3. IanChau State of the art CRT for rectal cancer 2018€¦ · ACCORD 12/ CAP 299 13.9% 0.09 67.9%...

THE ROYALMARSDEN

State of the art: Standard(s) of radio/chemotherapy for rectal cancer

Dr Ian ChauConsultant Medical OncologistThe Royal Marsden Hospital

London & Surrey

THE ROYALMARSDEN

Disclosure• Advisory Board: Eli-Lilly, Bristol Meyers Squibb,

MSD, Bayer, Roche, Merck-Serono, Astra-Zeneca, Oncologie International

• Research funding: Eli-Lilly, Janssen-Cilag, SanofiOncology, Merck-Serono

• Honorarium: Eli-Lilly, Five Prime Therapeutics

THE ROYALMARSDEN

Chemoradiotherapy in rectal cancer

• Pre-operative fluropyrimidine-based CRT is standard approach

• Distant metastases are now the main problem

• No recent practice-changing phase III trials

• Same crude treatment approach to majority of patients

• Therapy tailoring should be key for optimal care

THE ROYALMARSDEN

Why are we NOT improving survival with CRT?

Superior local control with surgery alone

Improving efficacy over CRT

Clinical benefit

Reducing distant

metastases

Sensitivity and resistance to

(C)RT

THE ROYALMARSDEN

Clinical benefit


THE ROYALMARSDEN

T3 (<5mm) N+ve rectal tumours

THE ROYALMARSDEN

Good prognosis rectal cancer managed by surgery alone (no RT) - MERCURY

T3 <5mm extramural spread, regardless of N stageLocal recurrence 1.7%5-year DFS: 81%5-year OS: 67.9%

Disease free survival Overall survival

Taylor et al Ann Surg 2011

THE ROYALMARSDEN




Clinical benefit

Reducing distant

metastases

THE ROYALMARSDEN

Pre-operative CRT: cT3-4 or N+Study n Local recurrence 5-year DFS 5-year OSGerman CAO/ARO/AIO-941

Pre-op CRT 421 5% 68% 74%Post-op CRT 402 9.7% 65% 76%

p=0.048 p=0.32 p=0.80FFCD 92032

Pre-op CRT 375 8.1% 59.4% 67.4%Pre-op RT 367 16.5% 55.5% 67.9%

p=0.004 p=0.684EORTC 229213

Pre-op CRT 506 7.6-8.7% 56.1% 65.8%Pre-op RT 505 17.1% 54.4% 64.8%

p=0.002 p=0.52 p=0.841Sauer et al J Clin Oncol 2012; 2Gerard J et al J Clin Oncol 2006;3Bosset et al N Engl J Med 2006

THE ROYALMARSDEN

Efficacy of adding oxaliplatin to FP/RT in rectal cancerTrials Arms n pCR p DFS OS

STAR-011 FU 379 16% 0.904 NR NROX/FU 368 16%

ACCORD 12/ CAP 299 13.9% 0.09 67.9% 87.6%0405 PRODIGE 22 CAPOX 299 19.2% 72.7% 88.3%

HR: 0.88 HR: 0.94German Rectal3 FU 623 13% 0.031 71.2% 88.0%CAO/ARO/AIO-04 OX/FU 613 17% 75.9% 88.7%

HR: 0.79 HR: 0.96NSABP R-044,5 FP 641 17.8% 0.42 64.2%* 79%*

OX/FP 643 19.5% 69.2%* 81.3%*

p=0.34 p=0.38PETACC-6 CAP 547 12% NR 71.3% 83.1%

CAPOX547 14% 70.5% 80.1%p=0.78 p=0.252

1Aschele et al J Clin Oncol 2011; 2Gerard et al J Clin Oncol 2012; 3Rodel et al Lancet Oncol 2015;4O’Connell et al J Clin Oncol 2014; 5Allegra et al J Natl Cancer Inst 2015; 6Schmoll et al ASCO 2018

*5-year survival rates

THE ROYALMARSDEN

Pre-operative CRT: randomised trialsStudy n Distant metastasis 5-year DFS 5-year OS

German CAO/ARO/AIO-941

Pre-op CRT 421 29.8% 68% 74%Post-op CRT 402 29.6% 65% 76%

p=0.32 p=0.80

FFCD 92032

Pre-op CRT 375 24% 59.4% 67.4%Pre-op RT 367 19% 55.5% 67.9%

p=0.684

EORTC 229213

Pre-op CRT 506 34.4% 56.1% 65.8%Pre-op RT 505 54.4% 64.8%

p=0.52 p=0.84

1Sauer et al J Clin Oncol 2012; 2Gerard J et al J Clin Oncol 2006;3Bosset et al N Engl J Med 2006

