Perioperative Treatment of Locally Advanced Rectal Cancer · HR 2.91 (1.74-4.88) HR 1.56 (0.6-4.04) 1. Sebag-Montefiore D, et al. ASCO 2006. Abstract 3511; 2. Reprinted from Int J

PERIOPERATIVE TREATMENT OF LOCALLY ADVANCED RECTAL CANCER

Rob Glynne-Jones

Mount Vernon Cancer Centre, Middlesex, UK

Preoperative short course radiotherapy SCPRT (5 X 5 Gy)

Preoperative long course chemoradiotherapy CRT (25-28 X 1.8Gy Gy)

3 OPTIONS FOR RADIOTHERAPY

IN LOCALLY ADVANCED RECTAL CANCER

(Post-op CRT as adjuvant )

Induction - Pre RT (Short-course(SCPRT) or chemoradiation (CRT)

Concurrent - With RT (CRT)

Consolidation - Post CRT or SCPRT if waiting 6 to 12 weeks before surgery

Neoadjuvant alone without RT

5 OPTIONS FOR CHEMOTHERAPY IN

LOCALLY ADVANCED RECTAL CANCER

Post-op adjuvant

The rationale for short course/

chemoradiationfor rectal cancer

The limitations

of short course/ chemoradiation

for rectal cancer

How to select patients

suitable for short

course/long course

chemoradiation

The role of postop adjuvant

chemotherapy after CRT and after surgery

alone

You will be able to tailor the treatment to the individual

patient

THE AIM OF THIS E-MODULE

IS TO EXPLAIN

The evidence base

Preoperative assessment/indications for treatment

Surgery alone

Preop RT -SCPRT (5x5Gy) or chemoradiation?

The radiotherapy

The chemotherapy/what drugs

Interval to surgery

Acute and late effects

TOPICS

APER - 65% perineal recurrence

Anterior resection - 50% anastomotic/central recurrence

Both associated with high proportion of failures in posterior pelvis

Similar to Dutch TME data (den Dulk, Kusters etc..)

HISTORICAL SURGERY/PRE TME

Landmark retrospective review:

Thomas A, et al., Rectal Cancer 1969

830 patients treated 1951-1960

HISTORICAL PERSPECTIVE

5 Year Survival

Dukes A 79%

Dukes B 25%

Dukes C 6%

5X5Gy in Europe (Stockholm Trials/ Swedish Rectal Cancer Trial)

Post-operative CRT in USA

EVIDENCE BASE

S alone

IMPACT ON OVERALL SURVIVAL OF

6 METHODS OF TREATMENT IN RECTAL

CANCER POOLED ANALYSIS

S+RT

Gunderson LL, et al., J Clin Oncol 2004;22(10):1785-1796. Reprinted with permission. © (2004) American Society of Clinical Oncology. All rights reserved

And then came TME

Radiotherapy extrapolated to SCPRT and TME/preoperative CRT (German

Trial CAO/ARO/AIO-94/Dutch TME/CR07 trial)

EVIDENCE BASE

PRE- VS. POST-OPERATIVE

CHEMORADIATION CAO/ARO/AIO-94

0.3

0.2

0.0

0.1

0 2412 4836 60

P=0.006

Months

Locoregional Recurrences

Post

Pre

13%

6%

Acute G3/4 adverse events

27% vs. 40% (p=0.001)

Long-term G3/4

adverse events

14% vs. 24% (p=0.01)

There is a standard

for chemoradiation

From N Engl J Med, Sauer R, et al., Preoperative versus Postoperative Chemoradiotherapy for Rectal Cancer;351:1731-39.

Copyright © 2004, Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Included Stage I, Stage II and Stage III patients

Higher RT dose (55.8Gy) mandated in postoperative arm



Median time to recurrence

19 vs 31 months

5/22 local recurrences i.e. 23% after 5 years

LONG-TERM DATA ON LOC REC

FROM GERMAN STUDY

Rolf S, et al., J Clin Oncol 2012; 30:1926-1933. Reprinted with permission. © (2012) American Society of Clinical Oncology. All rights reserved.

Is this simply a compliance issue?

No RT - local recurrence 29.6%

Inadequate RT 21.2%

Adequate RT 6.8% (p =0.0001)

FIETKAU R, IJROBP 2007

Fietkau R, et al., Int J Radiat Oncol Biol Phys. 2007;67:1008–19



Rolf S, et al., J Clin Oncol 2012; 30:1926-1933. Reprinted with permission. © (2012) American Society of Clinical Oncology. All rights reserved.

