chemotherapy in cancer of colon, what chemo to be used when

1. ROLE OF CHEMOTHERAPY IN CA
COLON
DR ANIL GUPTA

2. INTRODUCTION
Globally, nearly 1,200,000 new CRC cases are believed to occur, which accounts
for approximately10% of all incident cancers, and mortality from CRC is estimated
at nearly 609,000.

Third most diagnosed malignancy in USA, responsible for nearly 10% of cancer
mortality.

Majority are sporadic cancers, familial CRC are 5% .

Causes includes high fat diet, smoking,sedentary lifestyle, obesity

Familial factors include hereditary nonpolyposis colorectal cancer(HNCC) (3%),
Familial adenomatous polyposis(FAP) (1%) hamartomatous polyposis syndromes
such as peutz jeughers syndrome, juvenile polyposis, cowden syndrome

Presenting features include lower GI bleeding, change in bowel habits, abdominal
pain,weight loss, change in appetite, and weakness, and in particular, obstructive
symptoms

Incidence : 35.8/100,000 (USA)

Developing countries < 10/100,000

India: incidence - 7/1,00,000

Median age of diagnosis- 62 yrs

3. STAGING OF COLON CA
85-
95%
30-
60%
5%
60-
80%

4. TheAstler-Coller MODIFICATION
Of historical intrest

5. AJCC TNM STAGING

AJCC 7th
edition

Adapted from Duke's staging

Same for both clinical and pathological staging

Not included are staging of appendix, anal CA,
neuroendocrine tumors of colon

Based on clinical-radiological and
histopatholgical findings

6. T STAGING

7. N STAGING

8. M STAGING

9. COMPOSITE STAGE
IN SITU
STAGE I
STAGE II
STAGE III
STAGE IV

11. PROGNOSTIC FACTORSin colon
cancer

12. Category
I Definitively proven to be of prognostic value based on evidence from
multiple statistically robust published trials and used in patient m a n a
management.
IIA Factors extensively studied biologically and/or clinically and repeatedly
shown to have prognostic value but that remains to be validated in
statistically robust studies.
IIB Factors shown to be promising in multiple studies but lacking sufficient
data for inclusion in category I or IIA.
III Factors not yet sufficiently studied to determine their prognostic value.
IV Includes factors well studied and shown to have no prognostic
significance.

13. Category I Prognostic factorsCategory I Prognostic factors

The local extent of tumor assessed pathologically

Regional lymph node metastasis

Blood or lymphatic vessel invasion ---> poorer prognosis

Residual tumor following surgery with curative intent

Preoperative elevation of carcinoembryonic antigen elevation ---> poorer
prognosis
Category IIA Prognostic factorsCategory IIA Prognostic factors

Tumor grade --> higher grade poorer prognosis

Radial margin status---> poorer prognosis

Residual tumor in the resection specimen following NACT
Category IIB Prognostic factorsCategory IIB Prognostic factors

Histological type ---> signet ring cell and small cell has poor prognosis

Histological features associated with microsatellite instability (MSI)

High degree of MSI (MSI-H),

Loss of heterozygosity at 18q
STAGE

14. Category III Prognostic factorsCategory III Prognostic factors

DNA content

All other molecular markers except loss of heterozygosity 18q/DCC and
MSI-H---> eg KRAS, C myc-->insufficient data

Perineural invasion

Microvessel density

Tumor cell–associated proteins or carbohydrates, peritumoral fibrosis,
peritumoral inflammatory response, focal neuroendocrine differentiation,
nuclear organizing regions, and proliferation indices
Category IV Prognostic factorsCategory IV Prognostic factors

Tumor size Not prognostic factors

Gross Tumor configuration.

15. MICROSATELITE INSTABILITY

Microsatelite instabilty(MSI)
is due to gain or loss of
repeat units

MSI is due to defective
repair gene eg. MLH-1 and
MSH2 gene

Known as MSI-H instabilty
phenotype

In 15% CRC MSI is found----
>a/w, peritumoral lymphocytic
infiltration bigger 1º, Node
-ve, better prognosis

85% CRC typically have
genetic alterations involving
loss of hetrozygosity,
chromosome amplifications

Known as microsatelite
stable tumors/MSS

Poor prognosis
Microsatelites are sections of DNA in which a short sequence of
nucleotides are repeated many times

16. 18q deletion

Allelic LOH>50% of CRC

Involves DCC gene, smad 2 & smad4

Watanabe et al(2006)
Allelic status of 18q Number (N) 5 yr survival
No loss 112 69
Loss 109 50
P=0.005

17. TUMOR BODY CONFIGURATION
Zlobec et al

18. MANAGEMENT OF COLON
CANCER

19. 
Surgery is the mainstay of management of colon cancer

Pedunculated polypPedunculated polyp- polypectomy

Sessile polypSessile polyp- segmental colon resection

Stage II or IIIStage II or III- colectomy with en bloc removal of
regional lymph nodes

