Dr. Iain Tan -...

ESMO-ASIA 2017 Preceptorship (GI cancers)

Session: Metastatic colorectal cancer, liver limited metastases

Topic: Unresectable or borderline resectable : chemotherapy +/- targeted agents

Dr. Iain Tan

Senior Consultant GI Medical Oncologist

National Cancer Centre Singapore

1. The case for aggressive therapy in borderline resectable / unresectable liver limited metastases

2. Components Multidisciplinary / Multi-modality management

3. Chemotherapy & Targeted Therapy prior to surgery

4. Chemotherapy & Targeted Therapy after surgery

5. The left and right issue

6. How I choose systemic therapy in borderline resectable/unresectable

ESMO-ASIA 2017 Preceptorship (GI cancers)Session: Metastatic colorectal cancer, liver limited metastases


OUTLINE

Overall survival for patients with mCRC treated at MD Anderson and Mayo clinics, by year of diagnosis

Over the past decade, OS has improved substantially in patients with mCRC

• 2470 patients from two highly specialized centers were included

0 60483624120

20

40

60

80

100

Time (months)

OS

(%)

1990–19911992–19941995–19971998–20002001–20032004–2006

Kopetz S, et al. J Clin Oncol 2009;27:3677–3683

Multiple active systemic agents in mCRC

Overall Survival (months)

5-FU/LV bolus

5-FU/LV infusion

IFL

LVFU2/irinotecan

FOLFOX

IFL + bevacizumab

FOLFOX/FOLFIRI

XELOX/FOLFOX + bevacizumab

FOLFOX + cetuximab

FOLFIRI + cetuximab

FOLFOX + panitumumab

FOLFIRI + cetuximab

FOLFOXIRI + bevacizumab

*KRAS wildtype tumors.Note: Informal comparison as these are not head-to-head clinical trials.

1. Saltz. N Engl J Med. 2000; 2. Douilliard. Lancet. 2000; 3. Goldberg. J Clin Oncol. 2004; 4. Hurwitz. N Engl J Med. 2004; 5. Saltz. J Clin Oncol. 2008; 6. Falcone. J Clin Oncol. 2007; 7. Bokemeyer. Ann Oncol. 2011; 8. Van Cutsem. J Clin Oncol. 2011; 9. Douilliard. ASCO; 2011. Abstract 3510. 10.

Heinemann. ASCO 2013. Abstract LBA3506. 11. Falcone. ASCO 2013. Abstract 3505.

Treatment Approaches to First-Line mCRC

2000

2013

2011

2011

2008

2007

2004

2004

2000

2000

2000

2011

2013

2013

FOLFIRI + bevacizumab

ORR PFS PFS

HR

OS OS

HR

AVF2107g IFL 35% 6.4 15.6

+ Bevacizumab 45% 10.6 0.54 20.3 0.66

PRIME FOLFOX 7.9 20.2

+ panitumumab 10.1 0.72 26 0.72

CRYSTAL FOLFIRI 8.4 20.2

+ Cetuximab 11.4 0.56 28.4 0.69

TRIBE FOLFIRI/Bev 53% 9.7 25.8

FOLFOXIRI/Bev 65% 12.1 0.75 31 0.79

FIRE3 FOLFIRI/Bev 56% 10.2 25

FOLFIRI/Cet 71% 10.4 0.93 33.1 0.7

CALGB Chemo + Bev 57% 11.3 31.2

Chemo + Cet 69% 11.4 1.1 32 0.9

Landmark 1st line CRC studies

CORRECT

(3rd line) Regorafenib Placebo

HR

[n=760] p-value

Median PFS 1.9 mo 1.7 mo 0.49 <0.000001

Median OS 6.4 mo 5.0 mo 0.77 0.0052

VELOUR

(2nd line)

Placebo +

FOLFIRI

(n = 614)

Aflibercept +

FOLFIRI

(n = 612)

Hazard

ratio p-value

Median OS 12.1 mo 13.5 mo 0.82 0.0032

Median PFS 4.7 mo 6.9 mo 0.76 0.00007

Overall response 11.1% 19.8% — 0.0001

RECOURSE

(3rd line)

