Surgical Management of Liver Metastases from Colorectal Carcinoma

1
Surgical Management of Liver Metastases from
Colorectal Carcinoma

• Hernan Bazan, MD6 July 2004
• Team IV Conference

2

• Background
• Incidence
• Results
• Controversies
• R0 resection
• Anatomical vs. Non-anatomical
• Prognostic indicators
• Contraindications
• Portal Vein Embolization
• Increase resectability rate?
• Hepatic Artery Infusion
• Decrease the recurrence rate after liver
  resection?
• Natural History of Colorectal Liver Metastases

3

• Background
• Incidence
• Results
• Controversies
• R0 resection
• Anatomical vs. Non-anatomical
• Prognostic indicators
• Contraindications
• Portal Vein Embolization
• Increase resectability rate?
• Hepatic Artery Infusion
• Decrease the recurrence rate after liver
  resection?
• Natural History of Colorectal Liver Metastases

4
Colorectal Cancer Liver Metastases

• Colon Cancer
• In USA 150,000 new cases/year
• 3rd most common cancer
• Liver is the most commonly involved organ in
  patients with metastatic disease
• 20 patients with colon cancer present with
  liver metastases
• An additional 20 will develop metachronous liver
  metastases (usually within 3 years)
• Stage II 20
• Stage III 50
• Overall, 30,000 patients will present annually
  in the USA with liver metastases from colorectal
  cancer
• Only 10-20 patients with liver mets fulfill
  criteria for resection
• Overwhelming evidence that resection of liver
  metastases from colorectal cancer is beneficial
• May result in disease-free survival for 20 years
  and more
• Can cure a substantial number of patients

5
Results Liver resection with curative intent for
hepatic metastases from colorectal cancer

• Since 1980, single-institution series (gt100
  cases) reported 5-year survival figures from
  18-46
• German group (n597)
• 5-year survival 33
• MSKCC (n1,001 consecutive cases)
• 5-year survival 36
• Natural history of metastatic colon cancer to
  liver
• In the absence of treatment, median survival is 9
  months
• 5-year survival Rare

1,745 consecutive patients with colorectal liver
metastases, 1961-1993 Germany
Scheele and Altendorf-Hofmann. Langenbecks Arch
Surg 1999
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• Each year, 14,000 patients with colorectal
  cancer undergo liver resection to remove
  metastatic disease
• After 2 years
• 65 alive
• 25 have no detectable disease
• Recurrences are still observed in patients with
  liver resection
• Hence, the need for adjuvant treatments
• IV chemotherapy
• HAI

Penna and Nordlinger. British Medical Bulletin
2002
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Patient Selection

• Good cardiopulmonary function
• Liver function Sufficient functional hepatic
  reserve
• If normal liver, up to 75 liver may be resected
  (6 of 8 segments)
• Caveat Pre-op chemotherapy
• May alter liver function
• Surveillance primary and extra-hepatic sites
• DRE
• Colonoscopy
• CXR/Chest CT
• CT abdomen/pelvis
• Intra-abdominal assessment
• Exploration
• Intra-op ultrasound (IOUS)
• ?Laparoscopy

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Post-op Morbidity and Mortality

• Morbidity Up to 40
• Hemorrhage
• Bile leak/fistula
• Subphrenic abscess
• DVT
• Pneumonia
• Transient liver failure
• Mortality 0-5
• lt3

Scheele and Altendorf-Hofmann. Langenbecks Arch
Surg 1999
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Decisions to be Made During Primary Colorectal
Cancer Resection

• In case of synchronous metastasis (discovered
  during surgery for primary colorectal lesion), a
  wedge resection of an isolated, easily accessible
  metastasis may be done.
• Otherwise, it may be preferable to wait 2-3
  months
• Incision and exposure
• When resection of primary colorectal is combined
  with major liver resection, theres an increased
  mortality
• Bowel resection and peritoneal contamination
• Promote intra-abdominal and subphrenic abscess?
• Hemodynamic changes associated with Pringle
  maneuver/hemorrhage
• May compromise bowel anastomosis
• Offer systemic chemotherapy
• But not prospectively assessed
• Natural history of metastatic colon cancer
• Angiogenesis and rapid of growth of already
  present micrometastases

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• Background
• Incidence
• Results
• Controversies
• R0 resection
• Anatomical vs. Non-anatomical
• Prognostic indicators
• Contraindications
• Portal Vein Embolization
• Increase resectability rate?
• Hepatic Artery Infusion
• Decrease the recurrence rate after liver
  resection?
• Natural History of Colorectal Liver Metastases

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Controversies Resection

• Several series since 1990 have failed to
  demonstrate any prognostic significance when
  solitary, multiple unilateral, and multiple
  bilateral metastases were compared
• As long as patient undergoes R0 resection
• R0 resection Absence of microscopic residual
  disease and clear resection margins (1 cm)

Survival after an R0 resection Similar survival
in patients with a lt3 mets vs. gt4 mets
Scheele and Altendorf-Hofmann. Langenbecks Arch
Surg 1999
12
The number and distribution of colorectal liver
metastases does not alter survival as long as an
R0 resection is done 206 consecutive patients