Stage IV/RecurrentStage IV/Recurrent - Convert to resectable disease
f/b surgical debulking in selected
cases

20. RATIONALE FOR ADJUVANT
THERAPY

Routes of spread;- direct spread, transperiotoneal spread,
implantation, lymphatic spread, hematogenous spread and
venous extension

Cascade hypothesis- metastatic disease develops in discrete
steps, first to the liver, then to the lung, and finally to other sites

Stage I, II, III are at risk for having occult stage IV disease The
role of adjuvant therapy is to eradicate that microscopic
metastatic disease

Despite curative surgery half of these patients suffer incurable
tumor recurrence leading to cancer related death

Therefore there is a need of adjuvant therapy to improve
recurrence,DFS and OS

21. ADJUVANT CHEMOTHERAPY
THERAPY FOR CARCINOMA IN
SITU AND STAGE I

22. ADJUVANT THERAPY FOR
CARCINOMA IN SITU AND STAGE
I

After curative resection with negative CRM, 5yr
survival>95%

Local recurrence 0-3%
NO ADJUVANT THERAPY

23. MANAGEMENT OF CARCINOMA
IN SITU AND STAGE I

24. ADJUVANT CHEMOTHERAPY IN
STAGE II COLON CANCER

25. STAGE II COLON CANCER

Are at risk for having occult stage IV disease The role of
adjuvant therapy is to eradicate that microscopic metastatic
disease

5 yr survival rate after curative resection

Target of adjuvant chemotherapy is to prevent recurrence,
disease free survival and overall survival
T3N0M0 w/o high
risk factors
T3N0M0 with high
risk factors /T4N0M0
5 yr survival 70-80% 60-65%

26. OBSERVATION VS ADJUVANT
CHEMOTHERAPY
SEER-Medicare linkedSEER-Medicare linked database, Schrag et al (2002)database, Schrag et al (2002)
Erin S. O’Connor et al(2011)Erin S. O’Connor et al(2011)
IMPACT Metanalysis(1999)IMPACT Metanalysis(1999)
Arms Surgery only Adjuvant
chemotherapy
5 year survival 75% 78%
Arms Surgery only Adjuvant
chemotherapy
5 year survival 80% 82%
Arms Surgery only Adjuvant
chemotherapy
5 year survival 75% 78%
HIGH RISK FEATURES
- GRADE III OR IV
- LVI
- BOWEL OBSTRUCTION
- <12 LN DISSECTED
- PNI
- LOCALIZED PERFORATION
- UNDETERMINED OR POSITIVE

27. QUASAR (Quick and Simple and Reliable)(2007)

28. TRIAL WHICH SUPPORTED
ADJUVANT CHEMOTHERAPY IN
STAGE II COLON CANCER
NSABP
OBSERVATION 5-YEAR SURVIVAL IN 5-
FU+LV
62% 76%

29. ONGOING TRIAL

30. WHAT CHEMOTHERAPY SHOULD BE GIVEN??

31. Groups of Chemotherapy drugs in
Colon Cancer
ANTI-METABOLITES

5-Flourouracil

Capecitabine

Tegafur-uracil
PLATINUM COMPOUNDS

Oxaliplatin

CAMTOTHECIN
ANALOGUES

Irinotecan
MONOCLONAL
ANTIBODIES

Cetuximab

Pantimummab

Bevacizumab

TYROSINE KINASE
INHIBITORS

Regorafenib

32. 5-Fluorouracil

Virtually the entire history of chemotherapy for CRC has revolved around the
use of 5-FU.

Is a source of frustration and humility for investigators working to move
beyond it that over 50 years later this agent remains at the very core of most
chemotherapeutic approach

Developed by Heidleberger et al and patented in 1957.

Observed that tumor tissue used a larger amount of uracil than non tumor
tissues. He therefore substituted a fluorine atom at the number 5 position of
the uracil molecule

Cell cycle–specific with activity in the S-phase.

Requires activation to cytotoxic metabolite forms.

33. MOA
• Alterations in RNA processing and/or mRNA translation.
• Inhibition of DNA synthesis and function.
DISTIRBUTION
After IV administration, is widely distributed to tissues with highest
concentration in GI mucosa, bone marrow, and liver. Penetrates into
third-space fluid collections such as ascites and pleural effusions. Crosses
the blood-brain barrier and distributes into CSF and brain tissue.
METABOLISM
Undergoes extensive enzymatic metabolism intracellularly to cytotoxic metabolites.
Dihydropyrimidine dehydrogenase is the main enzyme responsible for 5-FU catabolism
Must be metabolized before it can exert cytotoxic activity
Greater than 90% of an administered dose of drug is cleared in urine and lungs.
The terminal elimination half-life is short, ranging from 10 to 20 min

34. TOXICITY

Myelosuppression- less frequently observed with infusional
therapy. Neutropenia and thrombocytopenia more common than
anemia.

