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Carcinoma Colon And Management Carcinoma Colon And Management Presentation Transcript

  • CARCINOMA COLON AND IT’S MANAGEMENT Dr. Manoj Kumar B. Moderator: Dr. R. Kapoor 30.10.08
  • INTRODUCTION
    • 2 nd commonest cancer in men and ranks 3 rd in frequency in women in the western countries
    • 2 nd m/c cause of cancer mortality (after Ca Lung)
    • Globally 800,000 new CRCs occur each year, accounting for 10% of all incident cancers with 450,000 deaths/year
    • About 75-80% present with localized disease
    • Incidence : 35.8/100,000 (USA)
    • Developing countries < 10/100,000
    • India: incidence - 7/1,00,000
    • Median age of diagnosis- 62 yrs
    • Unfavorable prognosis if age <40 yrs
    • SOURCE: RRCR 2007
  • CLINICAL ANATOMY
    • Large intestine- Colon and Rectum
    • Intraperitoneal- Caecum, Transverse colon
    • Retroperitoneal- Ascending colon, Descending colon, both flexures, initial part and end of Sigmoid
    • Significance
      • May have compromised sx margins
      • Tumor spread from these regions may involve retroperitoneal soft tissue, kidneys, ureters and pancreas
    • Cancer <12 cm anal verge – rectal cancer
    • Cancer >12 cm anal verge – colon cancer
  • Ascending Colon 4% Transverse Colon 8% Descending Colon 14% Sigmoid Colon 35.7% Rectum 39%
  •  
  • CLINICAL RISK FACTORS
    • Age > 40yrs
    • Male sex
    • Genetic syndromes- PJS/FAP/Gardener’s/Turcot /Oldfield’s
    • F/H- Lynch-I : Familial CRC syndrome
    • Lynch-II : Hereditary adenocarcinomatosis synd.
    • Other
      • Prior h/o CRC /Malignant colorectal polyps
      • Inflammatory bowel disease
      • High BMI / Low physical activity
      • Red meat / processed food/ ? Low fiber diet
      • Excessive alcohol consumption/ low folate intake
      • Prolonged cigarette smoking
      • Pelvic irradiation
  • CARCINOGENESIS: Adenoma to Carcinoma Pathway APC Loss/mutation Ch. 5q Normal Epithelium Early Adenoma Cancer Hyper- proliferation Intermediate Adenoma Late Adenoma K-ras Mutation Ch. 12p (50%) DCC loss Ch. 18q DPC4 Ch. 4 p53 Loss Ch. 17p Loss of DNA methylation
  •  
  • PATHOLOGY: WHO Classification
    • I . Epithelial
      • Benign
      • Malignant
        • Adeno ca >95%
        • Mucinous adenoca 17%
        • Signet ring cell ca 2-4%
        • SCC
        • Adenosquamous
        • Undiff/ Unclassified
    • II . Neuroendocrinal – carcinoid
    • III . Nonepithelial
      • Leiomyoma/ lipoma/hemangioma
      • Leiomyosarcoma
    • IV . Hematopoietic/ lymphoid(DLBCL)
    • V . Unclassified
    • VI . Secondaries
    • VII . Tumor like lesions
    • VIII . Epithelial atypia in Ulcerative colitis
  •  
  • SPREAD
    • Local
      • Multidirectional growth progression
      • Intramural- bowel wall penetration
      • Invasion into adjacent organs/ structures
      • Perineural invasion ~10 cm from primary lesion
    • Lymphomatous
        • Tumor grade
        • LVI
      • Normal lymphatic flow along major arteries to three echelons of LN
        • Pericolic/ Intermediate /Principal LN
    • Hematogenous
      • Liver- primary site – 40%
      • Lung- 2 nd m/c site
      • 10-15% have e/o distant metastasis at diagnosis
    • Peritoneal seeding/ implantation
      • Intraluminal/ serosal sheding/ by surgical manipulation
  • CLINICAL PRESENTATION
    • Related to tumor size/ type/ location
    • Ascending colon- large, exophytic/ bulky
      • Pain abdomen
      • Bleed PR
      • Unexplained anemia/ fatigability or weight loss
    • Descending colon- infiltrating/annular/obstructive
      • Altered bowel habits
      • Decreased stool calibre
      • Frequent gas pains, bloating, fullness ,cramps
      • Mass P/A
  • DIAGNOSIS
    • Complete history
    • Physical examination /DRE
    • Routine investigations
    • Confirmatory- Biopsy
    • Staging workup
      • CXR
      • Barium enema
      • Colonoscopy
      • USG
      • CECT abdomen- pelvis
      • Virtual colonoscopy
      • MRI
      • PET
    • Gold standard- Colonoscopy+ Biopsy
    • Others
      • FOBT
      • Stool cytology
      • CEA
      • IHC markers- keratin
      • Molecular markers- oncogenes
      • DNA flow cytometry
      • Immunoscintigraphy
    • Screening investigations
  • BARIUM ENEMA
      • Complementary for colonoscopy
      • Full column Ba enema misses 1/5 th -1/4 th of all colon ca and 2/5 th of all polypoidal lesions
