AUTONOMIC NERVOUS SYSTEM organization and functions
Medical Students 2011 - A. Cervantes - GASTROINTESTINAL CANCER - Epidemiology – Clinical Presentation – Diagnosis – Staging
1. NEW CHALLENGES IN COLORECTAL CANCER: FROM GENETICS TO SURGERY AND NEW TARGETED MEDICAL THERAPEUTICS A. Cervantes Hematology and Medical Oncology Dept. University Hospital Valencia
2. From Siegel R et al. CA Cancer J Clin 2011 Ten Leading Cancer Types for the Estimated New Cancer Cases, 2011
3. From Siegel R et al. CA Cancer J Clin 2011 Ten Leading Cancer Types for the Estimated Deaths, 2011
6. NEW CHALLENGES IN COLORECTAL CANCER: HEREDITARY CANCER MULTIDISCIPLINARY APPROACH TO LOCALIZED RECTAL CANCER TREATMENT OF METASTATIC DISEASE MAY OFFER A CURATIVE OPTION NEW TARGETED THERAPIES
7. WBC 12.0 10 9 /L HB: 10.1 g/Dl VCM 69 fl CHCM 28 Renal function and liver tests: normal Hemocult test: positive CEA: 0.6 ng/ml Colonoscopy : ulcerated and infiltrating tumor bellow the hepatic angle in right colon. No polips Biopsy: Colon Adenocarcinoma CASE 1 35 year old man. Family doctor in a village Weight loss by 5% in two months Colic abdominal pain, fever and chills in the last three weeks
8. The patient had a heavy history of colon cancer and other tumors in his family His father died of colon cancer at 45 years His paternal grand mother died of endometrial cancer at 46 years He has a paternal aunt with gastric cancer at 40 years and still alive
10. PATHOGENESIS OF COLON CANCER NORMAL MUCOSA HYPERPLASIA SMALL ADENOMA MODERATE ADENOMA BIG ADENOMA IN SITU CARCINOMA INVASIVE CANCER
11. PATHOGENESIS OF COLON CANCER VIA SUPPRESOR GENES NORMAL MUCOSA HYPERPLASIA SMALL ADENOMA BIG ADENOMA IN SITU CARCINOMA INVASIVE CANCER METASTATIC CA FAP GEN HYPERMETHYLATION K-RAS P53 DCC
15. Mismatch Repair status is prognostic: n=515 untreated stage II colon cancer HR: 0.51 p=0.009 deficient proficient Sargent DJ, et al. Abstract 4008 ASCO 2008
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18. CLINICAL FEATURES OF HEREDITARY NON-POLYPOSIS COLON CANCER (HNPCC) YOUNGER AGE (MEDIAN 42 Y) MORE PREVALENT IN RIGHT COLON SYNCHRONIC AND METHACHRONIC TUMORS UNDIFFERENTIATED, MUCINOUS AND RINGET CELL PATHOLOGY GOOD PROGNOSIS
19. STAGING Abdomen and pelvic CT-Scan: No liver mets Abscess at the right colon (14 x 9 cm) Chest X-ray: no lung mets SURGERY An abscessified mass at the right colon was detected without invasion of related organs A total colectomy plus ileoproctostomy was performed
20. PATHOLOGICAL STAGING Poorly differenciated adenocarcinoma, invading till pericolic fat (T3) None out of 15 resected nodes was involved Resection margins free of tumor ADJUVANT THERAPY NOT RECOMMENDED
21. FOLLOW UP ALIVE AND FREE OF RECURRENCE AT 9 YEARS AFTER SURGERY PROCTOSCOPY RECOMMENDED EVERY YEAR TO SCREEN FOR METACRONIC TUMORS GENETIC TESTING TO BE OFFERED TO THE PATIENT AND RELATIVES AT RISK A PATOGENIC MUTATION IN MSH-2 WAS FOUND IN DNA FROM LYMPHOCYTES OF THE PATIENT
