perioperative chemotherapy for colorectal cancer ... en...jy douillard m ducreux a falcone a grothey...

Perioperative chemotherapy for

colorectal cancer livermetastases:

what is the optimal strategy?

Prof Eric Van Cutsem, MD, PhD

Digestive Oncology

Leuven, Belgium [email protected]

mailto:[email protected]

OS

30 months

A classical case of mCRC in 2016 CONTINUUM OF CARE

5 months

first-line induction

3 months

reintroduction (or

treatment beyond

progression)

3 months

“rechallenge”

3 months

break

6 months

maintenance

4 months

second line

3 months

third line

3 months

preterminal phase

1991: OS 6 months

The continuum of care of mCRC

1st line cytotoxic 3rd line cytotoxic 2nd line cytotoxic

1st line biologic 2nd line biologic

Maintenance strategy

At progression

change chemo,

biologic or both?

Independent

sequences?

Fluoropyrimidines: 5FU, capecitabine, TAS102

Oxaliplatin

Irinotecan

Bevacizumab

Cetuximab/panitumumab

Aflibercept

Ramucirumab

Regorafenib

How to start?

What is best

strategy?

What to do for

liver metastases?

Locoregional therapy:

SIRS Surgery (RFA)

3nd line biologic

Liver metastases important factor in survival

death Vital organ

no way to compensate

for the absence of liver

function

Patients with unresectable liver metastases:

OS is the primary treatment goal

Resection

Overall survival / long-term disease control

Treatment strategy

Required

outcome Curative surgery

10% 20% 70%

Classification Upfront

resectable Borderline resectable Unresectable

CT ±

biologic

CT ±

biologic

≈12%1 ≈8%1

Relapse 14%2

4% 96%

1. Wong, et al. Ann Oncol 2011; 2. Zakaria, et al. Ann Surg 2007

3. Van Cutsem E et al. Ann Oncol 2014; 4. Adam R … Van Cutsem E et al. Cancer Treat Rev 2015

Easily resectable

Marginally resectable/

unresectable

Number

Size

Definitely

unresectable

Surgery

± FOLFOX

Optimal therapy +

surgery Palliative therapy…

Metastatic colorectal cancer

CHEMOTHERAPY: combinaton of cytotoxic and

biological targeted drugs

Cytotoxic agents Biological agents

5-FU/capecitabine (S1)

irinotecan

oxaliplatin

raltitrexed

(mitomycine)

TAS-102

bevacizumab

cetuximab

panitumumab

aflibercept

regorafenib

ramucirumab early: Sym004, dabrafenib,

trametenib,nintedanib,

nivolumumab, pembrozulimab,

atezolizumab, cobimetinib,

MABp1 …..

Other contributing factors to improved outcome: surgery,….

ESMO consensus on mCRC 2016

Chairs: Co-Chairs of working groups

E Van Cutsem A Sobrero Advanced mCRC

D Arnold R Adam Local and ablative treatment, oligometastasis

A Cervantes H Van Krieken Molecular Pathology and Biomarkers

Contributors

D Aderka

E Aranda

A Bardelli

A Benson

G Bodoky

F Ciardiello

A D’Hoore

A Diaz Rubio

JY Douillard

M Ducreux

A Falcone

A Grothey

T Gruenberger

K Haustermans

V Heinemann

P Hoff

K Köhne

R Labianca

P Laurent-Puig

B Ma

T Maughan

K Muro

N Normanno

P Österlund

W Oyen

D Papamichael

G Pentheroudakis

P Pfeiffer

T Price

C Punt

J Ricke

A Roth

R Salazar

W Scheithauer

HJ Schmoll

J Tabernero

J Taieb

S Tejpar

H Wassan

T Yoshino

A Zaanan

Treatment of metastatic disease

Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016; Online Ann Oncol, July 2016

Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016

Online Ann Oncol, July 2016



Figure 1: toolbox of ablative treatments

Recommendation 12: perioperative treatment.

Both technical criteria for resection and prognostic considerations

define the need for systemic perioperative therapy [IV, B].

In patients with clearly resectable disease and favourable prognostic

criteria, perioperative treatment may not be necessary and upfront

resection is justified [I, C; consensus >75%].

In patients with technically resectable disease where the prognosis

is unclear or probably unfavourable, perioperative combination

chemotherapy (FOLFOX or CAPOX) should be administered [I, B;

consensus >75%].

Targeted agents should not be used in resectable patients where the

indication for perioperative treatment is prognostic in nature [II, E].



Local and ablative treatment

(including surgery)

recommendation 12: perioperative treatment.