Mucositis and/or diarrhea.-May be severe and dose-limiting for
infusional schedules. Nausea and vomiting are mild and rare

Hand-foot syndrome -

35. 
Neurologic toxicity manifested by somnolence, confusion,
seizures, cerebellar ataxia, and rarely encephalopathy

Cardiac symptoms of chest pain, EKG changes, are rare but
increased risk in patients with history of ischemic heart disease

Dry skin, photosensitivity, and pigmentation of the infused vein
are common.

Metallic taste in mouth during IV bolus injection.

Blepharitis, tear-duct stenosis, acute and chronic conjunctivitis

Metallic taste in mouth during IV bolus injection

36. Discussion of singleagent 5-FU
regimen
Leucovorin(Citrovorum factor/folinic acid/5-formyl tetrahydrofolate
enhances the antitumor activity and toxicity
RATIONALE FOR LEUCOVORIN ADDITIONRATIONALE FOR LEUCOVORIN ADDITION
It potentiates inhibitory effect of 5-FU on TS.It potentiates inhibitory effect of 5-FU on TS.

37. MAYO REGIMEN
D1-D5, 4 weekly 2
Cycles 5 weeks
thereafter
LEUCOVORIN
20mg/m2/d
5 FU
425mg/m2/d
bolus
Poon et al.1989

38. 
5-FU+low dose LV(20mg/m2) vs 5-FU+high dose LV(200mg/m2)
vs 5-FU+high dose MTX with LV rescue

Survival benefit is similar ,although 5 FU+low dose LV is a/w slightly
better survival
5-FU+low
dose LV
5-FU+high
dose LV
5-FU+MTX
with LV rescue
Median
survival
12.7 months 12.7 months 8.4 months
P<0.1

39. Toxicity
Conclusion- Established efficacy of 5FU with Leucovorin and
also concluded that it is not necessary to use high dose
leucovorin
5-FU+low
dose LV
5-FU+high
dose LV
5-FU+MTX with LV rescue
Leukopenia(
<2,000/ul)
22% 15% 14%
<4000/ul- 77%
Severe
Stomatitis
28% 28% -
Severe
Diarrhea
19% 16% -
Rate of
Hospitalizatio
n
15% 5.4% 6.5%

40. Roswell Park Regimen
2-hour iv infusion weekly for 6 consecutive
weeks (on days 1, 8, 15, 22,29 and 36
of the treatment cycle) f/b 2 week rest period
After 1 hour
IV bolus weekly for 6 consecutive
weeks (on days 1, 8, 15, 22,29 and 36 of the
treatment cycle) f/b 2 week rest period
Patients were to receive three 8-week cycles
of therapy for a total treatment duration of 24 weeks (6 months).
Haller et al,1998
LEUCOVORIN
(500mg/m2)
5 FLOUROURACIL
(500mg/m2)
Original 600mg/m2

41. Roswell Park Regimen Vs Mayo Regimen
Roswell Park regimen Mayo Regimen
Median response 24.8 wks 23.1 wks
Median survival
time
55.1 wks 54.1 wks
Median
progression free
intervals
29.3 wks 23.1 wks
Grade III diarrhea 36 pts 20 pts
Grade IV diarrhea 4 pts 3 pts

42. Bolus Vs Continuous Infusion vs
Intermittent Infusion

Preclinical evidence suggested that increased duration of exposure could
improve efficacy. Because the plasma half-life of 5-FU is short (8 to 20
minutes),
Protracted venous infusion (PVI)/ continuous infusionProtracted venous infusion (PVI)/ continuous infusion
5-FU 300 mg/m2/day by continuous infusion

A meta-analysis (1998) involving 1,219 patients in six trials reported an
improved response rate of 22% versus 14% in favor of PVI. Survival with
PVI 5-FU was statistically superior, but this survival advantage was less than
1 month.
Interrmittent InfusionInterrmittent Infusion

A larger phase III confirmatory trial compared the weekly high-dose infusion
of 2,600 mg/m2, either alone or with 500 mg/m2 of leucovorin, with the Mayo
Clinic bolus schedule of 5-FU. No overall survival differences were seen.