22. CONSEQUENCES OF A POSITIVE GENETIC TEST IT MAY BE USEFUL TO STUDY RELATIVES AT RISK IF A RELATIVE DOES NOT HAVE SUCH A MUTATION, THE RISK OF DEVELOPING COLON CANCER IS SIMILAR TO THE NORMAL POPULATION IF THE RELATIVE SHARES THE MUTATION WITH THE PATIENT: HIGH RISK OF DEVELOPING COLON CANCER 75% AT 80 YEARS SCREENING COLONOSCOPY WILL INCREASE SURVIVAL
23. THE IMPORTANCE OF A THROUGHLY PERFORMED PEDIGREE TO ASSESS THE RISK OF HEREDITARY PERDISPOSITION TO COLON CANCER AND OTHER RELATED TUMORS SHOUDL BE EMPHASIZED ALL DOCTORS SHOULD CONSIDER ALLWAYS THE IMPORTANCE OF THE FAMILY HISTORY TO ALLOW A DIAGNOSIS OF HEREDITARY SUSCEPTIBILITY TO COLON CANCER ALL SUSPECTED CASES SHOULD BE FURTHER SUBMITTED TO A CANCER FAMILY CLINIC TO CONSIDER GENETIC ANALYSIS AND COUNCELING CONCLUSIONS
29. YEARS non curative CT Cured by the addition of CT Cured by surgery alone 0 20 40 60 80 100 0 1 2 3 4 5 TOXICITY % S U R V I V A L INTERPRETATION OF RESULTS OF TRIALS WITH ADJUVANT CT IN STAGE II COLON CANCER
36. SURGICAL EXPERTISE AND OUTCOMES IN RECTAL CANCER Increased in 7.1 % 3.2% 7.1% Non-expert surgeons
37. TME CAN BE LEARNED AND SURGICAL TRAINIG PROGRAMMS ARE USEFUL 8% 6%
38. PREOPERATIVE STAGING OF RECTAL CANCER BOWEL WALL INVASION REGIONAL LYMPH NODES CURRENT KEY CONCEPTS WELL DEFINED BY MRI DISTANCE TO MESORECTAL FASCIA DISTANT METASTASIS SPHICNTER INVOLVEMENT VENOUS INVASION
44. SURGICAL STAGING OF RECTAL CANCER: THE ROLE OF THE PATHOLOGIST BOWEL WALL INVASION REGIONAL LYMPH NODES CURRENT KEY PATHOLOGICAL CONCEPTS DISTANCE TO CIRCUMFERENTIAL RESECTION MARGIN DISTANT METASTASIS MACROSCOPICAL INTEGRITY OF MESORECTUM STAGING AFTER PREOPERATIVE CHEMORADIATION
59. Randomized Phase III Trials of Preoperative Short Course Radiotherapy vs Surgery Alone as initial therapy for Resectable Rectal Cancer PREOPERATIVE RADIATION GIVEN IN 5 FRACTIONS OF 5 Gy TO A TOTAL DOSE OF 25 Gy SURGERY WAS PERFORMED WITHIN 1 WEEK 583 No. NR NR 11% p<0.001 27% 585 SWEDISH (1997) CI at 95% Hazard Ratio Local Relapse Rate at 5 y Local Relapse Rate at 5 y No. PREOPERATIVE RADIATION CONTROL
60. “ Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish Rectal Cancer Trial”. LOCAL RELAPSE RATE : 27 % VS 11 % ( p < 0.001)
61. Randomized Phase III Trials of Preoperative Radiotherapy vs Surgery Alone as initial therapy for Resectable Rectal Cancer PREOPERATIVE RADIATION REDUCES SIGNIFICANTLY LOCAL RELAPSES EVEN IN TME RESECTED PATIENTS 1.61-3.79 2.47 5% P<0.0001 674 17% 676 MRC CR07 (2006) 6.9% 2194 17.3% 2185 TOTAL 937 583 No. 2.05-5.71 3.42 5.8% p<0.001 11.4% 924 DUTCH (2001) NR NR 11% p<0.001 27% 585 SWEDISH (1997) CI at 95% Hazard Ratio Local Relapse Rate at 5 y Local Relapse Rate at 5 y No. PREOPERATIVE RADIATION CONTROL
62. Randomized Phase III Trial of Preoperative vs Postoperative Conventional Fractionation Chemoradiation for Resectable Rectal Cancer PREOPERATIVE CHEMORADIATION INDUCES SIGNIFICANTLY BETTER LOCAL CONTROL THAN POSTOPERATIVE CHEMORADIATION, WITHOUT ANY EFFECT ON OVERALL SURVICAL THE GERMAN RECTAL CANCER STUDY GROUP, 2004 13% p:0.006 38% p:n.s 74% p:n.s 65% p:n.s 394 POSTOP ChRT 6% 36% 76% 68% 405 PREOP ChRT LR at 5 y DM at 5 y OS at 5 y DFS at 5 y No. PTS ARM