At two years, local recurrence was 2.4 percent in the group assigned to

radiotherapy and surgery and 8.2 percent in the group assigned to surgery alone

(P<0.001)

DUTCH TME TRIAL

KAPITEIJN, NEJM 2001

From Kapiteijn E, et al., N Engl J Med. 2001 30;345:638-46 Copyright ©2001 Massachusetts Medical Society.

Reprinted with permission from Massachusetts Medical Society

At two years, overall survival was 82.0 percent in the group assigned to

radiotherapy and surgery and 81.8 percent in the group assigned to surgery alone

(P=0.84)

DUTCH TME TRIAL

KAPITEIJN, NEJM 2001

From Kapiteijn E, et al., N Engl J Med. 2001 30;345:638-46 Copyright ©2001 Massachusetts Medical Society.

Reprinted with permission from Massachusetts Medical Society

MRC CR07 NCIC C016 TRIAL

n = 1350

Clinically operable adenocarcinoma of the rectum

<15 cm from anal verge

Adjuvant chemotherapy given per local policy

PREOP

SCPRT

SELECTIVE

POSTOP CRT

Pre-operative RT

25Gy / 5F

Surgery

Pathology

Surgery

Pathology

CRM-ve CRM+ve

Post-op CRTNo CRT

Sebag-Montefiore D, et al., Lancet 2009;373(9666):811-20

POLISH TRIAL – BUJKO K, ET AL.,

RADIOTHERAPY AND ONCOLOGY 2004

Short course pre-op RT Pre-op CRT 50.4 + 5FU/LV

Immediate surgery

Surgery

6-8 week interval

cT3/T4, resectable, not involving levators,

palpable on DRE, <75 yrs

Planned operation recorded

N=316

Bujko K, et al., Radiother Oncol. 2004;72:15–24

TROG AGIT LSSANZ RACS TRIAL

NGAN, JCO 2012

cT3 resectable

Short course pre-op RT Pre-op CRT 50.4 + 5FU/LV

Immediate surgery

Surgery

6-8 week interval

N=326

Ngan SY, et al., J Clin Oncol. 2012 Nov 1;30(31):3827-33

SCPRT VERSUS CRT:

NO DIFFERENCE IN LOCAL CONTROL

14.4% vs 18.6%

P = 0.17

Polish Trial (Bujko 2006)1 TROG-01 Trial (Ngan 2012)2

7.5% vs 4.4%

P = 0.24

1. Bujko K, et al., Br J Surg 2006;93(10):1215–1223; Copyright © 2006 British Journal of Surgery Society Ltd. Published by John Wiley & Sons Ltd;

2. Ngan SY, et al., J Clin Oncol. 2012 Nov 1;30(31):3827-33. Reprinted with permission. © (2012) American Society of Clinical Oncology. All rights reserved.

SCPRT VERSUS CRT:

EQUIVALENCE IN OVERALL SURVIVAL

1. Bujko K, et al., Br J Surg 2006;93(10):1215–1223; Copyright © 2006 British Journal of Surgery Society Ltd. Published by John Wiley & Sons Ltd;

2. Ngan SY, et al., J Clin Oncol. 2012 Nov 1;30(31):3827-33. Reprinted with permission. © (2012) American Society of Clinical Oncology. All rights reserved.

Anorectal and sexual function is worse after preoperative radiotherapy and TME

compared with TME alone: Results from many randomised studies

Peeters K, J Clin Oncol 2015;25:6199

Dahlberg M, Dis Colon Rectum 1998;41:543

Stephens RJ, J Clin Oncol 2010;28:4233

Marijnen CAM, J Clin Oncol 2005;23:1847

Lundby L, Lancet 1997;350:564

Lange MM, Br J Surg 2007;94:1278

LARS SCORE

Chen TY-T, et al. Clinical Colorectal Cancer, Vol. 14, No. 2, 106-14 ª 2015 The Authors. Published by Elsevier Inc. This is an open access article

under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Major LARS found in 38% of patients, but only 27% after surgery alone

After surgery alone longer rectal remnant had better function

In contrast, 80% reported major LARS after preoperative CRT and surgery

And length of remnant made no difference

Bondeven P, et al., Eur J Surg Oncol 2015;41(11):1493-9

LOW ANTERIOR RESECTION

SYNDROME

RECTAL STUMP: MR

No Radiotherapy

Radiotherapy

Bondeven P, et al., Eur J Surg Oncol. 2015 Nov;41(11):1493-9

SEVERE LATE TOXICITY SCPRT

VERSUS SCRT

SCPRT CRT

Polish Study

Severe late toxicity – G3/G4 10% 7%

TROG 01.04

Severe late toxicity – G3/G4 9% 13%

THE EVIDENCE BASE FOR SCPRT

OR CHEMORADIATION IS NO LONGER

STATE-OF–THE ART FOR MODERN MDT

Courtesy of Barnet MDT

CRM status

Extramural Vascular Invasion (EMVI)

