1. Management of
Metastatic Colorectal
Cancer
Dr Sujay Susikar
Post Graduate Student
Department of Surgical Oncology
Government Royapettah Hospital

2. The challenges of metastatic CRC
• A significant number of
patients present with ~40%
metastatic disease
~50% • Many newly diagnosed patients
eventually develop metastatic
disease
5-year survival rate —
2% (if unresectable) to 50% (if resectable)

3. Management of synchronous metastasis
Non Systemic
Synchronous obstructing therapy
addominal/
peritoneal Colon resection/
mets Obstructing or
diverting Systemic
imminent
colostomy/ therapy
obstruction
bypass/ stenting
Synchronous
Metastatic
colorectal
carcinoma Colectomy with
synchronous or staged
resection OR neoadjuvant
Resectable chemo OR colectolmy
Adjuvant
therapy
F/B chemo and staged
resection
Synchronous liver
and /or lung only
mets
Converted to resectable
– synchronous or
staged resection
Unresectable Systemic
therapy Remains unresectable –
continuum of care

4. Management of metachronous
metastasis

5. Management of potentially resectable
colorectal cancer liver metastases
Regional treatments for hepatic metastases from CRC
 Surgical resection
 Local tumor ablation
 Percutaneous injection
 Cryotherapy,
 Radiofrequency ablation
 Regional hepatic intraarterial chemotherapy
 Chemoembolization,
 Radiation therapy (RT).
Only surgery is associated with a survival advantage

6. Management of potentially resectable
colorectal cancer liver metastases
 Resection offers the greatest likelihood of cure
for patients with liver-isolated CRC.
 Five -year survival rates after resection range
from 24 to 58 percent, averaging 40 percent
 Surgical mortality rates are generally <5 %

7. Patient selection for resection
Criteria for absolute unresectability
 Nontreatable extrahepatic disease,
 Unfit for surgery
 Involvement of more than 70 percent of the liver or six
segments
 Radiographic evidence of involvement of the hepatic artery,
major bile ducts, main portal vein, or celiac/paraaortic
lymph nodes
Modern multidisciplinary consensus defines resectable CRC
liver metastases simply as tumors that can be resected
completely, leaving an adequate liver remnant

8. CRITERIA FOR RESECTABILITY
 General criteria for fitness
1. Good performance status
2. Absence of extra hepatic disease
 Specific Criteria that decides the outcome
1. Risk of recurrence- Clinical Risk Score for CRC
 Anatomical criteria for resectability
1. Number of metastases
2. Precise location
3. Relationship with the portal pedicle and the hepatic veins

9. Clinical Risk Score
5 clinical criteria each assigned 1 point:
1) Node-positive primary
2)<12 month disease-free interval
3) >1 liver tumors
4) Largest tumor >5 cm
5) CEA >200 ng/mL.

10. 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

11. 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

12. Conversion therapy for initially
unresectable metastases
Induction chemotherapy in patients with
isolated but initially unresectable CRC liver
metastases

13. 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.

14. 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

15. SURVEILLANCE AFTER
METASTASECTOMY
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 advanced adenoma repeat
in three years, then every five years; if advanced adenoma
is found, repeat in one year

16. ABLATION
Indications
 Patients who do not meet the criteria for
resectability
 Presence of liver-only disease.
 A complete margin-negative ablation can be
achieved

17. ABLATION
1. Cryotherapy
 Destruction of tumor cells by freeze thaw
cycle.
 Probe positioned inside tumor
 Liquid nitrogen is circulated through tip of
probe
 Temp lowered to -100° C
 1-3 cycles of freezing for 15 mins with
spontaneous periods of thaw
 Lethal temp -20° C
 Intracellular or extra cellular ice forms
 Ice ball of ~3-6cm
 Complications - biliary, abscess,
myoglobinuria, haemorrhage, coagulopathy,
cryoshock

