metastatic colorectal cancer

1. ROLE OF SURGERY IN METASTATIC
COLORECTAL CANCER
Dr.A.Joseph Stalin M.Ch PG
PROF.DR.R.RAJARAMAN’S UNIT
CENTRE FOR ONCOLOGY
GOVT.ROYAPETTAH HOSPITAL
CHENNAI

2. CONTENTS
• HISTORY OF COLORECTAL METASTASIS
• RATIONALE FOR SURGERY
• ROLE OF SURGERY IN
-ISOLATED LIVER METASTASIS
-ISOLATED METASTASIS –OTHER SITES
• CONCLUSION

3. NATURAL HISTORY OF
COLORECTAL METASTASIS

4. INCIDENCE
• 25 - 35% of patients presents with synchronous
metastasis.
• 50 – 60 % of patients will eventually develop
metastasis, mostly within 2 years of detecting the
primary.

5. SITES OF RECURRANCE
• Liver (most common site)
• Locoregional
• Lung
• Peritoneal deposits
• Non-regional nodes
• Bones
• Brain
• Thyroid
• Subcutaneous tissues

6. SITES OF RECURRANCE

7. PATTERN OF SPREAD
• Hematogenous/Lymphatic
• Directly to liver via portal venous circulation.
• Lymph node – Central lymphatic chain –
hematogenous spread.
• Metastasis occur in a stepwise pattern.

8. Published in: Jelena Urosevic; Angel R Nebreda; Roger R Gomis; Cell Cycle 2014, 13, 2641-2642.
DOI: 10.4161/15384101.2014.946374
Copyright © The Author(s)

9. RISK FACTORS
Tumor Factors
Disease stage
High-grade tumor (poorly differentiated)
Tumor location
Obstruction/perforation
Venous invasion
Perineural invasion
Mucin production
Diminished stromal immune reaction
Aneuploidy
Mutant p53 gene expression
Low microsatellite instability
Technical Factors
Inadequate resection margins (radial, distal, mesorectal)
Implantation of exfoliated cells
Tumor location (pelvis and splenic flexure is anatomically and technically more
difficult)

10. ISOLATED LIVER METASTASIS

11. What are the options for patients with
colorectal liver metastasis?
• Do nothing
– median survival of 6 to 9 months.
• Chemotherapy
– 14.5-month median survival,
• RFA
– 40% 3-year survival rate,
• Resection
– 5-year survival rate of 45% to 60%

12. RATIONALE FOR SURGERY
• Spread of colorectal cancer occurs in a step
wise pattern-primarily to liver and then from
liver to other sites.
• Treatment of liver metastasis with the ability
of liver to regenerate results in prevention of
metastasis to other sites and results in
increased survival.

13. • In 1986, Ekberg et al defined resectability as less than
four metastases (even if bilobar), absence of
extrahepatic disease, and a resection margin of at least
1 cm.
• Today, resections are based on the remnant liver. A
sufficient future remnant liver volume (>20% of the
total estimated liver volume) is a prerequisite.
• If R0 with negative surgical margins (≥1mm) is possible
and sufficient liver parenchyma remains to maintain
liver function, resection should be considered
The Role of Liver Resection in Colorectal Cancer Metastases
A Quality Initiative of the Program in Evidence-Based Care (PEBC), Cancer Care
Ontario (CCO) Report Date: June 15, 2012
What is a Resectable Tumor?

14. INDICATIONS
• The patient has no extrahepatic disease
• The intrahepatic disease is safely resectable
and the patient must also be in good
medical condition.

15. Contraindications to liver resection
• Non-treatable primary tumor.
• Widespread pulmonary disease.
• Peritoneal disease.
• Extensive nodal disease, such as retroperitoneal
or mediastinal nodes.
• Bone or CNS metastases.
Guidelines for resection of colorectal cancer liver metastases. Gut 2006; 55 (Suppl 3):iii1–iii8

16. Clinical Risk Score
• Nodal status of the primary disease
• Free interval from the discovery of the primary to the
discovery of the liver metastases of <12 months
• Number of tumors >1
• Preoperative CEA level of >200 ng/mL
• Size of the largest tumors >5 cm
• Each positive criterion is assigned one point. 5-year survival
is 60% with score of 0 points, and falls to 14% in patients
with 5 points.
• Fong , et al.,Ann Surg 1999;230:309–318; discussion 318–321

17. CLINICAL RECURRANCE SCORE

18. Bittoni, Giampieri et al, CROH 2012

19. Principles of Resection in Colorectal Liver
Metastases
• An R0 resection of both the intra- and extrahepatic
disease sites must be feasible.
• At least two adjacent liver segments need to be
spared.
• Vascular inflow and outflow, as well as biliary
drainage to the remaining segments, must be
preserved.
• The volume of the liver remaining after resection
(i.e., the future liver remnant) must be adequate

20. TECHNIQUE
• Anatomical resection
• Non Anatomical resection
• Anatomical resection preferred due to low
recurrance rate.