Involvement of levators

cT substage (cT3c and cT3d)

cN status

RELEVANT FACTORS WHICH CAN

BE IMAGED IN ORDER OF IMPORTANCE

MRI RISK STRATIFICATION

Courtesy of Prof Vicky Goh, Dept of Radiology, Guys and Thomas‘ NHS Hospitals trust, London, UK

Render resectable cancers resectable

If ≥1 mm predicted CRM/distance to mesorectal fascia (MRF) then shrink

tumour to give margin >2 mm (R0 resection)

(can be defined by MRI – i.e. tumour outside / breaching / close to MRF)

1. BORDERLINE/UNRESECTABLE

CANCERS

TRUS for early T1 cancers (for anatomical detail)

MRI for all cancers for CRM,EMVI, levator assessment, cTsubstage and

cNodal status

CT scan for all cancers (to image distant metastases)

PET/CT for extensive EMVI (very high risk of metastatic disease)

Colonoscopy to rule out synchronous tumours in colon

EUA often if very low at dentate line

RECOMMENDED STAGING

PROCEDURES

3 mm, 16 cm – 18 cm FOV, 4–6 NSA,

256 x 256 matrix, TR >3,000,

TE 80–100, ETL 16

In plane resolution 0.6 mm x 0.6 mm

MRI IS NOW STANDARDISED

Brown G, et al., Br J Radiol 2005;78:245-251

Courtesy of Prof Gina Brown

67% 5-year DFS for patients with a clear CRM predicted by MRI, versus 47%

for patients with a predicted involved CRM (p=0.003)

Local recurrence for MRI-involved CRM

HR 3.50 (95% CI, 1.53-8.00; P <0.05)

MRI-involved CRM - the only preoperative staging parameter that remained

significant for OS, DFS, and LR on multivariate analysis

CIRCUMFERENTIAL RESECTION

MARGIN STATUS (CRM) PREDICTED BY MRI

Taylor FG, et al., J Clin Oncol. 2014;32(1):34-43

MERCURY DATA

Taylor FG, et al., Magnetic Resonance Imaging in Rectal Cancer European Equivalence Study Group. J Clin Oncol. 2014 Jan 1;32(1):34-43

Reprinted with permission. © 2014 American Society of Clinical Oncology. All rights reserved

.

CIRCUMFERENTIAL RESECTION

1 MM MARGIN AND TREATMENT

CRM +ve 139

CRM -ve 1107

CR07 short course

5x5 Gy RT vs. none1

0 1 2 3 4 5 6 70

20

40

60

80

100

Ove

rall

surv

ival (

%)

Follow- up (years)

Mawdsley et al 2005

Luna Perez 2005

CRM -ve

CRM +ve

CRM -ve

CRM +ve

Chemoradiotherapy2,3

HR 2.91 (1.74-4.88)

HR 1.56 (0.6-4.04)

1. Sebag-Montefiore D, et al. ASCO 2006. Abstract 3511; 2. Reprinted from Int J Radiat Oncol Biol Phys, 63(3), Mawdsley S, et al. Can histopathologic assessment of

circumferential margin after preoperative pelvic chemoradiotherapy for T3-T4 rectal cancer predict for 3-year disease-free survival? 745-52; Copyright 2005 with

permission from Elsevier; 3. Luna Perez P, et al. J Surg Oncol. 2005;90:20–5. Copyright © 2005 Wiley-Liss, Inc.; 4. Reprinted from Clin Cancer Res Copyright 2007,

2007;13(22 Pt 1):6617-23 Gosens M, et al, Circumferential Margin Involvement Is the Crucial Prognostic Factor after Multimodality Treatment in Patients with Locally

Advanced Rectal Carcinoma, with permission from AACR.

