17th ESO-ESMO Masterclass in Clinical Oncology€¦ · radiotherapy and TME compared with TME alone: Results from many randomised studies •u Peeters K, J Clin Oncol 2015;25:6199

Leeds Institute of Cancer and Pathology

Radiation Therapeutics

17th ESO-ESMO-EONS MasterclassManagement of rectal cancer

David Sebag-Montefiore Audrey and Stanley Burton Professor of Clinical Oncology Leeds Cancer Centre UK.@MontefioreD

+ Razvan Popescu17th

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Summary of topics

• Quality of imaging, surgery and pathology• Effectiveness of pre-operative radiotherapy• ESMO treatment guidelines• Evidence for (C)RT from clinical trials• Future directions

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Histopathology

+ve CRM = microscopic tumour <=1mm from the painted margin

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MRI – mesorectal fascia

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Role of circumferential margin involvement in the local recurrence of rectal cancerAdam et al Lancet 1994;344;707-711

• All patients n=190 LR 29%

• “Curative resections” n=141 LR 23%

– CRM+ve (25%) n=35 LR 66%– CRM -ve (75%) n=106 LR 8%

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CR07 – Plane of surgical specimenQuirke et al 2009

0

20

40

60

80

100

Local R

ecurrenc

e rate (%

)

0 1 2 3 4 5Time (Years)

Muscularis Propria 32 154

Intramesorectal 27 398

Mesorectal 19 604

Events Total

At risk: 154 135 111 72 47 25398 351 281 220 155 88604 552 435 297 192 112

0

20

40

60

80

100

Local R

ecurrenc

e rate (%

)

0 1 2 3 4 5Time (Years)0

20

40

60

80

100

Local R

ecurrenc

e rate (%

)

0 1 2 3 4 5Time (Years)

Muscularis Propria 32 154

Intramesorectal 27 398

Mesorectal 19 604

Events Total

At risk: 154 135 111 72 47 25398 351 281 220 155 88604 552 435 297 192 112At risk: 154 135 111 72 47 25398 351 281 220 155 88604 552 435 297 192 112

020406080

100

Disease

Free sur

vival rat

e (%)

0 1 2 3 4 5Time (Years)

Muscularis Propria 45 154Intramesorectal 100 398Mesorectal 139 604

Events Total

At risk: 154 128 102 66 44 25398 336 262 202 140 81604 514 391 279 179 108

020406080

100

Disease

Free sur

vival rat

e (%)

0 1 2 3 4 5Time (Years)

Muscularis Propria 45 154Intramesorectal 100 398Mesorectal 139 604

Events Total

At risk: 154 128 102 66 44 25398 336 262 202 140 81604 514 391 279 179 108

Local recurrence

Disease free survivalMesorectal Intra-

mesorectal

n=59653%

n=38234%

Muscularis propria

n=14113%

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Radiation Therapeutics17th E

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Radiotherapy reduces LR for all planes of surgical excision Quirke et al Lancet 2009

Muscularispropria Intramesorectal% HR (95% CI) Mesorectal% HR (95% CI)All patients 13% 7% 0.48 (0.25-0.93) 4% 0.32 (0.16-0.64)

Selective post 16% 10% 0.49 (0.23-1.06) 7% 0.48 (0.23-1.00)Pre-op RT 10% 4% 0.52 (0.15-1.79) 1% 0.09 (0.02-0.49)

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Pre-operative radiotherapy and curative surgery for the management of localized rectal carcinoma – Wong et al Cochrane review 2007

• 19 trials >8000patientsOverall mortality

Cause specific mortality

Local recurrence17th

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Pre-operative chemoradiation for non-metastatic locally advanced rectal cancer-Caluwe Cochrane review 2012• 5 trials >2000 patients

Local Recurrence

Overall Survival

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Pre-operative chemoradiation for non-metastatic locally advanced rectal cancer-Caluwe Cochrane review 2012

Acute Toxicity

Late Toxicity

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• ESMO Guidelines statement“…….. rectal MRI for all tumours, including the earliest ones, is required in order to select patients for preoperative treatment and extent of surgery.”Mean extramural spread MRI 2.8mm Mean extramural spread path 2.81mm=

MERCURY Trial - Primary end point Radiology 2007 243: 132-139; BMJ 2006 333:779-783

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MERCURY results

• MRI assessment of the CRM predicts DFS and LR– Taylor FG et al, J Clin Oncol.2014 Jan 1;32(1):34-43• Comparison of MR and Histopath response to CRT– Patel UB et al Ann Surg 2012• MRI detected tumour response for locally advanced rectal cancer predicts survival outcomes– Patel U, Journal Of Clinical Oncology 2011; 29:3753-60 • Preop High-resolution MRI Can Identify Good Prognosis Stage I, II, and III Rectal Cancer Best Managed by Surgery Alone– Taylor FG et al Annals of Surgery 2011 253:711-719 17th