43. LV5FU2 REGIMEN
Both bolus and iv infusion form of 5FU
2 hr infusion D1, D2
D1, D2
22 hr infusion D1, D2
Over 12 cycles with a gap of 2 weeks
LEUCOVORIN
(200mg/m2)
5 FLOUROURACIL
(400mg)
5 FLOUROURACIL
(600mg/m2)
De Gramont et al,1997

44. LV5FU2 REGIMEN

Mayo regimen vs bimonthly LV+ 5 FU bolus and continuous
infusion
Mayo regimen LV5FU2
Response rate 14.4% 32.6%
Median PFS 22 wks 27.6 wks
Median
survival times
56.8wks 62wks
P=0.000
4
P=0.001
2
P=0.067

45. Conclusion- The bimonthly regimen (LV5FU2)was more effective
and less toxic than the monthly regimen and definitely increased
the therapeutic ratio. However, there was no evidence of
increased survival.
Mayo regimen LV5FU2
Grade 3-4 toxicities 23.9% 11.9%
Granulocytopenia 7.3% 1.9%
diarrhea 7.3% 2.9%
mucositis 7.3% 1.9%

46. CAPECITABINE
Is oral precursor of 5-FU
MOAMOA

Inhibition of the target enzyme thymidylate synthase (TS)

Alterations in RNA processing and/or mRNA translation.

Inhibition of DNA synthesis and function.
METABOLISMMETABOLISM
Dihydropyrimidine dehydrogenase is present in liver and extrahepatic tissues
such as GI mucosa, WBCs, and the kidneys catabolise into various
metabolites which clears through urine
ABSORPTIONABSORPTION
Readily absorbed by the GI tract. Peak plasma levels are reached in 1.5
hours, while peak 5-FU levels are achieved at 2 hours after
oraladministration. The rate and extent of absorption are reduced by food.

47. TOXICITY

Diarrhea is dose-limiting, observed in up to 55% of patients.

Hand-foot syndrome (palmar-plantar erythrodysesthesia). Severe hand foot
syndrome is seen in 15%–20% of patients.

Nausea and vomiting occur in 15%–53% of patients

Myelosuppression is observed less frequently than with IV 5-FU.
Leukopenia more common than thrombocytopenia.

Neurologic toxicity manifested by confusion, cerebellar ataxia, and rarely
encephalopathy.

Cardiac symptoms of chest pain, EKG changes, and serum enzyme
elevation. Rare event but increased risk in patients with prior history of
ischemic heart disease.

Tear-duct stenosis, acute and chronic conjunctivitis.

Elevations in serum bilirubin (20%–40%), alkaline phosphatase, and hepatic
transaminases (SGOT, SGPT). Usually transient and clinically
asymptomatic.

48. TEGAFUR-URACIL

Is oral precursor of 5-FU

Combination of two drugs--> Tegafur and Uracil (4:1 molar ratio)

Addition of uracil results in less neurotoxicity, more absorption

Similar toxic profiles as capecitabine

NSABP C-06- Similar efficacy as i.v LV/5 FU(roswell park regimen), both
are equitoxic

49. OXALIPLATIN

Platinum Analog

Cell cycle non-specific

MOA:- Inhibhits DNA synthesis

Widely distirbuted in body
ToxicityToxicity

Nausea/ vomiting 65% when used alone, 90% when used with
5FU/LV

Dose limiting- Neurotoxicity
Acute toxicity 80-85% pts- peripheral sensory neuropathy, distal
parasethesia within 1-3 days of therapy
Chronic toxicity- if cumulative dose >850 mg- impairment of
proprioception

Myelosupression

Should be used with precaution in abnormal renal function

50. IRINOTECAN

Trade name CPT-11/Camptosar

Topoisomerase I inhibitor

Inactive in its parent form, converted to SN-38 by enzyme carboxylesterase

Cell cycle–nonspecific agent with activity in all phases of the cell cycle

Rationale for use in CRC- Colorectal tumors express higher levels of
topoisomerase I than normal colonic mucosa

Given via I.V route
TOXICITY

Highly emetogenic

Early diarrhea- <24 hrs of adminstration

Late diarrhea- >24 hrs of adminstration

Moderate vesicant

Myelosupression
When to start?????

51. DOES TIMING MATTER?

Traditionally, should be started within 8 weeks of
surgery.

Guts et alGuts et al: Meta-analysis of pooled data of 13,158
patients concluded delaying treatment causes inferior
survival (RR=1.20)

Czaykowski et alCzaykowski et al: Concluded that delaying adjuvant
chemotherapy beyond 8 to 10 weeks appears to be
associated with diminished benefit.
CONSENSUS- Should be started within 8 weeks, if no
surgical/medical contraindications
For what duration it should be given???

52. OPTIMAL DURATION OF
ADJUVANT CHEMOTHERAPY

INT-0089(2005)INT-0089(2005) - The Intergroup study showed equivalence
between 6 months of LV/5-FU and12 months
of 5- FU/levamisole adjuvant chemotherapy

GERCOR trial(2007)GERCOR trial(2007)- 6 months of chemotherapy achieved
similar results than 9 months of the same
chemotherapy
A 6-month chemotherapy duration
became, and still is, the standard.