4

DUTCH TME TRIAL (NAGTEGAAL

2002) – UNIRRADIATED GROUP (N= 656)

Dutch TME study 3 year local recurrence

+CRM < or = 2 mm 16%

CRM >2 mm 5.8% p=0·0001

Nagtegaal ID, et al., Pathology Review Committee; Cooperative Clinical Investigators. Am J Surg Pathol. 2002 Mar;26(3):350-7

CRM of >2 mm is cutoff though the risk

of recurrence is likely to represent a

continuum with larger margins giving

lower risk of recurrence

A CRM of 2 mm or less impacts on the prognosis of tumours located 6-15 cm

above the anal verge

ENDRESETH BJS 2009 CRM

Bernstein TE, et al., Br J Surg 2009;96:1348–57. Copyright © 2009 British Journal of Surgery Society Ltd. Published by John Wiley & Sons Ltd

OVERALL CR07 DATA

(BOTH ARMS)

CR07 3 year local recurrence

+CRM (<1 mm) 17%

-CRM 6% p=0.0011

CR07 – PERCENTAGE OF PATIENTS

WITH + CRM OVER TIME

Quirke P, et al., MRC CR07/NCIC-CTG CO16 Trial Investigators; NCRI Colorectal Cancer Study Group. Lancet. 2009;373(9666):821-8

Open access funded by Medical Research Council. Copyright © 2009 Elsevier Ltd

WE CAN JUDGE THE QUALITY OF

THE SURGERY

Courtesy of Prof Phil Quirke

RANDOMISED TRIALS SCPRT

(5X5GY)

TrialMRI

mandated

EUS

mandated

TME

mandated

Good

Quality TME

Median no

of nodes

resected

Swedish

RectalNo No No ?No

Not stated

Dutch TMENo No Yes 50% 7

Polish No No ? ? 9

CR07No No No 50% 11

TROG-0104If US not

possibleYes No ? Not stated

RANDOMISED TRIALS PREOP CRT

TrialMRI

mandated

EUS

mandatedTME

Good

Quality TME

Median no

of nodes

resected

German

(Sauer 2004)No Yes ? No data

Collected but

not stated

EORTC

22921No No 38% No data 7 after CRT

FFCD 9203 No No No data No dataNot stated

NSABP R03 No ? No No dataNot stated

Polish No No ? No data 8

TROG-0104 some Yes ? No data Not stated

EBRT (IMRT/IGRT)

Contact

Brachytherapy

SABR

TECHNICAL ADVANCES IN RT

Immobilisation/precision

Intensity-modulated radiation therapy

(IMRT)

Image guided radiation therapy

(IGRT)

IMRT Rectum

Prone position

Seven 6 MV co-planer beams

Beam angles:

0°40°85°160°200°275°315°

Low rectal cancers within 7 cm of anal verge

Need to be palpable to finger

Regarded as candidates for APER

Routinely offered CRT in Brazil

Habr Gama set out to avoid APER with set doses/field sizes/ meticulous

follow-up

ANGELITA HABR GAMA SET OUT

TO AVOID SURGERY AND SELECTED

http://iwwd.org/news/

Sceptical surgeons who see a CCR and then operate need to submit their

data too

INTERNATIONAL WATCH & WAIT

DATABASE (IWWD)

http://iwwd.org/news/

SO WHAT ARE THE INDICATIONS FOR SCPRT/CRT

Chemoradiation is going to shrink the cancer

And interval +/- filled with chemotherapy

SCPRT (5x5Gy) and delay filled with chemotherapy prior to surgery may be

an alternative

EVIDENCE BASE

To reduce the risk of local recurrence

To compensate for inexperienced surgeon

If the surgeon finds other reasons for which he is not convinced that an R0

resection can be achieved

To treat lateral pelvic lymph nodes

A perforation which has now healed

To help to achieve sphincter sparing?

Frail, aged or unsuitable for radical surgery because co-morbidity

2. RESECTABLE CANCERS

OVERVIEW OF NCCN GUIDELINES

FOR RECTAL CANCER – V2.2016

NCCN Guideliens Version 2. 2016 – Rectal Cancer. Available at: https://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf. Accessed May 2016

Adjuvant treatment (6 mo perioperative treatment preferred

Primary treatment Neoadjuvant therapyClinical stage

T3, N0 or T any, N1–2 or T4

and/or locally unresectable or

medically inoperable

Chemo/RT

• Capecitabine/long-course RT or infusional 5-FU/long-course RT (category 1 and preferred for both) OR

• Bolus 5-FU/ leucovorin/long-course RT

Transabdominal resection

• FOFOX (preferred) or CapeOx (preferred)

• OR

• FLOX or 5-FU/ leucovorin or capecitabine

Surveillance

Resection contraindicated

Active chemotherapy regimen for advanced disease

RT

• Short-course RT (not recommended for T4 tumours)

Transabdominal resection

Resection contraindicated

Active chemotherapy regimen for advanced

disease

Chemotherapy

• FOLFOX (prefereed) or CapeOx (preferred) OR

• 5-FU/leucovorin or capetiabin

Surveillance

OR

OR

Capecitabine/RT (preferred) or

infusional 5-FU/RT (preferred) or bolus 5-

FU/leucovorin/RT

“ As in colon cancer stage III (and ‘high-risk’ stage II), adjuvant chemotherapy can be given, even if the level of scientific evidence for sufficient benefit is much lower than in colon cancer [33, 34, 35] [II, B].”

