NEW CHALLENGES IN COLORECTAL CANCER: FROM GENETICS TO SURGERY AND NEW TARGETED MEDICAL THERAPEUTICS A. Cervantes Hematolog...
From Siegel R et al.  CA Cancer J Clin 2011 Ten Leading Cancer Types for the Estimated New Cancer Cases, 2011
From Siegel R et al.  CA Cancer J Clin 2011 Ten Leading Cancer Types for the Estimated Deaths, 2011
Annual Age-Adjusted Cancer Death Rates* Among Males  for Selected Cancers, United States, 1930 to 2007.
Annual Age-Adjusted Cancer Death Rates* Among Females  for Selected Cancers, United States, 1930 to 2007.
NEW CHALLENGES IN COLORECTAL CANCER: HEREDITARY CANCER MULTIDISCIPLINARY APPROACH TO LOCALIZED RECTAL CANCER  TREATMENT OF...
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 n...
The patient had a heavy history of colon cancer and other tumors in his family  His father died of colon cancer at 45 year...
35y 40y 35y 40y 42y 54y 42y 52y 41y Endometrial colon  gastric  renal 25y
PATHOGENESIS OF COLON CANCER NORMAL  MUCOSA  HYPERPLASIA SMALL  ADENOMA MODERATE ADENOMA BIG ADENOMA IN SITU CARCINOMA INV...
PATHOGENESIS OF COLON CANCER VIA SUPPRESOR GENES NORMAL  MUCOSA  HYPERPLASIA SMALL  ADENOMA BIG ADENOMA IN SITU CARCINOMA ...
Wong JJL, et al. Gut 2007; 56:140
Imai, K and Yamamoto H. Carcinogenesis 2008; 29:673
Sargent DJ, et al. Abstract 4008 ASCO 2008
Mismatch Repair status is prognostic: n=515 untreated stage II colon cancer HR: 0.51  p=0.009 deficient proficient Sargent...
Towards individualization of adjuvant treatment for stage II:  E5202 Regi ster Tumor block  assessment for 18q/MSI <ul><li...
 
CLINICAL FEATURES OF HEREDITARY NON-POLYPOSIS COLON CANCER (HNPCC) YOUNGER AGE (MEDIAN 42 Y) MORE PREVALENT IN RIGHT COLON...
STAGING Abdomen and pelvic CT-Scan: No liver mets Abscess at the right colon (14 x 9 cm) Chest  X-ray: no lung mets SURGER...
PATHOLOGICAL STAGING Poorly differenciated adenocarcinoma, invading till pericolic fat (T3) None out of 15 resected nodes ...
FOLLOW UP ALIVE AND FREE OF RECURRENCE AT 9 YEARS  AFTER SURGERY PROCTOSCOPY RECOMMENDED EVERY YEAR TO SCREEN FOR METACRON...
CONSEQUENCES OF A POSITIVE GENETIC TEST IT MAY BE USEFUL TO STUDY RELATIVES AT RISK IF A RELATIVE DOES NOT HAVE SUCH A MUT...
THE  IMPORTANCE OF A THROUGHLY PERFORMED PEDIGREE  TO ASSESS THE RISK OF HEREDITARY  PERDISPOSITION TO COLON CANCER AND OT...
 
PROGNOSTIC FACTORS IN STAGE II-III  COLON CANCER <ul><li>STAGE </li></ul><ul><li>IIA:  T3N0 </li></ul><ul><li>IIB:  T4N0 <...
Primary end-point: disease-free survival Secondary end-points: safety, overall survival LV5FU2 FOLFOX4 :  LV5FU2   +  oxal...
Disease-free Survival (ITT) 1.0 0.9 0.8 0.7 0.6 0.5 0.3 0.4 0.2 0.1 0.0 0 66 6 12 18 24 30 36 42 48 54 60 Months Events  F...
Disease-free Survival in  Stage III Patients: N1 & N2 1.0 0.9 0.8 0.7 0.6 0.5 0.3 0.4 0.2 0.1 0.0 0 FOLFOX4 – 443 N1 LV5FU...