TAS-102

(n=534)

Placebo

(n=266) HR p-value

Median PFS 2.0 mo 1.7 0.48 <0.0001

Median OS 7.1 mo 5.3 mo 0.68 <0.0001

Low disease burden, generally with a single solitary site of spread

Stage 4 Colorectal Cancer is a Continuum of disease

Less extensive More extensive

Low disease burden, generally with a single solitary

site of spread


Chemotherapy & Surgical removal of the site of metastasis with the intention of achieving cure


Chemotherapy to reduce size of metastases with the intention of to convert to a situation where surgery becomes feasible

intermediate disease burden,

generally not operable upfront but with limited disease

spread


Chemotherapy to control tumor, improve symptoms, maintain quality of life and prolong life

Liver resection improves long-term survival

• 12-month landmark analysis evaluated the impact of liver resection on OS

70% of population included

Patient

status

Median

OS (mo)

5-year

OS rate

Resected 65.3 55%

Non

resected26.7 19.5%

HR 0.35

Liver resection dramatically improves long-term survival and offers a real chance for cure

Time (months)

012 24 36 48 60 72

20

40

60

80

100

Ove

rall

surv

ival

(%

)

Lan

dm

ark

No liver resection

Liver resection

0

Kopetz S, et al. J Clin Oncol 2009;27:3677–3683

Error bars represent 95% CIs

Simmonds PC, et al. Br J Cancer. 2006;94:982–99

Kanas GP, et al. Clin Epidemiol 2012;4:283–301;

Adam R. 2009

New definition of resectability

• All liver metastases that can be completely removed while leaving at least 30% of remnant liver...

• Even in cases with extrahepatic tumors, if these are also resectable…

‘Practical’ rather than ‘dogmatic’

• Easily resectable: – Complete resection with good margins

• Marginally resectable: – No margins, small liver remnant– Concomitant extrahepatic (resectable)

• Definitely non-resectable: – Widespread hepatic disease– Non-resectable extrahepatic– Multiple metastatic sites

In practice: 3 categories of patients

Strategies Liver metastases

resectable

neo CT +Liver resection

non optimal resectable

> 4 Metastases

synchronous CRCLM

Primary LN-positive

bilobar CRCLM

technically problematic:

Close to 3 hepatic veins

Close to portal bifurcation

Neoadjuvant Chemotherapy→ Operation

Primaryunresectable

PalliativeChemotherapy

possible






6. How to choose systemic therapy



OUTLINE

Components of Multidisciplinary / Multi-modality management

• Neoadjuvant systemic therapy

• Staged hepatectomy

• Portal vein embolization (PVE)

• Portal vein ligation (PVL)

• Radioembolization

• Locoregional ablative therapies

• Advanced imaging

The impact of a multidiscplinary team approach

in the treatment of colorectal cancer withliver metastases:

Liver-limited metastatic colorectal cancer as a curable disease

The multidisciplinary team









OUTLINE

General principles of systemic chemotherapy in borderline / unresectable liver-limited mCRC

• Give the most active regimen• Goal of treatment

– Achieve R0 resection; maximum tumor shrinkage– Early management of unseen micrometastases

• Consider surgery once it is resectable– Achieve resectability rather than a CR

• If convertible to surgery, – Sequencing of the different procedures– Management of the primary – role of post-operative chemotherapy

Resection rate of metastases and tumor response

Studies including non-selected patients with mCRC (solid line) (r=0.74; p<0.001)

Studies including selected patients(liver metastases only, no extrahepatic disease)(r=0.96; p=0.002)

Phase III studies including non-selected patients with mCRC (dashed line)(r=0.67; p=0.024)

Folprecht G, et al. Ann Oncol 2005;16:1311–1319

Response rate

0.90.80.70.60.50.40.3

Re

sect

ion

rat

e

0.6

0.5

0.4

0.3

0.2

0.1

0

Jones R et al. Eur J Cancer, 2014

When to send for surgery?

