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MANAGEMENT OF CA COLON

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management options
stage wise
metastatic colon cancer
targetted therapy

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MANAGEMENT OF CA COLON

  1. 1. MANAGEMENT OF COLON CANCERS Presented by: Dr. Isha Jaiswal Guided by :Prof Kamal Sahni Date :16th October 2015
  2. 2. TOPICS • Management options • Stage wise management • Follow up • Treatment of metastatic colon cancer
  3. 3. Management depends on Tumor related • Stage • Location Presentation • elective • emergency Patient related • Age • Performance status • Medical comorbidities Molecular markers Multimodality treatment • Surgery • Chemotherapy • Radiotherapy • Targeted therapy Treatment options
  4. 4. SURGERY Colectomy: principal treatment of Ca colon Intention  Curative  palliative  Accurate disease staging  Guides adjuvant treatment Indication  Stage 1 -3  Resectable stage 4
  5. 5. Aim of surgery R0 resection considered curative wide resection of involved colon segment +lymphatic + mesocolon +enblock resection of neighbouring organs with adequate margin f/b reconstituting bowel continuity  margin ~5 cm of normal bowel proximal and distal to tumor considered adequate  Minimum of 12 L.N removed ,suspicious LNs out side field of resection removed or biopsied  positive LN left behind considered R2 resection. Inspect abdomen viscera,peritoneum,non localized lymph nodes for mets Guidelines 2000 for colon and rectal cancer surgery. J Natl Cancer Inst 2001; 93:583.
  6. 6. TYPES OF COLECTOMY: anatomic resection • Right/left Hemicolectomy: • Extended Right/left Hemicolectomy • Transverse colectomy • Segmental resection • Total Abdominal Colectomy: UC, FAP Syndrome
  7. 7. Extent of colectomy dictated by the size and location of lesions, vascular and lymphatic supply.
  8. 8. Laparoscopic-assisted colectomy may be considered based upon the following criteria: • experience surgeon performing laparoscopically assisted colorectal operations. • no locally advanced disease. • not indicated for acute bowel obstruction or perforation. NCCN 2015
  9. 9. Laparoscopic vs. Open colectomy Randomized/non randomized prospective study data suggest no difference in oncologic outcome in open vs. laparoscopic resection (1-4) 1. prospective random assignment trial conducted by Clinical Outcomes of Surgical Therapy (COST) Study Group A comparison of laparoscopically assisted and open colectomy for colon cancer. N Engl J Med2004;350(20):2050–2059. 2. Fleshman J, et al. Laparoscopic colectomy for cancer is not inferior to open surgery based on 5-year data from the COST Study Group trial. Ann Surg2007;246(4):655–662; discussion 662–664. 3. Bonjer HJ, et al. Laparoscopically assisted vs open colectomy for colon cancer: a meta-analysis. Arch Surg 2007;142(3):298–303. 4. Jackson TD, et al. Laparoscopic versus open resection for colorectal cancer: a metaanalysis of oncologic outcomes. J Am Coll Surg 2007;204(3):439–446 Advantages: • Improved visualization of visceral structure • Better abdominal exploration • Increased no. of lymph node dissected • Small incision • Early return of bowel function • Better recovery • Less hospital stay Disadvantages: Concern regarding • inadequacy of resection margin • Inadequacy in L.N sampling • seeding of port sites • Cost
  10. 10. Pathologic report following parameters should be reported:  Depth  Number of L.N evaluated  Number of L.N positive  Status of margin: proximal, distal, and radial  Grade  LVI  PNI  Extranodal tumor deposits College of American Pathologists Consensus Statement NCCN 2015
  11. 11. Results of surgical resection • Resection results in excellent cure rates for lesions limited to the bowel wall with negative nodes (T1-T2 N0) • average 5-year survival, 97% for T1 N0; 85% -90% for T2 N0 • With a single high-risk feature of extension beyond the colonic wall (T3–4 N0) or involved nodes (T0–2 N+), 5-year survival with surgery falls to 65% to 75%, and adjuvant treatment is often indicated. • When both high-risk features (T3–4 N+), 5-year survival with surgery alone drops to approximately 50% (T3 N+) and 35% (T4 N+), and adjuvant treatment is recommended. Stage Mean 5 yr survival (%) T1N0 97 T2N0 85-90 T3N0 78 T2N+ 74 T4N0 63 T3N+ 48 T4N+ 35
  12. 12. ADJUVANT THERAPY BASIS • Despite curative surgery many patients suffer tumor recurrence leading to cancer related death • Therefore there is a need of adjuvant therapy to improve DFS and OS • Adjuvant therapy is indicated in T3-T4 & N+ disease (stage II & III)
  13. 13. Stage I • No adjuvant treatment Stage II • Role of adjuvant chemotherapy unclear for stage II  STAGE IIA:T3N0M0  STAGE IIB:T4aN0MO  STAGE IIC T4b N0M0 • Risk estimation
  14. 14. Who Needs Adjuvant Therapy in stage II? Indicated pT4 Grade 3-4 LVI + PNI + <12 L.N examined indeterminate, close or + margin obstruction, perforation
  15. 15. Stage II High Risk IIA & Stage IIB,IIC • FOLFOX • Cape-Ox • flox • Capecitabine • 5FU + leucovorin. Low Risk IIA • Observation • clinical trial. • Capecitabine • 5FU + leucovorin.