From a practical point of view, rectal cancers could be divided into four groups:

1. Very early (some cT1)

2. Early (cT1-2, some cT3)

3. Intermediate (cT3- some cT4a)

4. Locally advanced (cT3crm +, some cT4a, all cT4b)

Glimelius B, et al., Ann Oncol. 2013;24 Suppl 6:vi81-8

ESMO

Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up: Glimelius B, et al., Ann Oncol. 2013;24 Suppl 6:vi81-8.

By permission of Oxford University Press

TME NORTHERN EUROPE: GOOD

QUALITY MESORECTAL PLANE: NO RT

Study EligibleGood Quality

MesorectalLocal Recurrence Actuarial

Swedish Rectal

Cancer Trial 1997

(574)

T any N any <10% 150/557 27% >30%

CR07 overall

(592) Quirke 2009T any N any 51% 59/592 10% 11%

Dutch TME (180)

Nagtegaal 2005T any N any 56% Not stated 8.7% at 2 years

CR07 (301)

Quirke 2009T any N any

100% (MRI not

routinely used)27/301 9% 7% at 3 years

Mercury* (122)

Taylor 2011T3a/b N any crm- 70% 4/122 3%

3.3% at 5 years

* NB: MRI directed

Ext. Iliac A .

Sup. Vesical A

Obturator N

Ext. iliac V

Int.Iliac A .

Ureter

Head

Pelvic plexus

LATERAL NODE DISSECTION OF

RIGHT SIDE PELVIC WALL

Courtesy of Dr Hirofumi Ota, Japan

FREQUENCY OF LATERAL LYMPH

NODE INVOLVEMENT IN RECTAL CANCER

Ueno 2005 LPLND R0

resection T3/T4% Positive

Distance to anal margin 6.1 -8 cm 10.5%

4.1- 6 cm 12.9%

2.1-4 cm 26.1%

2 cm or less 41.7%

TOTAL 237 17.3%

WHAT HAPPENS IF A COMPLETE

CLINICAL RESPONSE AFTER CRT

OR SCPRT IS OBSERVED?

“Half of your patients don’t need surgery!”Rodrigo Perez

CHEMOTHERAPY

BRAZILIAN DATA: 22/28 SALVAGED

183 patients

CRT

93 surgery90 cCR

17 early regrowth 73 sustained response

62 FUP

11 late recurrence

8 salvage 3 unresectable

14 salvage 3 unresectable

Habr-Gama IJROBP 2014

Prospective since 2009

21/192 patients (11%) with CCR included in wait and see policy (how many

not?)

6/21 cT2 and 1 cT1! Patients expressed a strong preference to avoid surgery

All but 4 (17/21) received FOLFOX ‘adjuvant’ chemotherapy post CRT

Meticulous follow-up including MRI

Mean follow-up only 25 months

Only 1 endoluminal recurrence at 22 months

DUTCH DATA:

MAAS M, ET AL., J CLIN ONCOL 2011

Watch-and-wait seems safe for small early node negative low tumours with

standardised CRT and meticulous follow-up

Limits some potential risks and harms of radical surgery – particularly for

frail or elderly patients

There is a risk of eventual local tumour regrowth

No randomised trials

Still patient driven

No guarantee of same results for more advanced T3/T4 N+ cancers in

mid/upper rectum

Limit to specialist centres?

WATCH-AND-WAIT CONCLUSIONS

Author

(Year)Nr

Patient

selection

Poor risk

featuresTreatment

R0 RESECTION

RATE

pCR

Rate

Ishii et al.

(2010)26

T3-4 any N,

within 12 cm of

anal verge

T4:12%

CRM NRIFL 100% 3.8%

Cercek et al.

(2010)6 T2-3, N1

T4: 0%

CRM NRFOLFOX 100% 33%

Fernandez-

Martos et al.

(2014)

46T3 midd rectum,

no CRM+

T4:0%

CRM:0%CAPOX-BEV 95,6% 20%

Uehara et al.

(2013)32

T3c-d-T4, N2,

CRM+

T4a: 28%

T4b: 31%

CRM: NR

CAPOX-BEV 84,3% 12,5%

Schrag et al.