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 ...
<ul><li>52 year old man </li></ul><ul><li>No previous diseases </li></ul><ul><li>Rectal bleeding </li></ul><ul><li>Constip...
<ul><li>DRE: partially fixed tumor in the anterior part or the rectum located at 4 cm of anal edge </li></ul><ul><li>Rigid...
<ul><li>Systemic staging </li></ul><ul><li>CT scan of abdomen, pelvis and thorax </li></ul><ul><li>Local staging </li></ul...
<ul><li>Surgical resection </li></ul><ul><li>Pathology assessment and estimation of risk </li></ul><ul><li>Treatment based...
<ul><li>The concept of TME surgery </li></ul><ul><li>Optimal staging by MRI </li></ul><ul><li>Pathological assessment of t...
THE CONCEPT OF TOTAL MESORECTAL EXCISION
SURGICAL EXPERTISE AND OUTCOMES IN RECTAL CANCER   Increased in     7.1 %   3.2%     7.1% Non-expert surgeons
TME CAN BE LEARNED AND SURGICAL  TRAINIG PROGRAMMS ARE USEFUL 8% 6%
PREOPERATIVE STAGING OF RECTAL CANCER BOWEL WALL INVASION REGIONAL LYMPH NODES CURRENT KEY CONCEPTS WELL DEFINED BY MRI DI...
<ul><li>Systemic staging </li></ul><ul><li>CT scan of abdomen, pelvis and thorax </li></ul><ul><li>No metastatic disease w...
INVOLVEMENT OF MESORECTAL FASCIA
 
INVOLVEMENT OF PUBORECTAL SPHINCTER
EXTRAMURAL VEIN INVASION
SURGICAL  STAGING OF RECTAL CANCER: THE ROLE OF THE PATHOLOGIST BOWEL WALL INVASION REGIONAL LYMPH NODES CURRENT KEY PATHO...
THE CONCEPT OF TOTAL MESORECTAL EXCISION
THE PATHOLOGIST AUDITS SURGICAL SKILLS:  DEFINITION OF PLANE OF SURGERY Nagtegaal et al, J Clin Oncol  2002
MACROSCOPIC ASSESSMENT OF  MESORECTAL EXCISION García-Granero E, Cervantes A et al. Cancer 2009.
MACROSCOPIC ASSESSMENT OF  MESORECTAL EXCISION García-Granero E, Cervantes A et al. Cancer 2009.
THE PATHOLOGIST AUDITS SURGICAL SKILLS:  MACROSCOPIC ASSESSMENT OF MESORECTAL EXCISION García-Granero E, Cervantes A et al...
Quirke et al. Lancet 2009.
THE ASSESSMENT OF  CIRCUMFERENTIAL RESECTION MARGIN 43% 8% Gosens MJ et al. Clin Cancer Res 2007; 13:6617
THE ASSESSMENT OF  CIRCUMFERENTIAL RESECTION MARGIN 27% 59% Gosens MJ et al. Clin Cancer Res 2007; 13:6617
THE VALUE OF  CIRCUMFERENTIAL RESECTION MARGIN Nagtegaal ID and Quircke P. J Clin Oncol 2008; 26:303
THE ASSESSMENT OF  CIRCUMFERENTIAL RESECTION MARGIN
THE ASSESSMENT OF  CIRCUMFERENTIAL RESECTION MARGIN
THE ASSESSMENT OF  CIRCUMFERENTIAL RESECTION MARGIN
THE MICROSCOPIC ASSESSMENT OF  CIRCUMFERENTIAL RESECTION MARGIN
<ul><li>Locally advanced tumor: rT3 rN2 M0 </li></ul><ul><li>Treatment options:  </li></ul><ul><li>Preoperative radiation ...
Randomized Phase III Trials of Preoperative Short Course Radiotherapy vs Surgery Alone as initial therapy for Resectable R...
“ Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish Rectal Cancer Trial”.  LOCAL RELAP...
