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End Stage Metastatic Colorectal Carcinoma

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... the submissions to the Pharmacy and Therapeutic committees of the majority of the provinces ... likely to get Health Canada approval for third line therapy ... – PowerPoint PPT presentation

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Title: End Stage Metastatic Colorectal Carcinoma


1
End Stage Metastatic Colorectal Carcinoma
  • Dr. Michael Noble
  • Medical Oncologist
  • New Westminster, BC

2
Learning Objectives
  • As a result of reading the following case study,
    physicians will be able to
  • Review the palliative treatment of heavily
    pre-treated metastatic colon cancer
  • Describe treatment options with chemotherapy in
    addition to biological therapies that would be
    reasonable considerations
  • Discuss dealing with unrealistic expectations of
    patients and their families

3
Dr. J.M.
  • 68yo retired English professor
  • Otherwise healthy, history of hypertension
    controlled with Adalat XL
  • Presented with near obstructing lesion sigmoid
    colon… opted for primary resection and
    defunctioning ostomy.

4
Dr. J.M.
  • Liver and lung metastases on presentation
  • Underwent chemotherapy using FOLFIRI
  • Good response for 16 months with intermittent
    breaks from chemotherapy

5
Dr. J.M.
  • CEA increases from within normal limits to 15.6
    over three months.
  • On progression
  • ECOG 2
  • Developed clinically evident
    ascites
    while awaiting CT
  • Liver function preserved with
    slight
    elevation of ALP and
    LDH, ALB of 31.

6
Dr. J.M.
  • No second line trials available
  • Starts Oxaliplatin based therapy
  • Resolution of ascites within 4 weeks
  • CEA returns to normal over period of 8 weeks.

7
Dr. J.M.
  • After 6 months of therapy, significant Grade III
    neuropathy.
  • Requires walker
  • Difficulty with buttons
  • Numbness in stocking glove distribution
  • Oxaliplatin removed and 5FU infusional
    chemotherapy continued.

8
Dr. J.M.
  • Family presents with Government of Canada Special
    Access Program forms requesting strongly you
    place him on Bevacizumab and/or Cetuximab
  • CO 17 not available, technically not a candidate

9
Practice Point
  • Do EGFR inhibitors or VEGF inhibitors have a
    role?
  • Bevacizumab (Avastin) an antibody directed
    against the vascular endothelial growth factor
  • Avastin is active in other tumor sites with other
    chemotherapy regimens suggesting a broad spectrum
    effect.
  • Cetuximab (C225), (Erbitux) is an antibody
    directed against the epithelial growth factor
    receptor.
  • Despite its tempestuous history, this agent does
    clearly improve response rates when added to
    Irinotecan based chemotherapy and has some single
    agent activity in advanced disease.
  • Most of the studies have been done in late stage
    disease, and, pending trials, its role in initial
    treatment is less well defined than Bevacizumab.
  • Effectiveness combined with Oxaliplatin as
    opposed to Irinotecan is under study.

10
Practice Point
  • Assuming both agents were available, what
    regimens would you recommend?
  • FOLFOX Bevacizumab
  • Cetuximab (single agent)
  • Cetuximab Irinotecan
  • Cetuximab Bevacizumab
  • Cetuximab Bevacizumab Irintotecan
  • Best Supportive Care

11
Bevacizumab
  • The definitive trial was done using the now
    obsolete IFL regimen, (Irinotecan, bolus 5FU,
    Leucovorin).
  • When added to IFL, Bevacizumab improved
  • median survival from 15.6 to 20 months
  • progression free survival from 6.2 to 10.6 months
  • increased response rates from 34.8 to 44.8
  • all statistically significant

12
ECOG 3200
  • Phase III Trial of Bevacizumab, Oxaliplatin,
    Fluorouracil and Leucovorin vs. Oxaliplatin,
    Fluorouracil and Leucovorin vs. Bevacizumab Alone
    in Previously Treated Patients with Advanced
    Colorectal Cancer

13
ECOG 3200
Giantonio, B., Proc ASCO 2005
14
Results
Giantonio, B., Proc ASCO 2005
15
Bevacizumab with FUFA
  • Series of Phase II and III trials in previously
    untreated mCRC patients
  • Kabbinavar FF, et al. J Clin Oncol 233706-3712.
  • The analysis used primary efficacy data from
    three independent studies, including 241patients
    in a combined control group receiving either
    FU/LV or IFL and 249 patients receiving
    FU/LV/Bevacizumab (5 mg/kg once every 2 weeks)
  • The median duration of survival was 17.9 months
    in the FU/LV/Bevacizumab group compared with 14.6
    months in the combined control group,
    corresponding to a hazard ratio for death of 0.74
    (P .008).
  • The median duration of progression-free survival
    was 8.8 months in the FU/LV/Bevacizumab group,
    compared with 5.6 months in the combined control
    group, corresponding to a hazard ratio for
    disease progression of 0.63 (P .0001).
  • The addition of Bevacizumab also improved the
    response rate (34.1 v 24.5 P .019).