THE ROYALMARSDEN

Selecting patients for the right treatment

All comersmCRC

HR: 0.796; p=0.0093

Van Cutsem et al J Clin Oncol 2011, 2015

K-RAS wild type

K-RAS exon 2mutants

RAS wild type

K-RAS exons 2-4N-RAS exons 2-4

mutants

CRYSTAL: FOLFIRI ± cetuximab

THE ROYALMARSDEN

Are all rectal cancers born equal?• Circumferential resection margin (CRM)• Extramural spread (<5mm vs. >5mm)• T4 tumours• N0 vs. N1.vs N2 • Extramural venous invasion• Low lying tumours

Do we have the right tool to detect these high risk features?

THE ROYALMARSDEN

Baseline MRI

• Extramural spread threatening anterior circumferential resection margin

• Right pelvic side wall node

• Left pelvic side wall node

THE ROYALMARSDEN

Baseline MRI

Extramural venous invasion

THE ROYALMARSDEN

MERCURY Circumferential resection margin assessment1

Number Percentage 95% CIHistological CRM –ve 354/408 87% 83-90%MRI predicted CRM-ve 327/354 92% 90-95%

MRI prediction CRM-ve 349/408 86% 82-89%Histological CRM-ve 27/349 94% 91-96%

Extramural tumour spread assessment2

Mean extramural tumour spreadMRI 2.80mm (SD 4.60mm)Histopathology 2.81mm (SD 4.28mm)Mean difference -0.05mm (95%CI: -0.49mm to 0.40mm)

1MERCURY Study Group BMJ 2006 2MERCURY Study Group Radiology 2007

THE ROYALMARSDEN




Clinical benefit

Reducing distant

metastases

TNTTotal Neoadjuvant

Therapy

THE ROYALMARSDEN

Clinico-pathological poor risk factors

• Circumferential resection margin involvement (CRM)

• Extramural spread (<5mm vs. >5mm)• T4 tumours• N0 vs. N1.vs N2 • Extramural venous invasion• Low lying tumours

THE ROYALMARSDEN

Serial RMH phase II studies of neoadjuvant chemotherapy,

chemoradiation followed by TME

1Chau et al Brit J Cancer 2003; 2Chau et al J Clin Oncol 20063Chua et al Lancet Oncol 2010; 4Dewsbury et al J Clin Oncol 2012

Study No. of patients Recruitment period

Chemorad1 36 Jan 99 to Aug 01

EXPERT2,3 105 Nov 01 to Aug 05

EXPERT-C4 164 Aug 05 to Jul 08

THE ROYALMARSDEN

Trial schema

18 +12 weeks

ChemoradiationPost-operative chemotherapy

4-6 weeks rest for recovery of acute RT toxicity.

Repeat MRI then TME SURGERY

0Weeks

6 123 9

Neoadjuvantchemotherapy

MRI and CT scans at 12 weeks and after radiotherapy to reassess tumour response

THE ROYALMARSDEN

EXPERT trial schema

18 +12 weeks

RT 45Gy in 25# phase 19Gy boost phase 2

Capecitabine 1650mg/m2

/day continuously

Post operativelyCAPECITABINE

2500mg/m2/day for 14 days every 21 days

4-6 weeks rest for recovery of acute RT toxicity.

Repeat MRI then TME SURGERY

0Weeks

6 123 9

CAPECITABINE2000mg/m2/day for 14

days every 21 days

OXALIPLATIN 130 mg/m2

MRI and CT scans at 12 weeks and after radiotherapy to reassess tumour

response

Chau et al J Clin Oncol 2006, Chua et al Lancet Oncol 2010

THE ROYALMARSDEN

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8

Years from trial entry

Pro

babi

lity

of s

urviva

l / P

FS (%

)

OSPFS

EXPERT: Progression free and overall survival (ITT n=105)