Randomized Phase III Trials of Preoperative Radiotherapy vs Surgery Alone as initial therapy for Resectable Rectal Cancer ...
Randomized Phase III Trial of Preoperative vs Postoperative Conventional Fractionation Chemoradiation for Resectable Recta...
<ul><li>Locally advanced tumor: rT3 rN2 M0 </li></ul><ul><li>Treatment selected:  </li></ul><ul><li>Preoperative chemoradi...
Case 2: SURGICAL RESECTION .  NO LIVER OR PERITONEAL METS “ CURATIVE RESECTION” ANTERIOR RESECTION WITH TOTAL MESORECTAL  ...
Case 2: PATHOLOGY ASSESSMENT .  MACROSCOPIC:  INTEGRITY OF MESORECTUM IN BOTH ANTERIOR AND  POSTERIOR FACES FLAT FIBROTIC ...
THE ASSESSMENT OF  PATHOLOGICAL STAGING AFTER CHEMORADIATION
Case 2: PATHOLOGY ASSESSMENT .  MICROSCOPIC:  RESIDUAL ISOLATED TUMOR CELLS IN THE MUSCULAR  NOT REACHING THE PERIRECTAL F...
THE ASSESSMENT OF  PATHOLOGICAL STAGING AFTER CHEMORADIATION
Case 2: ADJUVANT CHEMOTHERAPY .  SIX MONTHS OF OXALIPLATIN BASED THERAPY WERE RECOMMENDED AFTER SURGERY ILEOSTOMY WAS REVE...
PATIENTS WITH LOCALLY ADVANCED RECTAL CANCER MAY BENEFIT FROM A MULTIDICISCIPLINARY TEAM APPROACH INTEGRATING RADIATION, C...
CASE 3 68 year old patient who goes to his family doctor  due to constipation and rectal bleeding Weight loss of 10% in th...
 
 
 
CASE 3 STAGING THORAX AND ABDOMINOPELVIC CT-SCAN: TWO LUNG METASTASES OF 23 AND 19 MM TWO LIVER METASTASES 72 AND 50 MM PA...
ACTIVE DRUGS IN ADVANCED COLORECTAL CANCER CONVENTIONAL CHEMOTHERAPEUTIC AGENTS 5-FLUOROURACIL ORAL FLUOROPIRYMIDINES (CAP...
CASE 3 THERAPEUTIC STRATEGY COMBINATION CHEMOTHERAPY  WITH OXALIPLATIN AND FU WAS STARTED  AFTER 4 COURSES OF TREATMENT A ...
 
 
CASE 3 THERAPEUTIC STRATEGY A PET SCAN WAS PERFORMED NO AREAS OF METABOLIC ACTIVITY WAS SEEN IN THE LUNGS TWO AREAS OF HIP...
 
Survival after neoadjuvant chemotherapy and surgery 58 patients: macroscopically complete resection 74 non operated patien...
CASE 3 THERAPEUTIC STRATEGY A SEGMENTECTOMY II-III WAS PERFORMED ON THE PATHOLOGY SPECIMEN SHOWED MOSTLY  NECROTIC TISSUE ...
ARE THERE ANY NEW APPROCHES DIFFERENT FROM CHEMOTHERAPY TO MEDICAL TREATMENT FOR COLORECTAL CANCER? YES, OF COURSE: TARGET...
 
BOND Study   Response Rate/TTP IRC – ITT cohort *CR+PR+SD Combination Monotherapy p-value (n=218)  [95% CI] (n=111)  [95% ...