53. STAGE II CANCER
NCCN

54. ADJUVANT CHEMOTHERAPY IN
STAGE III CANCER

55. MOSAIC TRIAL

56. MOSAIC TRIAL SCHEME
R
A
N
D
O
M
I
Z
A
T
I
O
N
FOLFOX4
LV5FU2
N=1123
N=1123
SII-40%
SIII-60%
Oxaliplatin 85mg/m2 on D1 with
LV via Y-conncetor, LV5FU2

57. MOSAIC TRIAL RESULTS
3 YR OVERALL
SURVIVAL
FOLFOX4 LV5FU2
ALL PATIENTS 77.9% 72.8%
STAGE II
PATIENTS
86.6% 83.9%
STAGE III
PATIENTS
71.8% 65.5%

58. ADVERSE EFFECTS
FOLFOX-4 LV5FU2
Grade 3-4
neutropenia
41% 5%
Neutropenic fever 1% 0%
Grade 3-4
diarrhea
1% 0%
Grade 3-4
vomiting
11% 7%
Neuropathy, any
grade
92% 0%
Neuropathy,
grade 3
12% 0%
Persistent
neuropathy, grade
2-3, 1 year after
t/t
5% 0%

59. DIFFERENT FOLFOX REGIMENS

60. mFOLFOX6

61. FOLFIRI Regimen

LV5FU2 + Irinotecan (180 mg/m2 as a 30- to 90-minute
infusion, day 1, every 2 weeks)
More dropouts
More neutropenia
UGTA1A1 Polymorphism
3yr DFS(%)
5FULV2 FOLFIRI
ACCORD II 60 51
PETACC 3(2009) 59.9 62.9

62. XELOX REGIMEN
XELOX FOLFOX 6
3 yr OS 86.9% 87.2%
3 yr DFS 79.8% 79.5%
Pectasides et al, 2010

63. STAGE III

64. CHEMOTHERAPY IN
METASTATIC/RECURRENCE
COLON CANCER

65. RECURRENCE
Serial elevation/ symptomatic
Suspect recurrence
Workup
Documented metachronus metastases
Resectable Unresectable

Resection adjuvant chemotherapy Convert to resectable

NACT resection adjuvant chemotherapy

66. UNRESECTABLE METASTATIC
DISEASE

Is generally not curable with current technology

Management centers around palliation and control of
symptoms, control of tumor growth, and attempts to lengthen
progression-free and overall survival.

For palliation risk vs benefit ratio should be taken into account

QOL should be discussed with patient and caregiver

End point of palliative treatment should be good quality of life
and if possible convert unresectable to resectable.

Surgical intervention can be a very effective method of
palliation and is often indicated in cases of impending
obstruction, perforation, bleeding, or pain, however a/w more
morbidity

NSABP C-10 concluded that good performance status patients
with asymptomatic primaries can be spared initial non curative

67. SINGLE AGENT CHEMOTHERAPY
N RR PFS OS
LV5FU2 175 32.6 6.9 month 15.5 month
CAPE 603 26 4.6 month 12.9 month
Bolus FU/LV 604 17 4.7 month 12.8 month
Van Cutsem et al, 2004- Pooled data

68. SINGLE AGENT CHEMOTHERAPY

LV5FU2 better tolerated (less granulocytopenia, diarrhea and mucositis)
and more efficacious than bolus 5 FU (de Gramont et al,1997)

Oral CAPE is superior to bolus 5 FU in first line setting( improved RR, less
diarrhea, nausea, stomatitis, alopecia, fewer hospitalizations) but more
hyperbilirubinemia and hand foot syndrome ( Van Cutsen et al,2004)

CAPE similar to infusional 5 FU in metastatic setting(Cassidy et al
metanalysis,2011)

Adding LV with 5 FU increases OS but high dose LV has no extra
benefit(NCCTG, 1989)

No obvious benefit of adding LV to protracted 5 FU(SOCG study,1995)

Single agent oxaliplatin and Irinotecan has limited role in first line setting
(Diaz-Rubio et al,1998;Saltz et al ,1998)
With singlet chemotherapy patient can expect 15% to 20%
RR, median PFS 5 to 6 months ,median OS 10 to 14
months

69. DOUBLET CHEMOTHERAPY

Combination of 5 FU with Oxaliplatin or Irinotecan has improved RR, OS,
PFS but with more toxicity (de Gramont et al,2000)

CAPOX has similar efficacy to FOLFOX and acceptable safety
profile.FOLFOX has mor e neutropenia, CAPOX has more diarrhea
(N016996,2011)

FOLFIRI a/w longer PFS than IFL, but less tolerable regimen, no longer
used(NAI trial,2006)

FOLFOX, CAPOX has similar efficacy(GERCOR study,2004)
With doublet chemotherapy patient can expect 40% to 50%
RR, median PFS 8 to 9 months ,median OS 16 to 19
months