18. ABLATION
2. Radiofrequency ablation
 Radiofrequency waves (high frequency
alternating current - 460khz) are
converted into thermal energy
 Friction from rapidly moving ions
results in heat
 Temp of ~60°C
 Coagulative necrosis
 Open/laparoscopic or percutaneous
technique
 Effective with tumors upto 5 cm
 Complications – bilioma, biliary
fistula, stricture, abscess

19. ABLATION
3. Laser interstitial thermal
therapy (LITT)
 Placement of laser fiber or
fibers directly into the tissue to
be treated.
 Infrared laser producing lethal
thermal injury to tumor cells
 LITT utilizes diode laser or
more frequently Nd-YAG laser
 Coagulative necrosis
 Procedure is usually performed
under MRI guidance

20. ABLATION
4. Microwave coagulation therapy
 Uses microwave of frequency 2450 Mhz
 Produces heat by stimulation of water
molecule
 Produces rapid frictional heating and
coagulative necrosis
5. Intratumoral alcohol injection
 Causes denaturation of protein leading to
cell death
 Can be used for tumors <3cm

21. RADIOTHERAPY
Stereo tactic body radiation
 Tolerance of liver to radiation is poor.
 Conformational radiation therapy using
multiple field & beam angles is used to
deliver large doses to a target sparing
surrounding normal tissues.

22. Selective Interstitial Radiation Therapy
 Injecting micro spheres containing
yttrium 90 via hepatic artery
 Percutaneous cannulation of hepatic
artery
 Spheres selectively lodge into tumor cells
 200-300 Gy to tumor ,15-50 Gy to liver
 Emits Beta radiation with a penetrance
of 2-3 mm
 Half life of 64 hours.

23. Chemotherapy for Metastatic Colorectal
Cancer
Conventional chemotherapy
 Thymidylate synthase inhibitors
 Fluoropyrimidines: 5-FU (intravenous), capecitabine (oral)
 Raltitrexed
 Topoisomerase I inhibitors
 Irinotecan
 Alkylating agents
 Oxaliplatin
Traditional 5-FU–based chemotherapy associated with modestly
improved survival
 Newer agents (ie, irinotecan, oxaliplatin) lengthen survival outcomes

24. Chemotherapy for Metastatic Colorectal
Cancer
Targeted therapies
 Bevacizumab ( Avastin)—binds the vascular
endothelial growth factor ( VEGF).
 Cetuximab ( Erbitux)– targets the epidermal growth
factor receptor ( EGFR).
 Pantumumab ( Vectibix)– targets the EGFR, in a
different way than Cetuximab.

25. First- line chemotherapy
 FOLFOX( Oxaliplatin plus 5-FU and leucovorin Q2W)
FOLFIRI( Irinotecan plus 5-FU and leucovorin Q2W)
 Patients should have a central line and a portable IV pump.
 In the U.S.A, most patients are offered first- line FOLFOX, and
FOLFIRI is reserved for second- line therapy.
CAPOX (capecitabine plus oxaliplatin)
 Benefit of adding Bevacizumab
A significant higher response, it prolongs survival.
 Patients who can’t tolerate Irinotecan or
Oxaliplatin
 Less toxic alternative: 5-FU+ leucovorin( +Bevacizumab)

26. Multiple Active Agents Associated With
Increased Survival
 Combinations of multiple active agents associated with better
outcome
 5-FU, irinotecan, oxaliplatin
 Compared with 5-FU/LV, use of all 3 active therapies associated
with improved survival
 Median survival with triple-drug regimens: ~ 20 months
 First-line doublet chemotherapy
 Associated with increased exposure to all 3 active agents
during therapeutic course

27. Metastatic CRC: Which Chemotherapy
First?
 FOLFOX = FOLFIRI
 CapeOx = FOLFOX
 Sequencing = combinations
FOLFOX FOLFIRI FOLFIRI FOLFOX
(1st line 2nd line) (1st line 2nd line)
N pts (229) 111 69 109 81
RR 54% 4% 56% 15%
Liver
21% 9%
resection
PFS (mos) 8.1 2.5 8.5 4.2
OS (mos) 20.6 21.5
GERCOR study

