Management of early rectal cancer: any role for adjuvant ... · RECTAL CANCER: WHAT IS THE EVIDENCE WE HAVE? The QUASAR TRIAL UK QUASAR uncertain indication trial Approx 30% rectal

ESMO Preceptorship Programme

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

Andrés Cervantes

Colorectal Cancer – Valencia – 12,13 May 2017

ESMO PRECEPTORSHIP PROGRAM

Disclosures

Consulting and advisory services, speaking or writing engagements,

public presenations:

Servier, Merck Serono, Amgen, Roche, Lilly, Bayer, Novartiis, Takeda, Beigene

Direct research support to the responsible project lead:

Servier, Roche, Genentech, Bayer, Janssen, Merck Serono, Medimmune

• 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

CURRENTS CONCEPTS IN RECTAL CANCER

DIAGNOSIS AND THERAPY

4

• 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

5

INDICATIONS FOR PREOPERATIVE TREATMENT IN

RECTAL CANCER ACCORDING TO MRI STAGING

TUMOR CARACHTERISTICS T1-T2 T3a-b T3c-d

MRF negative

T4a

UPPER THIRD

10-15 CM

Not

Required

Not

Required

RT 5x5 RT 5x5

MEDIUM THIRD

5-10

Not

Required

Not

Required

Vs RT 5x5

RT 5x5 RT 5x5

LOWER THIRD

0-5

Not

Required

Vs RT 5x5

RT 5x5 RT 5x5 RT 5x5

6

INDICATIONS FOR PREOPERATIVE TREATMENT IN

RECTAL CANCER ACCORDING TO MRI STAGING

TUMOR

CARACHTERISTICS

T4b N1 N2 MRF + Lateral

Nodes

EMVI+

UPPER THIRD

10-15 CM

RT 5x5

Vs CHRT

Not

Required

RT 5x5 CHRT CHRT CHRT

MEDIUM THIRD

5-10

RT 5x5

Vs CHRT

Not

Required

Vs RT 5x5

RT 5x5 CHRT CHRT CHRT

LOWER THIRD

0-5

RT 5x5

Vs CHRT

RT 5x5 RT 5x5 CHRT CHRT CHRT

THE ROLE OF ADJUVANT CHEMOTHERAPY IN LOCALISED

RECTAL CANCER: WHAT IS THE EVIDENCE WE HAVE?

IF NO PREOPERATIVE CHRT OR RT IS GIVEN…

• American Intergroup data

• Quasar data

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

• Cochrane Meta-analysis on individual data

THE ROLE OF SYSTEMIC CHEMOTHERAPY IN LOCALISED RECTAL

CANCER:

Gunderson et al. J Clin Oncol 2004



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 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

2012



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



IF PREOPERATIVE CHRT OR RT 5x5 IS GIVEN…

• Chronicle trial/Proctor/Script trial

• Meta-analysis on single patient data of 4 trials

• Adore trial

• CAO/ARO/AIO-04 trial

• PETACC 6 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 from 60 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)



A single patient data Meta-analysis of 4 RCTs

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

Adding Oxaliplatin to 5-FU based adjuvant

therapy in localised colon/rectal cancer

Trial N Control Exp. Stage DFS HR

P value

OS HR

P value

Absolute

Gain in OS

G3

Neuro

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%

AIO044 1233 FU mFOLFOX6 II/III 0.79

0.030

0.96

NS

0.7 at 3 y 9%

NSABP R045 1284 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



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




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 by

8% 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


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

DOWNSTAGING AFTER NEOADJUVANT

TREATMENT : NEOADJUVANT RECTAL SCORE

NEOADJUVANT RECTAL SCORE

A SERIES OF 158 LOCALLY ADVANCED RECTAL CANCER

PATIENTS TREATED WITH CT-RT

Log Rang Test p: 0.004

(Mantel Cox)

Roselló S, et al. Manuscript submitted

THE WAY FORWARD: THE PHASE III RADOMIZED RAPIDO TRIAL

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%

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

POLISH TRIAL: OVERALL SURVIVAL FAVORS PREOPERATIVE SCPRT + CHT

VERSUS PREOPERATIVE CHEMORADIATION IN LACR

HR: 0.73 p: 0.046


RECTAL CANCER: CONCLUSIONS

• Adjuvant Chemotherapy should be considered for patients at risk after direct surgery

• Adjuvant Chemotherapy (oxaliplatin based) should be given after neoadjuvantChemoradiation for patients at high risk

• Adjuvant Chemotherapy could be also selectively considered for locally advanced patients with intermediate response to Chemoradiation

Documents

Management of early rectal cancer: any role for adjuvant ... · RECTAL CANCER: WHAT IS THE EVIDENCE WE HAVE? The QUASAR TRIAL UK QUASAR uncertain indication trial Approx 30% rectal