  16. 16. Stage III Role of adjuvant chemotherapy established Preferred • FOLFOX • CapeOx Other option • Flox • Capecitabine • 5FU plus leucovorin.
  17. 17. Adjuvant Chemotherapy In Resected Colon Cancer
  18. 18. Evolution of chemotherapy regimen for Ca Colon 1. 5FU + Levamisole 2. 5FU + Leucovorin 3. oral 5 FU analogue 4. Addition of oxaliplatin to 5FU/LV 5. Addition of irinotecan to 5FU/LV 6. Capecitabine + oxaliplatin: 7. Monoclonal Antibodies:
  19. 19. 1990 1993 1995 2005 2006 2007 2009 2011 2012 Pooled analysis High dose bolus 5FU/LV vs. obs. Bolus 5FU+Levamisole vs. observation Bolus 5FU+LV vs MOF Xeloda-ACT similar OS/DFS less toxicity to Mayo regimen Tegafur Irinotecan with 5FU/LV: No significant benefit. Cetuximab with FOLFOX Bevacizumab with FOLFOX Cape-OX vs FU/LV 1. Mayo Clinic: monthly bolus 5FU D1-D5 +LDLV 2. Roswell: weekly bolus 5FU+ HDLV 3. 5- FU/levamisole, 4. 5-FU/LV/ levamisole. Overall survival similar, toxicity different Dec neutropenia & mucositis, Increased diarrhoea with weekly regimen infusion 5FU/LV vs bolus (Mayo) Bolus 5FU/LV vs. FLOX Improve DFS Oxalipl.with infusion 5FU/LV improved DFS & OS
  20. 20. Some Important Trials
  21. 21. Between October 27, 1998 and January 16, 2001, 2,246 patients were enrolled randomly assigned to receive infusion LV5FU2 or FOLFOX4 for 6 months. 1,123 pt. in each treatment arm The primary end point was DFS. Secondary end points were OS and safety. Intention to treat analysis median follow-up time of 81.9 months
  22. 22. CONSORT diagram A:3 pt. assigned to FOLFOX4 arm but did not receive oxaliplatin. Therefore, these patients were considered in FOLFOX4 arm for efficacy analysis and LV5FU2 arm for safety analysis. B:1 pt. assigned to LV5FU2 arm received oxaliplatin. Therefore, this patient was considered in the LV5FU2 arm for efficacy analysis and in FOLFOX4 arm for safety analysis.
  23. 23. In both groups,40% and 60%of patients had stage II and stage III disease, respectively The planned 12 cycles of CT received by 74.7% and 86.5% of patients in FOLFOX4 and LV5FU2, respectively.
  24. 24. After a median follow-up time of 81.9 months, the probabilities of surviving at 6 years Six-year OS rates were 78.5% and 76.0% in the FOLFOX4 and LV5FU2 groups, respectively 6-year OS rates for patients with stage III disease were 72.9% and 68.7%, respectively No difference in OS was seen in the stage II population. II III
  25. 25. After a median follow-up time of 73.5 months in the FOLFOX group and 73.4 months in theLV5FU2group Results Five-year DFS rates were 73.3% and 67.4% in the FOLFOX4 and LV5FU2 groups, respectively (hazard ratio [HR] = 0.80; 95% CI, 0.68 to 0.93; P = .003).
