Altorjay István dr. Occurance of gastrointestinal malignancies in world HO statistics (2002) incidency males females total place M.S. CRC 550 465 472 687 1 023 152 3. 18-24 mo Stomach 603 419 330 518 933 937 4. 8-10 mo Liver 442 119 184 043 626 162 6. 4-6 mo Esophagus 315 394 146 723 462 117 8. 8-10 mo Pancreas 124 841 107 465 232 306 13. 4-6 mo GI total 2 036 238 1 241 436 3 277 674 Total (without skin) 5 801 839 5 060 657 10 863 496 1
Gastrointestinal tumours registered in GLOBOCAN (WHO) 2000 database in Europe Major risk factors of gastrointestinal neoplasms Environmental components Smoking Alcohol-consumption Chewing of Betel-nut Deficiency of oral hygiene Obesity (BMI > 30) Lack of physical activity Hormonal factors Insulin, IGF-1,2 IGFBP1-6 adiponectin Infective agents Human papillomavirus (16, 18) Hepatitis B virus Hepatitis C virus Helicobacter pylori Nutritive factors Meat (red meats: hem, nitrosopeptidek, O6- carboxymetyl guanine etc.) Vegetables, fruits, fibers 2
Natural course of carcinoma Detectable preclinic phase A B C D E Biologic origin Detectable by screening Onset of symptoms (patient delay) Diagnosis (doctor s delay) Cancer deaths Death from other cause 1. Carcinoembrionic antigen (CEA): glucoprotein, 180 000 kd, present in fetal nutritional channel, pancreas. Normal value: 3-5 ng/ml Clinical significance: colorectalis cc, follow-up, breast, lung, pancreas 2. Alfa-foetoprotein (AFP): glucoprotein, 70 000 kd, produced by fetal liver and graafian follicle, maximum level at 13. Week of pregnancy. Normal value: 8-15 ng/ml. Clinical significance: primary liver cc, non seminoma type of testicular cancer, stomach cancer, biliary tract tumours 3. CA 19-9 (carbohydrate) Normal value: < 35 U/ml, clinical significance: pancreas cancer, biliary tract tumours, liver metastases etc. 4. CA 72-4 (glucoprotein) normal value: < 4 mg/ml, clinical significance: stomach cancer, ovarian cancer. 3
1. Size of primary tumour: T in situ - T4 (involving surrounding organs) 2. Regional lymphnodes: N 1-3 3. Distant metastases: M0 - Mx - M1 4. Histologic grading: well differentiated -.. undifferentiated 5. Histologic invasivity (lymphatic vessel invasion) CRC is the second most frequently diagnosed tumour in both men and women, in male patients following pulmonary cancer, in women following breast cancer. In Hungary around 8000 new cases are discovered yearly, and the mortality is about 4700-4800. One third of the cases is discovered in early stage and one forth with distant metastases. 70 % of the tumours is found in the left colon! 4
5 year survival depending on the stage of the disease is between 90% - 9%. 90 % of the patients is older than 50 years 80-85 % of the cases is considered as sporadic CRC, <1 % is FAP, 3-5 % HNPCC Accumulations in the family is well known, among first line relatives CRC is 3x more frequent. Polyps smaller <1 cm may develop into CRC roughly in 10 years. 5
Low (general) risk: age above 50 high intake of fat/low fibers smoking, obesity, alcohol-abusus Medium risk: colorectal adenoma in the own history, CRC and/or colorectal polyps in the family High risk: previous CRC in the history, herediter disease forms (HNPCC, FAP, Gardner sy, P-J sy, krónikus IBD etc. 6
Bleeding: - macroscopic - microscopic (FOBT) Rapid new development of hemorrhoids Iron deficiency of unknown origin in elderly Changes in stool-habits palpable abdominal mass, loss of bodyweight, dull pain, loss of appetite (not early signs anymore) A: tumour within the mucosa B1: involving the wall, but not reaching the serosa, no known positive lgl B2: involving the entire wall, reaching the serosa, but no known positive lgl C1: involving the wall, not reaching the serosa, but positive lgl involvement C2: involving the entire wall, including serosa and positive lgl involvement D: distant metastases 7
Detection of occult blood in stool (benzidin, human albumin) rectal digital investigation ( ~ 25 % of the tumours can be found) pathologic reflection above the bowel by US colonoscopy, (+) histology, barium enema, abd. CT, CT-colonography, EUS (rectal) tumour markers (CEA) mainly for follow up 8
FAP (autosom, dominant) is caused by the inherited mutation and inactivation of APC (adenomatosus polyposis coli) gen (5q21), which is responsible for the degradation of β-catenin. This plays a role - together with E-cadherin - in the cellular adhesion, and connected to TCF-4 (T cell factor) also activates different proliferating gens (c-myc, cyclin D1, PPARδ). The mutation of the oncoprotein K-RAS (12p), that plays a role in the intracellular signal-transduction can be shown in half of the tumours. Following its binding to the membrane-receptor of the epithelial growth factor (EGF) the RAS-GDP turns into RAS-GTP, that will induce proliferating gens. The mutant form of RAS is unable to detach from the GTP, thus the induction goes on. These events are accompanied by the activation of COX-2, then gastrin, DNA-methyltransferase upregulation, and finally the mutation of p53 (17p) and DCC supressor gens occur. The mutation of p53 is characteristic for the later phase of the adenomacarcinoma progression and can be detected in about half of the cases of CRC. 9
The HNPCC is caused by the inactivation of the DNA mismatch repair system (MMR). In the process the mutation of about 6 gens (hmsh2, hmsh3, hmsh6-2p21; hmlh1-3p21; hpms1-2q31-33, hpms2-7p22) plays a role. Therefore the so-called microsatellita instability (MSI) can be detected, in about 15 % of the tumours. This process can involve such inportant regulating and supressor gens, like TGF-β II receptor, Insulin-like GF II receptor, TCF-4, BAX etc. The accumulating mutations lead to uncontrolled cell-proliferation. 10