• Achieve resectability rather than a CR

• 83% of lesions that disappear whilst on chemotherapy are still active

• Need to resect before metastases completely disappear

Chemotherapy:The use of triplets

PFS 10 m vs 7 m

OS 23 m vs 17 m

+ Greek Study (R0 resectn)

Chemotherapy:The use of triplets

ORR PFS PFS

HR

OS OS

HR

AVF2107g IFL 35% 6.4 15.6

+ Bevacizumab 45% 10.6 0.54 20.3 0.66

Targeted Therapy:The use of anti-VEGF

Modest, if any impact on ORRIssues of surgical safety/timing

Targeted Therapy:The use of anti-EGFR

Response and R0 resection rates:CRYSTAL and OPUS (KRAS exon2 wt)

n RR (%)R0 resections

(%)

CRYSTAL

FOLFIRI + Cetuximab

FOLFIRI

316

350

57

40p<0.001

5.1

2.0p=0.03

OPUS

FOLFOX + Cetuximab

FOLFOX

82

97

57

34p<0.003

7.3

3.1p=0.22

FOLFIRI + Cetuximab

FOLFIRI

68

72

71

44p=0.002

13.2

5.6p=0.15

FOLFOX + Cetuximab

FOLFOX

25

23

76

39p=0.018

16.0

4.3p=0.35

Left vs Right & extended Ras not considered

All

pat

ien

tsLi

ver

limit

ed

PRIME study post-hoc analysis

Mean (95% CI) percentage change in tumour load

(sum of all target lesions)† (WT RAS)

Douillard JY, et al. Eur J Cancer 2015;51:1231−42.

*Tumour shrinkage at nadir versus baseline tumour load

(sum of the longest diameters of all target lesions).

Mean c

hange fro

m b

aselin

e (

%)

−40

−20

0

−60

Week number of measurement

−80

0 8 16 24 32 40 48 56

Panitumumab + FOLFOX4 (n = 236)

FOLFOX4 (n = 224)

−100

Median DpR*, % (Q1, Q3)

46 (23, 66)

54 (31, 72) P = 0.0149

245

242

219

221

195

183

157

147

116

110

96

71

71

39

55

25

Patients at risk:

Panitumumab + FOLFOX4

FOLFOX4


Resection rates (WT RAS and LLD)

Douillard JY, et al. Eur J Cancer 2015;51:1231−42. *Descriptive P-value (Fisher exact test).

Patients

(%

)

∆ = 6.5%

P = 0.644*

Any resection0

10

20

30


35

25

15

5

Complete resection

FOLFOX4 (n = 41)

Updated analysis

33%

27%

31%

17%

∆ = 14.2%

P = 0.145*

Events,n

Median OS, months


16 57.4

FOLFOX4 (n = 29) 15 54.5


OS in patients with any resection

(WT RAS, LLD and non-LLD)

Douillard JY, et al. Eur J Cancer 2015;51:1231−42.

Censor indicated by vertical bar.

WT RAS = WT KRAS and NRAS exons 2/3/4.

RFS, relapse-free survival.

• Median RFS after resection (n = 38) was 22.0 vs 12.4 months with panitumumab +

FOLFOX4 vs FOLFOX4, respectively (HR = 0.66; P = 0.3419)

Ka

pla

n−

Me

ier

estim

ate

100

80

60

40

20

0

0 4 8 12 16 20 24 28

Months

32 36 40 44 48 52 56 60 64 68

HR = 0.66 (95% CI, 0.32–1.35)

P = 0.2534

Four RCTs involving 484 WT KRAS patients were included:PRIME (Douillard et al. 2010)COIN (Maughan et al. 2011)CRYSTAL (Van Cutsem et al. 2011)OPUS (Bokemeyer et al. 2011)WT KRAS = WT KRAS exon 2 (codons 12 and 13) for PRIME, CRYSTAL and OPUS plus WT KRAS exon 3 (codon 61) for COIN





liver-confined metastases deemed nonresectable by a

local multidisciplinary team, which included > three liver surgeons and one radiologist.

