ROLE OF CHEMOTHERAPY IN CA COLON

DR ANIL GUPTA

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

STAGING OF COLON CA

85-95%

30-60%

5%60-80%

The Astler-Coller MODIFICATION

Of historical intrest

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

T STAGING

N STAGING

M STAGING

COMPOSITE STAGE

IN SITU

STAGE I

STAGE II

STAGE III

STAGE IV

PROGNOSTIC FACTORS in colon cancer

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.

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

Tumor border configuration (infiltrating vs pushing border).

STAGE

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.

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

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

TUMOR BODY CONFIGURATION

Zlobec et al

MANAGEMENT OF COLON CANCER

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/Recurrent Stage IV/Recurrent - Convert to resectable disease

f/b surgical debulking in selected

cases

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

ADJUVANT CHEMOTHERAPY THERAPY FOR CARCINOMA IN

SITU AND STAGE I

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

MANAGEMENT OF CARCINOMA IN SITU AND STAGE I

ADJUVANT CHEMOTHERAPY IN STAGE II COLON CANCER

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%

OBSERVATION VS ADJUVANT CHEMOTHERAPY

SEER-Medicare linked SEER-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 CRM

QUASAR (Quick and Simple and Reliable)(2007)

TRIAL WHICH SUPPORTED ADJUVANT CHEMOTHERAPY IN

STAGE II COLON CANCERNSABP

OBSERVATION 5-YEAR SURVIVAL IN 5-FU+LV

62% 76%

ONGOING TRIAL

WHAT CHEMOTHERAPY SHOULD BE GIVEN??

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

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.

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

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 -

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

Discussion of single agent 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.

MAYO REGIMEN

D1-D5, 4 weekly 2 Cycles 5 weeks thereafter

LEUCOVORIN20mg/m2/d

5 FU425mg/m2/d bolus

Poon et al.1989

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 monthsP<0.1

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 Hospitalization

15% 5.4% 6.5%

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

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

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.

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

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=0.0004P=0.0012P=0.067

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%

CAPECITABINEIs 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 oral\administration. The rate and extent of absorption are reduced by food.

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.

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

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

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?????

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???

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.

STAGE II CANCER

NCCN

ADJUVANT CHEMOTHERAPY IN STAGE III CANCER

MOSAIC TRIAL

MOSAIC TRIAL SCHEME

RANDOMIZATION

FOLFOX4

LV5FU2

N=1123

N=1123

SII-40%SIII-60%

Oxaliplatin 85mg/m2 on D1 with LV via Y-conncetor, LV5FU2

MOSAIC TRIAL RESULTS3 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%

ADVERSE EFFECTSFOLFOX-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%

DIFFERENT FOLFOX REGIMENS

mFOLFOX6

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

XELOX REGIMEN

XELOX FOLFOX 6

3 yr OS 86.9% 87.2%

3 yr DFS 79.8% 79.5%

Pectasides et al, 2010

STAGE III

CHEMOTHERAPY IN METASTATIC/RECURRENCE

COLON CANCER

RECURRENCE Serial elevation/ symptomatic

Suspect recurrence

Workup

Documented metachronus metastases

Resectable Unresectable

Resection adjuvant chemotherapy Convert to resectable

NACT resection adjuvant chemotherapy

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 resection of their primaries

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

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

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

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

Better results but poor tolerability

ewf

N Febrile neutropenia

Diarrhea Stomatitis Neurotoxicity

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

TARGETED THERAPY Monoclonal antibodies against EGFR Monoclonal antibodies against VEGF Multiple tyrosinase kinase inhibitor

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– P–

Migration, permeability, DNA synthesis, survival

LymphangiogenesisAngiogenesis

Agents targeting the VEGF pathway

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

EGFR INHIBITORSCetuximabCetuximab (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 CetuximabMedian OS 10.4 months vs 10 monthsSimilar toxicity profile but lesser infusion reaction 3% vs 14%

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

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

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

TRIPLET CHEMOTHERAPY + panitumumab

Fornaro et al, 201337 patients

FOLFOXIRI+Panitumumab

RR 89%

Median PFS 11.3 months

Neutropenia 48%

Diarrhea 35%

Asthenia 27%

Stomatitis 14%

Further trials required

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)

VEGF INHIBITORSBevacizumabBevacizumab (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)

DOUBLET CHEMOTHERAPY+ VEGF INHIBITOR

E3200E3200: Response Rates

FOLFOX+ BEVACIZUMAB

FOLFOX+Bevacizumab

FOLFOX Bevacizumab alone10mg/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

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

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

FOLFIRI+ZIV-AFLIBERCEPT

Randomized study done in patients with mCRC where FOLFOX±bevacizumab already tried and it progressed within 6 months

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%)

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

IF RECURRENCE IN <12 MONTHS

Chemotherapy for metastatic disease

CHEMOTHERAPY FOR METASTATIC DISEASE

For patient appropriate for intensive therapy

Single agent Single agent cetuximab/ cetuximab/

panitumumabpanitumumab

/regorafenib/regorafenib

VsVs

clinical trialclinical trial

VsVs

best supportive carebest supportive care

Initial therapy 1st progression 2nd progression

If patient is not appropriate for intensive therapy

CHEMOTHERAPY FOR METASTATIC DISEASE

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.

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

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

INVESTIGATIONAL ADJUVANT THERAPIES

Intra hepatic artery chemotherapy(IAHC) Portal vein infusion Intraperitoneal chemotherapy Vaccines Edrecolomab

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

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

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

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

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

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