28. Second- line chemotherapy
 If FOLFOX( or Capecitabine+ Oxaliplatin) plus
Bevacizumab was the first line regimen, the patient is
usually switched to FOLFIRI with or without
Bevacizumab.
 FOLFIRI+ Bevacizumab → FOLFOX( or
Capecitabine+ Oxaliplatin) with or without
Bevacizumab.
 Adding Cetuximab to Irinotecan can shrink tumors in
patients who stop responding FOLFIRI regimen.
 Cetuximab plus Irinotecan is used for third- line therapy
after failure of both FOLFOX and FOLFIRI.
 It is also used as second– line therapy if there is progression
on FOLFIRI plus Cetuximab.

29. New paradigm: continuum of care
 Exposure to all active agents and modalities
 Maximal Overall Survival and Quality Of Life by
minimizing toxicity and unnecessary treatment
No more distinct “lines of therapy”

30. Achievements in the first-line treatment of mCRC
BSC (1980s)
5-FU/FA (1990s)
FOLFOX, FOLFIRI
CT combination + MAbs
CT combination +
Tailored MAb therapy
0 6 12 18 24 30
Time (months)

31. CRC: Adenoma-Carcinoma Sequence
Normal Hyperproliferative
Adenoma Carcinoma
Colon Epithelium
APC Methylation APC KRAS 18q p53 Further
hMSH2 abnormalities hMSH2 mutation deletion deletion accumulation
hMLH1 hMLH1 of genetic
abnormalities inactivation abnormalities
(hereditary)
32% to 57%
KRAS mutant

32. Toward Personalized Therapy of CRC
Ligand:
AREG/EREG
Target for EGFR-ERBITUX
Target for EGFT-TK inhibitor EGFR-TK
pY GRB2
pY SOS
P13K pY RAS RAF
STAT MEK
AKT
PTEN
MAPK
Gene transcription
P Cell-cycle progression
P
MYC Cyclin D1
JUN FOS
MYC Cyclin D1
Proliferation/
maturation
Chemotherapy/ Survival
Invasion and
radiotherapy resistance Angiogenesis (anti-apoptosis)
metastasis

33. Toward Personalized Therapy of CRC
 EGFR antibodies
 KRAS and BRAF mutations correlate
with lack of response to treatment with
monoclonal antibodies targeting EGFR
 VEGF antibodies
 Patients who do not have a
contraindication may benefit from
bevacizumab, although no predictive
marker has been identified
 Combining EGFR and VEGF
antibodies
 Data do not demonstrate benefit

34. NCCN: KRAS Mutation Testing
Recommended to guide treatment plan
 KRAS codons 12 and 13
 Testing considerations
 Qualified laboratories
 Formalin-fixed paraffin-embedded tissue
 Primary tumor and/or the metastasis

35. NCCN: BRAF Mutation Testing
Not yet recommended, but noted in the guidelines
 Testing considerations
 Formalin-fixed paraffin-embedded tissues
 Typically PCR and direct DNA sequence analysis
 Qualified laboratories

36. Chemotherapy side effects
Drug Side effects
5-FU and Leucovorin Diarrhea, mucositis, temporary low
blood counts
Xeloda Hand- foot syndrome
diarrhea and mucositis
Irinotecan Diarrhea, low blood counts, fatigue,
hair loss

37. Chemotherapy side effects
Drug Side effects
Oxaliplatin Sensory neuropathy, acute paresthesias and
dysesthesias of the hands, feet and perioral
region, jaw tightness, and
pseudolaryngospasm
Avastin Increase BP, impair wound healing, bleeding,
bowel perforation(1.4~2%) and fistula formation,
proteinuria, thromboembolic events(4.5%):
stroke, heart attack
Erbitux Allergic reactions, skin rash, headache,
nausea, low blood magnesium