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MRI – Selection for pre-op (C)RT

Margin at risk = Pre-op CRT

Options

•Surgery alone•Surgery then post-op CRT•Pre-op SCPRT then surgery

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Local recurrence by T3 substageSebag-Montefiore et al ESTRO 2012

N=184 N=309 N=150

3% vs 6%3% vs 10%

10%vs 22%

T3a <=1mmT3b >1-5mmT3c>5-15mm

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NICE guidelines 2011 -Risk of locoregional failure

MRI findingsHigh risk A threatened (<1 mm) or breached

resection margin or low tumours encroaching onto the inter-sphincteric plane or with levator involvement

Moderate risk

Any cT3b or greater, in which the potential surgical margin is not threatened or any suspicious lymph node not threatening the surgical resection margin or the presence of extramural vascular invasion

Low risk T1 or cT2 or cT3a and no lymph node involvement

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Rectal Cancer: ESMO Clinical Practice Guidelines Annals of Oncology 2017

Intermediate/ bad Advanced(ugly)Early(good)cT1-2; cT3aT3 (b) if mid or high N0 (or cN1 if high)MRF –ve; EMVI –ve

cT2 very low,cT3 mrf –ve (unless cT3a(b) and mid or high rectum, N1-2, EMVI +ve, limited cT4aN0

cT3 MRF +vecT4a,bLateral node +ve

Surgery (TME alone)

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Complete data (Surgery MRI and Pathology) n=477Consented to follow up n=386Complete data with FU n=374

MRI defined good prognosis n=141 MRI defined bad prognosis n=234Surgery alone n=122 Pre operative radiotherapy n=19LR 4/122 (3%)5yr DFS 85%

MR stage T2N0 57T3aN0 24T3bN0 19T2N+ 7T3a N+ 6T3bN+ 9

“Good prognosis” rectal cancer best managed by surgery alone Taylor et al Annals of Surgery 2011

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Side effects of Preop RT

Rectal and sexual function is worse after preoperative radiotherapy and TME compared with TME alone: Results from many randomised studies

•u Peeters K, J Clin Oncol 2015;25:6199 •u Dahlberg M, Dis Colon Rectum 1998;41:543 •u Stephens RJ, J Clin Oncol 2010;28:4233 •u Marijnen CAM, J Clin Oncol 2005;23:1847 •u Lundby L, Lancet 1997;350:564 •u Lange MM, Br J Surg 2007;94:1278 17th

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Dutch TME and MRC CR07 trial design

n = 1350

Clinically operable adenocarcinoma of the rectum <15cm from anal verge; no metastases

Adjuvant chemotherapy given as per local policy – CR07

PRE SEL POST

Pre-operative RT25Gy / 5F

Surgery

Pathology

Surgery

Pathology

CRM-ve CRM+ve

Post-op (C)RTDutch RTCR07 CRT

No CRT

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CR07 and Dutch TME trial data

PRE SEL POST NNTDutch TME trial Lancet Oncology 2011

Stage I <1% 3% 10 yreligible 50MRC CR07 ESTRO 2012

Stage I 3% 5% 5 yr ITT 50T2 or less 5% 7% 5yr ITT 50T3a 3% 6% 5 yr ITT 3317th

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Dutch TME and MRC CR07 trialsVan Gijn et al Lancet Oncology 2011Sebag-Montefiore et al Lancet 2009

Dutch TME trial

MRC CR07

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CRT – 5FU 225mg/m2 cont50.4Gy CRT

Short coursePre op (25Gy in 5F)

N=326S

5FU/LV x4S

5FU/LV x 6

TROG AGIT LSSANZ RACS trial Ngan et al JCO 2012

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TROG AGIT LSSANZ RACS trial Ngan et al JCO 2012

CRT

SCPRT

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Pre vs. Postop CRTCAO/ARO/AIO-94

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Surgery (TME alone)25Gy in 5ForCRTFollowed by TME

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Surgery (TME alone)25Gy in 5ForCRTFollowed by TME

CRT? Neoadjuvant ChemoFollowed by TME

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ESMO 2017 Guidelines Risk Groups

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Pre-operative Chemoradiotherapyregimen

• Fluorpyrimidine– 5FU bolus or as continuous infusion– Oral Capecitabine• Radiotherapy dose– ESMO guidelines• 45-50.4Gy intermediate risk• 50.4Gy advanced• Radiotherapy target volume– External iliac nodes not routinely included– In intermediate risk superior limit can be lowered to S2/3– Low level evidence for the role of boost in advanced17th