Ye et al. JCO 2013

CELIM: Study design

Randomization

Primary endpoint: Response rate

Patients with technically unresectable/ ≥5 liver metastases of CRC without extrahepatic metastases

BiopsyEGFR screening

FOLFOX6 + cetuximab FOLFIRI + cetuximab

Therapy: 8 cycles (~4 months)

Evaluation of resectability

Technically resectableTechnically unresectable

4 further treatment cycles Resection

Therapy continuation for 6 cycles (~3 months)

Blinded surgicalreview

Folprecht G, et al. Lancet Oncol 2010;11:38–47

liver-confined metastases deemed nonresectable

CELIM :Objective Response and Resection Rates

Objective

Response

Rate

KRAS

wild-type

(n=67)

CR/PR, % 70

95% CI, % 58–81Responses confirmed by 2nd CT scan according to RECIST or by resection

Folprecht G, et al. Lancet Oncol 2010;11:38–47 ; Van Cutsem ASCO-GI 2011

FOLFOX6 +

cetuximab

(n=53) (%)

FOLFIRI

+cetuximab

(n=53) (%)

All

patients

(n=106) (%)

R0 resections 38 30 34

R1-resect / Resect + RFA 2 8 5

RFA 9 6 8

R0/R1 resect / RFA 49 43 46

Folprecht. Lancet Oncol 2010;Alberts. JCO 2005

Time to intervention

0

10

20

30

40

50

60

0 2 4 6 8 10 12 14 16

Pro

bab

ility

, %

CELIM: Time to intervention

44 patients were resected, 5 patients had exploratory laparotomyMedian time to intervention (resection/laparotomy): 5.1 monthsMedian number of cycles prior to intervention: 8

Time of chemotherapy 1 month shorter than with FOLFOX alone

Time (months)

CELIM: Prolonged survival after R0 resection

Folprecht G, et al. EMCC 2011 (Abstract No 6009)

— R0 resected— Not R0 resected

HR=2.34 (1.37-4.01)

p=0.002

— R0 resected— Not R0 resected

OSPFS

HR=2.07 (1.35-3.16)p=0.001

Depth of Response and Early Tumour Shrinkage

Chemo + / - Anti-EGFR Median DpR% w ETS >

20%(>20% vs <20%)

:PFS HR OS HR % w ETS > 30%(>30% vs <30%):

PFS HR OS HR

Study n +EGFR-ab chemo +EGFR-ab chemo +EGFR-ab chemo +EGFR-ab chemo +EGFR-ab chemo +EGFR-ab chemo +EGFR-ab chemo

PRIME (updated RAS analysis) 440 54% 46% 72% 57% 0.62 0.67 0.47 0.50 59% 38% 0.56 0.62 0.52 0.46

CRYSTAL WT KRAS 631 62% 39% 0.32 0.58 0.53 0.71

OPUS WT KRAS 168 69% 54% 0.22 0.89 0.43 0.89

20060314: 1 arm Pan/FOLFIRI 65 59% 74%13.3 vs

5.9 49% 14.3 vs 7.8

Chemo + / - Biologic Median DpR % ETS > 20%PFS HR (ETS

>20% vs< 20%)OS HR (ETS

>20% vs< 20%) % ETS > 30%PFS HR (ETS

>30% vs<30%)OS HR (ETS

>30% vs<30%)

Study n +EGFR-ab +VEGF-ab +EGFR-ab +VEGF-ab +EGFR-ab +VEGF-ab +EGFR-ab +VEGF-ab+EGFR-

ab+VEGF-

ab +EGFR-ab+VEGF-

ab +EGFR-ab +VEGF-ab

PEAK WT-RAS (final analysis) 154 65% 46% 75% 62%13.1 vs

9.811.3 vs

9.543.4 vs

21.232.5 vs

21.8 64% 45%13.0 vs

11.611.1 vs

9.743.8 vs

34.235.1 vs

23.9

FIRE3 WT-RAS (wk 6) 330 49% 32% 68% 49% 0.59 0.71 0.52 0.49CALGB 1137 ORR: 69% ORR: 54%

Triplet chemo: (combined analysisTRIP/MACBETH/TRIBE (wt RAS/RAF)