38. Duration of therapy
 Traditional practice – continue till
 Unacceptable toxicity
 Clinical deterioration or
 Disease progression
 Newer approach – discontinuation of treatment
after fixed time period

39. Treatment-Free Intervals
 Rationale
 Decrease intensity of therapy
 Reduce toxicity
 Prevent discontinuation of therapy
 Increase QOL
 Types of treatment breaks
 Treatment break with maintenance regimen
 Complete Chemotherapy-free intervals (CFI)

40. Metastatic CRC: Progress in OS
BSC 4–6 months
5-FU/AF 11–14.7 months
IFL or FOLFIRI 15–17.4 months
5-FU/AF + bevacizumab 18.3 months
FOLFOX4 or CapeOx 16.2–20 months
IFL + bevacizumab 20.3 months
FOLFOX6  FOLFIRI 20.6 months
Bevacizumab+ FOLFOX/CAPOX
21.3 months
FOLFIRI  FOLFOX6 21.5 months
Cetuximab + Std CT*0 23.5 months
* KRAS wild type patients 6 OS (months) 18
12 24

41. Assessment during therapy
 CT scan, PET ( every 2~3 cycles)
 CEA ( every 1~3months)
 Persistently rising CEA levels should prompt restaging, but
suggest disease progression and the need for an alternative
treatment strategy.
 Caution should be used when interpreting a rising CEA level
during the first 4 to 6 weeks of a new therapy, since spurious
early elevation in serum CEA may occur, especially after
Oxaliplatin.

42. Management of metastatic colorectal
cancer
General Principles
 Patients with mCRC, particularly those with liver or lung only metastases,
should be carefully evaluated upfront to determine the feasibility of curative
resection
 The current approach to the treatment of mCRC is to use various agents (5-
fluorouracil/leucovorin [5-FU/LV], capecitabine, irinotecan, oxaliplatin,
bevacizumab, cetuximab, and patitumumab) in combination or as single
agents
 FOLFIRI (infusional 5-FU, leucovorin, plus irinotecan) and FOLFOX
(infusional 5-FU, leucovorin, plus oxaliplatin) exhibit similar efficacy in
mCRC.
 5-FU/LV in patients who cannot tolerate intensive therapy , either may be
combined with bevacizumab

43. Unusual colorectal
tumors

44. Carcinoid tumors
 Neuroendocrine tumors
 More common in appendix and rectum
 Half are functional – MC produce seratonin
 Appendicial carcinoids
 < 1 cm – no risk of metastasis and managed with
appendectomy
 Tumors 1 – 2 cm – controversial
 > 2 cm – managed with formal right hemicolectomy
 Rectal carcinoids – typically not functional
 < 1 cm never metastasize – managed with local excision
or fulguration
 1 – 2 cm controversial
 > 2cm – more radical surgery

45. High grade neuroendocrine carcinoma
Extrapulmonary small cell
carcinoma
 Chest imaging always performed to
rule out mets from lung
 Nonspecific presentation and clinical
features similar to adenocarcinoma
 Distant spread common
 Recommendations extrapolated
from small cell lung cancer
 Combined modality treatment with
chemo and surgery

46. Lymphoma
 Majority non Hodgkins type
 Maybe low, intermediate or high grade
histology
 B cell diffuse large cell histology most
common
 Majority affect cecum or rectum
 Usually present with non specific
abdominal pain, rectal bleeding,
obstruction or a mass
 Diagnosis made n histology
 Work up – bone marrow biopsy, full body
scanning
 Treatment – combined modality with
chemotherapy and surgery
 Role of radiation therapy unclear

47. Conclusion
 Patients with mCRC, particularly those with
liver or lung only metastases, should be carefully
evaluated upfront to determine the feasibility of
curative resection
 The availability of multiple therapies and the
judicious use of surgery have improved
outcomes for metastatic CRC
 Use of these agents may soon be individualized
as data about predictive factors evolves