Title: Natural History of Colorectal Liver Metastases Angiogenesis
1Surgical 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
4Colorectal 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
5Results 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
6- 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
7Patient 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
8Post-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
9Decisions 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
10- 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
11Controversies 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
12The 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
13Impact 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
14Anatomic 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
15- 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
16Other 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
17- LVRT
- n 245 patients Curative liver resections for
colorectal metastases - Italy
- Retrospective, single-institution
- 1984-2000
18Percentage 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
20Potential 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
21- 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
22Curative Resection is Only Possible in 20
Patients with Colorectal Cancer Metastases to the
Liver
Possible to Increase Resectability Rate?
23Portal 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
24- 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?
25- 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
26- 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
29- 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
30- 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
31Kemeny N et al. NEJM 1999
32Intra-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.
34 35Given 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
38Angiogenesis 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
39Endostatin 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
40Cristofanilli M et al. Nature Reviews 2002