Management of Colorectal Liver Metastasis Bert H. O

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Management of Colorectal Liver MetastasisBert
H. ONeil, MDAssociate Professor of
MedicineDirector, GI Oncology ResearchUniversity
of North CarolinaLineberger Comprehensive Cacer
Center
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Case

• 22 y/o female college student presents with
  abdominal pain and BRPBR
• CT showed intussusception at hepatic flexure,
  colonoscopy showed fungating mass in same region,
  mod diff adeno
• MRI shows liver mets
• Patient undergoes R hemicolectomy prior to visit
  with medical oncology

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Question 1

• Surgeon tells you disease is unresectable, what
  is the reason? (show MRI again)
• Bilobar disease
• Greater than 3 metastases
• Vascular involvement
• Insufficient expected liver reserve

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• RIGHT HEPATIC LOBECTOMY FOR METASTATIC CARCINOMA
  OF THE LARGE BOWEL. FIVE-YEAR SURVIVAL.
• PEDEN JC Jr, BLALOCK WN.
• Cancer. 1963 Sep161133-40.

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Hepatic Resection Prognostic Factors

• 1) Positive margin
• 2) Extrahepatic disease
• 3) Node-positive primary
• 4) Disease-free interval lt 12 months
• 5) Number hepatic tumors gt 1
• 6) Largest hepatic tumor gt 5 cm
• 7) CEA level gt 200 ng/mL
• Fong et al, Ann Surg 230309, 1999

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Hepatic ResectionSurvival

• Score 5 Year Survival () Median Survival
• 0 60 74 mo
• 1 44 51
• 2 40 47
• 3 20 33
• 4 25 20
• 5 14 22
• 
  Fong et al, Ann Surg 230309, 1999

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Resectable Liver Metastasis- Adjuvant Therapy

• Precise definition of this entity is difficult,
  but most would agree that 4 or less mets to a
  single lobe are readily resectable
• Coceptually similar to stage III disease
• Prior studies of 5-FU based therapy suggested
  trend toward OS
• Many oncologists have empirically added
  bevacizumab in this setting

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Studies of 5FU in Resected CLM
Study N Tx DFS vs. Control P value
Lorenz 98 219 HAI 14.2 vs. 13.7 NS
Kemeny 99 156 HAI 37.4 vs. 17.2 0.06
Mitry 06 278 FU/LV 264 vs 186 0.059
Portier 173 FU/LV 244 vs 176 0.028
NS for OS
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EORTC 40983- Perioperative FOLFOX vs. Surgery for
resectable CLM

• Eligibility
• 1-4 Liver metastases that were technically
  resectable
• No extrahepatic (non-primary) disease
• No prior oxaliplatin
• Design
• Experimental arm 6 cycles (12 weeks) FOLFOX4
  pre- and post surgery

Lancet. 2008 Mar 22371(9617)1007-16
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Complications of surgery
Peri-op CT Surgery
Post-operative complications 40 /159 (25.2) 27 / 170 (15.9)
Cardio-pulmonary failure 3 2
Bleeding 3 3
Biliary Fistula 12 5
(Incl Output gt 100ml/d, gt10d) (9) (2)
Hepatic Failure 11 8
(Incl. Bilirubingt10mg/dl, gt3d) (10) (5)
Wound infection 4 4
Intra-abdominal infection 8 2
Need for reoperation 5 3
Other 25 16
Incl. post-operative death 1 patient 2 patients
P0.04
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Results
N ptsCT N pts Surgery absolute differencein 3-year PFS HazardRatio P-value
All patients 182 182 7.2 (28.1 to 35.4) 0.79(0.62-1.02) P0.058
All eligible Patients 171 171 8.1 (28.1 to 36.2) 0.77 (0.60-1.00) P0.041
All resected Patients 151 152 9.2 (33.2 to 42.4) 0.73(0.55-0.97) P0.025
Lancet. 2008 Mar 22371(9617)1007-16
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Progression-free survival in resected patients
HR 0.73 CI 0.55-0.97, p0.025
100
90
9.2At 3 years
80
Periop CT
70
60
50
42.4
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Surgery only
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33.2
20
10
(years)
0
0
1
2
3
4
5
6
O
N
Number of patients at risk
104
152
85
59
39
24
10
93
151
118
76
45
23
6
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Conclusions- Resectable Liver Metastasses

• 5FU-based therapy never proven effective
• FOLFOX probably standard, but less effective than
  we would have thought based on stage III results
• No evidence that pre-operative therapy is
  necessary vs. postoperative
• Bevacizumab is of unproven benefit in this group
  of patients, and C08 suggests it may not be
  helpful as adjuvant therapy
• What to do with resectable disease that arises
  after adjuvant FOLFOX???