      • DOUBLE CONTRAST Ba enema detects almost all colonic lesions~5mm
      • C/I- Acute /severe IBD, suspected perforation, recent bowel surgery
  • FLEXIBLE SIGMOIDOSCOPY
    • Can examine about half of the colon
    • Less incidence perforations
      • 1-2/1000 Colonoscopy
      • 1/10,000 Sigmoidoscopy
    • Misses proximal lesions, usually used in conjunction with FOBT or BE
    • Sensitivity-90% /Specificity- 99% (For areas examined by scope)
  • COLONOSCOPY
    • Essential procedure for the proper diagnosis/ t/t / and surveillance of patients with nonfamilial colorectal polyps/ patients treated with curative intent
    • Detect the lesions and biopsy ± removal
    • Rule out synchronous lesions/ anastomotic recurrence - aggressive colonoscopy indicated in patients with a proven diagnosis
    • Asymptomatic patients with well documented FOBT and symptomatic patients should have a colonoscopy of entire colon even with normal sigmoidoscopic findings and normal or equivocal Ba enema
    • Limitations - failure to reach / examine fully
      • Splenic flexure (10%)
      • Hepatic flexure (15%)
      • Caecum (20%)
  •  
    • VIRTUAL COLONOSCOPY :Thin section helical CT using air contrast and glucagon for bowel sedation and has same efficacy to standard colonoscopy in detecting lesions≥ 6mm.
    • USG: minimal role of TAUSG
      • Useful when augmented with retrograde instillation of water into colon k/a HYDROCOLONIC SONOGRAPHY
      • which permits detailed evaluation of bowel wall permitting more precise preop staging
  • CECT ABDOMEN/ PELVIS
    • More accurate for T 4 than T 2/3 lesions
    • Asses extraluminal extent of locally advanced dis.
    • Limitation: can't detect
      • Tumor infiltration of pericolic fat
      • Focal tumor spread external to muscularis propria
      • Pericolonic LN <1 cm
      • Liver mets <1cm
    • Overall accuracy staging primary – 70%
    • Sensitivity LN detection- 45%
    • FDG-PET
      • To asses response to RT/CCT
      • Detect occult areas of recurrent CRC patients considered for re exploration
    • MRI- not superior to CT
    • TUMOR MARKER : CEA
      • No role in diagnosis/ screening of ca colon
      • Correlate with tumor burden and prognosis
      • Monitoring tool for patients treated with curative intent
      • Post op CEA level is more sensitive indicator of recurrence
      • Normal :
  • AJCC/ UICC STAGING
  •  
  •  
  • TREATMENT
    • SURGERY- Primary
    • RADIOTHERPY- Adjuvant
    • CHEMOTHERAPY-Adjuvant and metastatic
    • TARGETED / IMMUNOTHERAPY- Adjuvant and metastatic
  • SURGERY
    • SURGRY is the GOLD STANDARD and principle therapy of primary and non metastatic ca colon
      • Curative
      • Palliative
      • Accurate disease staging
      • Guides adjuvant treatment
    • Likelihood of cure is greater when disease is detected at early stage
  • SURGERY
    • PRINCIPLE: Standard treatment
      • WIDE RESECTION of the involved segment including the lymphatic drainage areas+ mesocolon+enblock resection of the neighbouring involved organs
    • AIM
      • To excise the primary lesion with adequate margin ~5 cm of normal bowel proximal and distal to the tumor
      • To reconstitute bowel continuity
      • To avoid complications
      • To inspect the other viscera for mets
    • TYPES OF SURGICAL RESECTION
      • Right Hemicolectomy
      • Extended Right Hemicolectomy
      • Left Hemicolectomy
      • Segmental resection
      • Total Abdominal Colectomy: UC, FAP Syndrome/ FH
    • Sx approach dictated by the lesion size and location
    • Location determines what region of bowel is removed, and the extent of its resection is dictated by its vascular and lymphatic supply
    • Minimum of 12-15 LNs should be removed
  •  
  • ADJUVANT THERAPY
    • BASIS
    • Despite curative surgery half of these patients suffer INCURABLE TUMOR RECURRENCE leading to cancer related death
    • Therefore there is a need of adjuvant therapy to improve DFS and OS
    • Establishment of adjuvant therapy as a standard treatment in stage III colon cancer based on improvement in overall survival
    • In stage II colon cancer adjuvant treatment remains controversial
  • Adjuvant Therapy for Colon Ca
    • Stage I Colon: Surgery alone
    • Stage II Colon: Adjuvant chemotherapy use is controversial. Indicated beyond stage IIA. Considered for the following:
      • Obstructed or perforated colon cancer
      • High-risk histology-LVI +/ extramural spread or PD histo.