  26. 26. J Clin Oncol 2012
  27. 27.  multicenter, randomized trial between April 2003 and October 2004  compared capecitabine plus oxaliplatin (XELOX) with bolus FU/LV as adjuvant therapy for patients with stage III colon cancer.  primary end point = DFS  Secondary end points were OS, relapse-free survival (RFS), and safety.  intention-to-treat analysis  Follow-up is ongoing ,cut-off date for the primary analysis was April 30, 2009.  median follow-up duration was 55 months for DFS and RFS, and 57 months for OS
  28. 28. TREATMENT 1:XELOX (oxaliplatin 130 mg/m2 on day 1 plus capecitabine 1,000 mg/m2 twice daily on days 1 to 14 every 3 weeks for 24 weeks) 2: bolus FU/FA adjuvant regimen (Mayo Clinic for 24 weeks or Roswell Park for 32 weeks). Overall,69%of pts in XELOX grp and 85% of pts in the FU/FA grp (MC, 87%; RP, 79%) completed the planned number of cycles. Median relative dose intensities of capecitabine and oxaliplatin were 78% and 84%, respectively. For FU/FA MCand RP regimens, median relative 5FU dose intensities were 86% and 82%, respectively safety population was defined as patients who underwent random assignment and received at least 1 dose of study medication
  29. 29. • addition of oxaliplatin to oral capecitabine improves DFS & RFS in patients with stage III colon cancer. • Treatment-related grade 3/4 adverse events were 55% in XELOX group and 47% in FU/FA group (P<.05) • additional treatment option for patients with stage III disease.
  30. 30. Conclusion: Adjuvant therapy in stage III colon cancer
  31. 31.  Addition of oxaliplatin increased benefit : i. FOLFOX is superior to5FU/LV therapy in stage III increased DFS & OS ii. benefit for the addition of oxaliplatin to 5-FU/leucovorin in patients ≥ 70 not been proven iii. survival benefit has not been demonstrated in stage II colon cancer.  Indicated in stage III & High risk stage II  FOLFOX or CapeOx are preferred regimen in stage III colon cancer  Capecitabine/oxaliplatin is superior to bolus 5-FU/ leucovorin for stage III colon cancer.  Capecitabine equally effective to bolus 5-FU/LV
  32. 32. Among the various 5FU/LV regimen • Schedule of 5-FU/LV administration does not affect efficacy, but toxicities may be different i. Mayo Clinic monthly regimen - more commonly associated with leucopenia and stomatitis ii. Roswell Park weekly regimen - more commonly associated with diarrhea iii. Infusional 5-FU/LV may have less toxicity vs. bolus • Irinotecan no benefit the adjuvant setting • No targeted agents are approved for use in the adjuvant setting
  33. 33. Adjuvant Radiation therapy in colon cancer Aim: • tumor bed irradiation to decrease local failure. • should be delivered in a highly conformal manner.
  34. 34. Rationale local failure in colon cancer depends on stage & location • anatomic constraints on radial resection margins, • tumors adherent/ invading adjacent structures increases risk of LF  LF high in ascending/descending colon : • anatomically immobile,” limits wide surgical resection LF less in mid-sigmoid and mid-transverse colon: • relatively “mobile,” with a wide mesentery, wide margins LF rates for ceacal, hepatic/splenic flexure, proximal/distal sigmoid tumors are variable, • depending on amount of mesentery present, tumor extension, and adequacy of radial margins.