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Intensification of CRT

• Addition of drug or targeted therapy to CRT– Disappointing (0xaliplatin ph III, VEGF/EGFR ph II)– Clinical trials• Neoadjuvant chemotherapy + pre-op CRT– More evidence (encouraging ph II eg EXPERT)• Short course radiotherapy + neoadjuvant chemotherapy– RAPIDO trial ongoing• Neoadjuvant chemotherapy – PROSPECT trial ongoing• Radiotherapy dose escalation– Clinical trials17th

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Summary of doublet and triplet CRT

• Oxaliplatin– Phase III disappointing• Irinotecan– ARISTOTLE trial recruiting• EGFR– Single arm phase II – inferior early pathological end points• Vascular targeted– Limited data

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RAPIDO Ph III Trial n=940Hospers et al ECCO 2017

1 week 18 weeks 2-4 weeksS

5x5 CAPE + OXALIPLATIN

1 week

5.5 weeks 6-8 weeks 6-8 weeks 24 weeksRT+CAPE CAPE + OXALIPLATIN

35

MRI definedcT4a,cT4b,cN2, EMVI+, Lat LN+

S

14 weeks

24 weeksOverall ypT0 = 23%

Variable use by countryDiffering Standards of Care

Use of 5x5

MRI defined Locally advanced

18 weeks NAC

Standard of care control arm

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Intensification of treatment using neoadjuvant chemo separate from RT

SELECTION FOR NEOADJUVANT CHEMOTHERAPY •u Extensive EMVI •u Disease breaching/outside the mesorectal fascia

• NEO-ADJUVANT BEFORE CRT• IN THE INTERVAL BETWEEN CRT AND TME OP

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NEO-ADJUVANT CHEMO BEFORE CRTEXPERT, EXPERT-C Trials

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SUMMARY

• Preoperative CRT better than postop • SCPRT=CRT for resectable cancers • SCPRT/CRT improves local recurrence but not DFS or OS • If CRM threatened on MRI needs response so CRT • Low rectal cancers (below the levators) often have threat to CRM and may have LPLN 17th

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ESMO Rectal Cancer GuidelinesAnnals of Oncology 28 (Supplement 4): iv22–iv40, 2017

SoCTME aloneAVOID RTTME alone if high quality or plusSCPRT/CRT

SCPRTorCRTThen TMECRT orSCPRT + FOLFOXthen TME

KeyMessages

cT1-2; cT3a/b if middle or high cN0 (cN1 ighigh) MRF clear; no EMVIcT3a/b very low levatorsclear. 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 +vecT3 with MRF involvedcT4b, levators threatened, lateral node +ve

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Organ Preservation

Low risk Moderate risk Highrisk

SCPRT CRTConsider Consider

CCR W+W

Organ preservation trialsAllows intensification

• Highly selected• CRT not changed• Surgery plan changed• Intensive FU for LR

(C)RTCCR W+WTEMContact

• RT not given• Intensification poss• “Double jeopardy”• Highest CCR• Intensive FU for LR17th

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Habr Gama data IJROBP 2014 88:822-8

CRT n=183CCR n=90

Early regrowthn=178 weeks

12 months Sustained CRn=73

Sustained CRn=62

Late regrowthn=11

AR n=7APER n=4FTLEn=5 Unresn=1

AR n=0APER n=7FTLE n=2Brachy n=1 Unresn=1

Unres n=2

Unres n=2Organ preservation n= 70 Unresectable pelvic disease n=6

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Organ Preservation – Key publications

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TREC - Study Design

50

Rectal CancerT1-2 N0

RandomiseRadical Surgery Organ Preservation

Clinical Equipoise?YesNo No

25Gy in 5F8-10 weeks

TEMS• Feasibility – yes 63 randomised• Early information on OP17th

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Deferral of rectal surgery studyRoyal Marsden Study – [email protected] cancer receiving CRT and ,agrees to surgery in needed

MRI 4 weeks post CRT + MDT discussionNo visible tumour Visible tumour good PR Stable disease

CONSIDERATION OF TRIALMRI and FDG PET at 8 weeks

No visible tumour or further regression No further regression / growth of disease

Surgical resectionProtocol defined follow up17th

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STARTREC – Study designPhase II/III clinical trial

TME

W&W TEM

Poor/inadequate responseLittle or no residual disease Good response:residual disease

high risk conversion TME

evaluation

cT1-3b N0

TMEOrgan preservationRadical Surgery

5x5 GyOrgan preservation

CRT

week 11-13 – central review

week 1-5

CCR Not CCRweek 16-20 – central review

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Documents

17th ESO-ESMO Masterclass in Clinical Oncology€¦ · radiotherapy and TME compared with TME alone: Results from many randomised studies •u Peeters K, J Clin Oncol 2015;25:6199