Median FU: 55 months3-year 5-year

OS 83% 75%PFS 68% 64%

Chua et al Lancet Oncol 2010

THE ROYALMARSDEN

EXPERT-C trial design

• Investigator’s sites in UK, Spain and Sweden

• Recruitment finished in July 2008

R

EXPERTNeoadjuvant oxaliplatin/capecitabine→Capecitabine chemoradiation→Total mesorectal excision →Adjuvant oxaliplatin/capecitabineEXPERT-CNeoadjuvant oxaliplatin/capecitabine/cetuximab →Capecitabine/cetuximab chemoradiation→Total mesorectal excision →Adjuvant oxaliplatin/capecitabine/cetuximab

n=165

Dewdney et al J Clin Oncol 2012

THE ROYALMARSDEN

After neoadjuvant chemotherapy plus cetuximab

Baseline

After neoadjuvant chemotherapy

THE ROYALMARSDEN

After neoadjuvant chemotherapy plus cetuximab

Baseline After neoadjuvant chemotherapy

THE ROYALMARSDEN

After chemoradiation

• Pathological complete response was achieved on surgical specimen from TME

THE ROYALMARSDEN

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8

CAPOX

CAPOX-C

HR 0.62 (0.29-1.35)

p=0.23

Time from randomisation (years)

%

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8

OS

%

HR 0.56 (0.23-1.38)

p=0.20CAPOX

CAPOX-C

Time from randomisation (years)

PFS

Sclafani et al J Nat Cancer Inst 2014

EXPERT-C trial: 5 -year results

5-year PFSCAPOX 67.8% vs. CAPOX+C 75.4%

5-year OSCAPOX 72.3% vs. CAPOX+C 84.3%

Median follow-up = 64 months

THE ROYALMARSDEN

Another TNT schema

18 +12 weeks

CRTPost-operative chemotherapy

TME SURGERY

0Weeks

6 123 9

Neoadjuvantchemotherapy

THE ROYALMARSDEN

Non-randomised phase II trial of adding FOLFOX post CRT in locally advanced CRT

Garcia-Aguilar et al Lancet Oncol 2015; Marco et al Dis Colon Rectum 2018

n=71

n=74

n=71

n=76

THE ROYALMARSDEN

Non-randomised phase II trial of adding FOLFOX post CRT in locally advanced CRT

Marco et al Dis Colon Rectum 2018

THE ROYALMARSDEN

Alliance Intergroup PROSPECT TNT study

• Clinical stage T2N1, T3N0, or T3N1 (stage IIA, IIIA, or IIIB)

• Determined by 1) Clinical examination2) CT3) Either MRI or Endorectal US• Candidate for sphincter preservation

TME before neoadjuvant therapy• No encroachment on the mesorectal

fascia based on preoperative imaging

NCCTG-N1048; N1048; NCT01515787

n=1,120

THE ROYALMARSDEN




Clinical benefit

Reducing distant

metastases

TNTTotal Neoadjuvant

Therapy

THE ROYALMARSDEN

Cure

Balancing survival with quality of life

Short term toxicities

Clinical benefit

Long term complications

Local recurrence

Distant metastases

Permanentsequelae

Responding to response

THE ROYALMARSDEN

What constitutes a good response after CRT?Pathological complete response1

• pCR seen in 16%

• Significant more T1/2 achieved pCR

• Do T1/2 tumours need pCR to have better survival?

Pathological Tumour regression grade2

1Maas et al Lancet Oncol 2010; 2Fokas et al J Clin Oncol 2014

THE ROYALMARSDEN

Efficacy of adding oxaliplatin to FP/RT in rectal cancerTrials Arms n pCR p DFS OS

STAR-011 FU 379 16% 0.904 NR NROX/FU 368 16%

ACCORD 12/ CAP 299 13.9% 0.09 67.9% 87.6%0405 PRODIGE 22 CAPOX 299 19.2% 72.7% 88.3%

HR: 0.88 HR: 0.94German Rectal3 FU 623 13% 0.031 71.2% 88.0%CAO/ARO/AIO-04 OX/FU 613 17% 75.9% 88.7%

HR: 0.79 HR: 0.96NSABP R-044,5 FP 641 17.8% 0.42 64.2%* 79%*

OX/FP 643 19.5% 69.2%* 81.3%*

p=0.34 p=0.38PETACC-6 CAP 547 12% NR 71.3% 83.1%

CAPOX547 14% 70.5% 80.1%p=0.78 p=0.252

1Aschele et al J Clin Oncol 2011; 2Gerard et al J Clin Oncol 2012; 3Rodel et al Lancet Oncol 2015;4O’Connell et al J Clin Oncol 2014; 5Allegra et al J Natl Cancer Inst 2015; 6Schmoll et al ASCO 2018