In situations where the criteria for prognosis and resectability are not sharply defined,

perioperative therapy should be considered (as part of a continuum of treatment option)

[IV, B] (Figure 2). Patients with synchronous onset of metastases should be allocated to

this group and therapeutic pathway.

In patients with favourable oncological and technical (surgical) criteria, who have not

received perioperative chemotherapy, there is no strong evidence to support the use of

adjuvant chemotherapy [II, C], whereas patients with unfavourable criteria may benefit

from adjuvant treatment [III, B].

In patients who have not received any previous chemotherapy, adjuvant treatment with

FOLFOX or CAPOX is recommended (unless patients were previously recently

exposed to oxaliplatin-based adjuvant chemotherapy) [IV, B].

Decision-making should include patients’ characteristics and preferences [IV, B].




(including surgery)

EORTC 40983 Peri-operative chemotherapy FOLFOX PFS in eligible patients

Nordlinger B…Van Cutsem E, et al. Lancet 2008;371:100716. CT, chemotherapy.

HR = 0.77 (95% CI, 0.601.00)

P = 0.041

3-year PFS: + 8.1%

28.1%

36.2%

Years

0 1 2 3 4 5 6

0

10

20

30

40

50

60

70

80

90

100

No. at risk:

171 83 57 37 22 8 171 115 74 43 21 5

PF

S (

%)

LV5-FU + oxaliplatin peri-operative CT

Surgery only

New EPOC Study: Trial Design

in resectable and borderline resectable

patients

Chemotherapy 3 months

Liver resection

Chemotherapy 3 months Operable (including borderline operable)

colorectal liver metastases

Chemotherapy + Cetuximab 3 months

Liver resection

Chemotherapy + Cetuximab 3 months

R

Primrose J, et al. Lancet Oncology 2014

Chemo

•FOLFOX (68% vs 67%)

•CAPOX (27% vs 24%)

KRAS wild-type

672 pts screened

272 pts

randomised

New EPOC PFS of all randomised WT KRAS patients (primary analysis)

Primrose J, et al. Lancet Oncol 2014;15:601–11.

60 54 48 42 36 30 24 18 12 6 0

0

25

50

75

100

HR = 1.48 (95% CI, 1.042.12); P = 0.03

Arm A (CT) 20.5

Arm B (CT + cetuximab) 14.1

0

0

1

0

1

1

2

2

6

3

12

5

23

15

38

24

65

53

89

87

117

119

Time (months) No. at risk:

PF

S (

%)

Median (months)

Tumour characteristics Patient characteristics Treatment

characteristics Clinical presentation:

Tumour burden

Tumour localisation

Age Toxicity profile

Tumour biology Performance status Flexibility of treatment

administration

RAS mutation status Organ function Socio-economic factors

BRAF mutation status Comorbidities, patient attitude,

expectation and preference Quality of life

Table 4.

Drivers for first-line treatment




Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016; Online Ann Oncol, July 2016

Recommendation 13: conversion therapy.

In potentially resectable patients (if conversion is the goal), a regimen leading to high

RRs and/or a large tumour size reduction (shrinkage) is recommended [II, A].

There is uncertainty surrounding the best combination to use as only few trials have

addressed this specifically:

In patients with RAS wild-type disease, a cytotoxic doublet plus an anti-EGFR

antibody seems to have the best benefit risk/ratio, although the combination of

FOLFOXIRI plus bevacizumab may also be considered and, to a lesser extent, a

cytotoxic doublet plus bevacizumab [II, A].

In patients with RAS-mutant disease: a cytotoxic doublet plus bevacizumab or

FOLFOXIRI plus bevacizumab [II, A].

Patients must be re-evaluated regularly in order to prevent the overtreatment of

resectable patients as the maximal response is expected to be achieved after 12–16

weeks of therapy in most patients.




(including surgery)

Ruers T. …Van Cutsem E et al. Presented at 2015 ASCO Annual Meeting; J Clin Oncol 2015; 33 (Suppl): Abs 3501.

• Unresectable liver metastases

• Number of metastatic deposits <10

• Max. diameter of lesions to be treated by RFA =4cm

RF performed during laparotomy, laparoscopy, or percutaneously

LOCOREGIONAL THERAPY

CLOCC Study in patients with unresectable CLM

Median follow-up = 9,7 years

Ruers T. …Van Cutsem E et al. Presented at 2015 ASCO Annual Meeting; J Clin Oncol 2015; 33 (Suppl): Abs 3501.