      • Involvement of adjacent organs (T4 lesion)
      • Inadequate LN sampling (<13 LNs retrieved)
      • Elevated preop CEA
      • High S-phase fraction
      • Tumor not having high level of MSI
      • 18q deletion
    • Stage III Colon
      • FOLFOX (5-FU + leucovorin + oxaliplatin)
      • Improved both overall survival and disease-free survival (MOSAIC Trial)
    • Adjuvant XRT is reserved for selected T4 lesions that involve penetration to fixed structures
  • Stage Mean 5 yr survival rate (%) T 1 N 0 97 T 2 N 0 90 T 3 N 0 78 T 2 N + 74 T 4 N 0 63 T 3 N + 48 T 4 N + 38
  • RADIATION
    • Rationale of adjuvant radiation
      • Based on patterns of failure following potential curative surgery
      • Primary determinant of failure patterns in CRC is the location of tumors in reference to peritoneal reflection
      • T/t recommendation are based on the stage of disease and tumor location in reference to peritoneal reflection. If tumor is completely above the peritoneal reflection, its treated as colon ca and if its below, then treated as rectal ca
    • RT is an effective but a local modality
    • Adjuvant RT role less well defined due to difference in natural history of Ca colon
    • All stages combined m/c failure site in ca colon is abdominal (liver) rather than local
    • When local failure, its extrapelvic and symptoms are less debilitating as seen in ca rectum
    • Overall incidence of local failure relatively low, depends on stage and as high as 35% in stage III & IV
    • Higher risk- Partially retroperitonealized regions
    • Adjuvant RT use limited to
      • Clinical presentations with the risk of local failure is sufficiently high enough (10%)
      • When an adequate dose can be delivered to the site at the highest risk of failure
  • Failure pattern following curative surgery Series Stage n LF (%) Abdominal failure (%) Distant failure(%) Gunderson et al All T3-4 and /or N1-2 91 72 22 17 4 6 7 7 Willet et al All T3-4 and /or N1-2 533 395 6 8 11 14 4 Minsky et al All T3-4 and /or N1-2 284 229 6 4 8 10 3 5
    • Indications of RT
      • Incomplete excision/ Residual disease
      • Positive resection margins
      • B 2 , B 3 , C 2 tumors arising in the immobolized bowel with close CRM(<1 cm)
      • Fixed tumors i.e. caecal and sigmoidal ca
      • Tumor a/w perforation/ obstruction/fistula/abscess
  • Technique
    • Bowel preparation
    • Positioning
      • NON SIGMOID CA- Lat. Decubitus position by two parallel opposed fields
      • SIGMOID CA- Prone position by 3-4 fields to exclude small bowel and maximize homogeneity in treatment volume
    • Immobilization
    • Target volume delineation
    • Simulation- Conventional/CT
    • Portal delineation and check films
    • Marking on the body
    • TUMOR BED / FIELD
    • Involved segment of large bowel and, when present, the adjacent organ or structures to which it was adherent or invading
    • If adherent to partially resected organ-> whole organ has to be treated if within tolerance
    • If adherent to structure (pelvic side wall, psoas, diaphragm) -> 3-5 cm margins beyond area of adherence
    • Pelvic nodal groups at risk
    • Tumor bed + immediate adjacent PA or pelvic LNs+ 3 cm margin
      • Dose- 45- 50 Gy/25#/ 4.5-5 weeks
    • KIDNEY SHIELDING after 8#
  • Caecum and proximal ascending colon
  • Mid ascending colon
  • Distal descending colon
  • Middle sigmoid colon adherent to left pelvic sidewall or proximal sigmoid