*5-year survival rates

THE ROYALMARSDEN

MERCURY: MRI post -CRT TRGBased on similar principles to Dworak’s pathologic TRG

• mrTRG 5: no fibrosis evident; tumour signal visible only

• mrTRG 4: predominantly tumour signal intensity with minimal fibrotic low-signal intensity

• mrTRG 3: mixed areas of low-signal fibrosis and intermediate signal intensity present but without predominance of tumour signal

• mrTRG 2: in-between mrTRG1 and 3

• mrTRG 1: absence of any tumour signal

Patel et al J Clin Oncol 2011

Unfavourable: TRG 4-5 Favourable: TRG 1-3

THE ROYALMARSDEN

“Responding to response –challenging the paradigm”

What is the optimal time for surgery?

To wait (a long time) seems better

THE ROYALMARSDEN

Low-lying rectal cancer

THE ROYALMARSDEN

Watch & Wait/ Deferral of Surgery with post CRT complete clinical response

InterCoRe1 IWWD2

N 602 8802-yr local regrowth 21.4% 25.2%Salvage surgery 89% 69%R0 resection ~100% 88%5-yr overall survival 87% 84.7%3-yr distant metastasis 9.1% 8.1%

• InterCoRe consortium: IPD meta-analysis; 11 studies 602 patients• International Watch & Wait Database: registry data; 880 patients from 47 centres/ 15 countries

1Chadi et al Lancet Gastroenterol Hepatol 2018; 2van der Valk et al Lancet 2018

THE ROYALMARSDEN

InterCoRe consortium

2-year local regrowth incidence- cT1-2: 18%; cT3: 29%; cT4: 31%

Chadi et al Lancet Gastroenterol Hepatol 2018

THE ROYALMARSDEN

Royal Marsden Deferral of Surgery Prospective Study

• MRI defined complete response: mrTRG1-2: low signal intensity fibrotic scar tissue only seen at MRI performed 4 weeks after long-course CRT, confirmed at 8-12 week MRI

NCT01047969

Clinical follow-up 1M, 2M, 3Mly – 1-2 yrs, 6Mly – 3-4 yrs, then annually

MRI 1M, 2M, 3Mly – 1st yr, 6Mly – 2nd yr, annually

PET 2M, 4M, 1 yr

Sigmoidoscopy 3Mly – Yr 1, 6Mly – Yr 2, annually

CT & colonoscopy As per current NICE guidelines

• Primary endpoint: Local Failure – Powered for unacceptable failure rate – 80% power <15% local recurrence at 2 years

• Safe deferral– 90% power –≥10% defer – expected to be at least 25%

– Success ≥11 of 59 patients safely defer surgery at 2 years

THE ROYALMARSDEN

MSK TNT to increase clinical complete response

Resectable LARCN=811

CRT with adjuvant chemoN=320

Total neoadjuvant therapyN=410

pCR = 17%cCR + W&W = 6%

Tumour regrowth = 9%

pCR = 18%cCR + W&W = 22%

Tumour regrowth = 13%

Cercek et al JAMA Oncol 2018

THE ROYALMARSDEN

TRIGGER: mrTRG as biomarker for stratified management of rectal cancer patients

ClinicalTrials.gov NCT02704520

THE ROYALMARSDEN

“Responding to response –challenging the paradigm”

What is the optimal time for surgery?

To wait (longer) seems better

THE ROYALMARSDEN

Timing after CRT? When is maximum response reached?

• After completing CRT, patients undergoing surgery with a delay ≥8 weeks are 3x more likely to undergo T downstaging than patients <8 weeks (OR, 3.79; CI: 1.11 –12.99; P<0.03).