Benign tumours of the bowel Sporadic polyps (tubular, tubulovillous, villous, serrated) malignancy on the surface is related to size: <1 cm, 1% >3 cm, 50 % pseudopolyps (hyperplastic, hamartoma, lipoma, haemangioma) Inherited polyps - FAP (autosom, dominant, manifestation between 15-20, malignization 35-40) - Gardner sy: FAP + dermoid tumours, osteomas - Peutz-Jeghers sy: multiplex hamartomas + mucocutan pigmentation Primary treatment: following a correct staging colon cancer needs surgical resection; in case of rectal cancer perioperativ irradiation (5 x 4Gy or 20 x 1,8 Gy) and/or chemoradiotherapy is performed and subsequent surgery. Adjuvant chemotherapy: stage Dukes B/2, C : Mayo protoc. 5-FU 425 mg/m2 (infusion/bolus) + leucovorin or levamisol day 1-5, repeated every 28 days, 6 cycles. (5 year survival 7, 33 % better respectively); 11
In stage Dukes D (IV): palliative chemotherapy De Gramont protocol: Leukovorin 200 mg/m2/die, then 5- FU 1000 mg/m2/die continuous infusion for 2 days, repeated by 14 days Irinotecan (Campto) in combination with 5-FU (FOLFIRI) or oral capecitabine (Xeloda) Oxaliplatin (Eloxatin) in combination with 5-FU (FOLFOX) of oral capecitabine (Xeloda) Recently bevacizumab (Avastin) or cetiximab (Erbitux) addition is attempted. Bevacizumab (Avastin) monoclonal antibody against vascular endothelial growth factor (VEGF) in combination with 5FU seems to be more effective, than chemoth. alone. New trials with Avastin + irinotecan Cetuximab (Erbitux) monoclonal antibody against epidermal growth factor (EGF) in combination with chemotherapeutics in trials Dendritic cell vaccination following inoculation with tumour extract or activated against CEA. 12
In case of liver metastases: local chemotherapy or chemoembolisation via arteria hepatica, using floxuridine (FUDR) and adriamycin and mitomycin and/or systemic administration of 5FU/leucovorin (neoadjuvant chemotherapy followed by resection of the liver resulted in prolongation of survival) RFA treatment, cryotherapy, ethanol infiltration Diet instructions: more fibers (min. 30 g/die) more Calcium intake more vegetables vitamines C and E more physical activity less animal fat less alcohol 13
Mostly accepted strategies of screening CRC FOBT + sigmo/colonoscopy sigmoidoscopy once in 5 years colonoscopia once in lifetime (between 57-62 years) Comment CRC mortality reduced by 15-33%, 60 % of adenomas and CRC can be detected in case of positive sigmoidoscopy pancolonoscopy is indicated, but so the mortality of CRC is reduced by 59-88 %! Rationalistic solution. M. Crespi 2001 in half of the above cases total colonoscopy will be indicated, majority of colon adenomas appear by the age of 60! In group of patients with general risk: from the age of 50 annual FOBT, this can reduce CRC mortality by 15-33 % (Hardcastle et al Lancet 1996). Flexibil sigmoidoscopy once in 5 years, if polyp larger than 1 cm is detected, subsequent total colonoscopy! Double contrast enema once in 5 years may replace endoscopy, as alternative, sensitivity 83 % vs. 95%. Suggestion of ACS: colonoscopy once in 10 years enough. 14
Prolonged history of IBD (both CU and MC) (in case of pancolitis after 8 years, in leftg side colitis after 15 years) colonoscopy is indicated in each 1-3 years, together with mapping biopsies. Real polyps should be treated as in non-ibd patients. In familial accumulation of CRC, especially if there were cancer or adenoma cases below the age of 60, close relatives should be screened once in 5 years, starting at minus 10 years of the age of the earliest detected CRC. 15
Amsterdam criteria: 3 relatives have tumours, 2 of them must be first grade relatives 2 generations have to be involved, and at least one tumour has to be detected under the age of 50. In HNPCC families from the age of 25 biannual endoscopy should be done, or at least it should be started 5 years earlier, than the onset of the earliest tumour. From the age of 40, annual investigation is indicated. If CRC in the patients own history, increased risk for metachron tumours, therefore total colonoscopy within 6 months following the operation is compulsory. If preoperative total colonoscopy was performed, after curative resection first control after 1 year and subsequently every 3 years. Following successful complete polypectomy with stalk, control colonoscopy once in 3 years. Followiong removal of big, sessile polyps, control endoscopy is indicated after 6 and 12 months. If residuum remained, that cannot be rfemoved by endoscopy, surgery is needed! 16
In genetically proven FAP annual endoscopy is indicated from the age of 12, when polyps are detected, total colectomy is indicated and if the rectum was preserved, the residual rectum remnant has to be controlled every 6 months! If no polyps are detected at the age of 40, subsequently endoscopy in every 3 years is enough. FAP (genet. proven) CRC 100% duodenum cc 10% HNPCC CRC: >80% endometrium cc 40-60% ovarium 10% stomach 13-19% bile duct 2-18% urinary bladder 5-10% kidney 3,3% glioblastoma 3,7 % Peutz-Jeghers sy CRC 2-13 % duodenum 2-13% Sertoli cell tumor 10-20 % SCTAT 20% Juvenilis polyposis CRC upto 50 % rarely stomach Cowden sy CRC rarely, thyroid gland 3-10 % breast cc 25-50 % 17