  • Distal ascending colon and hepatic flexure
  • Splenic flexure and proximal descending colon
  • Middle descending colon
  • Palliative - Sigmoid colon adherent to the UB
    • Critical normal (dose limiting) tissues
      • Small intestine: max 45 Gy (30 Gy by WART)
      • Liver : 2/3 rd of liver should get <30 Gy
      • Kidneys: 2/3 rd of one kidney should get <20 Gy
      • Spinal cord: max dose to spinal cord< 50 Gy
  • 5 yr Local/Regional failure (%) DFS (%) Group Stage N Surgery Sx+RT Surgery Sx+RT Adjuvant T3N0(B2) 163 10 9 70 72 T4N0(B2) 83 31 7 63 79 T3N1-2 (C2) 100 35 30 44 47 T4N1-2 (C3) 49 53 28 37 53 Perforation/fistula T4N0 21 48 6 43 91 Residual disease All 47 37
  • HISTORICAL
    • WART
      • To treat the volume at risk with a potentially curative dose of radiation required for microscopic disease……the whole abdomen need to receive 45 Gy
      • Rationale- High incidence of local failure
      • Dose- 30 Gy , then cone down to the primary tumor bed
      • Combined results- In 3 series – 5FU- in field (abdominal) failure rate: 12-50% and 3 yr survival ~50%
      • SWOG 8572- T3N1-2M0-> WART+ CVI 5FU f/b a monthly cycle of CVI 5FU. WART 30 Gy f/b boost of 1.6 Gy for 10#
        • Median FU 5yr: DFS-58%, OS- 67%, Toxicity-17%
  • NEWER RT Techniques
      • IOERT - Radiation boosting for dose intensification
          • T4 tumors with uncertain margins/ invading adjacent structures
          • Preop EBRT + 5-FU based CCT followed by resection with or without IOERT and postop systemic therapy
        • Advantage
          • Visual contrast of target volume
          • Homogenous treatment of controlled thickness of tissue with tumor
          • Protection of mobile uninvolved normal tissue
        • Disadvantage
          • Increase incidence of late normal tissue complications
        • Dose - With 9-15 Mev electron, 10-20 Gy normalized at 90%
  • CHEMOTHERAPY
    • Adjuvant: Aim is to destroy microscopic metastatic disease and preventing death from metastasis as substantially no. of patients treated surgically with curative intent eventually died of metastatic disease
    • Metastatic setting/Palliative
  •  
  • Historical data in favor of chemotherapy FU, semustine & VCR (MOF) NSABP-C-01 randomized N(-), N(+) patients BCG Sx alone MOF – 5 yrs DFS 58%, OS – 67% INT-0035
    • NCI 1990 consensus established adjuvant CCT as standard of care of patients with node (+) resected ca colon
    DFS(%) OS(%) Stage II Sx alone 71 72 Sx-> 5FU+Levamisole 79 72 Stage III Sx alone 44 Sx-> 5FU+Levamisole 61 Death rate ↓ 33% Rec. rate ↓40% Sx-> Levamisole NS
  • 5FU 370-400mg/m 2 + LCV 200mg/m 2 D 1 -D 5 x4 weeklyx6 cycles NCCTG/ NCI 3 yr survival (%) RFS(%) Gr 3 toxicity 5FU+LCV(Mayo)x 6 months 83.2 68.6 High PVI 5FU 200mg/ m 2 /d x 12 weeks 87.9 80 Less
    • QUASAR (Quick and Simple and Reliable)
      • No difference in survival b/w HDLCV and LDLCV
      • Worse survival with levamisole
      • No difference in outcomes for dailyx5 and weekly schedules
      • Once weekly regimen less toxic
    INT-0089 Treatment duration (weeks) 5 yr DFS(%) 5 yr OS(%) 5-FU +levamisole 52 56 63 5-FU + weekly HDLCV (Roswell park ) 32 59 65 5-FU +LDLCV on d1- 5 (Mayo clinic) 24 60 66 Mayo Clinic schedule of 5-FU/LCV + levamisole. 24 60 67
    • LV5FU2 vs Mayo clinic regimen
      • LCV 2 hr infusion f/b 5FU bolus and then a 22 hr CVI of 5FU d1-2 x biweekly