• Number and distribution of liver metastases does
  not matter as long as R0 resection is done

Scheele and Altendorf-Hofmann. Langenbecks Arch
Surg 1999
13
Impact of R-classification
Radicality of the procedure is the overwhelming
predictor of prognosis R0 vs. R1 resection
(histologically-involved)
Scheele and Altendorf-Hofmann. Langenbecks Arch
Surg 1999
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Anatomic vs. Non-anatomic Resection

• Ongoing controversy Optimal mode of liver
  resection
• Anatomic approach (segmentectomy or lobectomy)
• Reduces incidence of histologically-involved (R1)
  liver resections
• German group Slight survival advantage to
  anatomic resection, even in R0 group
• MSKCC Minor advantage for nonanatomical
  resections
• May be due to lower operative risk
• May also reflect the reduced tumor load

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• Background
• Incidence
• Results
• Controversies
• R0 resection
• Anatomical vs. Non-anatomical
• Prognostic indicators
• Contraindications
• Portal Vein Embolization
• Increase resectability rate?
• Hepatic Artery Infusion
• Decrease the recurrence rate after liver
  resection?
• Natural History of Colorectal Liver Metastases

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Other Prognostic Indicators

• R0
• As opposed to the number of metastases, the
  maximum diameter of the tumor
• Significant prognostic factor
• Percentage of liver volume replaced by tumor
  (LVRT)
• Weak prognostic indicators
• Operative blood loss
• Intra-operative hypotension
• Need for blood transfusion
• Rather than being immunosuppressive, it may
  reflect a more complex operative procedure due to
  a greater tumor load
• Others
• Performance status
• Weight loss
• Serum albumin
• Pre-op CEA
• Future

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• LVRT
• n 245 patients Curative liver resections for
  colorectal metastases
• Italy
• Retrospective, single-institution
• 1984-2000

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Percentage of liver involvement by tumor
Tumor volume
Total volume of metastases, not number and
location, seems to be the strongest predictor of
survival
Ercolani G et al. Arch Surg 2002
19

• Background
• Incidence
• Results
• Controversies
• R0 resection
• Anatomical vs. Non-anatomical
• Prognostic indicators
• Contraindications
• Portal Vein Embolization
• Increase resectability rate?
• Hepatic Artery Infusion
• Decrease the recurrence rate after liver
  resection?
• Natural History of Colorectal Liver Metastases

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Potential Contraindications

• Ekberg criteria (1986) 3 contraindications
• 4 or more metastases
• Extrahepatic disease
• Resection margin lt1 cm
• Minimum No.
• Presence of 1-3 metastases (whether unilateral or
  bilateral) Clear indication for liver resection
• Maximum No.
• Small series show survival advantage even for
  resection of five or more liver lesions (versus
  no treatment)
• Survival was the same as in 36 patients who had
  2-4 metastases resected

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• Background
• Incidence
• Results
• Controversies
• R0 resection
• Anatomical vs. Non-anatomical
• Prognostic indicators
• Contraindications
• Portal Vein Embolization
• Increase resectability rate?
• Hepatic Artery Infusion
• Decrease the recurrence rate after liver
  resection?
• Natural History of Colorectal Liver Metastases

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Curative Resection is Only Possible in 20
Patients with Colorectal Cancer Metastases to the
Liver
Possible to Increase Resectability Rate?
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Portal Vein Embolization

• Clinical experience in the 1950s Fatal liver
  failure did not occur after major liver
  resections when PV of resected liver was
  obstructed (tumor)
• Resection is contraindicated if remnant liver is
  too small to provide sufficient function
• Portal Vein Embolization (PVE)
• Induces ipsilateral atrophy
• Contralateral, compensatory hypertophy
• Prevents post-op liver failure

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• 1990-1998
• n30 consecutive colorectal liver mets deemed
  inelligeble for resection b/c remnant liver was
  too small (lt40 by CT scan volumetry)
• All received 11 /- 7 courses of chemotherapy
• PVE
• Does pre-op PVE increase the safety of
  hepatectomy?

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• PVE was feasible in all patients
• Mortality None
• Post-PVE liver volume was increased (compared to
  pre-PVE)
• PVE and Surgery
• 30 ? 28
• 1 refused
• 1 contralateral progression of disease
• 28 ? 19 Resection
• 9 Resection was cancelled at laparotomy b/c tumor
  extension
• 19 Resection
• 2-6 segments resected

Resection of 4 or more segments with (n19) and
without (n88) PVE
Azoulay D et al. Ann Surg 2000
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• PVE safe and feasible
• Allowed resection in 19/28, previously deemed
  unresectable
• Removed contraindication, increasing
  resectability rate
• Survival benefit is comparable to primary liver
  resection (at 5 years, 40 vs 38)
• Very small study