70. TRIPLET CHEMOTHERAPY

FOLFOXIRI – role remains controversial

FOLFOXIRI compared with FOLFIRI by

Irinotecan 165 mg/m2 day 1, oxaliplatin 85 mg/m2 day 1, leucovorin
200mg/m2 day 1, fluorouracil 3,200 mg/m2 48-hour continuous infusion
starting on day 1, every 2 weeks
N RR(%) PFS(months) OS
(months)
Reference
FOLFOXIRI 122 60 9.8 22.6 Falcone et al,2007
FOLFIRI 122 34
P<0.0001
6.9 P<0.0006 16.7
P=0.32
FOLFOXIRI 137 43 8.4 21.5 Souglakos et al, 2006
FOLFIRI 146 33.6 6.9 19.5

71. Better results but poor tolerability
ewf
N Febrile
neutropenia
Diarrhea Stomatitis Neurot
oxicity
Refernce
FOLFIRI 122 28 11 3 0 Falcone et
al,2007
FOLFOXIRI 122 50 20 5 2
FOLFIRI 147 28 11 0 0 Souglakos et al,
2006
FOLFOXIRI 138 35 28 6 6

72. TARGETED THERAPY

Monoclonal antibodies against EGFR

Monoclonal antibodies against VEGF

Multiple tyrosinase kinase inhibitor

73. VEGF
VEGF
receptor-2
Cation channel
 Permeability
Antibodies inhibiting VEGF
(e.g. bevacizumab)
Antibodies inhibiting
VEGF receptors
Soluble VEGF receptors
(VEGF-TRAP)
Small-molecules
inhibiting VEGF receptors (TKIs)
(e.g. PTK-787)
Ribozymes
(Angiozyme)
– P
– PP–
P–
– P
– P
P–
P–
–
– P
P–
P–
Migration, permeability, DNA synthesis, survival
LymphangiogenesisAngiogenesis
Agentstargeting theVEGF pathway

74. EGFR EXPRESSION

EGFR is involve in progression of mCRC

EGFR is expressed in 75-89% of mCRC

Expression is associated with shorter survival

Monoclonal antibodies have been developed against
EGFR receptors

Inhibition of EGFR signaling pathway results in inhibition of
critical mitogenic and anti-apoptotic signals involved in
proliferation, growth, invasion ,metastasis, angiogenesis

Inhibition also enhances response to chemo/radiation
therapy

Only for wild KRAS type

75. EGFR INHIBITORS
CetuximabCetuximab (ERBITUX)(ERBITUX)

Chimeric antibody

Precise MOA unknown, causes EGFR inhibition

Has nearly 10 fold higher affinity to EGFR than other ligands

400 mg/m2 IV first infusion given over 2 hours, then 250
mg/m2 weekly or 500 mg/m2 IV every 2 weeks

Infusional related toxicity more
PanitumumabPanitumumab (VECTIBIX)(VECTIBIX)

Fully humanised antibody

40 fold affinity to EGFR

6 mg/kg IV over 60 minutes every 2 weeks

Lower infusion related toxicity
ASPECCT STUDY(2014)ASPECCT STUDY(2014)
Panitumumab vs
Cetuximab
Median OS 10.4 months vs
10 months
Similar toxicity profile but
lesser infusion reaction 3%
vs 14%

76. DOUBLET CHEMOTHERAPY +
EGFR INHIBITOR
CRYSTAL Trial- FOLFIRI+ Cetuximab
Patients with previously untreated EGFR-expressing metastatic
colorectal cancer
The addition of cetuximab to FOLFIRI as first-line therapy improves
survival in patients with KRAS wild-type mCR

77. TRIPLET CHEMOTHERAPY + EGFR
INHIBITOR
Folprecht et al, 2010Folprecht et al, 2010
20 patients
FOLFOXIRI+ Cetuximab

RR 75%

PFS 16 months

Median OS 33 months

Median time to response 3 months- potential value for
neoajuvant setting

78. DOUBLET CHEMOTHERAPY +
PANITUMUMAB
PRIME STUDY(2010)PRIME STUDY(2010)
FOLFOX4+Panitumumab vs FOLFOX
Median OS 19.3 months vs 15.5 months wild KRAS
PFS 9.6 months vs 8 months

79. TRIPLET CHEMOTHERAPY +
panitumumab
Fornaro et al, 2013
37 patients
FOLFOXIRI+Panitumumab

RR 89%

Median PFS 11.3 months

Neutropenia 48%

Diarrhea 35%

Asthenia 27%

Stomatitis 14%
Further trials required

80. VEGF EXPRESSION

Is a predominant angiogenic factor in CRC

70% percent of patients with stage IV CRC had positive VEGF-
1 expression

While 50% and 47%, respectively of patients with stage II and
III CRC had positive VEGF-1 expression