• pCR: 17.8% in delayed group; 5.5% in standard group

6 weeksymrT3b

12 weeksymrT2

BaselinemrT4 invading

Bladder and peritoneum

Final Pathology: ypT2N0

Evans et al Dis Colon Rectum 2011

THE ROYALMARSDEN

GRECCAR-6 (7 vs.11 weeks)Surgery 7 weeks post CRTn=133

n=132

MRI or EUS staged rectal cancer:cT3 or T4N+

Primary endpoint: pathological complete response

To detect ↑ in pCR rate from 12% in the 7 weeks’ arm to 26% in the 11 weeks’ arm, 264 patients would be required (80% power; 2-sided α =0.05) accounting for 10% drop-out rate

Lefevre et al J Clin Oncol 2016

Surgery 11 weeks post CRTR

THE ROYALMARSDEN

7 weeks 11 weeks p

N 133 132pCR 15% 17.4% 0.5983Post-op morbidity 32% 44.5% 0.04Medical complications

19.2% 32.8% 0.01Quality of mesorectal resection (complete mesorectum)

90% 78.7% 0.0156

GRECCAR-6 (7 vs.11 weeks)

Lefevre et al J Clin Oncol 2016

THE ROYALMARSDEN

TURKISH ( ≤8 vs.>8 weeks)Surgery ≤8 weeks post CRTn=160

n=167

Rectal cancer:cT3 or T4±N+ (uncertain staging modalities)

Primary endpoint: pathological complete response

To detect ↑ in pCR rate from 13% in the ≤8 weeks’ arm to 26% in the >8 weeks’ arm, 316 patients would be required (80% power; 2-sided α =0.05) with no drop-out

Akgun et al Br J Surg 2018

Surgery >8 weeks post CRTR

THE ROYALMARSDEN

≤8 weeks >8 weeks p

N 160 167pCR 10.0% 18.6% 0.027 Overall staging ↓↓↓ 0.004T-staging ↓↓↓ 0.001N-staging ↓ 0.048R0 92.5% 91.0% 0.626Post-op morbidity = = 0.3Quality of mesorectal = = 0.713

resection

TURKISH (≤8 vs.>8 weeks)

Akgun et al Br J Surg 2018

THE ROYALMARSDEN

RCT Optimal timing for surgery after pre-operative CRT (6 vs. 12 weeks)

Surgery 6 weeks post CRTn=122

n=115

MRI-defined poor risk rectal cancer:CRM <1mmLow-lying tumourT3 (>5mm extramural spread)EMVI +veN2

Primary endpoint: Tumour downstaging rates as defined as the proportion of patients downstaged by T staging seen on post CRT MRI

To detect ↑ in mrT downstaging from an expected 40% in the 6 weeks’ arm to 60% in the 12 weeks’ arm, 218 patients would be required (80% power; 2-sided α =0.0492)

Surgery 12 weeks post CRT

Evans et al ESCP, ESMO 2016

R

THE ROYALMARSDEN



6 weeks 12 weeks

N 122 115Primary endpoint:mrT-downstaging 52 (43%) 67 (58%)

Relative Risk: 1.4; 95% CI: 1.1, 1.8; p=0.019

Recruited from 22 centres from UK, Brazil, Canada and Cyprus between Oct 09 and Dec 14

THE ROYALMARSDEN


6 weeks 12 weeksmrTRG

1 7 (6%) 21 (22%)2 31 (28%) 29 (30%)3 45 (41%) 81 (39%)4 22 (20%) 31 (15%)5 6 (5%) 8 (4%)

Differences in mrTRG between the two arms were significant (p=0.0006)


THE ROYALMARSDEN

RCT Optimal timing for surgery after pre-operative CRT (6 vs. 12 weeks) Pathological findings

6 weeks 12 weeksN 96 96ypCR 11 (11%) 23 (24%)ypT0 9 (9%) 23 (24%)ypN0 48 (50%) 62 (65%)ypCRM +ve 8 (8%) 11 (11%)Specimen grade1 complete 68 (71%) 65 (68%)2 near complete 14 (15%) 13 (14%)3 incomplete 4 (4%) 10 (10%)


THE ROYALMARSDEN

RCT Optimal timing for surgery after pre -operative CRT (6 vs. 12 weeks)

6 weeks 12 weeks

Post-operative complicationsAny 25 (45%) 35 (48%)Wound infection/ 14 (25%) 13 (18%)Delayed healingAnastomotic leak 6 (11%) 1 (1%)Medical (MI, PE etc) 2 (4%) 7 (10%)Other 10 (18%) 20 (27%)

Differences in post-operative complications between the two arms were non-significant (p=0.48)

