Adjuvant Therapy for Colon Cancer

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Adjuvant Therapy for Colon Cancer

• Benjamin Tan, MD
• October 29, 2004

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Case 1 The Eldest

• 42 year old man with Fe-deficiency anemia and a
  cecal mass
• Biopsy Mod Diff mucinous adenoca
• Right hemicolectomy done 5/18/04 in Pinckneyville
• T3 N0 Mx- Stage IIA
• Only 6 lymph nodes examined
• () neurovascular invasion

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Case 2 The youngest

• 39 year old woman with abdominal pain
• Colonoscopy showed an ascending colon mass
• Bx Adenoca
• Right hemicolectomy in Pinckneyville
• T3N2 (5/14 lymph node ) Stage IIIC

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Case 3 The middle

• 41 year old man
• Routine colonoscopy Tubullovillous adenomas in
  ascending and descending colon with severe
  dysplasia 1 hyperplastic polyp
• Laparoscopic ileocolectomy
• T3N1 (2/22 lymph node )
• Stage IIIB

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The Family

• Probably with HNPCC
• MSI determination
• Who has the best/worst prognosis?
• Who should be treated?- with what?
• The eldest? Stage IIA
• The youngest? Stage IIIC
• The middle? Stage IIIB

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What are their prognoses?

• Without Adjuvant Therapy?
• With Adjuvant Therapy?

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Stage III OS
Greene, Ann Surg 2002 236416
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Gills pooled analysis for Stage II/III Colon
Cancer
Gill, ASCO 2003
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5-year DFS Estimates
Gill, ASCO 2003
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What Chemotherapy to Use?

• 5FU/Levamisole
• 5FU/Leucovorin
• Infusional 5FU regimens
• Capecitabine
• Irinotecan-based regimen
• Oxaliplatin-based regimen
• Cetuximab or Bevacizumab

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Intergroup 0035
Observation
Stage B
Levamisole 5FU x 1 year
Observation
Stage C
Levamisole 5FU x 1 year
Levamisole alone x 1 year
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Stage III (n929)
plt.0001 (5FULEV vs obs) p.0007 (5FULEV
vs obs)
Moertel, Ann Int Med 1221995
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Survival- Stage II (n318)
7 year-median ff-up
Moertel, JCO 131995
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Impact of Adjuvant Rx
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NSABP C-03
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Intergroup 0089
Haller, Proc ASCO,1998
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Quasar Study
Andre JCO 212003
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Adjuvant Therapy of Colon Cancer
Lev levamisole. Moertel et al. Ann Intern Med.
1995122321. Francini et al. Gastroenterol.
1994106899. Wolmark et al. Proc Am Soc Clin
Oncol. 199615205. Abstract OConnell et al. J
Clin Oncol. 199816295. Haller et al. Proc Am
Soc Clin Oncol. 199817256a. Abstract
982. Andre et al. Proc Am Soc Clin Oncol. 2002.
Abstract 529.
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Moving beyond 5FU

• Capecitabine
• Oxaliplatin
• Irinotecan
• Cetuximab
• Avastin

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Capecitabine/UFT

• X-ACT study
• 1987 patients
• Capeciatbine 1250 mg/m2 BID x 14 days vs Mayo
  5FU/LV q month x 24 weeks
• Trend to superiority for capecitabine
• Better toxicity profile
• NSABP C-06
• UFT vs Roswell 5FU
• Equivalent OS and DFS and toxicity

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MOSAIC Phase III Trial
R A N D O M I Z A T I O N
FOLFOX4 x 6 months
N1123
40 Stage II 60 Stage III
LV5FU2 X 6 months
N1123
de Gramont A et al. NEJM 2004
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MOSAIC Phase III TrialResults

• FOLFOX4 LV5FU2 Rel benefit
• 3-yr Overall DFS 77.9 72.8 23
• Stage III Pts 71.8 65.5 24
• Stage II Pts 86.6 83.9 18
• Plt.01

de Gramont A et al. NEJM 2004
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3-year DFS vs 5-yr OS

• Allows reporting of results sooner
• 17 randomized studies
• Over 17,000 patients
• 87 with gt5 year follow-up

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(No Transcript)
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3-yr DFS predicts for 5year OS
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Oxaliplatin Bolus 5FU NSABP results pending
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CALGB 89803

• IFL vs Bolus 5FU
• 1264 patients
• Toxicity higher in IFL arm
• 42 (vs 5) Gr 3-4 ANC
• 2.8 deaths during therapy (vs 1)
• No OS and FFS difference
• No role of IFL in adjuvant setting
• ?FolFIRI? Aventis/accord trials pending

Saltz, ASCO 2004
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Current Protocol

• FOLFOX C225
• - C225
• FOLFIRI C225
• -C225

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Summary

• Stage III patients
• Benefit for adjuvant therapy
• Oxaliplatin-based therapy merits discussion
• Although 3-year DFS correlates with 5-yr OS
• Toxicity issues
• No role for Irinotecan with bolus 5FU
• Capecitabine an option
• Stage II patients
• ASCO recommends no adjuvant therapy in general

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Are there any Stage II patients we need to
consider for adjuvant therapy?

• Inadequate lymph node sampling
• T4 lesions
• Tumor characteristics

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T3N0 Kaplan-Meier Curve based on lymph nodes
examined
Swanson, Ann Surg Oncol 2003
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Overall Survival in Node negative CRC Based on
lymph node removed
Le Voyer , JCO 212003
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N1
N2
Le Voyer , JCO 212003
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Survival- Stage II (n318)
7 year-median ff-up
Moertel, JCO 131995
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Microsattelite Instability

• -15 CRC with high frequency MSI
• Frame shift mutations or base pair substitutions
  in short tandemly repeated nucleotide sequences
  (microsattelite)
• Due to loss of DNA mismatch repair function-
  MLH1, MSH2, MSH6, etc
• Hallmark of HNPCC or Lynch syndrome (5 of all
  CRC)

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MSI

• MSI High tumors
• Usually proximal to splenic flexure
• Poor differntiation
• Mucinous cell type
• Lymphocyte infiltration
• Diploid (vs aneuploid in MS stable)
• Larger tumors
• Better survival vs stage matched MS stable
  patients

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Summary

• ASCO recommends no routine adjuvant therapy for
  Stage II CRC
• Adjuvant therapy considered in
• Inadequate sampling
• Adverse tumor characteristics
• ?MSI high

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Medicare Data- Who we Treat

• Stage III Colon Ca
• 1991-1996
• 6262 patients
• M 61 F 50
• AA 45 C 55

Schrag, JNCI 2001
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Stage II- Who we treat
5-year OS Treated 78 Untreated 75
Schrag, JCO 2002
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Cost Analysis

• Roswell x 24 17,616
• Folfox x 12 90,000
• In 2004, 106,000 with dx of Colon Ca
• 34,000 stage III
• 60 treated 20,400 x FOLFOX 1.8 Billion
• x Roswell
  359 M
• 25,000 stage II
• 30 treated 7,500 x FOLFOX 675 M
• x Roswell
  132 M

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Thank You.