Patients who died of the disease more frequently had a VEGF-
1-expressing tumour than did those who survived for 10 years
Bendardarf et al(2008)

81. VEGF INHIBITORS
BevacizumabBevacizumab (AVASTIN)(AVASTIN)

Recombinant humanized monoclonal antibody directed against
the VEGF

Binding to VEGF prevents subsequent interaction with its
receptors subsequently inhibiting VEGFR signalling

Inhibits formation of new blood vessels in primary tumor and
metastatic tumors

With FOLFOX it is given as 10mg/kg infusion after a test dose

May cause thromboembolic events,GIT perforations, wound
healing complications, hpertension or nephrotic syndrome,
Reversible posterior leukoencephalopathy syndrome (RPLS)

82. DOUBLET CHEMOTHERAPY+
VEGF INHIBITOR
E3200E3200: Response Rates
FOLFOX+ BEVACIZUMAB
FOLFOX+Bevaci
zumab
FOLFOX Bevacizumab alone
10mg/kg
OR 21.8% 9.2% 0%
CR 1.9% 0.7% 0%
FOLFOX+B vs FOLFOX: P < 0.0001
Giantonio BJ, et al. ASCO 2005

83. TRIPLET CHEMOTHERAPY+ VEGF
INHIBITOR
TRIBE STUDYTRIBE STUDY
FOLFIXIRI+BEVACIZUMAB vs FOLFIRI+BEVACIZUMAB

RR 65% vs 53%

PFS 12.2 months vs 9.7 months P=0.0012

More neutropenia

More diarrhea

More stomatitis
Needs Further study

84. SOLUBLE VEGF RECEPTORS
Ziv-afliberceptZiv-aflibercept (ZALTRAP)(ZALTRAP)

Binds to human VEGF-A and VEGF-B

Results in inactivation of these growth factors thus causing
decreased neovascularisation and vascular permeabeality

Approved as 4mg/kg 1 hr i.v infusion every 2 weeks just
before FOLFIRI regimen for mCRC

Has serious adverse effects fistula formation,
thromboembolic events, proteinuria, neutropenia,diarrhea,
reversible posterior leukoencephalopathy syndrome

85. FOLFIRI+ZIV-AFLIBERCEPT
Randomized study done in patients with mCRC where
FOLFOX±bevacizumab already tried and it progressed within 6
months

87. MULTIPLE TYROSINASE KINASE
INHIBITOR
RegorafenibRegorafenib (STIVARGA)(STIVARGA)

MOA: Inhibition of neoangiogenesis, inhibition of proliferation by
acting on VEGFR1-3 TIE2 receptors

Given as 160mg/day D1-D21 oral tablets
CORRECT Trial;-CORRECT Trial;-
Regorafenib vs placebo:

OS: 6.4 vs 5.0 months, HR=0.77, p=0.0052(17%), grade III
fatigue (10%)

88. DOUBLE TARGETED THERAPY+
CHEMOTHERAPY
CAIRO-2- Randomized phase III Trial

No increase in GI toxicity

Skin related toxicity increased
N RR(%) PFS(month) OS(month)
CAPOX +
Bevacizumab
378 50 10.7 20.3
CAPOX +
Bevacizumab+
cetuximab
377 52.7 9.4 19.4

89. IF RECURRENCE IN <12 MONTHS
Chemotherapy
for
metastatic
disease

90. CHEMOTHERAPY FOR
METASTATIC DISEASE
For patient appropriate for intensive therapy
Single agentSingle agent
cetuximab/cetuximab/
panitumumabpanitumumab
/regorafenib/regorafenib
VsVs
clinical trialclinical trial
VsVs
best supportive carebest supportive care
Initial therapy 1st
progression 2nd
progression

91. If patient is not appropriate for intensive therapy
CHEMOTHERAPY FOR
METASTATIC DISEASE

92. This heterogeneous group of metastatic colon cancer patients,
which had been given various modalities of treatment, could be
able to achieve a median survival of around 18 months and 2
year PFS of 28%.
Conclusion: So metastatic colon cancer is no longer an acutely
fatal disease, rather it is in the ambit of chronic disease.