BULKY RETROPERITONEAL METASTASES PRETREATMENT irinotecan+CETUXIMAB LDH 1306 MU/ml
PARTIAL RESPONSE OF RETROPERITONEAL METASTASES  AFTER 6 WEEKS TREATMENT WITH irinotecan+CETUXIMAB LDH 444 MU/ml
BULKY HEPATIC METASTASES WITH CEA 6000 ng/ml  BEFORE TREATMENT WITH irinotecan+CETUXIMAB
BULKY HEPATIC METASTASES WITH F ALC 820 mU/ml  BEFORE TREATMENT WITH irinotecan+CETUXIMAB
PARTIAL RESPONSE OF THE HEPATIC METASTASES  CEA 52 ng/ml  AFTER TREATMENT WITH irinotecan+CETUXIMAB
PARTIAL RESPONSE OF THE HEPATIC METASTASES F. alc 320 mU/ml  AFTER TREATMENT WITH irinotecan+CETUXIMAB
EGFR-inhibitor induced skin reactions <ul><li>1 2 3 4 5 6 7 8 9 </li></ul>Description of  severe  cases THERAPY SUGGESTION...
NCIC CTG CO.17:  Randomized Phase III Trial in mCRC EGFR  testing  by IHC   * Cetuximab 400 mg/m 2  IV week 1 then 250 mg/...
NCIC CTG CO.17: Overall Survival CETUXIMAB + BSC CENSORED BSC CENSORED HR 0.77  (95% CI =0.64 – 0.92)  Stratified log rank...
Grb2 Sos Shc Grb2 Sos PI3K Akt Ras Raf MEK1/2 MAPK BAD Survival Proliferation PTEN mTOR Cell   cycle   progression FKHR GS...
ACTIVACIÓN DEL EGFR Y SEÑALIZACIÓN
<ul><li>Cuando el gen KRAS está mutado, la proteina KRAS (p21 Ras) está activa independientemente de la activación de  EGF...
Figure 5.30  The Biology of Cancer  (© Garland Science 2007)
Figure 5.31  The Biology of Cancer  (© Garland Science 2007)
 
  FOLFIRI Irinotecan (180 mg/m 2 )  + 5-FU 400 mg/m 2  bolus +  2400 mg/m 2  as 46-h  continuous infusion)  + FA  every 2 ...
Magnitud del beneficio adicional CETUXIMAB + CT CETUXIMAB + CT KRAS wt CT Eficacia en 1 ª -linea ¿QUÉ AÑADE KRAS COMO MARC...
Van Cutsem E, et al. NEJM 2009 OBJETIVO PRINCIPAL :  SUPERVIVENCIA LIBRE  DE PROGRESIÓN EN LA MUESTRA KRAS WT 32% risk red...
Consistent superiority  of Cetuximab+Folfiri across efficacy  endpoints for the updated KRAS wild-type population p = 0.00...
CONFIDENTIAL – for internal use only
Clinical anti-VEGF pathway therapies Tyrosine kinase inhibitors (TKIs) (SU5416, SU6668, SU11248, Vatalanib, Sorafenib, ZD6...
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 Surviv...
 
SOME KEYS FOR THE FUTURE: BE POSITIVE GO ON AND MAKE STRONGER THE  MULTIDISCIPLINARY APPROACH CREATE A TEAM AND WORK HARD ...
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Medical Students 2011 - A. Cervantes - GASTROINTESTINAL CANCER - Epidemiology – Clinical Presentation – Diagnosis – Staging

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  • 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.
  • xx/xx/xxxx Editor: Presentation name here
  • Medical Students 2011 - A. Cervantes - GASTROINTESTINAL CANCER - Epidemiology – Clinical Presentation – Diagnosis – Staging

    1. 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. 2. From Siegel R et al. CA Cancer J Clin 2011 Ten Leading Cancer Types for the Estimated New Cancer Cases, 2011
    3. 3. From Siegel R et al. CA Cancer J Clin 2011 Ten Leading Cancer Types for the Estimated Deaths, 2011
    4. 4. Annual Age-Adjusted Cancer Death Rates* Among Males for Selected Cancers, United States, 1930 to 2007.
    5. 5. Annual Age-Adjusted Cancer Death Rates* Among Females for Selected Cancers, United States, 1930 to 2007.
