Metastatic Colorectal Carcinoma

1
Metastatic Colorectal Carcinoma

• Dr. Sharlene Gill
• Medical Oncologist
• British Columbia Cancer Centre
• Vancouver, BC

2
Ms. J.P.

• 71yo Female
• PMHx
• Hypertension controlled on diuretic.
• No hx of arterial or venous thromboembolic
  events.
• Meds
• HCTZ 25mg/day
• ASA 81 mg/day

3
Ms. J.P.

• 4 month history
• Fatigue
• microcytic anemia (Hgb 85)
• Intermittent abdominal pain
• Colonoscopy
• Near-obstructing mass in ascending colon, scope
  passes easily
• Biopsy shows Adenocarcinoma
• Preop Abdo U/S
• multiple hepatic metastases

4
Ms. J.P.

• Right hemicolectomy
• Mucinous moderately differentiated
  adenocarcinoma,
• T3, N2 (7/7 nodes positive).
• Liver biopsy Adenoca
• Now 6 weeks post resection intermittent RUQ
  pain, ECOG PS 2

5
Practice Point

• What is the role of resecting the tumor in
  already metastatic situation?
• Who would send patient to the OR for colostomy?
• Other viable options?
• Colonic stenting?
• Chemotherapy followed by
  
  resection if good response?

6
Resecting the Primary

• Relative void of information.
• Most data pre-dates current chemotherapy regimens
• Data from the year lt2000 show survival benefit in
  retrospective studies
• Data from other studies showed selected patients
  with asymptomatic primary colorectal tumors who
  present with incurable metastatic disease may
  safely avoid resection of their primary lesions
• with an anticipated low rate of hemorrhage
• perforation,
• obstruction before death from systemic disease.
• No survival advantage is gained by resection of
  an asymptomatic primary lesion in the setting of
  incurable stage IV colorectal cancer.

7
Ms. J.P.

• Labs
• WBC 10.2
• Hgb 106 MCV 76
• Plt 724
• Bili 7 ALP 532 (50-200)
• AST 98 (10-38) LDH 389 (90-210)
• Albumin 28
• Creat 74
• CEA 420

8
Ms. J.P.

• Imaging
• CXR negative
• CT abdo/pelvis multiple bilobar hypoechoic
  lesions, largest 6.4X5.9
• No obvious extrahepatic disease

9
Ms. J.P.

• Status post resection of a symptomatic primary
  lesion
• Unresectable liver-limited metastases
• Less fit criteria for this pt
• age gt 70
• PS 2
• Elevated LDH
• Low albumin

10
Practice Point

• What are the options for palliative systemic
  therapy in someone deemed unfit for aggressive
  chemotherapy regimes?
• Single agent Capecitabine
• 5FUFA (bolus or infusional)
• Single agent Irinotecan
• Tomudex
• FOLFIRI
• FOLFOX

11
5FU based Monotherapy

• Evidence that patients greater than age 70y have
  similar survival benefit with first-line IV 5FU
  based monotherapy but with greater toxicity
  diarrhea, stomatitis, infection
• Capecitabine equivalent to bolus 5FU/LV in
  first-line MCRC with less toxicity
• Data supporting efficacy of Capecitabine in
  older, less fit with treatment-related grade3-4
  toxicity observed in 12-22 of patients
• Clinical discretion to start at 1250mg/m2 BID or
  1000mg/m2 BID (most choose the latter then
  escalate as tolerated)

12
5FU based Monotherapy

• Feliú et al. at ASCO 2004, reported a very
  ambitious trial looking at single agent
  Capecitabine in the more senior elderly patients,
  those between 71 and 90.
• Feliú reported a very favorable safety data set
  as well as reasonable response rates.

13
Xeloda in the Elderly and Unift

• Derek Jonker at the London Regional Cancer Centre
  in London, ON presented at the inaugural GI ASCO
  meeting in San Francisco in 2004.
• For those patients that were deemed not to
  benefit from the Saltz regimen (ECOG gt1, age gt65,
  abnormal liver function testing), using single
  agent Capecitabine has afforded a treatment
  regimen that has well tolerated side effects and
  documented efficacy.
• Jonker et al. reported that of 93 evaluable
  patients
• Response is 12, with 73 disease control
  (CRPRSD).
• Median PFS was 5.1 months.
• Of 63 patients that progressed, 40 went on to
  receive further chemotherapy.
• The median overall survival for all patients is
  14.8 months.
• Median survivals for ECOG PS 0, 1, and 2 are
  17.4, 13.4 and 6.8 months respectively.