93. MANAGEMENT OF DRUG
TOXICITY
5 FLUOROURACIL/ CAPECITABINE/ TEGAFUR5 FLUOROURACIL/ CAPECITABINE/ TEGAFUR

Hand and foot syndrome- Vitamin B6 /pyridoxine,Celecoxib ,low-dose
nicotine patch , moisturizer

Mucositis- Use of ice chips in mouth 10–15 minutes pre- and 10–15
minutes post-IV bolus injections of 5-FU may reduce the incidence and
severity of mucositis

Unexpected severe myelosupression, GI toxicity, Cardiac toxicity -can be
due to deficiency of dihydropyrimidine dehydrogenase. Immediately stop
treatment.
OXALIPLATINOXALIPLATIN

Neurotoxicity- Reversible on discontinuation for 3 to 4 months
IRINOTECANIRINOTECAN

Diarrhea- Inj.atropine 0.25mg to 1mg, stoppage of treatment beyond
gradeIII diarrhea, no laxatives to be used, loperamide, iv antibiotics,
adequate rehydration

94. CETUXIMABCETUXIMAB

Infusion related toxicity- test dose should be give, inj avil, inj dexa should be
given, inj adrenaline should be kept prepared
BEVACIZUMABBEVACIZUMAB

Thromboembolic events- drug not to be given in age >65 years and history
of angina, stroke, and prior arterial thromboembolic events

GI perforations- drug should be given only after 28 days of surgical
intervention, in liver resection should be given after 6-8 weeks

Hypertension- Anti hypertensive drugs, should be permanently discontinued
in uncontolled hypertension

Reversible posterior leukoencephalopathy sundrome (RPLS)- self limiting

95. INVESTIGATIONAL ADJUVANT
THERAPIES

Intra hepatic artery chemotherapy(IAHC)

Portal vein infusion

Intraperitoneal chemotherapy

Vaccines

Edrecolomab

96. INTRA ARTERIAL HEPATIC
CHEMOTHERAPY(IAHC)

Liver mets derive their blood supply predominantly from hepatic
arteries

Wheras normal liver parenchyma has a predominant portal vein
supply

IAHC aims to increase drug concentration in liver mets, therby
improving response rates

Kemeny et al, 2009
IAHC with oxaliplatin 100mg/m2 with i.v LV5FU2 regimen used in
36 pts with extensive non resectable metastasis, found to have
overall response of 90% with 40% downstaged to R0 resection

97. PORTAL VEIN INFUSION

Tumors less than 5 mm in diameter obtain substantial portions of their blood
supply from both the hepatic and portal circulations

Substantially higher doses of 5-FU can be safely given by intraportal than
by intravenous infusion

Metanalysis- 4% improvement in 5 yr survival with portal vein infusion

At present, intraportal adjuvant chemotherapy should remain limited to
clinical investigations

98. INTRAPERITONEAL
CHEMOTHERAPY

The peritoneal cavity is drained by portal lymphatics into the portal vein

High concentrations of drug to the portal circulation can be delivered,
without the need for portal vein canalization

Pharmacokinetic studies of intraperitoneal 5-FU and floxuridine show that
intraperitoneal administration of these agents results in intraperitoneal
concentrations 200- to 400-fold higher than those achieved systemically

Scheithaueret et al- A randomized trial of 241 pts done ---> No benefit seen
in IInd stage colon cancer, however, a 43% reduction in mortality was seen in
stage III

Needs further study

99. VACCINES

Stimulate the patient's immune system to recognize and eradicate the
patient's tumor cells

CEA is a commonly expressed antigen in colorectal carcinomas, However it
is not very immnunogenic

Vaccines has been developed against CEA---> ALVAC-CEA B7.1, ALVAC-
KSA

Administration of ALVAC-CEA B7.1 has been shown to induce CEA-specific
T-cell response in patients with advanced adenocarcinoma when given alone

ALVAC-KSA developed a weak T-cell response

Use of vaccine therapy for treatment of resected colon cancer remains
highly investigational

100. EDRECOLOMAB

Murine monoclonal IgG2a antibody directed against the cell
surface glycoprotein 17-1A

Shown in nude mice to inhibit growth of human colon cancer
xenografts

An initial trial in patients with metastatic disease revealed
several minor responses with remarkably little toxicity

A total of 166 patients were randomized to edrecolomab at a
dose of 500 mg by 1-hour infusion 2 weeks after surgery, and
then 100 mg during 1 hour given every 4 weeks for four doses,
or to surgery only

This small trial showed a 32% reduction in mortality for the
edrecolomab arm at a median follow-up of 7 years

Similar results not found in larger studies

101. CONCLUSION

Stage II, III are at risk for having occult stage IV disease The
adjuvant therapy is to eradicate that microscopic metastatic diseasemicroscopic metastatic disease

Most effective regimen are based on 5 Flourouracil

Stage IStage I- No adjuvant therapy

Stage IIA with no high risk factorStage IIA with no high risk factor- Observation> 5FU+LV regimen

Stage IIA with high risk factor, IIB, IICStage IIA with high risk factor, IIB, IIC- 5FU+LV regimen

Stage IIIStage III- FOLFOX regimen

Recurrence/Stage IVRecurrence/Stage IV- For Palliation intentFor Palliation intent
Good performance status- FOLFOX± Targeted therapy
Poor performance status – 5FU+LV regimen/ best supportive care
Better patient selection- avoid unnecessary toxicity

There is scope for improvement, participation in clinical trials is
encouraged