  35. 35. INDICATIONS OF RT Adjuvant tumor bed irradiation with concurrent 5-FU–based chemotherapy should be considered for patients with tumors • invading adjoining structures: T4 • where incomplete resection is performed • those complicated by perforation or fistula Perez & Brady's Principles and Practice of Radiation Oncology
  36. 36. Data evaluating the use of adjuvant radiation therapy in high-risk colon cancer patients have largely been limited to single-institution retrospective analyses • Massachusetts General Hospital (MGH), • Mayo Clinic, • University of Florida
  37. 37. • randomized, prospective phase III trial in high risk post op cases • inclusion: complete resected pts with: 1) T4 (any site), or 2) T3N+ (of ascending or descending colon only). • Ineligible patients :incomplete resection, medical comorbidities, prior radiation/chemotherapy • pts. were randomized to PORT with 5-FU/Levamisole or 5-FU/Levamisole alone. • recommended dose: 45 Gy in 25 # over 5 weeks, optional 5.4 Gy boost. • primary goal :to determine whether addition of RT to CT improve survival among high risk pts. • secondary objectives :DFS, patterns of recurrence, and toxicity. • study was closed in 1996 due to poor accrual (Initial goal:700 pts. Total accrual 222 patients between 1992-1996)
  38. 38. 222 patients were enrolled onto this study.  34 patients were ineligible (Table 1),  one patient withdrew before receiving any treatment  remaining 187 patients :subject of primary analyses
  39. 39. Information about pathologic radial margin status was not reliably provided & not used in determination of protocol eligibility. Critical caveat :related to the method of determining the tumor volume to guide radiation therapy planning. clip placement :in only 18 (19%) of 94 patients. Preop. radiologic imaging (ie, barium enema or abdominal/pelvic CT): 45 patients (48%). For 17 patients (18%), the tumor volume defined by operative notes 6/94 eligible patients assigned to receive chemo-RT refused RT but all included in primary analysis of chemo-RT arm results Caveats
  40. 40. Results  median duration of follow-up of living patients was 6.6 years  reduced statistical power to detect differences between the groups.  No difference in OS or DFS was seen between the two groups.
  41. 41. Grade III or IV hematologic toxicity was higher in patients receiving radiation therapy no significant difference in non hematologic toxicity.
  42. 42. Interpretation of study results was handicapped by  decreased statistical power  high ineligibility rates,  lack of appropriate target volume definition for Rtplanning No definitive conclusion
  43. 43. Technique: • Bowel preparation • Positioning: Supine: Prone: lateral decubitus: • Immobilization: • Contrast: oral& iv Oral contrast aids in delineating small-bowel, may be useful to compare films in decubitus & supine positions to determine bowel shift • Simulation- Conventional/CT • CT based planning preferred:facilitate defining the tumor bed, beam orientation, and estimating the volume of small bowel,kidney included within treatment fields
  44. 44. Target volume delineation • TUMOR BED/TARGET • Involved segment of colon and, when present, the adjacent 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 • Surgical clips aid in the identification of high-risk areas (i.e., positive margins) to assist in target delineation • The nodal basins in the mesentery beyond surgical margins are usually not treated .However the final inclusion of local & regional nodal group is based on operative & pathologic findings. • MARGINS: • Tumor bed covered with a 4- to 5-cm margin proximally and distally and with a 3- to 4-cm margin medially and laterally to cover areas of potential residual disease
  45. 45. FIELD RRANGEMENT • Field arrangement will vary, depending on the site of the primary disease, as well as on areas judged to be at high risk for local recurrence • parallel opposed or other multifield techniques are used to treat target & spare OAR: small bowel, kidney, liver, S.C
  46. 46. Postoperative AP-PA Irradiation Fields Of Extra pelvic Colon Cancer (Tumor Bed And Nodal Regions). Para-aortic nodes may be at risk, due to tumor adherence to posterior abdominal wall with descending colon cancer. External and common iliac nodes may be at risk, from a proximal ceacal/ascending colon cancer