21. Preoperative Patient Evaluation
• Colonoscopy
• Chest / abdominal/ pelvic CT
• CBC, Platelets, Chemistry
• CEA
• Determination of tumor K- RAS status
• Needle biopsy – if clinically indicated
• PET – CT only if potentially surgically curable M1
disease

22. TIMING OF HEPATECTOMY IN PATIENTS PRESENTING
WITH SYNCHRONOUS METASTASES
• Staged – Allows biological behavior of the metastatic
disease become evident, improving the selection of
patients
• Simultaneous resection of the primary and metastatic
disease - preferable from the patient's perspective
No proof of inferior survival or greater morbidity for a
one-stage procedure as compared to delayed (staged)
hepatic resection

23. How to increase RESECTABILITY
• Portal Vein Occlusion
• Two-Stage Hepatectomy
• Downstaging chemotherapy
• Local Ablation Techniques

24. Synchronous tumors
What are the possible options?
• Colon first: Staged approach
• Colon and liver: Simultaneous
approach
• “Reverse Strategy”

25. Criteria for synchronous approach
• Age<70 years
• good surgical fitness.
• an adequate tumor-free margin,
• lesions that are not advanced(T4),
• less than 4 colorectal lymph node metastases
• histology that is not poorly differentiated or mucinous
adenocarcinoma.
• 3 or fewer liver metastases.
• a minor liver resection (less than 3 segments) is planned
Ann Acad Med Singapore 2010;39:719-33

26. Surgical incisions according to primary tumor
and liver metastases

27. Advantages of simultaneous resection
• The performance of only a single surgical
procedure.
• Reduced length of hospital stay
• The removal of all neoplastic foci and
interruption of the “metastatic cascade”.
• The avoidance of immunodepression after
isolated primary tumor resection
• No delay in initiating systemic treatment

28. Disadvantages of simultaneous resections
• The combination of a “clean” and a
“contaminated” surgical procedure and thus
the higher risk of septic complications, which
could cause or worsen a liver dysfunction
• The increased risk of anastomotic leak due to
splanchnic congestion if prolonged pedicle
clamping is needed.
• The inadequate surgical exposure through a
single incision.

29. • The need for a double surgical team for liver
and colorectal surgery/inadequate treatment
if a single team performs the entire
procedure.
• Small occult metastases may not be evident
during the evaluation and therefore not
addressed during the operation.

30. “Test of time”
• Scheele et al suggested a “test of time” approach
of waiting up to 6 months to observe the tumor
biology and evolution of metastases as a means
of natural selection for operable disease.
• World J Surg 1995;19:59-71.

31. “Reverse Strategy”
• Brouquet et al. and the group from M.D.
Anderson Cancer Center
• preoperative chemotherapy is followed by
resection of the hepatic metastases and then
by resection of the colorectal primary at a
second operation.
• J Am Coll Surg 2010;210:934-41.

32. The rationale for this approach
• complications related to the primary
colorectal tumor are rare and treatment of
metastatic disease is not delayed by local
therapy for the primary tumor or
complications associated with treatment of
the primary tumor
• It can be considered as an alternative option
in patients with advanced hepatic metastases
and an asymptomatic primary.

33. REVERSE APPROACH

34. STUDIES ON LIVER RESECTION
Gayowski et al. (1994) -
Pittsburg Medical Center
0 33 32%
Jamison et al. (1997) -
Mayo Clinic
4 33 27%
Fong et al. (1999) -
Memorial Sloan Katering
3 42 36%
Choti et al. (2002) - Johns
Hopkins
1 46 40%
Fernandez et al. (2004) -
Washington University
1 – 59%
Pawlik et al. (2005) - M.D.
Anderson
1 74 58%
Hospital A.C. Camargo
(2005)
0 – 51%
Hospital A.C. Camargo
(2010) 1.8 – 66.2%
Author (year) Mortality %
Mean
survival
(months)
Five-year
survival

35. – Neoadjuvant chemotherapy
• Resectable liver metastases:
– Facilitate surgery
– Obtain predictive and prognostic information
– Early systemic therapy for poor-prognosis pts
– Conversion chemotherapy
• Unresectable liver metastases:
– Allow R0 resection via downsizing
– Postoperative (adjuvant) chemotherapy
ROLE OF CHEMOTHERAPY

36. – 5-FU: hepatic steatosis, associated with increased
postoperative morbidity - yellow liver
– Irinotecan: non-alcoholic steatohepatitis (especially in obese
patients), can affect hepatic reserve and increase morbidity and
mortality after hepatectomy - orange liver
– Oxaliplatin: hepatic sinusoidal obstruction syndrome, does
not appear to be associated with increased risk of perioperative
death - blue liver
– Both response rate and toxicity should be considered when
selecting preoperative CT in patients with colorectal liver
metastases
Adapted from Zorzi D, et al. Br J Surg 2007;94:274-86.
Liver Toxicities

