recently, an intensive search for specific chromosomal and gene abnormalities in the hereditary colon cancer syndromes led to the location of the familial adenomatous polyposis (FAP) gene at chromosome 5q21–q22. Significant is that the loss of alleles on chromosome 5 has also been observed in the tumor cells of at least 20% of sporadic colon cancer patients. This type of association between constitutional genetic change and genetic aberration in the cells of sporadic tumors is reminiscent of other malignant diseases with a genetic component (e.g., retinoblastoma and Wilms' tumor). The disclosure of the FAP gene might ultimately provide a basis for the presymptomatic or prenatal diagnosis of FAP as well as some forms of sporadic colorectal cancer; however, it can be anticipated that other markers linked to colorectal cancer susceptibility genes will eventually be discovered, with potentially wider application in presymptomatic diagnosis and screening.

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Resumen El propósito de un sistema primario de tamizaje para detección de cáncer es identificar las lesiones premalignas y los carcinomas susceptibles de cirugía curativa. Aunque algunos de los marcadores tumorales clásicos han logrado reconocida aplicación en el manejo clínico, ninguno es de utilidad para propósitos de diagnóstico en la fase presintomática o para tamizaje. En el caso del carcinoma colorrectal, la capacidad de tamizaje del antígeno carcinoembriónico (ACE), del antígeno relacionado con cáncer gastrointestinal, CA19-9, y de otros marcadores bioquímicos recientemente identificados es virtualmente nula, aún en pacientes con alto riesgo de desarrollar enfermedad.Algunas perspectivas promisorias han comenzado a emerger a partir de enfoques de biología molecular y genética. Como fenómeno común con otros neoplasmas epiteliales, se han demostrado alteraciones en la expresión oncogénica de los cánceres colorrectales que probablemente son reflejo de eventos importantes en el proceso de transformación maligna y progresión de la enfermedad. Sin embargo, los estudios de expresión oncogénica aún no aportan información que sea de utilidad clínica.Recientemente una investigación intensa en búsqueda de alteraciones cromosónicas y genéticas en los sindromes de cáncer colónico hereditario ha logrado establecer la ubicación del gen de la poliposis adenomatosa familiar en el cromosoma 5q21–q22. Como un hecho significante, la pérdida de alelas en el cromosoma 5 tambien ha sido observado en las células tumorales de por lo menos 20% de los pacientes con cáncer de colonesporádico. Este tipo de asociación entre el cambio genético constitucional y la aberración en las células de los tumores esporádicos es reminiscente de otras enfermedades neoplásicas con componente genético (por ejemplo, el retinoblastoma y el tumor de Wilms).El descubrimiento del gen de la poliposis adenomatosa familiar provee un fundamento para el diagnóstico presintomático o prenatal de esta entidad, así como de ciertas formas de cáncer colorrectal esporádico. Sin embargo, se puede predecir que otros marcadores ligados a los genes de susceptibilidad del cáncer colorrectal, con una más amplia capacidad de aplicación en el diagnóstico presintomático y en el tamizaje, habrán de ser eventualmente descubiertos.

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Résumé Le but d'un système de dépistage primaire est de détecter des lésions pré-malignes et malignes susceptibles d'être traitées chirurgicalement de façon curative. Bien qu'un certain nombre de marqueurs tumoraux classiques soient utiles dans la surveillance du traitement, aucun ne s'est encore montré capable de servir pour le diagnostic ou dépistage précoce. En ce qui concerne le cancer colorectal, la valeur de l'antigène carcinoembryonnaire (ACE), de l'antigène gastrointestinal (CA19-9), et d'autres marqueurs biochimiques plus récents, est virtuellement non-existante, même chez des patients à haut risque.Des progrès nouveaux ont été accomplis, en génétique cellulaire somatique et en chimie moléculaire. Comme pour d'autres épithéliomes, des perturbations de l'expression oncogénique ont été mis en évidence dans les cancers colorectaux, et reflètent probablement un événement important dans la transformation maligne. Cependant, les études d'expression oncogène n'ont pas encore fourni de renseignement cliniquement utiles.Récemment, une étude de recherche pour mettre en évidence des anomalies génétiques et chromosomiques spécifiques dans le syndrome de cancer colique familial a amené à découvrir le gène de la polypose familiale (GPF) au niveau du duodénum (5q21–q22). La perte d'allèles du chromosome 5 a été observée dans les cellules tumorales chez au moins 20% des patients présentant un cancer colique sporadique. Le type d'association, c'est à dire, entre un changement génétique constitutionnel et un changement acquis, rappelle ce que l'on observe dans d'autres cancers (par exemple rétinoblastome et tumeur de Wilms).La découverte d'un GPF peut éventuellement servir de base au diagnostic pré-symptomatique ou pré-natal pour cette maladie, voire même pour quelques cas sporadiques. Cependant, on pense que d'autres marqueurs liés au cancer colorectal seront découverts et auront une plus large application dans le dépistage précoce présymptomatique.