      • Superior response rate and PFS of LV5FU2
      • DFS and OS similar yet toxicities are less with LV5FU2
    • Oral fluoropyrimidines- Capecitabine and UFT
      • In metastatic disease efficacy comparable with Mayo schedule
  • MOSAIC Trial: LV5FU2 vs LV5FU2 + FOLFOX-4 LV5FU2 (n = 1,123) (%) FOLFOX-4 (n = 1,123) (%) 3 yr DFS stage III 66 72 3 yr DFS stage II 84 87 OS NA NA Grade 3-4 neutropenia 5 41 Neutropenic fever 0 1 Grade 3-4 diarrhea 0 1 Grade 3-4 vomiting 7 11 Neuropathy, any grade 0 92 Neuropathy, grade 3 0 12 Persistent neuropathy, grade 2-3, 1 year after t/t 0 5
  • Commonly Used Fluorouracil (5-FU) Regimens Regimen Reference Schedule Mayo clinic Poon et al., 1989 LV 20 mg/m 2 , followed by bolus 5FU, 425 mg/m 2 each daily d1-d5 repeated 4 weekly for 1 st 2 cycles, than q35d thereafter Roswell Park Haller et al., 1998 LV 500 mg/m 2 over 2 h; 5-FU 500 mg/m 2 bolus 1 h into LV infusion. weekly x 6 wks, every 8 wks Low-dose weekly LV., Jager et al., 1996 LV 20 mg/m 2 over 5-15 min, followed by bolus 5-FU 500 mg/m 2 ; weekly x 6 wks, every 8 weeks Protracted venous infusion Lokich et al., 1989 5-FU 300 mg/m 2 /day by continuous infusion AIO (weekly 24-h infusion) Kohne et al., 1998 LV 500 mg/m 2 over 2 h, followed by 5-FU 2,600 mg/m 2 over 24 h, weekly LV5FU2 de Gramont et al., 1997 LV 200 mg/m 2 over 2 h days 1, 2, followed by bolus 5-FU 400 mg/m 2 /day 1 and 2, f/b 5-FU 600 mg/m 2 over 22 h, day 1 and 2: every 14 days Simplified LV5FU2 Adapted from Andre et al., 1999 LV 400 mg/m 2 over 2 h, followed by bolus 5-FU 400 mg/m 2 , followed by 5-FU 2,400-3,000 mg/m 2 over 46-48 h; cycles repeated every 14 days
  • Commonly Used Irinotecan/5-FU Combination Regimens Regimen Study Schedule IFL Saltz et al; 2000 Irinotecan 125 over 90 min, followed by LV 20 mg/m 2 by brief infusion, followed by bolus 5-FU 500 mg/m 2 ; weekly for 4 weeks , repeated every 6 weeks FOLFIRI Douillard et al., 2000 Irinotecan 180 mg/m 2 over 2 h; LV 200 mg/m 2 concurrently with irinotecan (can be given in same line through Y connector); followed by 5-FU bolus 400 mg/m 2 , followed by 5-FU 600 mg/m 2 infusion over 22 h. Irinotecan given day 1 only. All other meds given days 1 and 2. Cycle repeated every 14 days FOLFIRI (simplified) Andre et al., 1999 Irinotecan 180 mg/m 2 over 2 h; LV 400 mg/m 2 concurrently with irinotecan (can be given in same line through Y connector); followed by 5-FU bolus 400 mg/m 2 , followed by 5-FU 2,400-3,000 mg/m 2 infusion over 46-48 h. Cycle repeated every 14 days FUFIRI Douillard et al., 2000 Irinotecan 80 mg/m 2 , then LV 500 mg/m 2 , followed by 5-FU 2,300 mg/m 2 ; all drugs given weekly for 6 weeks, repeated every 7 weeks
  • Selected Commonly Used Oxaliplatin/5-FU Combination Regimens Regimen Study Schedule FOLFOX-4 de Gramont et al., 2000 Oxaliplatin 85 mg/m 2 over 2 h; LV 200 mg/m 2 concurrently with oxaliplatin (can be given in same line through Y connector); followed by 5-FU bolus 400 mg/m 2 , followed by 5-FU 600 mg/m 2 infusion over 22 h. Oxaliplatin given day 1 only. All other meds given days 1 and 2. Cycle repeated every 14 days FOLFOX-6 Tournigand et al., 2004 Oxaliplatin 100 mg/m 2 over 2 h; LV 400 mg/m 2 concurrently with oxaliplatin (can be given in same line through Y connector); followed by 5-FU bolus 400 mg/m 2 , followed by 5-FU 2,400-3,000 mg/m 2 infusion over 46-48 h. Cycle repeated every 14 days Modified FOLFOX-6 (mFOLFOX-6) Widely used in current phase III trials, but not published Oxaliplatin 85 mg/m 2 over 2 h; LV 400 mg/m 2 concurrently with oxaliplatin (can be given in same line through Y connector); followed by 5-FU bolus 400 mg/m 2 , followed by 5-FU 2,400-3,000 mg/m 2 infusion over 46-48 h. Cycle repeated every 14 days FUFOX Grothey et al., 2002 Oxaliplatin 50 mg/m 2 over 2 h, followed by LV 500 mg/m 2 , followed by 5-FU 2,000 mg/m 2 over 24 h, weekly for 5 weeks, repeated every 6 weeks.