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Unresectable CLM
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Hopital Paul Brousse Experience
Response to chemotherapy 69 7.2 Complete Path.
Response
Adam et al, Ann Surg 2004
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Hopital Paul Brousse Experience
Adam et al, Ann Surg 2004
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What Therapy for Initially Unresectable CLM?
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FOLFIRI vs. FOLFOXIRI
A. Falcone et al, ASCO GI Symposium, Jan 2006,
Abstract 227
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FOLFIRI vs. FOLFOXIRI
A. Falcone et al, ASCO GI Symposium, Jan 2006,
Abstract 227
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NO16966 (post hoc analysis)Surgery with
curative intent
ITT population
Liver mets only
19.2
8.4
12.9
6.1
Percent of patients
n701
n699
n178
n177
XELOX / FOLFOX4 placebo
XELOX / FOLFOX4 bevacizumab
Cassidy, WCGIC 2007
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Retrospective Study of Chemo with or without
Bevacizumab Pathologic Response and Toxicity
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CRYSTAL trial Surgery with curative intent
ITT population(pre-planned)
Liver metastases only population(exploratory)
p0.0034 odds ratio 3.0 95 CI 1.4 - 6.5
n599 / group
n599 / group
CMH test
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Case Contd

• Patient was enrolled on CALGB/SWOG 80405,
  randomized to bev arm (FOLFOX was chosen
  backbone)
• After 3 cycles of therapy (beginning 6 weeks
  post-op), she developed pain in pelvis and right
  thigh
• MRI Peripherally enhancing fluid collection
  tracking along the right intra-pelvic iliopsoas
  musculature into the anterior right thigh and
  about the sartorius and gracilis muscles,
  consistent with abcess.
• Yikes!

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Question 3

• What do we lose by omitting bevacizumab?
• Chance of response decreases by 10 compared with
  FOLFOX alone
• Chance of resectability decreases by 10 compared
  to FOLFOX alone
• Median PFS decreases by 2 months
• Median overall survival decreases by 2 months
• None of the above is true

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SBRT for Unresectable mCRC
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Prospective Trials of Stereotactic Body Radiation
Therapy for Hepatic Metastases
Actuarial Local Control Actuarial Local Control
Study No. of Lesions Study No. of Lesions Fractionation Median Follow -Up Time
Herfarth et al 55 1 x 14 Gy to 1 x 26 Gy 6 months 18 months 67
Hoyer et al 141 3 x 15 Gy 4.3 years 2 years 79
Milano et al 293 10 x 5 Gy 41 months 2 years 67
Mendez-Romero 45 3 x 12.5 Gy 13 months 2 years 82
Rusthoven et al 49 3 x 20 Gy 16 months 2 years 92
Total number of colorectal cancer metastases 44 liver metastases Total number of lesions treated 45 of patients were treated for hepatic metastases. In surviving patients Different fractionation (3 x 10 Gy or 5 x 5 Gy) used for patients with hepatocelluar carcinoma or with lesions cm. Total number of colorectal cancer metastases 44 liver metastases Total number of lesions treated 45 of patients were treated for hepatic metastases. In surviving patients Different fractionation (3 x 10 Gy or 5 x 5 Gy) used for patients with hepatocelluar carcinoma or with lesions cm. Total number of colorectal cancer metastases 44 liver metastases Total number of lesions treated 45 of patients were treated for hepatic metastases. In surviving patients Different fractionation (3 x 10 Gy or 5 x 5 Gy) used for patients with hepatocelluar carcinoma or with lesions cm. Total number of colorectal cancer metastases 44 liver metastases Total number of lesions treated 45 of patients were treated for hepatic metastases. In surviving patients Different fractionation (3 x 10 Gy or 5 x 5 Gy) used for patients with hepatocelluar carcinoma or with lesions cm. Total number of colorectal cancer metastases 44 liver metastases Total number of lesions treated 45 of patients were treated for hepatic metastases. In surviving patients Different fractionation (3 x 10 Gy or 5 x 5 Gy) used for patients with hepatocelluar carcinoma or with lesions cm. Total number of colorectal cancer metastases 44 liver metastases Total number of lesions treated 45 of patients were treated for hepatic metastases. In surviving patients Different fractionation (3 x 10 Gy or 5 x 5 Gy) used for patients with hepatocelluar carcinoma or with lesions cm.
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Local Control by SBRT
Rusthoven et al JCO 2009 27 (10) 1572
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Response to CyberKnife
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90-Ytrrium Microspheres
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90Y Microspheres for Refractory LC-mCRC
Hendlisz A et al, JCO 2010 28(23) 3687
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90Y Microspheres for Refractory LC-mCRC
10 PR rate for 90Y spheres 5FU, 0 for 5FU
alone
Hendlisz A et al, JCO 2010 28(23) 3687
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RFA
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Non-curative Ablation for mCRCDoes it Improve
Survival in FOLFOX era?

• EORTC 40004 (CLOCC) RPII adding RFA to systemic
  CT in patients with 9 unresectable CRC LM and
  no extrahepatic disease
• 119 patients randomized 2002-2007
• CT was FOLFOX ( bev beginning in 2005)
• 30-months OS rate (primary endpoint)
• 61.7 (95 CI, 48.21-73.93) in the RFA CT
• 57.6 (44.07-70.39) in the CT arm (higher than
  anticipated in study design!)
• PFS 16.9 mos vs 9.9
• Conclusion- liver only mets have better
  prognosis, not clear if RFA changes it

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Our patient

• Underwent R hepatectomy with biopsy of SBRT site
  and repair of anastamosis/fistula
• Still some viable disease at SBRT site
• Now back on FOLFOX (without bevacizumab)

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Conclusion

• Surgical therapy can be curative of CLM
• Adjuvant therapy remains standard, but actual
  proof is lacking (even after EORTC study)
• Modern systemic therapy has allowed for the pool
  of eligible patients to increase
• The best conversion therapy remains to be
  defined
• Newer options exist, but more data needed on use
• Non-curative RFA does not obviously prolong
  survival in liver-only CLM, but larger studies
  may be necessary