  47. 47. Dose prescription • total dose depends on the amount of suspected residual disease and tolerance constraints of surrounding normal tissue. • initial dose of 45 Gy/25 # at 1.8/# delivered through larger fields to primary tumor and at-risk tissues followed by reduced boost fields. • For patients with T4 tumors, the general goal is to treat the tumor bed to a total dose of 50.4-54Gy • Any treatment beyond 50 Gy generally mandates exclusion of all small bowel from the field
  48. 48. Critical normal (dose limiting) tissues • Small intestine: 45-50 Gy • Liver : 2/3rd of liver should get <30 Gy • Kidneys: 2/3rd of one kidney should get <20 Gy • Spinal cord: max dose to spinal cord< 50 Gy
  49. 49. Surveillance for colon cancer History, physical examination & S.CEA: every 3–6 month for 2 y, then every 6 month for a total of 5 yr  Colonoscopy: In 1st yr: Abnormal repeat in one yr. Normal: repeat in 3rd yr then every 5 yrs If it was not done before: 3-6 months post surgery.  CT scan chest & abdomen: Annually for pts. with high risk for recurrence(eg. LVI/PNI ,poorly differentiated tumors NCCN 2015
  50. 50. Treatment Options for Metastatic Colon Cancer (Stage IV) with synchronous liver only or lung only metastases 1. For resectable lesions  Colectomy with synchronous resection of liver or lung metastases followed by adjuvant chemotherapy with FOLFOX or CapeOx  Neoadjuvant CT to increase curative resection rates 2. For unresectable lesions  Treated with chemotherapy and evaluated every 2 months to assess resectability of liver and/or lung metastases,colon resection if risk of obstruction or significant bleeding.  Combination chemotherapy for 2-3 months followed by chemo-radiation with 5-FU or capecitabine and then resection of metastases and primary 3. For patients that are able to undergo resection of metastatic disease  6 months of adjuvant therapy with an active regimen for advanced disease, observation, or shortened course of palliative chemotherapy
  51. 51. NEOADJUVANT CHEMOTHERAPY i. FOLFIRI, CapeOx, or FOLFOX ± bevacizumab ii. FOLFIRI or FOLFOX + panitumumab if KRAS wild type (WT) iii. FOLFIRI + cetuximab if KRAS WT ADJUVANT CHEMOTHERAPY Adjuvant First-Line Therapy Adjuvant Second-Line Therapy Good Performance Status • FOLFOX with or without Bevacizumab. • FOLFIRI with or without Bevacizumab. • 5-FU + Leucovrin with bevacizumab If first line Irinotecan • FOLFOX ±Bevacizumab. • Irinotecan ±Cetuximab. • Capecitabine or 5-FU + Leucovorin Poor Performance Status • Capecitabine or 5-FU + Leucovorin ±Bevacizumab. If first line Oxaliplatin • FOLFIRI ± Bevacizumab. • Irinotecan ±Cetuximab. CHEMOTHERAPY OPTIONS
  52. 52. Pts. with unresectable mCRC treated with BSC have poor prognosis( median OS= 5 months). In contrast, pts. who receive CT have been shown to have a median OS of ≈ 2 yrs. Metastatic colon cancer: impact of chemotherapy
  53. 53. Chemotherapy in metastatic colon cancer
  54. 54. Targeted agents
  55. 55. Cetuximab • Cetuximab is monoclonal antibody against the epidermal growth factor receptor (EGFR). • Indicated in KRAS wild type ,EGFR expressing colon cancer • can be added to either FOLFIRI or FOLFOX as first-line treatment of metastatic colorectal cancer Panitumumab • Panitumumab indicated in wild type KRAS metastatic colorectal cancer • The U.S. Food and Drug Administration approved panitumumab for use in patients with metastatic colorectal cancer refractory to FOLFIRI chemotherapy • All patients with mCRC should have tumor tissue genotyped for RAS mutations performed only in certified laboratories • The testing can be performed on the primary colorectal cancers and/or the metastasis Patients with any known KRAS mutation should not be treated with either cetuximab or panitumumab
  56. 56. Bevacizumab • monoclonal antibody that binds to vascular endothelial growth factor. • can be added to either FOLFIRI or FOLFOX as first-line & second line treatment of metastatic colorectal cancer Aflibercept • Aflibercept is anti-VEGF molecule • evaluated as a component of second-line therapy in patients with metastatic colorectal cancer • use of FOLFIRI plus aflibercept is an acceptable second-line regimen for patients previously treated with FOLFOX-based chemotherapy
  57. 57. Regorafenib • Regorafenib is an inhibitor of multiple tyrosine kinase pathways including VEGF, PDGF,FGFR,B-Raf, RET,KIT • Indicated in metastatic colon cancer progressed to 5FU,oxaliplatin irinotecan & bevacizumab, aflibercept, cetuximab & panitumumab based chemotherapy • In September 2012, the FDA granted approval for the use of regorafenib in patients who had progressed on prior therapy.
  58. 58. Thank you

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