Management of early rectal cancer: Any role for adjuvant ... · SURGERY AND ADJUVANT CT IN MRI...

Management of early rectal cancer:Any role for adjuvant chemotherapy?

Andrés CervantesProfessor of Medicine

DISCLOSURE SLIDE

Employment: None; Stock Ownership: None

Consultant or Advisory Role: Merck Serono, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda, Astelas.

Research Funding: Genentech, Merck Serono, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda, Astelas, Fibrogen, Amcure, Sierra Oncology, Astra Zeneca, Medimmune, BMS, MSD

Speaking: Merck Serono, Roche, Angem, Bayer, Servier, Foundation Medicine. Grant support: Merck Serono, Roche.

Others: Executive Board member of ESMO, Chair of Education ESMO, General and Scientific Director INCLIVA, Associate Editor: Annals of Oncology and ESMO Open, Editor in chief: Cancer Treatment Reviews.

ESMO PRECEPTORSHIP PROGRAM

� TME surgery

� Optimal staging by MRI

� Pathological assessment of the quality of surgery

� Preoperative radiation or chemoradiation

� Integration of knowledge in a multidisciplinary team approach

� Selective approach for preoperative treatment

� Non surgical approach for patient with complete remision

CURRENTS CONCEPTS IN RECTAL CANCERDIAGNOSIS AND THERAPY

ESMO PRECEPTORSHIP PROGRAM

IMPROVEMENT IN RECTAL CANCER TREATMENT

OUTCOMES IN NORWAY

Local Recurrence Distant Metastases

Distant metastases 4x greater risk than local recurrence

Guren MG, et al Acta Oncol 2015; 54:1714-1722.

ADJUVANT THERAPY FOR LOCALIZED RECTAL CANCER

Ann Oncol 2017; 28(suppl 4):iv22-iv40.

ESMO PRECEPTORSHIP PROGRAM 7

� MRI Staging

� MDT discussion

� Preoperative treatment if indicated

� TME Surgical resection

� Pathology assessment and estimation of risk

� Postoperative chemotherapy if indicated

CURRENT APPROACH TO RECTAL CANCER

8

THE ROLE OF ADJUVANT CHEMOTHERAPY IN LOCALISED RECTAL CANCER: WHAT IS THE EVIDENCE WE HAVE?

• The pre-TME/preoperative RT or ChRT data• The TME/preoperative RT or ChRT data• How to integrate ChT in patients with locally

advanced disease?

ESMO PRECEPTORSHIP PROGRAM

THE ROLE OF ADJUVANT CHEMOTHERAPY IN LOCALISED RECTAL CANCER: WHAT IS THE EVIDENCE WE HAVE IN THE PRE-TME PRE-

RT/CHRT PREOPERATIVE ERA?

� American Intergroup

� Quasar

� Japanese Society of Colon and Rectal Meta-analysis on individual data

� Cochrane Meta-analysis on individual data

ESMO PRECEPTORSHIP PROGRAM

THE ROLE OF SYSTEMIC CHEMOTHERAPY IN LOCALISED RECTAL CANCER:

Gunderson et al. J Clin Oncol 2004

THE ROLE OF ADJUVANT CHEMOTHERAPY IN LOCALISED

RECTAL CANCER: WHAT IS THE EVIDENCE WE HAVE?

The American Intergroup* Pooled Analysis

* NSABP, NCCTG and US-GI Intergroup

THE ROLE OF SYSTEMIC CHEMOTHERAPY IN LOCALISED RECTAL CANCER:

The QUASAR Collaborative Group. Lancet 2007; 370:2020.

THE ROLE OF ADJUVANT CHEMOTHERAPY IN LOCALISED

RECTAL CANCER: WHAT IS THE EVIDENCE WE HAVE?

The QUASAR TRIAL

UK QUASAR uncertain indication trial Approx 30% rectal.