  • Single Agents: 5FU/Leucovorin (Mayo, Roswell, DeGramont)‏ Capecitabine Oxaliplatin Irinotecan Combinations: Oxaliplatin + 5FU (FOLFOX)‏ Irinotecan/5FU/Leuco (IFL, Saltz)‏ Irinotecan + 5FU (FOLFIRI)‏ Capecitabine + Oxaliplatin (Capox)‏ Capecitabine + Irinotecan (Capiri)‏ Chemotherapy in CRC
  • 5-Fluorouracil + Leucovorin (Mayo Clinic Schedule) NCCTG 5-FU: 425 mg/m2 IV on d1 – 5 LCV : 20 mg/m 2 IV on d1 – 5 before 5 - FU Repeat cycle every 4 – 5 weeks for a total of 6 cycles Oxaliplatin + 5-Fluorouracil + Leucovorin (FOLFOX4) Oxaliplatin: 85 mg/m 2 IV on day 1 5-Fluorouracil 400 mg/m 2 IV bolus, followed by 600 mg/m 2 IV continuous infusion for 22 hours on days 1 and 2 Leucovorin: 200 mg/m 2 IV on days 1 and 2 as a 2-hour infusion before 5-Fluorouracil Repeat cycle every 2 weeks Chemotherapy as adjuvant in CRC
  • Stage IV/ Metastatic Ca Colon
    • Selectively resectable group
      • Options: Regional strategies
        • Organ-specific infusional therapy
        • Isolated or continuous perfusion therapy
        • Radiofrequency ablation
        • Cryotherapy
        • Surgical debulking
        • Radiation
      • Surgical metastsectomy
    • Unresectable disease- generally incurable
      • Goal: Palliation- symptom control/ control of tumor growth/ lengthen PFS and OS
      • Palliative chemotherapy: indication if following guidelines are met
        • Favorable performance status
        • Acceptable BM / renal / hepatic function
        • Reasonable nutritional status
        • Well motivated patients
  • Oxaliplatin + 5-Fluorouracil + Leucovorin (mFOLFOX7) Oxaliplatin: 100 mg/m 2 IV on day 1 5-Fluorouracil: 3000 mg/m 2 IV continuous infusion on days 1 and 2 for 46 hours Leucovorin: 400 mg/m 2 IV on day 1 as a 2-hour infusion before 5-fluorouracil Repeat cycle every 2 weeks Irinotecan + 5-Fluorouracil + Leucovorin (FOLFIRI Regimen) Irinotecan: 180 mg/m2 IV on day 1 5-Fluorouracil: 400 mg/m 2 IV bolus on day 1, followed by 2400 mg/m2 IV continuous infusion for 46 hours Leucovorin: 200 mg/m 2 IV on day 1 as a 2-hour infusion prior to 5-fluorouracil on days 1 – 5 administered before 5 - Fluorouracil Repeat cycle every 2 weeks Capecitabine Capecitabine: 1250 mg/m 2 PO bid on days 1 – 14 Repeat cycle every 21 days for a total of 8 cycles. Dose may be decreased to 850-1000 mg/m 2 PO bid on days 1-14 to reduce the risk of toxicity without compromising clinical efficacy Chemotherapy as adjuvant in CRC
  • Capecitabine + Oxaliplatin (XELOX) Capecitabine: 1000 mg/m 2 PO bid on days 1 - 14 Oxaliplatin: 130 mg/m 2 IV on day 1 Repeat cycle every 21 days. May decrease dose of capecitabine to 850 mg/m 2 PO bid and dose of oxalioplatin to 100 mg/m 2 IV to reduce the risk of toxicity without compromising clinical efficacy Capecitabine + Irinotecan (XELIRI) Capecitabine: 1000 mg/m 2 PO bid on days 1 - 14 Irinotecan: 250 mg/m 2 IV on day 1 Repeat cycle every 21 days. May decrease dose of capecitabine to 850 mg/m 2 PO bid and dose of irinotecan to 200 mg/m 2 IV to reduce the risk of toxicity without compromising clinical efficacy Chemotherapy as adjuvant in CRC