(2014)32

T2N1, T3 any N,

No N2, No lower

third

T4:0%

CRM:0% FOLFOX-BEV 100% 25%

TRIALS OF NEOADJUVANT CT

WITHOUT RT IN LOCALLY ADVANCED

RECTAL CANCER

Sclafani F, Cunningham D. Future Oncol 2014;10:2243-2257

NACT AND THEN CRT IN MRI

DEFINED HIGH RISK RECTAL

CANCER (EXPERT AND EXPERT-C)

Clinical Response after NACT ITT population n=269 %

Complete response 11 4.1

Partial response157 58.4

Stable disease 76 28.3

Progressive disease 3 1.1

Unassessable/not known 22 8.2

NACT is feasible and does not compromise delivery of CRT

High response rates and few progress in phase II single arm or

randomised phase II

But…. still should be considered experimental

Requires validation in randomised phase III trials in patients with MRI defined

high risk rectal cancer

NACT

WE ALREADY USE IMAGING BIOMARKERS WHICH ARE ROBUST ENOUGH TO MAKE DECISIONS

or SCPRT + chemo

MRI

Glynne-Jones R, et al., Oncology, 2014;28 (8):667-77

Extensive EMVI

Disease breaching/outside the mesorectal fascia

IN FUTURE – SELECTION FOR

NEOADJUVANT CHEMOTHERAPY

Good evidence for fluoropurimidine’s benefit in Stage III (stage II QUASAR)

Good evidence for Oxaliplatin stage III

Small benefit for 5FU in stage II

No benefit in OS for Stage II for oxaliplatin

Benefit in elderly over 70 years?

Virgin Histopathology (uncorrupted by RT/CRT)

Need 12 nodes for decision-making

ADJUVANT CHEMOTHERAPY

IN COLON CANCER

OVERALL SURVIVAL HIGH RISK

STAGE II IN MOSAIC (TOURNIGAND 2012)

Tournigand C, et al., J Clin Oncol. 2012;30 :3353-60. Reprinted with permission © 2012 American Society of Clinical Oncology. All rights reserved.

Good evidence for fluoropurimidines after surgery alone and LPLND

(Japanese data)

Benefit for over 70 years in stage II (QUASAR)?

No evidence for 5FU after CRT

No large phase III trial evidence for adjuvant Oxaliplatin - excluded from

landmark randomised studies?

Chronicle / Adore trial/PETACC6/AIO discordant


IN RECTAL CANCER

Good evidence for fluoropurimidines after surgery alone and LPLND

(Japanese data)


IN RECTAL CANCER

META-ANALYSIS

Meta-analysis Group of the Japanese Society for Cancer of the Colon

and Rectum and the Meta-analysis Group in Cancer

DFS is improved after

adjuvant CT

Using oral 5FU

P=0.002

Even in Dukes’ A

Sakamoto J, et al., J Clin Oncol 2004;22:484-92. Reprinted with permission © 2004 American Society of Clinical Oncology. All rights reserved.

GITSG 7175 – 4-arm trial

Survival benefit at 8 years for CRT - chemo reducing DM (20% vs. 30%) and

RT decreasing LR (16% vs. 25%)

NSABP R-01 – 3-arm trial

Chemo improved 5 yr OS (60 vs. 37%) – RT decreased LR (16% vs. 25%) but

no OS

NSABP R-02 – Chemo vs. CRT (gender specific design)

RT decreased LR (8% vs. 13%) but no OS impact

POSTOP STUDIES SHOWING

BENEFIT OF CHEMO

IMPACT ON OVERALL SURVIVAL

OF 6 METHODS OF TREATMENT IN RECTAL

CANCER POOLED ANALYSIS

S alone

Gunderson LL, et al., J Clin Oncol 2004;22(10):1785-1796. Reprinted with permission. © (2004) American Society of Clinical Oncology. All rights reserved.

S+RT

SUBSET analysis

198/3239 = 6% overall

198/968 = 20% of rectal cancer

Reprinted from Lancet, 371(9623), Gray R, McConkey RT, Adjuvant chemotherapy for rectal cancer – Authors' reply, 1503,

Copyright 2008, with permission from Elsevier.

10 year OS 51.8% vs 48.4%

(HR 0.91- 95% CI 0.77–1.09; p=0.32)

EORTC 22921 –

OVERALL SURVIVAL

Reprinted from the Lancet Oncology, Bosset JF, et al., Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal

cancer: long-term results of the EORTC 22921 randomised study, Vol 15(2), 184-190, Copyright 2014, with permission from Elsevier

Only 1/21 trials received preoperative CRT

Only 2/21 received SCPRT

META-ANALYSIS

Reduction in risk of disease recurrence (25%) with adjuvant

chemotherapy compared to observation (HR=0.75, CI: 0.68-0.83)

Level 1 evidence for fluoropurimidines after surgery alone (Japanese data)

Benefit for over 70 years in stage II (QUASAR)?