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64. Case 2: SURGICAL RESECTION . NO LIVER OR PERITONEAL METS “ CURATIVE RESECTION” ANTERIOR RESECTION WITH TOTAL MESORECTAL ESCISION ESPHYNCTER PRESERVATION PROCEDURE TEMPORAL DERIVATIVE ILEOSTOMY
65. Case 2: PATHOLOGY ASSESSMENT . MACROSCOPIC: INTEGRITY OF MESORECTUM IN BOTH ANTERIOR AND POSTERIOR FACES FLAT FIBROTIC ULCER OF 1.8 CM WITH NO RESIDUAL TUMOR AT 2 CM OF THE LOWER MARGIN OF THE SURGICAL SPECIMEN
67. Case 2: PATHOLOGY ASSESSMENT . MICROSCOPIC: RESIDUAL ISOLATED TUMOR CELLS IN THE MUSCULAR NOT REACHING THE PERIRECTAL FAT (ypT2) NONE OUT OF THE 17 LYMPH NODES STUDIED IN THE PERIRECTAL FAT SHOWED TUMOR INVOLVEMENT (ypN0) THE CIRCUMFERENTIAL RESECTION MARGIN WAS LOCATED AT 2.8 CM OF THE TUMOR DEPOSITS
69. Case 2: ADJUVANT CHEMOTHERAPY . SIX MONTHS OF OXALIPLATIN BASED THERAPY WERE RECOMMENDED AFTER SURGERY ILEOSTOMY WAS REVERTED AFTER COMPLETING ADJUVANT CHEMOTHERAPY No evidence of local or systemic relapse after 39 months
70. PATIENTS WITH LOCALLY ADVANCED RECTAL CANCER MAY BENEFIT FROM A MULTIDICISCIPLINARY TEAM APPROACH INTEGRATING RADIATION, CHEMOTHERAPY AND SURGERY THE QUALITY OF SURGERY AND THE EXTENSION AND DETAILS OF THE PATHOLOGY REPORT ARE CRITICAL POINTS TO GET BETTER RESULTS IN THE TREATMENT OF RECTAL CANCER CONCLUSIONS
71. CASE 3 68 year old patient who goes to his family doctor due to constipation and rectal bleeding Weight loss of 10% in the las 3 months Sigmoidoscopy reveals a tumor obstructing completely the large bowel at 20 cm from the anal verge Blood, kidney and liver tests normal excepting LDH 1015 mU/ml CEA 1500 NG/ML
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75. CASE 3 STAGING THORAX AND ABDOMINOPELVIC CT-SCAN: TWO LUNG METASTASES OF 23 AND 19 MM TWO LIVER METASTASES 72 AND 50 MM PALLIATIVE SURGERY A PALLIATIVE SIGMOIDECTOMY WAS PERFORMED PATHOLOGY CONFIRMED THE DIAGNOSIS OF MODERATELY DIFFERENTIATED ADENOCA. pT3 pN1 M1. A biopsy of the liver confirmed liver mets
76. ACTIVE DRUGS IN ADVANCED COLORECTAL CANCER CONVENTIONAL CHEMOTHERAPEUTIC AGENTS 5-FLUOROURACIL ORAL FLUOROPIRYMIDINES (CAPECITABINE, UFT, S1, ETC…) IRINOTECAN OXALIPLATIN ANTI-EGFR MONOCLONAL ANTIBODIES CETUXIMAB PANITUMUMAB ANTI-ANGIOGENICS BEVACIZUMAB
77. CASE 3 THERAPEUTIC STRATEGY COMBINATION CHEMOTHERAPY WITH OXALIPLATIN AND FU WAS STARTED AFTER 4 COURSES OF TREATMENT A PARTIAL RESPONSE WAS OBSERVED THE RESPONSE WAS CONFIRMED AND CT WAS CONTINUED FOR 18 COURSES EVERY 14 DAYS CEA WENT DOWN TO 3 ng/ml CT SCAN SHOWED TWO LUNG NODULES OF LESS THAN 10 mm AND LIVER NODULES WERE SMALLER THAN 2 CM
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80. CASE 3 THERAPEUTIC STRATEGY A PET SCAN WAS PERFORMED NO AREAS OF METABOLIC ACTIVITY WAS SEEN IN THE LUNGS TWO AREAS OF HIPERMETABOLIC ACTIVITY WERE OBSERVED IN THE LIVER, MEASURING 1 AND 1,5 CM. A SURGICAL RESECTION OF LIVER RESIDUAL DISEASE WAS PERFORMED
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82. Survival after neoadjuvant chemotherapy and surgery 58 patients: macroscopically complete resection 74 non operated patients 30% 50% S. Giacchetti et al., Ann. Oncol., 1999; 10, 6: 663-69 77 operated patients Time (Years) Patients (%) 100 0 80 60 40 20 0 1 2 3 4 5 6 7 8 9 151 patients with initially unresectable liver metastases