16
Practice Point
  • Bevacizumab has activity in both first and second
    line settings with any 5FU containing regimen.
  • This will likely serve as the basis for the
    Health Canada submission and approval as well as
    the submissions to the Pharmacy and Therapeutic
    committees of the majority of the provinces

17
Practice Point
  • What about the addition of both Cetuximab and
    Bevacizumab to cytotoxic therapy?
  • BOND I and II trials
  • Phase III and II trials respectively
  • Both Response Rate Trials with no control arms
    (ie. no arm with no therapy)
  • BOND I showed Cetuximab had small benefit as
    single agent (design flaw in trial)

18
BOND I
R A N D O M I Z A T I O N
Irinotecan at the same schedule Cetuximab
(400mg/m2 loading the 250 mg/m2 weekly)
Crossover at randomization
Cetuximab (400mg/m2 loading the 250 mg/m2 weekly)
Cunningham, D. et al., N Engl J Med. 2004 Jul
22351(4)337-45
19
BOND II
R A N D O M I Z A T I O N
Irinotecan at the same schedule Bevacizumab
(5mg/kg) IV q2W Cetuximab (400mg/m2 loading the
250 mg/m2 weekly)
Bevacizumab (5mg/kg) IV q2W Cetuximab (400mg/m2
loading the 250 mg/m2 weekly)
Saltz, L. et al., Proc ASCO 2005
20
Results
BOND II
BOND I
Saltz, L. et al., Proc ASCO 2005 Cunningham, D.
et al., N Engl J Med. 2004 Jul 22351(4)337-45
21
NCIC CO 17
R A N D O M I Z A T I O N
Cetuximab (400mg/m2 loading the 250 mg/m2 weekly)
Best Supportive Care
Results pending…
22
Practice Point
  • Potential small benefits seen in second and third
    line trials need to be weighed with budgetary
    costs and quality of life issues.
  • Chemosensitive tumor based on experience of
    responses to therapy
  • Patient debilitated by grade III neuropathy
  • Patient heavily pretreated, not exactly second
    line therapy
  • Would he tolerate Irinotecan again

23
Practice Point
  • Cetuximab likely to get Health Canada approval
    for third line therapy in the face of Irinotecan
    failure

24
Dr. J.M.
  • After a long discussion with Dr. M. and his
    family, there is obvious family dynamics that the
    son wants dad treated at all costs.
  • Dr. M. clearly states that he is tired and does
    not wish to pursue any further cytotoxic /
    cytostatic therapeutic options.
  • He and family decide that BSC and hospice
    discussions should ensue.

25
References
  • Kalfonos H.P. et al Irinotecan or Oxaliplatin
    combined with leukovorin 5FU first line
    advanced colorectal Ca…. Ann. Oncol. 16
    869-877, (2005)
  • Tournigand C, et al FOLFIRI followed by FOLFOX
    6 or the reverse sequence in advanced colorectal
    Ca…. J Clin. Oncol 22 229-237 (2004)
  • Punt, CJA Irinotecan or Oxaliplatin for first
    line treatment of advanced colorectal Ca?
    Editorial Ann. Oncol 16 845-6 (2005)
  • Grothey A. et al Survival of patients with
    advanced colorectal Ca improves with the
    availability of 5FU-leukovorin, Irinotecan, and
    Oxaliplatin…. J Clin Oncol. 22 1209-1214 (2004)
  • Knight, RD, et al First line Irinotecan, 5FU,
    Leukovorin especially improves survival in
    metastatic colorectal patients with favorable
    prognostic indicators. Proc Am Soc Clin. Oncol.
    19255a (2000) (abstr 991)
  • Hurwitz, H. et al Bevacizumab plus Irinotecan
    5FU and Leukovorin for metastatic colorectal Ca
    N. Eng. J. Med. 350 2335-42 (2004)
  • Tabah-Fisch, I et al Oxaliplatin plus 5FU/LV
    is feasible safe and active in elderly colorectal
    cancer patients Proc Am Soc Clin. Oncol. 21
    (abstr 556) (2002)
  • Grothey A. et al Randomized Phase II trial of
    CAPIRI vs CAPOX as first line therapy of advanced
    colorectal Ca Proc. Am. Soc. Clin. Oncol. 22,
    255 (Abstr. 2003)

26
References
  • Vincent, M. et al Reduced dose Capecitabine
    monotherapy in older or less fit patients with
    advanced colorectal cancer Proc. Am. Soc. Clin.
    Oncol. 22 (Abstr. 1297) (2003)
  • Kabbinavar F.F. Combined Analysis of Efficacy
    The Addition of Bevacizumab to 5FU/Leukovorin
    Improves Survival for patients with metastatic
    colorectal Ca J. Clin. Oncol. 23 3706-3712
    (2005)
  • Cunningham D, et al Cetuximab (C225) alone or
    in combination with Irinotecan in patients with
    epidermal growth factor receptor positive
    Irinotecan refractory, metastatic colorectal Ca
    Proc Am. Soc. Clin. Oncol 22, Abstr. 1012 (2003)
  • André, T. et al Oxaliplatin, 5FU, Leukovorin as
    adjuvant treatment for colon Ca N. Engl. J. Med.
    350 2343-51 (2004)
  • Kabbinavar F.F. et al Addition of Bevacizumab to
    bolus 5FU and Leukovorin in first line metastatic
    colorectal Ca….. J. Clin. Oncol. 23. 3697-3705
    (2005)
  • Maughan TS, et al Comparison of intermittent
    and continuous palliative chemotherapy for
    advanced colorectal cancer… Lancet 361 457-464
    (2003)
  • Lal, R et al A randomized trial comparing
    defined-duration with continuous Irinotecan until
    disease progression…. J. Clin. Oncol. 22
    3023-31 (2004)
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