But… level of benefit may be smaller

No evidence for 5FU after CRT in individual trials

No large phase III trial evidence for adjuvant Oxaliplatin - excluded from

landmark studies?

Chronicle trial / Adore trial

ADJUVANT CHEMOTHERAPY IN

RECTAL CANCER

NB: pathological stage II no significant difference

THE ADORE PHASE II TRIAL:

DISEASE FREE SURVIVAL

Hong YS, et al., Lancet Oncol. 2014;15:1245–53. Reprinted from The Lancet Oncology. Copyright 2014, with permission from Elsevier.

Consistent HR for chemo after CRT if randomised post CRT

We need more accurate risk stratification

So MRI is essential (mrTRG)

Consider postop histology rather than preop

ypN+/ ypEMVI+ high risk

Start chemotherapy asap after surgery

Start with modified doses (pelvic RT) to achieve better compliance?

CONCLUSIONS

CAPECITABINE

Disease-free survival

Reprinted from The Lancet Oncology, 13(6), Hofheinz RD, et al., 579-88, Copyright 2012, with permission from Elsevier.

PHASE III TRIALS – INVESTIGATING

OXALIPLATIN

Trial EligibilityFluoropyrimidine

Platform

CAO/ARO/AIO-04<12 cm from anal verge

T3/T4 cN0/N+ TRUS, CT and/or MRI

5FU 1000 mg/2 X 5 days

1-5 + 29-33

NSABP R04

N=1606

<12 cm; resectable stage II, III TRUS or MRI

– CT if T4/ N1-2

PVI 5FU vs.

capecitabine

FFCD

N=598

Palpable; resectable; T3/4 N0-2; T2 distal

anterior

Capecitabine in both

arms

STAR – 01

N=747

Resectable stage II, III (c stage) <12 cm

from anal vergePVI 5FU in both arms

PETTAC 6

N=1090

Stage II or III resectable or expected to

become resectable <12 cm from anal verge

Capecitabine in both

arms

Median follow-up of 50 months

At 3 years, cumulative incidence of local recurrences after R0/1 resection was

2·9% in the oxaliplatin group versus 4·6% in control group

THE GERMAN CAO/ARO/AIO-04

TRIAL

Rödel C, et al., Lancet Oncol. 2015;16(8):979-89.

Reprinted from The Lancet Oncology, Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German

CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial, Copyright (2015), with permission from Elsevier.

At 3 years, the cumulative incidence of distant recurrences 18·5% in the oxaliplatin

group 22·4% in the control group


TRIAL


Rödel C, et al. Lancet Oncol. 2015;16(8):979-89.


CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial , Copyright (2015), with permission from Elsevier.

3 year DFS 75·9% in the investigational group vs. 71·2% in the control group

(hazard ratio [HR] 0·79, 95% CI 0·64-0·98; p=0·03).


TRIAL


Rödel C, et al., Lancet Oncol. 2015;16(8):979-89.


CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial, Copyright (2015), with permission from Elsevier.

UNKNOWN WHETHER THESE BENEFITS RELATE TO THE ADDITION OF PREOPERATIVE OR POSTOPERATIVE OXALIPLATIN, OR BOTH

After SCPRT (5x5Gy)

WHAT IS THE OPTIMAL INTERVAL

TO SURGERY?

No downstaging

SCPRT normally recommended to be followed by surgery within 1-7 days

An “ideal” SCPRT schedule, delivers 5 X 5 Gy from Monday to Friday with

surgery the following Monday or Tuesday – i.e. an interval of less than 10 days

AFTER SCPRT

But Short-course RT induces tumour downstaging if surgery is performed

after an interval of 4-8 weeks

STOCKHOLM III TRIAL

Pettersson D, et al., Br J Surg 2015;102(8):972-8

R

A

N

D

O

M

I

S

A

T

I

O

N

SCPRT 5X5 GY

Standard CRT

RAPIDO TRIAL

N = 885 PATIENTS

CapOx + 6

Capecitabine: 825 mg/m2

Oxaliplatin: 130 mg/m2

T4

EMVI+

N2

CRM+

T

M

E

Primary endpoint 3 year DFS

Nilsson PJ, et al., BMC Cancer. 2013;13:279

After SCPRT (5x5Gy)

After long course CRT

WHAT IS THE OPTIMAL INTERVAL

TO SURGERY?