83. CASE 3 THERAPEUTIC STRATEGY A SEGMENTECTOMY II-III WAS PERFORMED ON THE PATHOLOGY SPECIMEN SHOWED MOSTLY NECROTIC TISSUE IN BOTH RESECTED NODES WITH SOME RESIDUALLY ACTIVE TUMOR CELLS MARGINS WERE COMPLETELY FREE OF TUMOR THE PATIENT IS FREE OF RECCURRENCE AT TWO YEARS OF LIVER RESECTION
84. ARE THERE ANY NEW APPROCHES DIFFERENT FROM CHEMOTHERAPY TO MEDICAL TREATMENT FOR COLORECTAL CANCER? YES, OF COURSE: TARGETED THERAPY MONOCLONAL ANTIBODIES AGAINST RECEPTORS: EGFR GROWTH FACTORS: VEGF
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86. BOND Study Response Rate/TTP IRC – ITT cohort *CR+PR+SD Combination Monotherapy p-value (n=218) [95% CI] (n=111) [95% CI] PR 22.9% [17.5–29.1] 10.8% [5.7–18.1] 0.0074 Disease control* 55.5% [48.6–62.2] 32.4% [23.9–42.0] 0.0001 Median TTP 4.1 months 1.5 months <0.0001
96. Grb2 Sos Shc Grb2 Sos PI3K Akt Ras Raf MEK1/2 MAPK BAD Survival Proliferation PTEN mTOR Cell cycle progression FKHR GSK3 p27 Cyclin D1, E Why KRAS is involved in the EGFR pathway?
103. Magnitud del beneficio adicional CETUXIMAB + CT CETUXIMAB + CT KRAS wt CT Eficacia en 1 ª -linea ¿QUÉ AÑADE KRAS COMO MARCADOR PREDICTIVO?
104. Van Cutsem E, et al. NEJM 2009 OBJETIVO PRINCIPAL : SUPERVIVENCIA LIBRE DE PROGRESIÓN EN LA MUESTRA KRAS WT 32% risk reduction for progression HR=0.68 p:0.017 mPFS CETUXIMAB+FOLFIRI: 9.9mo mPFS FOLFIRI: 8.7mo SLP a 1 año: 25% vs 43%
105. Consistent superiority of Cetuximab+Folfiri across efficacy endpoints for the updated KRAS wild-type population p = 0.0094 p = 0.0012 p < 0.0001 Overall survival time: HR=0.796 95% CI [ 0.670, 0.946] PFS time (IRC) : HR=0.696 95% CI [ 0.558, 0.867] Best Overall Response (IRC) : OR=2.07 95% CI [ 1.52, 2.83]
107. Clinical anti-VEGF pathway therapies Tyrosine kinase inhibitors (TKIs) (SU5416, SU6668, SU11248, Vatalanib, Sorafenib, ZD6474, AEE788, AMG-706) Anti-VEGFR monoclonal antibodies (Mabs) (IMC-1C11) Signal Transduction R R K K Ligands Anti-VEGF monoclonal antibodies (Mabs) (Bevacizumab) Soluble receptors (VEGF Trap) Ribozymes
108. IFL +/- BEVACIZUMAB IN FIRST LINE ADVANCED COLON CANCER Probability of survival 1.0 0.8 0.6 0.4 0.2 0 0 10 20 30 40 Survival (months) IFL + placebo IFL + bevacizumab Median survival (months) IFL + placebo: 15.6 vs IFL + bevacizumab: 20.3 HR: 0.66, p=0.00004 HR = hazard ratio Hurwitz H, et al. N Engl J Med 2004;350:2335–42
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110. SOME KEYS FOR THE FUTURE: BE POSITIVE GO ON AND MAKE STRONGER THE MULTIDISCIPLINARY APPROACH CREATE A TEAM AND WORK HARD WITHIN IT CAREFUL PLANNING OF RESEARCH OUR PATIENTS DESERVE NO LESS
Notas do Editor
First, looking the prognostic ability of MMR status, we see that in the 512 treated patients, there is no difference in outcomes between patients with proficient versus deficient MMR. However, in the 515 untreated patients, MMR status is a clear prognostic factor, with the 5 year disease free survival increasing from 56% in patients with pMMR tumors to 80% in patients with dMMR tumors, p = 0.009, with a hazard ratio of 0.51.