153 49% 38% 70% 62%

VEGF + 2 vs 3 chemo n + Ox Bev/5FU-iri + Ox Bev/5FU-iri

TRIBE (no RAS analysis) 441 44% 38% 63% 52%









OUTLINE

Adjuvant Chemo post resection of colorectal liver mets

% absolute

difference

in 3-year PFS

Hazard

Ratio

P-value

All patients

(n=182 per

arm)

+7.2% (28.1% to 35.4%)

0.79 P=0.058

All eligible

Patients

(n=171 per

arm)

+8.1% (28.1% to 36.2%)

0.77 P=0.041

All resected

Patients

(n=151 per

arm)

+9.2%(33.2% to 42.4%)

0.73 P=0.025

The NEW EPOC StudyA randomised clinical trial of chemotherapy compared to chemotherapy in

combination with cetuximab in KRAS wild-type patients with operable metastases from colorectal cancer

ChemotherapyResults

HR 1.49 95%CI (1.04, 2.12); p=0.030

0.0

00.2

50.5

00.7

51.0

0

Pro

port

ion p

rogre

ssio

n fre

e

117 87 54 24 15 5 3 2 1 0 0Arm B116 89 65 38 23 12 5 2 1 1 0Arm A

Number at risk

0 6 12 18 24 30 36 42 48 54 60

Time to progression or death (months)

Arm A Arm B

HR 1.48 95%CI (0.85, 2.58); p=0.163

0.0

00.2

50.5

00.7

51.0

0

Pro

port

ion e

ve

nt fr

ee

127 99 81 55 38 22 7 2 1 0 0Arm B127 113 90 61 40 29 12 4 2 1 0Arm A

Number at risk

0 6 12 18 24 30 36 42 48 54 60

Time to death (months)

Arm A Arm B

ORR PFS PFS

HR

OS OS

HR

Chemo 42% 20.5 NR

+ Cetuximab 50% 14.1 1.49 39.1 1.48

The NEW EPOC StudyA randomised clinical trial of chemotherapy compared to chemotherapy in

combination with cetuximab in KRAS wild-type patients with operable metastases from colorectal cancer









OUTLINE

Primary CRC tumor localization (left vs right)

Iacopetti, B. Int J Cancer 2002;101:403–408;

Brule SY, et al. ASCO 2013 (Abstract No. 3528);

Adams R, et al. ASCO 2012 (Abstract No. 3516)

Right-sided tumors ~40% (increasing)*

● Associated with:

● Older, female patients

● Mucinous, signet-ring histology

● Microsatellite instability

● Poorly differentiated

● KRAS and BRAF mutations

● EGFR expression

Left-sided tumors ~60%*

● Associated with:

● Chromosomal instability

● p53 mutation

● COX2 expression

● Aneuploidy

● High EGFR ligand expression (COIN

study)

*High-incidence CRC populations

Transverse colon

Right colon

(ascending)Left colon

(descending)

Rectum

Anus

Small

intestine

Sigmoid

(colon)

Right versus left: RAS WTData from retrospective analysis

• 1st line– PRIME– CRYSTAL– FIRE-3– CALGB– PEAK

• 2nd line– 181

• ? 3rd line and beyond– CO-17

Left sided primary mCRC, anti-EGFR leads to better clinical

outcome compared to chemotherapy or chemotherapy

plus bevacizumab

Right sided primary results suggest little survival benefit for anti-EGFR 1st line +/- 2nd line, but

small numbers does impact on interpretation

Holch et al, EJC 2017 (70) 87-98

Arnold et al, Annals of Oncology 28: 1713–1729, 2017

Targeted Therapy: Head-to-head ORR (1st line)

FIRE3PEAK









OUTLINE

RIGHT LEFT

RAS wildtype FOLFOXIRI Anti-EGFR/FOLFOX or FOLFOXIRI

RAS mutant FOLFOXIRI FOLFOXIRI

All FOLFOXIRI (+/- Bev)



How I choose systemic therapy in borderline resectable/unresectable

Colorectal Liver Metastasis :

A Continuum of

disease

Low disease burden, generally with a single solitary site

of spread


intermediate disease burden, generally not operable upfront but potentially

“convertible” to an operable state

Chemotherapy to control tumor, improve symptoms, maintain quality

of life and prolong life









CONCLUSION

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