5yr survival 5 yr recurrence

Chemo No chemo

P-value

Chemo No chemo

P-value

Whole cohort 80.3% 77.4% 0.02 22.2% 26.2%, 0.001

Rectal subgroup p=0.05 19.6% 26.8%, 0.005

The QUASAR Collaborative Group. Lancet 2007; 370:2020.

WHAT IS THE EVIDENCE WE HAVE?

The Quasar trial

Sakamoto et al. Br J Cancer 2007

WHAT IS THE EVIDENCE WE HAVE?

The Japanese Society of Cancer of Colon

and Rectum Meta-analysis on UFT trials

2012

THE ROLE OF ADJUVANT CHEMOTHERAPY IN LOCALISED

RECTAL CANCER: WHAT IS THE EVIDENCE WE HAVE?

The Cochrane Meta-analysis

Petersen et al, Cochrane Data Base of Systenatic Rev 2012; CD004078

Petersen et al, Cochrane Data Base of Systenatic Rev 2012; CD004078

17

THE ROLE OF ADJUVANT CHEMOTHERAPY IN LOCALISED RECTAL CANCER: WHAT IS THE EVIDENCE WE HAVE?

• The pre-TME/preoperative RT or ChRT data• The TME/preoperative RT or ChRT data• How to integrate ChT in patients with locally

advanced disease?

18

THE ROLE OF ADJUVANT CHEMOTHERAPY IN LOCALISED RECTAL CANCER: WHAT IS THE EVIDENCE WE HAVE IN THE TME/PREOPERATIVE RT OR CHRTERA?

• Chronicle trial • Proctor/script trial • Meta-analysis by Breugomon

individual data from 4 trials and 1200 pts

• Adore trial• CAO/ARO/AIO -04 trial

CHRONICLE TRIAL: ASSESSING THE VALUE OF ADJUVANT CHEMOTHERAPY IN THE TREATMENT OF RECTAL CANCER AFTE R

PREOPERATIVE CHEMORADIATION

Glynne Jones et al. Ann Oncol 2014; 25:1356

Glynne Jones et al. Ann Oncol 2014; 25:1356

� Target population 800 pts

� Primary end point: DFS at 3 years (HR:0.75)

� Accrued nr. Patients 113

� Underpowered to detect any potential benefit of Chemotherapy

� HR for DFS: 0.80 (95%CI: 0.38-1.69; p:0.56)

� HR for OS: 1.18 (95%CI: 0.43-3.26; p:0.75)

WHAT IS THE EVIDENCE WE HAVE?

The Chronicle trial

Breugom et al, Ann Oncol 2015; 26:696-701

PROCTOR/SCRIPT TRIAL: ASSESSING THE VALUE OF ADJUVANT CHEMOTHERAPY IN THE TREATMENT OF

RECTAL CANCER AFTER PREOPERATIVE CHEMORADIATION OR 5X5 RADIATION

� Target population 840 pts� Primary end point: OS at 5 years improved from60 to 70%� Accrued nr. Patients 437 over 14 years� Underpowered to detect any potential benefit of

Chemotherapy� 5 year OS for observation: 79.2%� 5 year OS for adj therapy: 80.4%

� HR for DFS: 0.80 (95%CI: 0.60-1.07; p:0.13)� HR for OS: 0.93 (95%CI: 0.61-1.29; p:0.73)

22

Breugom et al. Lancet Oncol 2015; 16:200-207.

WHAT IS THE EVIDENCE WE HAVE?

The Breugom’s Meta-analysis

Adding Oxaliplatin to 5-FU based adjuvant therapy in localised colon/rectal cancer

Trial N Control Exp. Stag

e

DFS HR

P value

OS HR

P value

Absolute

Gain in OS

G3

Neur

o

Tox

MOSAIC1 2246 FULV2 FOLFOX4 II/III 0.80

0.003

0.84

0.046

4,2% at 6 y

stage III

12%

NSABP-C072 2407 FULV

Roswell

FLOX II/III 0.80

0.0034

0.82

0.002

2,7 at 5 y

Stage III

8,2%

XELOXA3 1886 FULV

Mayo

CAPEOX III 0.80

0.0038

0.83

0.04

6 % at 7 y 11%

1André T, et al. J Clin Oncol 2007; 27:3109-3116. 2Kuebler JP, et al. J Clin Oncol 2007; 25:2198-2204.3Schmoll HJ et al. J Clin Oncol 2015; 33:3733-3740.