    6. 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. 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. 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
    9. 9. 35y 40y 35y 40y 42y 54y 42y 52y 41y Endometrial colon gastric renal 25y
    10. 10. PATHOGENESIS OF COLON CANCER NORMAL MUCOSA HYPERPLASIA SMALL ADENOMA MODERATE ADENOMA BIG ADENOMA IN SITU CARCINOMA INVASIVE CANCER
    11. 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
    12. 12. Wong JJL, et al. Gut 2007; 56:140
    13. 13. Imai, K and Yamamoto H. Carcinogenesis 2008; 29:673
    14. 14. Sargent DJ, et al. Abstract 4008 ASCO 2008
    15. 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
    16. 16. Towards individualization of adjuvant treatment for stage II: E5202 Regi ster Tumor block assessment for 18q/MSI <ul><li>High Risk </li></ul><ul><li>MSS + 18q LOH </li></ul><ul><li>MSI-L + 18q LOH </li></ul><ul><li>Low Risk </li></ul><ul><li>MSS, no 18q LOH </li></ul><ul><li>MSI-L, no 18q LOH </li></ul><ul><li>MSI-H +/- 18q LOH </li></ul>Observation mFOLFOX6 mFOLFOX6 + bevacizumab R Planned accrual: 3610 patients
    17. 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
    18. 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
    19. 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
    20. 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
    21. 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
    22. 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
    23. 25. PROGNOSTIC FACTORS IN STAGE II-III COLON CANCER <ul><li>STAGE </li></ul><ul><li>IIA: T3N0 </li></ul><ul><li>IIB: T4N0 </li></ul><ul><li>IIIA: T1-2N1 </li></ul><ul><li>IIIB: T3N1 </li></ul><ul><li>IIIC: T1-4N2 </li></ul><ul><li>PREOPERATIVE CEA </li></ul><ul><li>BOWEL OBSTRUCTION/PERFORATION/ EMERGENCY SURGERY </li></ul><ul><li>VASCULAR, LYMPHATIC OR PERINEURAL INVASION </li></ul><ul><li>HISTOLOGIC GRADE </li></ul><ul><li>POOR LYMPHATIC YIELD AT STAGING </li></ul>
    24. 26. Primary end-point: disease-free survival Secondary end-points: safety, overall survival LV5FU2 FOLFOX4 : LV5FU2 + oxaliplatin 85 mg/m² N=2246 Stage II: 40% Stage III: 60% MOSAIC: Study Design R
    25. 27. Disease-free Survival (ITT) 1.0 0.9 0.8 0.7 0.6 0.5 0.3 0.4 0.2 0.1 0.0 0 66 6 12 18 24 30 36 42 48 54 60 Months Events FOLFOX4 279/1123 (24.8%) LV5FU2 345/1123 (30.7%) HR [95% CI]: 0.77 [0.65 – 0.90] DFS probability Data cut-off: January 16, 2005 6.6% p <0.001
    26. 28. Disease-free Survival in Stage III Patients: N1 & N2 1.0 0.9 0.8 0.7 0.6 0.5 0.3 0.4 0.2 0.1 0.0 0 FOLFOX4 – 443 N1 LV5FU2 – 443 N1 FOLFOX4 – 229 N2 LV5FU2 – 232 N2 Months DFS probability 66 6 12 18 24 30 36 42 48 54 60 Data cut-off: January 16, 2005 7.2% 11.5% HR: 0.76 HR: 0.72
    27. 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
    28. 30. <ul><li>52 year old man </li></ul><ul><li>No previous diseases </li></ul><ul><li>Rectal bleeding </li></ul><ul><li>Constipation </li></ul><ul><li>Obstructive defecation with false diarrhea </li></ul>Case 2 Presentation .
    29. 31. <ul><li>DRE: partially fixed tumor in the anterior part or the rectum located at 4 cm of anal edge </li></ul><ul><li>Rigid rectoscopy: Obstructing circumferential tumor at 4 cm of anal edge </li></ul><ul><li>Colonoscopy not able to explore beyond the tumor due to almost complete obstruction </li></ul>Case 2: Findings related to the tumor .
