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management of metastatic colorectal cancer
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
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)
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
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