Adding Oxaliplatin to 5-FU based adjuvant therapy in localised colon/rectal cancer

Trial N Control Exp. Stag

e

DFS HR

P value

OS HR

P value

Absolute

Gain in OS

G3

Neur

o

Tox

MOSAIC1 224

6

FULV2 FOLFOX4 II/III 0.80

0.003

0.84

0.046

4,2% at 6 y

stage III

12%

NSABP-C072 240

7

FULV

Roswell

FLOX II/III 0.80

0.0034

0.82

0.002

2,7 at 5 y

Stage III

8,2%

XELOXA3 188

6

FULV

Mayo

CAPEOX III 0.80

0.0038

0.83

0.04

6 % at 7 y 11%

AIO044 123

3

FU mFOLFOX

6

II/III 0.79

0.030

0.96

NS

0.7 at 3 y 9%

NSABP R045 128

4

FU/Cap

e

+ Oxali II/III 0.94

NS

0.94

NS

NR 6%

PETACC66 898 Cape + Oxali II/III 1.04

NS

NR NR 8%1André T, et al. J Clin Oncol 2007; 27:3109-3116. 2Kuebler JP, et al. J Clin Oncol 2007; 25:2198-2204.3Schmoll HJ et al. J Clin Oncol 2015; 33:3733-3740. 4Roedel C et al. Lancet Oncol 2015; 16:979-989. 5Allegra CJ et al. J Natl Cancer Inst 2015; 107: pii: djv248.

Hong YS et al. Lancet Oncol 2014; 15:1245-1253.

THE ROLE OF ADJUVANT CHEMOTHERAPY IN LOCALISED

RECTAL CANCER: WHAT IS THE EVIDENCE WE HAVE?

THE ADORE TRIAL

BOLUS 5FU-LV

Mayo Clinic Schedule

FOLFOX

Rectal Cancer

patients who

completed

preoperative

Long course

chemoradiation

and Surgery with

free margins

ypT3-4N0

or

anyTN1-2

1:1 Randomization

Hong YS et al. Lancet Oncol 2014; 15:1245-1253.

THE ROLE OF ADJUVANT CHEMOTHERAPY IN LOCALISED

RECTAL CANCER: WHAT IS THE EVIDENCE WE HAVE?

THE ADORE TRIAL

� No observational arm

� Randomised phase II trial 80% Power

� Unilateral hypothesis

� Target population 320 pts

� Primary end point: DFS at 3 years improved by8% from 70 to 78%

� Accrued nr. Patients 322 over 3.5 years

ADORE TRIAL: ADJUVANT CHEMOTHERAPY IN STAGE II/III RECTAL

CANCER AFTER PREOPERATIVE CHEMORADIATION

DISEASE FREE AND OVERALL SURVIVAL

Hong YS et al. Lancet Oncol 2014; 15:1245-1253.

28

THE ROLE OF ADJUVANT CHEMOTHERAPY IN LOCALISED RECTAL CANCER: WHAT IS THE EVIDENCE WE HAVE?

• The pre-TME/preoperative RT or ChRT data• The TME/preoperative RT or ChRT data• How to integrate ChT in patients with locally

advanced disease?