Azoulay D et al. Ann Surg 2000
27

• Background
• Incidence
• Results
• Controversies
• R0 resection
• Anatomical vs. Non-anatomical
• Prognostic indicators
• Contraindications
• Portal Vein Embolization
• Increase resectability rate?
• Hepatic Artery Infusion
• Decrease the recurrence rate after liver
  resection?
• Natural History of Colorectal Liver Metastases

28

• Two years after liver resection for metastatic
  colorectal cancer, only 25 of patient are free
  of disease and 65 alive

Dual blood supply liver Normal liver
parenchyma Derive their blood supply largely
from PV Metastases HA Hepatic artery infusion
(HAI ) chemotherapy exposes liver metastases to
high concentrations toxic drug sparing normal
liver
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• n156 resectable liver mets from colorectal
  cancer
• Single center (MSKCC)
• Randomized
• Median f/u 63 months
• HAI pump
• Floxuridine
• Dexamethasone
• Compared
• HAI systemic chemotherapy
• Chemotherapy alone (5-fu /- leucovorin)
• Complications 16
• Pocket/pump infection
• HA thrombosis

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• Combination Systemic
• Chemotherapy
• Survival
• 2-year 86 72
• Median 72 59
• (months)
• Recurrences
• At 2 years 30/74 44/82
• Hepatic
• Recurrences 7/74 30/82

Kemeny N et al. NEJM 1999
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Kemeny N et al. NEJM 1999
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Intra-arterial Chemotherapy Following Resection
of Colorectal Liver Metastases
Geoghegan JG and Scheele J. British Journal of
Surgery 1999
33

• n174
• 1990-1999
• Though many studies show mixed results, HAI pump
  seems to prolong overall survival for those with
  unresectable liver metastases from colorectal
  carcinoma, but it is not equal to resection.

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• Neoadjuvant Treatment?

35
Given proven benefits of surgery (vs. systemic
chemotherapy), difficult to justify trial of
neoadjuvant treatment in patients with resectable
tumors Surgery remains first line of treatment

• Neoadjuvant treatment
• Another way to increase resectability rate?
• For unresectable tumors, only a few
  non-randomized, retrospective studies and case
  series ? downstaging to resectable by chemotherapy

Studies Reporting Downstaging to Resectable
Liver Metastases with Chemotherapy
Geoghegan JG and Scheele J. British Journal of
Surgery 1999
36

• Background
• Incidence
• Results
• Controversies
• R0 resection
• Anatomical vs. Non-anatomical
• Prognostic indicators
• Contraindications
• Portal Vein Embolization
• Increase resectability rate?
• Hepatic Artery Infusion
• Decrease the recurrence rate after liver
  resection?
• Natural History of Colorectal Liver Metastases

37

• Cancer metastases is a highly complex process
• Multiple changes in gene expression
• Conventional therapy is only rarely able to stop
  the lethal path of metastasis
• Tumor growth and metastasis depends on
  (pathological) angiogenesis (1971, J Folkman)
• Activation and recruitment of new blood vessels
• Formation of a capillary network
• Intensive search 1970s 1990s factors
  Angiogenic Switch
• VEGF, bFGF, IL-8, PLGF, TGF-b, PD-EGF
• Angiogenesis is essential for growth of dormant
  micrometastases into clinically detectable
  metastatic lesions
• Autopsy studies
• Clinically, the angiogenic switch is evident when
  tumor mass expands to a detectable size or local
  bleeding or metastasis occur
• Neovascularized tumors

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Angiogenesis Inhibitors

• New class of drugs
• Target vascular endothelial cells (ECs)
• Inhibit proliferation, migration
• Less likely to induce resistance not targeting
  tumor cell
• Stable genome
• no multi-drug resistance gene (MDR)
• Potential broad applicability
• Few angiogenic markers may be shared by various
  tumors
• Experimentally, when tumors are treated with
  angiogenesis inhibitors ? Remain in a microscopic
  state of dormancy
• Initial Phase 2/3 trials, have not shown benefit
  for single inhibitors (advanced cancer)
• Future, test inhibitors not only to regress
  growth in already advanced cancers, but in
  blocking the progression of dormant lesions in
  aggressive cancers or the development of
  metastases in high-risk cancer patients

Kerbel R and Folkman J. Nature Reviews 2002
39
Endostatin An Endogenous Inhibitor of
Angiogenesis
Systemic Therapy with Recombinant Endostatin
Regresses Lewis Lung Carcinoma Primary
Tumors Subcutaneous dorsa of mice- implanted
with Lewis lung carcinomas Systemic therapy with
recombinant mouse endostatin (20 mg/kg/day)
initiated when tumors were 200 mm3 (1 of body
weight) Tumors in mice treated with endostatin
rapidly regressed Treated and control mice 11
days after systemic therapy with
endostatin Saline-treated mice had
rapidly growing red tumors with ulcerated
surfaces Endostatin- treated mice had small
pale residual tumors However, residual disease
in endostatin treated mice Sacrificed after 16
days of therapy Autopsy revealed small white
residual tumors at the site of the original
primary implantation

OReilly MS et al Cell 1997
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Cristofanilli M et al. Nature Reviews 2002