    • Stage II: IMPACT metaanalysis
      • Sx alone-81% / Adj. 5FU+ LCV – 83%
      • Long term OS statistically insignificant
      • Satge II patients with poor prognostic factors should be considered for adjuvant chemotherapy
    • Stage III:
      • In the absence of medical or psychiatric C/I, patients with node(+) colon ca should receive postop chemotherapy
      • Daily X 5d Mayo schedule – more toxic, shouldn’t be used
      • At the very least, a 5-FU based regimen be appropriate, and ~a half year of therapy supported by the majority of trials
      • Oral capecitabine or UFT/LCV acceptable alternatives if a fluoropyrimidine-only approach is selected
      • FOLFOX schedule is now the most widely used adjuvant t/t
      • Modified FOLFOX -6 –NCI intergroup adjuvant trials, is routinely used because of its greater convenience
      • FOLFIRI shouldn’t be used in the adjuvant setting due to increased risk of early death and no long-term benefit
  • Investigational adjuvant approaches
    • Portal vein infusion (↑DFS by 10%)
    • Intraperitoneal chemotherapy- stage III- 43% ↓mortality
    • Edrecolomab- not used
    • Vaccine- Canarypox virus encoded gene induce CEA specific T-cell response in patients with advanced adenoca
    • ASI
  • Targeted agents in CRC
    • Targeted therapy in advanced colon cancer
    • 40% patients undergoing systemic CT for advanced disease do not achieve tumor shrinkage
    • Molecular warfare focusing on dissection of molecular pathways resulting in tumor growth and progression
    • Targeting the angiogenesis process
    • Tumor growth and metastasis is strongly linked with angiogenesis process. The vascular network in the tumor growth involves different complex pathways. VEGF is the most potent and specific angiogenic factor and its expression in CRC is correlated with recurrence and prognosis. Two different strategies devised to target VEGF are:
    • 1) Developing MCA directed against VEGF
    • 2) Developing intervention to VEGF pathway involving small different molecules with tyrosine kinase inhibition activity directed towards the VEGF receptors
  • Bevacizumab Anti – VEGF monoclonal antibody
  • Bevacizumab
    • Approved for use in metastic colo rectal carcinoma in cimbination with IV 5FU as first-line
    • Dose: 5 mg/kg IV over 90 mins every 2 weeks
    • Avastin 100 mg (4 ml) & 400 mg (16 mg)‏
    • Toxicities: GI perforation, wound dehiscence, hemorrhage, risk of arteriel TE events (MI, stoke), hypertension, infusion-related toxicity, proteinuria and nehprotic syndrome
  • E3200: Response Rates 0.7% 3.0% 9.2% 21.8% OR* 0 1.9% CR 29.1% 3.0% 230 Bevacizumab 45.0% 51.7% SD 8.5% 19.9% PR 271 271 FOLFOX4 FOLFOX4 + bevacizumab Giantonio BJ, et al. ASCO 2005 *FOLFOX+B vs FOLFOX: P < 0.0001
  • The importance of EGFR in metastatic colorectal cancer
    • EGFR is involved in the progression of mCRC
    • Patients with EGFR-expressing tumors have a shorter survival
    • EGFR is expressed in 75 – 89% of mCRC
  • Cetuximab (C225) ‏
    • Chimeric MCA to EGFR
    • Binds with high affinity to transmembrane domain of EGFR and blocks binding of natural ligands (EGF, TGF)‏
    • Inhibits EGFR function and downstream signal transduction pathways, promoting apoptosis
    • Synergistic inhibition with chemotherapy and radiation
    O‘Dwyer PJ, Benson AB III. Semin Oncol. 2002;29(suppl 14):10 .