LOCOREGIONAL THERAPY

CLOCC Study in patients with unresectable CLM

SIRFLOX Study Design Prospective open-label RCT

Primary endpoint: Progression-Free Survival (PFS) in the ITT population by independent central imaging

1. Bevacizumab allowed at investigator’s

discretion, per institutional practice

Stratified by

•Presence of extra-

hepatic metastases

•Degree of liver

involvement

•Intended use of

bevacizumab

•Institution

Randomised

1:1

n = 530

Eligible patients

•Non-resectable

liver-only or liver-

dominant mCRC*

•No prior chemo for

advanced disease

•WHO performance

status 0–1

mFOLFOX6 (+ bevacizumab) (1)

Y-90 resin

microspheres

n = 263 enrolled

n = 267 enrolled

mFOLFOX6 (+ bevacizumab) (1)

Secondary endpoints:

• PFS in the liver

• Tumour response rate in the liver

• Tumour response rate at any site (RECIST 1.0)

• Hepatic resection rate

• Toxicity & safety (NCI CTCAEv3.0)

• Health-related quality of life

• Overall survival, in a pre-planned combined analysis

Van Hazel G et al, J Clin Oncol 2016

SIRFLOX trial

Van Hazel G et al, J Clin Oncol 2016

Investigator n Treatment ORR ORRL PFS PFSL Survival

Gibbs 267 SIR-Spheres† + 76.4% 78.7% 10.7 20.5 mo nr

‘SIRFLOX’ mFOLFOX6

2016 (+bev)

263 mFOLFOX6 68.1% 68.8% 10.2 12.6 mo nr

(+bev)

P=0.042 P=0.429

statistically significant data

† SIR-Spheres Y-90 resin microspheres; nr: not reported; L in the liver

van Hazel GA et al. J Clin Oncol 2016; 34: 1723–1731.

P=0.002 HR 0.69

P=0.113

Evidence of SIR-Spheres Y-90 resin microspheres in

1st-line

Recommendation 16: Embolisation

For patients with liver-limited disease failing the available

chemotherapeutic options

Radioembolisation with yttrium-90 microspheres should be considered

[II, B] Chemoembolisation may be also considered as a treatment option [IV,

B].

Radioembolisation (and chemoembolisation) of CLM in earlier

treatment lines may be interesting as “consolidation treatment” but

should be limited to clinical trials.




SCENARIO 1: Asymptomatic CRC and resectable

synchronous CRCLM:

No strong evidence on best scenario

Expert recommendation: chemotherapy first – 4-6 cycles

But: LiverMetsSurvey: 5 y survival: 42 vs 47 % for CT first

vs Surgery of primary first

For mid and low rectal primary tumours:

* RT is often needed

* One-stage surgery should not be performed, unless

limited hepatic disease and ‘easy’ to resect primary

Synchronous liver metastases:

clinical scenarios

SCENARIO 2: Asymptomatic CRC and non-resectable

synchronous CRCLM:

Most frequently observed scenario

Chemotherapy first (expert opinion): optimal

chemotherapy (doublets or triplets + biologicals)

But: LiverMetsSurvey: no 5 y survival difference: 31 vs 33%

for CT first vs Surgery of primary first

One-stage surgery should not be performed

If metastases become resectable: experts recommend

reverse approach: liver first

LiverMetsSurvey: 5 y survival 42 % for reverse strategy vs

33% for colon first and 28% for one stage surgery

RT: either before starting CT or in window between CT and

surgery


clinical scenarios

SCENARIO 3: Symptomatic CRC and resectable

synchronous CRCLM:

No strong evidence on best scenario

More difficult for rectal cancer than colon cancer (where

often resection of the primary tumour is adviced)

Bleeding: start with CT or RT

Obstruction: derivative colostomy for rectal cancer if not

resectable

Results with stents have been poor

Expert recommendation: chemotherapy first – 4-6 cycles

For mid and low rectal primary tumours:

* RT is often needed

* One-stage surgery should not be performed, unless

limited hepatic disease and ‘easy’ to resect primary


clinical scenarios

SCENARIO 4: Symptomatic CRC and non-resectable

synchronous CRCLM:

Aim: make the liver metastases resectable

Bleeding: start with CT or RT

Obstruction: derivative colostomy for rectal cancer if not

resectable

Results with stents have been poor

Chemotherapy first (expert opinion): optimal

chemotherapy (doublets or triplets + biologicals)

One-stage surgery should not be performed

If metastases become resectable: experts recommend

reverse approach: liver first (unless primary is still very

symptomatic)

RT: either before starting CT or in window between CT and

surgery


clinical scenarios

perioperative chemotherapy for colorectal cancer ... en...jy douillard m ducreux a falcone a grothey...

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