    30. 32. <ul><li>Systemic staging </li></ul><ul><li>CT scan of abdomen, pelvis and thorax </li></ul><ul><li>Local staging </li></ul><ul><li>Endorectal ultrasonography </li></ul><ul><li>MRI </li></ul><ul><li>Clinical assessment </li></ul><ul><li>CBC, renal and liver tests </li></ul><ul><li>CEA </li></ul>Case 2: Optimal staging of rectal cancer .
    31. 33. <ul><li>Surgical resection </li></ul><ul><li>Pathology assessment and estimation of risk </li></ul><ul><li>Treatment based upon classical TNM factors </li></ul><ul><li>Postoperative concurrent chemoradiation </li></ul>OLD APPROACH TO RECTAL CANCER NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer JAMA, Sep 1990 ; 264: 1444 - 1450.
    32. 34. <ul><li>The concept of TME surgery </li></ul><ul><li>Optimal staging by MRI </li></ul><ul><li>Pathological assessment of the quality of surgery </li></ul><ul><li>Preoperative radiation or chemoradiation </li></ul><ul><li>Integration of knowledge in a multidisciplinary team approach </li></ul><ul><li>Selection of patients for preoperative Txt </li></ul>RECENT CHANGES IN RECTAL CANCER DIAGNOSIS AND THERAPY
    33. 35. THE CONCEPT OF TOTAL MESORECTAL EXCISION
    34. 36. SURGICAL EXPERTISE AND OUTCOMES IN RECTAL CANCER Increased in 7.1 % 3.2% 7.1% Non-expert surgeons
    35. 37. TME CAN BE LEARNED AND SURGICAL TRAINIG PROGRAMMS ARE USEFUL 8% 6%
    36. 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
    37. 39. <ul><li>Systemic staging </li></ul><ul><li>CT scan of abdomen, pelvis and thorax </li></ul><ul><li>No metastatic disease was found </li></ul><ul><li>Local staging </li></ul><ul><li>Endorectal ultrasonography </li></ul><ul><li>Puborectal muscle not involved, advanced tumor involving perirectal fat, but the instrument could not pass through the tumor due to obstruction </li></ul><ul><li>MRI in next slide </li></ul><ul><li>Clinical assessment </li></ul><ul><li>CBC, renal and liver tests: Normal values </li></ul><ul><li>CEA: 50 ng/ml (UNL: 6 ng/ml) </li></ul>Case 2: Optimal staging of rectal cancer .
    38. 40. INVOLVEMENT OF MESORECTAL FASCIA
    39. 42. INVOLVEMENT OF PUBORECTAL SPHINCTER
    40. 43. EXTRAMURAL VEIN INVASION
    41. 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
    42. 45. THE CONCEPT OF TOTAL MESORECTAL EXCISION
    43. 46. THE PATHOLOGIST AUDITS SURGICAL SKILLS: DEFINITION OF PLANE OF SURGERY Nagtegaal et al, J Clin Oncol 2002
    44. 47. MACROSCOPIC ASSESSMENT OF MESORECTAL EXCISION García-Granero E, Cervantes A et al. Cancer 2009.
    45. 48. MACROSCOPIC ASSESSMENT OF MESORECTAL EXCISION García-Granero E, Cervantes A et al. Cancer 2009.
    46. 49. THE PATHOLOGIST AUDITS SURGICAL SKILLS: MACROSCOPIC ASSESSMENT OF MESORECTAL EXCISION García-Granero E, Cervantes A et al. Cancer 2009.
    47. 50. Quirke et al. Lancet 2009.