ESMO Rectal Cancer Guidelines: Staging

SoC

TME alone

AVOID RT

TME alone if

high quality or

plus

SCPRT/CRT

SCPRT

or

CRT

Then TME

CRT or

SCPRT +

FOLFOX

then TME

Key

Messages

cT1-2; cT3a/b if

middle or high cN0

(cN1 ig high) MRF

clear; no EMVI

cT3a/b very low

levators clear. MRF

clear, cT3a/b in mid or

high rectum, cN1-2 (not

extranodal), no EMVI

cT3c/d or very low,

levators not threatened,

MRF clear. cT3c/d mid

rectum, cN1-N2

(extranodal), EMVI +ve

cT3 with MRF involved

cT4b,

levators threatened,

lateral node +ve

Glynne Jones, R et al. Ann Oncol 1017;28 (Supplement 4): iv22–iv40.

George TG , et al. Curr Colorectal Cancer Rep 2015; 11:275-280

DOWNSTAGING AFTER NEOADJUVANTTREATMENT : NEOADJUVANT RECTAL SCORE

NEOADJUVANT RECTAL SCOREA SERIES OF 158 LOCALLY ADVANCED RECTAL CANCER

PATIENTS TREATED WITH CT-RT

Log Rang Test p: 0.004

(Mantel Cox)

Roselló S, et al. Clin Colorectal Cancer 2018; 17:104-112

NEOADJUVANT RECTAL SCORE IN CAO/ARO/AIO04 TRIAL

Fokas E, et al, Ann Oncol 2018; 29:1521-1527

NEOADJUVANT CT PLUS CT-RT VERSUS CT-RT FOLLOWED BY SURGERY AND ADJUVANT CT IN MRI DEFINED HIGH RISK RE CTAL

CANCER: THE PHASE II RADOMIZED VALENCIAN EXPERIENCE

Fernández-Martos et al. Ann Oncol 2015; 26: 1722-1728

Concurrent CRT with

CAPOX

CAPOX x 4

MRI defined

Locally advanced

Rectal Cancer

patients

N=108

1:1 Randomization

S Adjuvant

CAPOX

Concurrent CRT with

CAPOXS

POLISH PHASE III TRIAL CRT VS 5X5 AND FOLFOX

S

5x5 FOLFOX 4 x 3

S

RT+5FU LV wk1,5

Ox weekly

34

Primary end point R0 resectionLocally advanced

Unresectable

Locally recurrent

• MRI defined 66%

• Oxaliplatin became

optional

• Short duration FOLFOX

• Weekly Ox single agent

wk 2,3,4

Bujko et al Ann Oncol. 2016;27:834-842.

Primary end point R0 resection

Bujko K, et al. Ann Oncol 2016; 27:834-842

POLISH TRIAL: OVERALL SURVIVAL FAVORS PREOPERATIVE

SCPRT + CHRT VERSUS PREOPERATIVE CHEMORADIATION IN

LOCALLY ADVANCED RECTAL CANCER

HR: 0.73 p: 0.046

THE WAY FORWARD: THE PHASE III RADOMIZED RAPIDO TRI AL

PI: Prof. C. van de Velde

CRT with

CAPECITABINE

Week 1-6

5x5 RT

Week 1

MRI defined

Locally advanced

Rectal Cancer

patients

N=920

1:1 Randomization

SURGERY

Week12

Adjuvant

CT

OPTIONAL

Neoadjuvant XELOX x6

Week 3-16SURGERY

Week 24-28

DFS at 3 years improved by 10% from 50 to 60%

ESMO PRECEPTORSHIP PROGRAM

THE ROLE OF ADJUVANT CHEMOTHERAPY IN LOCALISED RECTAL CANCER: CONCLUSIONS

� Adjuvant Chemotherapy is not standard of care for all localized

rectal cancer patients

� Adjuvant Chemotherapy should be considered for patients at risk after direct surgery without neoadjuvant therapy

� Adjuvant Chemotherapy should be also considered after neoadjuvant Chemoradiation for patients with stage ypIII and high risk stage ypII. LoE: II GoR: C

� The decision on postoperative Chemotherapy (FU alone or combined with oxaliplatin) should be risk balanced, taking into account both the predicted toxicity for a particular patient and the risk of relapse, and should be made jointly by the individual and the clinician

ESMO PRECEPTORSHIP PROGRAM

Thank you