THE ROYALMARSDEN

Summary of 6 vs. 12 trial

Clinical benefit

6 weeks 12 weeks

↑ mrT-downstaging

↑ FavourablemrTRG ↑ pCR, pT0

↔ Post-operativecomplications

THE ROYALMARSDEN

Cure

Balancing survival with quality of life

Short term toxicities

Clinical benefit

Long term complications

Local recurrence

Distant metastases

Permanentsequelae

THE ROYALMARSDEN

Circulating tumour DNA in rectal cancer

Corcoran & Chabner N engl J med 2018

THE ROYALMARSDEN

Detecting minimal residual diseasectDNA in stage II colon cancer

Tie et al Sci Transl Med 2016

THE ROYALMARSDEN

Detecting minimal residual diseasectDNA in rectal cancer post CRT and surgery

Tie et al GUT 2018

THE ROYALMARSDEN

RMH ctDNA in rectal cancer pre, during and post CRT and surgery

Pre-treatment

End of CRT

ctDNA undetectable

ctDNA detectable

Waterfall Plots showing response in primary tumour at the end of CRT by RECIST according to ctDNA status at each sampling time-point

Developed metastases on completion of CRT but before surgery

Developed metastases on completion of CRT after surgery

Mid-CRT

Khakoo et al ESMO 2018

THE ROYALMARSDEN

RMH ctDNA in rectal cancer pre, during and post CRT and surgery

• There was no difference in response by RECIST between ctDNA positive and ctDNAnegative patients pre-treatment (P=1.00), mid CRT (P=0.42) or on completion of CRT (P=1.00)

• ctDNA detection at the end of CRT was higher in patients that developed metastases (64%) compared with those who did not (8.3%, P<0.001)

• Detection of ctDNA pre-treatment that persisted at the mid CRT time-point was also higher in patients that developed metastases (33%) compared to those that did not (11%; P=0.07)

• 14% of ctDNA positive patients pre-treatment that became ctDNA negative by the end of CRT developed metastases

• 86% of ctDNA positive patients pre-treatment that were ctDNA positive at the end of CRT developed metastases

• None of the ctDNA negative patients pre-treatment that were ctDNA negative at the end of CRT developed metastases Khakoo et al ESMO 2018

THE ROYALMARSDEN

Part A(Feasibility)

First 48 eligible patients with stage II or III CRC

Part BAll patients with stage I, II or III CRC

Stage I Low risk stage IIHigh risk stage II or

stage III CRCHigh risk stage II or

Stage III CRC

Part C: ctDNA guided adjuvant chemotherapy cohort of the study

Eligible and willing patients will be enrolled intothis cohort at the point of starting adjuvantchemotherapy

Ongoing Observational Study• Patients with stage I, low risk stage II CRC will be enrolled in the

currently open observational study.

• High risk stage II and stage III patients not eligible or those who do notwish to take part in the ctDNA guided interventional cohort of the study(Part C) will be enrolled within the currently open observational study

TRACC: overall schema

THE ROYALMARSDEN

Month60

Discharge

Pre-operative phase Surgery Post-operative phase

4-8 weeks post-op with optionalstaging CT= Month 0

Eligible adult patients with newly diagnosed CRC with no evidence of metastatic disease

due to undergo curative surgery recruited

Excluded:-Patients scheduled to have post-operative radiotherapy

Baseline blood sample within 4 weeks prior to surgery OR

neoadjuvant CRT

In patients having neo-adjuvant CRT,

additional blood sample on completion

of CRT, within 4 weeks prior to surgery

1 yearwith staging

CT

Month18

2 years with

staging CT

3 years with

staging CT

Month30

Month48

Month

3 6 9

-Additional blood sample to be taken within 2-8 weeks of radiologically confirmed relapse

cfDNA will be tested for genes such as:KRAS, NRAS, BRAF, PIK3CA, TP53 and APC based on sequencing results in the primary tumour

Excluded:-Patients post-CRT having further pre-operative treatment or no longer having surgery

Time-points for blood samples and CT scans for stage II and III patients

THE ROYALMARSDEN

Part A(Feasibility)

First 48 eligible patients with stage II or III CRC

Part BAll patients with stage I, II or III CRC

Stage I Low risk stage IIHigh risk stage II or

stage III CRCHigh risk stage II or

Stage III CRC

Part C: ctDNA guided adjuvant chemotherapy cohort of the study

Eligible and willing patients will be enrolled intothis cohort at the point of starting adjuvantchemotherapy

Ongoing Observational Study• Patients with stage I, low risk stage II CRC will be enrolled in the

currently open observational study.