14
Options for palliative systemic therapy
15
Doublet FOLFOX or FOLFIRI

• In N9741and Tournigand, PS 2 patients were
  included (5 and 11 respectively)
• Equivalent benefit from FOLFOX based strategy in
  age gt75 subset of OPTIMOX
• Capecitabine oxaliplatin (XELOX) similar
  efficacy to FOLFOX in non-randomized comparison
  with manageable toxicity in older patients
• neutropenia 7
• diarrhea 16
• HFS 3
• neuropathy 17

16
Options for palliative systemic therapy
17
In combination with Bevacizumab

• Data supporting superior efficacy of Bevacizumab
  in combination with first-line IFL and 2nd-line
  FOLFOX.
• Hurwitz trial younger, fit patients mean age
  59y, PS1/2 41/lt1
• ECOG 3200 incl some less fit med age 62 (upper
  age range was 85y), PS1/2 45/6
• 5FU/LV plus Bevacizumab
• Randomized phase II in pts not candidates for
  first-line Irinotecan
• Mean age 71y/ PS1/2 65/7
• Median survival 16.5 mos with FU/LV/bev and 12.9
  mos with FU/LV
• Toxicity
• Gr3 HTN 16 vs 3
• Bowel perforation 2 vs 0
• Proteinuria 38 vs 19
• Gr3 bleeding 5 vs 3

18
Options for palliative systemic therapy
19
Bevacizumab toxicities

• Hypertension, proteinuria, bleeding, 1-2 risk of
  GI perforation
• Increased risk of arterial thromboembolic events
  with Bevacizumab (4.5 vs 2.0), particularly in
  patients aged gt65 years or previous history of
  arterial thromboembolic events.
• Based upon a retrospective analysis of five
  clinical trials in 1745 patients with mCRC,
  metastatic breast or advanced NSCLC (Hoffman La
  Roche data)
• Despite this risk, overall patients age gt65 years
  still benefited from Bevacizumab therapy.

20
Ms. J.P.

• Assuming FU monotherapy based regime used
  initially, either FUFA or Capecitabine
• What regimen do you use second line?
• Single agent Irinotecan
• FOLFIRI
• FOLFOX4

21
Ms. J.P.

• One of the most recent published trails in this
  specific area (older patient, poorer performance
  status, pre-treated) comes from Benavides et al..
  
• Thirty-four patients with poor performance status
  (Karnofsky score between 60 and 80) and/or
  progressing on one or more previous 5-FU-based
  chemotherapy lines for advanced colorectal
  adenocarcinoma were enrolled in this study.
• The dosing protocols used Irinotecan at 100 mg/m2
  administered as a 60-min iv infusion every week
  for four consecutive weeks followed by a 2-wk
  rest period until disease progression or
  unacceptable toxicity.
• The overall objective response rate was 20.6
  95 confidence interval (CI) 6.3-34.9.
• Stable disease was obtained in 13 patients
  (38.2) and 14 patients (41.2) progressed.
• The median time to disease progression was 5.5 mo
  (range 0.9-17.5)
• The median survival was 8.3 mo (95 CI
  1.7-16.9).
• The main toxicities were grade 3/4 neutropenia as
  the main hematological toxicity (11 patients
  32.4 14 infusions 3.3), and delayed diarrhea
  (10 patients 29.4 16 infusions 3.8) as the
  main grade 3/4 non-hematological toxicity

22
Ms. J.P

• Patient starts Irinotecan and does well.
• After 6 more months chemotherapy, CEA is rising,
  patient is developing more abdominal cramping and
  intermittent partial bowel obstructions.
• CT is suggestive of abdominal carcinomatosis
• Chemotherapy stopped

23
Ms. J.P.

• Octreotide started at 100µg SC BID
• After 1 week
• Bowels functioning normally
• Cramping abdominal pain is resolved
• Appetite improving
• Patient decides to go to hospice

24
References

• Au HJ, Mulder K, Fields A. Systematic Review of
  Management of Colorectal Cancer in Elderly
  Patients. Clin Colorectal Ca, 3(3),165-171, 2003
• Folprecht G, Cunningham D, Ross P, Glimelius B,
  etal Efficacy of 5-fluorouracil based
  chemotherapy in elderly patients with metastatic
  colorectal cancer a pooled analysis of clinical
  trials. Ann Oncol 151330-1338, 2004
• DAndre S, Sargent DJ, Cha SS, Buroker TR, Kugler
  JW etal 5-Fluorouracil-Based Chemotherapy for
  Advanced Colorectal Cancer in Elderly Patients.
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• Van Cutsem E, Hoff PM, Harper P, Bukowski RM,
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• Cripps MC, Vincent M, Jonker D, Kerry I, Dingle B
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• Feliu J, Escudero P, Llosa F, Bolanos M, Vicent
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• Tournigand C, Andre T, Achille E, Lledo G, Flesh
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25
References

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