    48. 51. THE ASSESSMENT OF CIRCUMFERENTIAL RESECTION MARGIN 43% 8% Gosens MJ et al. Clin Cancer Res 2007; 13:6617
    49. 52. THE ASSESSMENT OF CIRCUMFERENTIAL RESECTION MARGIN 27% 59% Gosens MJ et al. Clin Cancer Res 2007; 13:6617
    50. 53. THE VALUE OF CIRCUMFERENTIAL RESECTION MARGIN Nagtegaal ID and Quircke P. J Clin Oncol 2008; 26:303
    51. 54. THE ASSESSMENT OF CIRCUMFERENTIAL RESECTION MARGIN
    52. 55. THE ASSESSMENT OF CIRCUMFERENTIAL RESECTION MARGIN
    53. 56. THE ASSESSMENT OF CIRCUMFERENTIAL RESECTION MARGIN
    54. 57. THE MICROSCOPIC ASSESSMENT OF CIRCUMFERENTIAL RESECTION MARGIN
    55. 58. <ul><li>Locally advanced tumor: rT3 rN2 M0 </li></ul><ul><li>Treatment options: </li></ul><ul><li>Preoperative radiation (short or long course) </li></ul><ul><li>Preoperative chemoradiation </li></ul><ul><li>Surgical resection followed by radiation or chemoradiation </li></ul><ul><li>Surgical resection followed by adjuvant chemotherapy </li></ul>Case 2: TREATMENT PLAN .
    56. 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
    57. 60. “ Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish Rectal Cancer Trial”. LOCAL RELAPSE RATE : 27 % VS 11 % ( p < 0.001)
    58. 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
    59. 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
    60. 63. <ul><li>Locally advanced tumor: rT3 rN2 M0 </li></ul><ul><li>Treatment selected: </li></ul><ul><li>Preoperative chemoradiation : Oxaliplatin+capecitabine plus 45.0Gy (180cGy/day during 5 weeks) </li></ul><ul><li>Surgical resection </li></ul><ul><li>Adjuvant chemotherapy </li></ul>Case 2: TREATMENT PLAN .
    61. 64. Case 2: SURGICAL RESECTION . NO LIVER OR PERITONEAL METS “ CURATIVE RESECTION” ANTERIOR RESECTION WITH TOTAL MESORECTAL ESCISION ESPHYNCTER PRESERVATION PROCEDURE TEMPORAL DERIVATIVE ILEOSTOMY
    62. 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
    63. 66. THE ASSESSMENT OF PATHOLOGICAL STAGING AFTER CHEMORADIATION
    64. 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
    65. 68. THE ASSESSMENT OF PATHOLOGICAL STAGING AFTER CHEMORADIATION
    66. 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
    67. 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
    68. 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
    69. 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
    70. 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
    71. 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
    72. 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
    73. 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
    74. 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
    75. 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
    76. 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
    77. 87. BULKY RETROPERITONEAL METASTASES PRETREATMENT irinotecan+CETUXIMAB LDH 1306 MU/ml
    78. 88. PARTIAL RESPONSE OF RETROPERITONEAL METASTASES AFTER 6 WEEKS TREATMENT WITH irinotecan+CETUXIMAB LDH 444 MU/ml
    79. 89. BULKY HEPATIC METASTASES WITH CEA 6000 ng/ml BEFORE TREATMENT WITH irinotecan+CETUXIMAB
    80. 90. BULKY HEPATIC METASTASES WITH F ALC 820 mU/ml BEFORE TREATMENT WITH irinotecan+CETUXIMAB
    81. 91. PARTIAL RESPONSE OF THE HEPATIC METASTASES CEA 52 ng/ml AFTER TREATMENT WITH irinotecan+CETUXIMAB
    82. 92. PARTIAL RESPONSE OF THE HEPATIC METASTASES F. alc 320 mU/ml AFTER TREATMENT WITH irinotecan+CETUXIMAB