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Supported by the Cancer Research Campaign of Great Britain and the North West Regional Health Authority.     

Phase I clinical trial on adjuvant active immunotherapy of human gliomas with GD2-conjugate

The objective of this study was to determine the feasibility, toxicity, and potential therapeutic benefits of an adjuvant active immunotherapy using a tumour specific ganglioside (GD2) conjugate for the adjuvant treatment of recurrent or progressive gliomas. Seven patients with proven GD2 expression in surgical specimens underwent a vaccination course with GD2-KLH/MPL-A conjugate. The follow-up was performed according to WHO guidelines regarding common toxicity criteria. Antibody titres against the ganglioside and the adjuvants were analysed. All patients developed a local type 4 reaction. Anti-GD2-antibody titres could not be detected, despite high titres against the immunoadjuvants. No tumour regression was observed. The disease remained stable for a median of 21.5 weeks (6-34 weeks). The median survival time after the first immunization was 47 weeks. The medial total survival time was 76 weeks. Adverse effects have not been observed. Active GD2-KLH/MPL-A immunization was technically feasible, but did not elicit anti-GD2 antibody generation.     

肌层浸润性膀胱癌新辅助与辅助免疫治疗的现状与展望

<正>根治性膀胱切除术(radical cystectomy,RC)是肌层浸润性膀胱癌(muscle-invasive bladde cancer,MIBC)的主要治疗方式,国内外指南推荐为T_2～4aN₀M₀期及高危非肌层浸润性膀胱癌患者提供RC^[1]。但MIBC患者接受RC后,仍有50%的患者出现术后复发^[1],从新辅助和辅助治疗的层面减少复发,提高患者生存率和生活质量就显得尤其重要。新辅助和辅助化疗的研究已从二十世纪八十年代开展,推荐c T_2～4aN₀M₀期MIBC患者采用以顺铂为基础的新辅助化疗,未行新辅助化疗的p T₃～p T₄或淋巴结转移的患者建议术后辅助化疗^[1]。     

Randomized trial of adjuvant chemotherapy after curative resection for gastric cancer

BACKGROUND: The aim of the study was to evaluate the efficacy of adjuvant chemotherapy on survival after resection for gastric cancer. METHODS: Patients were enrolled if they underwent resection of gastric cancer but had lymph node or serosal involvement or both. Surgical resection was either total or partial gastrectomy according to the site of the tumor, and surgeons were allowed to perform either D1 or D2 gastrectomy. The subjects were random assigned in two treatment groups as follows: surgery alone as the control group, or surgery and adjuvant chemotherapy. Nine cycles of 5 days protocol every 4 weeks was proposed to the patients of the chemotherapy group. The protocol included a daily administration of 200 mg/m(2) of folinic acid, 5-fluorouracil (375 mg/m(2) during the first session increasing 25 mg by session until reaching 500 mg/m(2)) and CDDP 15 mg/m(2). Two hundred patients were required. Kaplan-Meier survival curves were compared according to the log-rank and the Mantel-Haenszel methods. RESULTS: In all, 205 patients were enrolled in the study; 104 had surgery alone and 101 had surgery and adjuvant chemotherapy. The patients' characteristics were similar except for the mean age, which was 4 years less in the control group. Because of toxicity, 54% of the patients stopped the protocol before the end of the nine courses, and 46% of the patients received the nine courses including 32% with a decreased dose and 14% with a full dose. The 5-year survival rate was 39% in the control group and 39% in the chemotherapy group. CONCLUSIONS: This protocol of adjuvant chemotherapy failed to improve the 5-year survival after resection for gastric cancer.