  • Cetuximab
    • Approved for use in EGFR expressing metastatic CRC in combination with irinotecam in patients refractory to irinotecam or as mono therapy in pts intolerant to irinotecam
    • Dose: Loading dose of 400 mg/s.m., then 250 mg.s.m. IV weekly
    • Erbitux: 50 ml vials, 2 mg/ml
    • Infusion-related toxicity (40-50%), rash, ILD, asthenia & fatigue, paronychia
  • Cetuximab in EGFR expressing metastatic CRC: first line trials Hoehler T. et al. Proc ESMO 2004 Van Cutsem E. et al. Proc ESMO 2004 Reference 21% resection of livermetastases remarks 21 % 2% PD 24 % 17% SD 55 % 81% (74% conf.)‏ (61-88)‏ CR + PR (95% CI)‏ 38 43 Total patients FUFOX + cetuximab FOLFOX + cetuximab
  • FOLFIRI 5-FU bolus 400 mg/m 2 , infusion 2400 mg/m 2 + Irinotecan 180 mg/m 2 + Leucovorin 400 mg/m 2 every 2 wks (n = 609) Patients with previously untreated EGFR-expressing metastatic colorectal cancer, stratified by geographical region, ECOG PS (N = 1217)‏ FOLFIRI + Cetuximab 5-FU bolus 400 mg/m 2 , infusion 2400 mg/m 2 + Irinotecan 180 mg/m 2 + Leucovorin 400 mg/m 2 every 2 wks Cetuximab 400 mg/m 2 initial dose, then 250 mg/m 2 wkly (n = 608)‏ Van Cutsem E, et al. ASCO 2007. Abstract 4000. CRYSTAL Trial FOLFIRI ± Cetuximab
  • PROGNOSITC FACTORS
    • ADVERSE C/F
      • Younger age < 40 yr
      • Long symptomatology
      • Obstruction/ perforation
      • Ulcerative lesion
      • BT
    • ADVERSE PATHOLOGY
      • High grade
      • Colloid/ Signet ring cell
      • LVI
      • Perineural invasion
      • Aneuploidy
      • ↑↑ CEA/ collagen
      • Cell surface antigens CA-19.9
      • Local immune response
    • Most important guide to prognosis is STAGE of the disease i.e. depth of penetration and number of LNs involved
  • Rational post therapy surveillance programme
    • CEA every 3 month x 1 st 3 yrs, than 6 monthly up to 5 yrs (CEA detects 80% recurrence) and
    • Complete physical examination on each FU
    • CECT abdomen pelvis yearly x 1 st 3 yrs
    • Colonoscopy every 3 to 5 yrs
    • FDG-PET- rising CEA in two consecutive tests in absence of imageable disease by CT
  • NORMAL CXR RISING CEA COLONOSCOPY FDG-PET CECT
  • ACS colorectal cancer screening guidelines *
    • Fecal occult blood test (FOBT) † or fecal immunochemical test (FIT) every year, or
    • Flexible sigmoidoscopy every 5 years, or
    • An FOBT † or FIT every year plus flexible sigmoidoscopy every 5 years (of these first three options, the combination of FOBT or FIT every year plus flexible sigmoidoscopy every 5 years is preferable), or
    • Double-contrast barium enema every 5 years, or
    • Colonoscopy every 10 years
    • * Beginning at age 50, men and women who are at average risk for developing colorectal cancer should have one of the five screening options listed. Those at increased risk for colorectal cancer should undergo screening earlier and at more frequent intervals.
    • † For FOBT or FIT, the take-home multiple sample method should be used.
    • Source: “Can colorectal polyps and cancer be found early?” American Cancer Society (www.cancer.org); 2005 Accessed Sept 2008.
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  • THANK YOU
  • Population Screening
    • Simple
    • Cheap
    • Reliable
    • Safe
    • Acceptable
    CRC fulfills many of these criteria for effective screening