• High risk stage II and stage III patients not eligible or those who do notwish to take part in the ctDNA guided interventional cohort of the study(Part C) will be enrolled within the currently open observational study

TRACC: overall schema

THE ROYALMARSDEN

Month60

Discharge

Pre-operative phase Surgery Post-operative phase (Part C)

4-8 weeks post-op with staging CT= Month 0*

Eligible adult patients with newly diagnosed CRC with no evidence of metastatic disease

due to undergo curative surgery recruited

Excluded:-Patients scheduled to have post-operative radiotherapy

Baseline blood sample within 4 weeks prior to surgery OR

neoadjuvant CRT

In patients having neo-adjuvant CRT,

additional blood sample on completion

of CRT, within 4 weeks prior to surgery

1 yearwith staging

CT**

Month18

2 years with staging CT**

3 years with

staging CT

Month30

Month48

Month

3** 6** 9

-Additional blood sample to be taken within 2-8 weeks of radiologically confirmed relapse

Excluded:-Patients post-CRT having further pre-operative treatment or no longer having surgery

Time-points for blood samples and CT scans for high risk II and III patients in ctDNA guided adjuvant chemotherapy cohort of study (Part C)

* Patients can enter into Part C of the study following curative surgery i.e., month 0

** ctDNA samples at month 3, month 6, year 1 and year 2 will be analysed in real-time and if ctDNA positive , patients will require CT scans at these time points

THE ROYALMARSDEN

De-escalate treatment;

escalate/start if ctDNA becomes positive*

High risk stage 2 and Stage 3 Colorectal Cancer (n=1621)

Clinician to decide standard of care chemotherapy and de-escalation regimen if ctDNA negative

Randomisation 1:1

Arm A: standard of care

810 patients

Arm B: ctDNA informed

810 patients

Stratification1. High risk stage 2 vs stage 32. Site of primary tumour (right colon

versus left colon vs rectum3. Geographical region

5FU or Capecitabine

FOLFOX or CAPOX

Patient consents to study andpost- op ctDNA collected (by week 8 post surgery)

~ 90% for stage 2)

ctDNA negative(~80-85% for stage 3

~ 90% for stage 2)

ctDNA positive(~15%-20% for stage 3

~10% for stage 2)

Adjuvant

care)

Adjuvant treatment

(standard of care)

THE ROYALMARSDEN

De-escalation/ Escalation strategy in ctDNAnegative group in the ctDNAguided arm

No chemotherapy

No chemotherapy

Capecitabine for 3 months or 5-

FU for 3 months

Capecitabine for 3 months or 5-

FU for 3 months

CAPOX for 3 months or

FOLFOX for 6 months

CAPOX for 3 months or

FOLFOX for 6 months

Capecitabine or 5FU for 6 monthsCapecitabine or

5FU for 6 months

If patients become ctDNA becomes positive during

follow-up at month 3 or month 6, systemic chemotherapy will be started or escalted as

per clinician’s discretion*

Capecitabine or 5-FU for 6 months

Capecitabine or 5-FU for 6 months

CAPOX for 3 months or FOLFOX

for 6 months

CAPOX for 3 months or FOLFOX

for 6 months

De-escalate

De-escalate

Start Monitor ctDNA

Monitor ctDNA

Escalate

* A CT scan will be performed at month 3 or month 6, if ctDNAbecomes positive to assess for macroscopic disease

THE ROYALMARSDEN

Sequencing the ctDNA and not primary tumour DNA

THE ROYALMARSDEN

Conclusions• Pre-operative fluropyrimidine-based CRT is

standard approach

• Distant metastases are now the main problem

• No recent practice-changing phase III trials

• Same crude treatment approach to majority of patients

• Therapy tailoring should be key for optimal care

THE ROYALMARSDEN

Pre-op FP-based CRT

Excellent response (favourable

mrTRG± clinical)

Wait beyond 6 weeks for surgery

Active surveillance/

Watch & wait)

Total neoadjuvant

therapy (TNT)

Poor risk assessed on staging pelvic

MRI

Circulating tumour DNA

More favourable short term surrogate endpoint

?guide post-operative adjuvant chemotherapy

THE ROYALMARSDEN

AcknowledgementNational Health Service funding to the National Institute for Health Research

Biomedical Research Centre

3. IanChau State of the art CRT for rectal cancer 2018€¦ · ACCORD 12/ CAP 299 13.9% 0.09 67.9%...

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Transcript of 3. IanChau State of the art CRT for rectal cancer 2018€¦ · ACCORD 12/ CAP 299 13.9% 0.09 67.9%...