Longer intervals up 15 weeks

Associated with an increased chance of a pCR (Sloothak, Kalady)

HYPOTHESIS

Cumulative complete pathological response (pCR) rate

But no increase in negative CRM!

Sloothaak DA, et al., Dutch Surgical Colorectal Audit. Br J Surg. 2013;100(7):933-9. © 2013 British Journal of Surgery Society Ltd.

Published by John Wiley & Sons Ltd

HYPOTHESIS

TIMING OF RECTAL CANCER

RESPONSE TO CRT

Single-arm Simon’s two-stage minimax design

Reprinted from The Lancet Oncology 2015,16(8); 957-966, Garcia-Aguilar J, et al., Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in

locally advanced rectal cancer: a multicentre, phase 2 trial. Copyright 2015, with permission from Elsevier

Radiotherapy was given 5 days per week for 5 weeks for a total of 45 Gy with a minimum boost of 5.4 Gy.Fluorouracil was given as a 225 mg/m2 per day continuous infusion for 7 days/week during radiation therapy for 5-6 weeks, depending on the number of radiation boosts given. mFOLFOX6 was given in 2-week cycles of leucovorin 200 mg/m2 or 400 mg/m2 and oxaliplatin 85 mg/m2 in a 2-h infusion, bolus fluorouracil 400 mg/m2 on Day 1, and a 46-h infusion of fluorouracil 2400 mg/m2. *Interim assessments were done by proctoscopic examination; total mesorectal excision was done if the patient had stable or progressive disease.

TUMOUR RESPONSE – PCR

Cohort 1 (60)

SG1

Cohort 2 (67)

SG2

Cohort 3 (67)

SG3

Cohort 4 (65)

SG3

pCR 11 (18%) 17 (25%) 20 (30%) 25 (38%)

Post CRT

ChemoNone

2 cycles

FOLFOX

4 cycles

FOLFOX

6 cycles

FOLFOX

Interval to

surgery8 weeks 11 weeks 15 weeks 19 weeks

N0/N+ 75%/25% 75%/25% ? ?

Garcia-Aguilar J, et al., The Lancet Oncology 2015;16(8): 957-966

TOXICITY/COMPLIANCE

Cohort 1 (60)

SG1

Cohort 2 (67)

SG2

Cohort 3 (67)

SG3

Cohort 4 (65)

SG3

Post CRT

ChemoNone 2 cycles FOLFOX

4 cycles

FOLFOX

6 cycles

FOLFOX

Interval to


Treatment

interruptions7% 35% 40%

Dose

reductions2% 13% 35%


TOXICITY/COMPLIANCE

Cohort 1 (60)

SG1

Cohort 2 (67)

SG2

Cohort 3 (67)

SG3

Cohort 4 (65)

SG3

Post CRT

ChemoNone

2 cycles

FOLFOX

4 cycles

FOLFOX

6 cycles

FOLFOX

Interval to


Pelvic Fibrosis

(1-10)2.4 3.4 4.4

3.9

p=0.0001

Technical

difficulty (1-10)4.6 4.9 5.1 4.8 (p=0.8)


Medical Oncology trials EXPERT, EXPERT C, SPANISH (Fernandez-Martos)/

RAPIDO use systemically active chemotherapy outside chemoradiation

Radiation Oncology trials ACCORD 12, STAR-01, CAO/ARO/AIO-04, NSABP

R04 use oxaliplatin as radiosensitiser (non systemic doses)

CURRENTLY –

DIFFERENT PHILOSOPHIES

Induction - Pre RT (Short-course(SCPRT) or chemoradiation (CRT)1

Preoperative long course chemoradiotherapy CRT (25-28 X 1.8Gy Gy)

Consolidation - Post CRT or SCPRT if waiting 6 to12 weeks before surgery2

3 PREOP OPTIONS FOR

CHEMOTHERAPY AND RT IN LOCALLY

ADVANCED RECTAL CANCER

1. Expert C, Fernandez-Martos, Cercek; 2. Garcia-Aguilar J, FOLFOX, Bujko K, RAPIDO –Nordic Countries/Holland

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

CURRENT WISDOM

THANK YOU

Documents

Perioperative Treatment of Locally Advanced Rectal Cancer · HR 2.91 (1.74-4.88) HR 1.56 (0.6-4.04) 1. Sebag-Montefiore D, et al. ASCO 2006. Abstract 3511; 2. Reprinted from Int J