    83. 93. EGFR-inhibitor induced skin reactions <ul><li>1 2 3 4 5 6 7 8 9 </li></ul>Description of severe cases THERAPY SUGGESTIONS Post inflammatory effects Acne-like rash paronychia dry skin Topical anti-acne creams (drying effect) +/- tetracyclines +/- antihistamines pruritus <ul><ul><ul><li>Pulse dye laser </li></ul></ul></ul><ul><ul><ul><li>Emollients </li></ul></ul></ul><ul><ul><ul><li>Hydrocolloid dressing </li></ul></ul></ul><ul><ul><ul><li>or </li></ul></ul></ul><ul><ul><ul><li>Propylene glycol+/-acetylsalicyl </li></ul></ul></ul><ul><ul><ul><li>Anti-septic soaks </li></ul></ul></ul><ul><ul><ul><li>Silver nitrate (pyogenic granuloma) </li></ul></ul></ul>fissura Photos kindly provided by Prof. Segaert
    84. 94. NCIC CTG CO.17: Randomized Phase III Trial in mCRC EGFR testing by IHC * Cetuximab 400 mg/m 2 IV week 1 then 250 mg/m 2 IV weekly Disease Progression or Unacceptable Toxicity <ul><li>Stratification: </li></ul><ul><li>Centre </li></ul><ul><li>ECOG PS (0 or 1 vs. 2) </li></ul>REGISTER R ANDOMI ZE 1:1 Cetuximab* + BSC BSC alone Failed or intolerant to all recommended therapies
    85. 95. NCIC CTG CO.17: Overall Survival CETUXIMAB + BSC CENSORED BSC CENSORED HR 0.77 (95% CI =0.64 – 0.92) Stratified log rank p-value = 0.0046 SUBJECTS AT RISK CET+BSC 287 217 136 78 37 14 4 0 0 0 BSC 285 197 85 44 26 12 8 2 1 0 Proportion Alive 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 MONTHS 0 3 6 9 12 15 18 21 24 27 4.2 – 4.9 4.6 BSC alone 5.4 – 6.7 6.1 Cetuximab + BSC 95% CI MS (months) Study arm
    86. 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?
    87. 97. ACTIVACIÓN DEL EGFR Y SEÑALIZACIÓN
    88. 98. <ul><li>Cuando el gen KRAS está mutado, la proteina KRAS (p21 Ras) está activa independientemente de la activación de EGFR </li></ul><ul><li>Las mutaciones KRAS son un hecho temprano y ocurren en 40–45% de los pacientes con CC </li></ul><ul><li>Las mutaciones KRAS se asocian a un peor pronóstico </li></ul>Cetuximab EGFR Y KRAS
    89. 99. Figure 5.30 The Biology of Cancer (© Garland Science 2007)
    90. 100. Figure 5.31 The Biology of Cancer (© Garland Science 2007)
    91. 102. FOLFIRI Irinotecan (180 mg/m 2 ) + 5-FU 400 mg/m 2 bolus + 2400 mg/m 2 as 46-h continuous infusion) + FA every 2 weeks Cetuximab + FOLFIRI Cetuximab IV 400 mg/m 2 on day 1, then 250 mg/m 2 weekly + irinotecan (180 mg/m 2 ) + 5-FU (400 mg/m 2 bolus + 2400 mg/m 2 as 46-hr continuous infusion) + FA every 2 weeks R EGFR-expressing mCRC Van Cutsem E, et al. ASCO 2007 (Abstract No. 4000) <ul><li>Primary endpoint: </li></ul><ul><ul><li>Progression-free survival time (IRC) </li></ul></ul><ul><li>Secondary endpoints: </li></ul><ul><ul><li>Overall response rate (IRC) </li></ul></ul><ul><ul><li>Disease-control rate (CR+PR+SD) </li></ul></ul><ul><ul><li>Overall survival time </li></ul></ul><ul><ul><li>Quality of life (EORTC QLQ C30) </li></ul></ul><ul><ul><li>Safety </li></ul></ul>CRYSTAL: Study design
    92. 103. Magnitud del beneficio adicional CETUXIMAB + CT CETUXIMAB + CT KRAS wt CT Eficacia en 1 ª -linea ¿QUÉ AÑADE KRAS COMO MARCADOR PREDICTIVO?
    93. 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%
    94. 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]
    95. 106. CONFIDENTIAL – for internal use only
    96. 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
    97. 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
    98. 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

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