37. CHEMO
• There is not a chemotherapy schedule indicated as standard
treatment in neoadjuvant setting of colorectal liver metastases: all
schedules could be used
• Triplet seems to be more effective
• Adding molecular drugs, there is an activity increase in term of
response rate and resectability
• Prospective studies on predictive factors of response and
resectability could be useful to select the better treatment for each
patient

38. Selecting patients for neoadjuvant therapy
• Resection was always preferred, if possible, over local
ablation strategies (cryosurgery, radiofrequency ablation
[RFA], laser techniques).
• Immediate resection appropriate if adequate margins
could be radiographically defined, there was no portal
lymph node involvement, and four or fewer lesions.
Resection could be considered for more than four lesions if
they were localized to a single lobe.
• For patients with more than four metastases or bilobar
involvement, resection considered appropriate only after
tumor shrinkage using neoadjuvant chemotherapy.

39. • 364 patients randomized
• Potentially resectable (≤ 4 liver
metastases)
• Goal: Improve PFS
• Interim objective: Evaluate tumor
response to perioperative CT
• Perioperative CT (n = 182)
– 159 (87.3%) underwent surgery
– 151 (83.0%) resected
• Surgery (n=182)
– 170 (93.4%) underwent surgery
– 152 (83.0%) resected
R
Nordlinger B, et al. Lancet 2008
FOLFOX4
for 6 cycles (12 wks)
(n = 182)
Surgery FOLFOX4
for 6 cycles (12 wks)
Surgery
(n = 182)
Colon Cancer: EORTC 40983 (the EPOC trial)

40. Efficacy Results
No. pts
CT
No. pts
Surgery
% absolute difference
in 3-year PFS
Hazard ratio
(confidence interval) p Value
All patients 182 182
+7.2%
(28.1% to 35.4%)
0.79
(0.62-1.02)
0.058
All eligible
patients
171 171
+8.1%
(28.1% to 36.2%)
0.77
(0.60-1.00)
0.041
All resected
patients
151 152
+9.2%
(33.2% to 42.4%)
0.73
(0.55-0.97)
0.025
Adapted from Nordlinger B, et al. Lancet 2008;371(9617):1007-16.

41. •High (anatomical) response rate
•Good toxicity profile
– No hepatotoxicity
– No interference with surgery
– No interference with liver regeneration
What Do We Expect from Ideal Conversion Chemo?

42. • The use of chemotherapy as an adjunct to
liver resection has resulted in a 5-year survival
in the range of 37 to 58%. ¹
• Ten-year survival is reported to be between 16
to 30%.²
1. Clin Colon Rectal Surg 2009;22:225–232.
2. Ann Surg Oncol 2008;15(9): 2458–2464

43. RECURRANT LEISION
• Common site of recurrance after hepatic
resection is liver.
• Liver is the sole site of recurrance in 15-40 %
of cases.
• Repeat hepatectomy considered in patient
with good clinical reserve and absence of
extra hepatic disease

44. VANISHING HEPATIC LEISION
• Complete radiological response occurs in 6-9%
of patients after noeadjuvant chemo.
• Due to pathologically complete response or
inability of imaging to pick leision due to
hepatic stenosis.
• OBSERVATION OR RESECTION ?

45. ISOLATED METASTASIS IN LUNG
• Incidence less than 10 %
• Only 2% will be eligible for resection.
• In resectable patients, 5 yr survival is around 27-40 %.
• Guidelines are similar to that of liver.

46. ISOLATED METS IN PERITONEUM
• Cytoreductive surgery with HIPEC in pateints with localised
leisions.
• 5 yr survival of about 20-45 %

47. ISOLATED METS IN BRAIN
• Rare incidence(<1%).
• If resectable patient should undergo resection.
• Unresectable patients treated with steroids and RT

48. ISOLATED METS IN BONE
• If unstable,internal fixation done.
• Palliative RT given.

50. SURVEILLANCE AFTER METASTECTOMY
Surveillance strategy for patients with stage IV disease
who are rendered surgically NED (no evidence of
disease)
• CEA every three months for two years, then every six
months for three to five years
• CT of the chest/abdomen and pelvis every three to six
months for two years, then every 6 to 12 months up to
a total of five years
• Colonoscopy in one year; if no adenoma repeat in
three years, then every five years; if adenoma is found,
repeat in one year

51. CONCLUSION
• Metastasis in colorectal cancer follows a
stepwise pattern.
• Liver is the most common site and most often
the first site to get involved.
• Median survival is around 15 months and 5 yr
survival less than 2 % in patients without any
treatment.
• Surgical resection improves the 5 yr survival
rate to around 50 % .

52. • Intent of surgical resection is cure.
• Resectable metastatic leisions are best
managed with surgical resection.

53. Thank U ……….