E-Learning Peri-Operative Treatment of Locally Advanced

PERI-OPERATIVE TREATMENT OF LOCALLY ADVANCED RECTAL CANCER ESMO E-Learning module

Dr Francesco Sclafani, MD PhD

Institut Jules Bordet, Brussels, Belgium

INTRODUCTION

Aims of this E-Learning module

Explain the rationale behind the use of peri-operative treatment

Discuss main risk factors that should be considered in the decision making

Highlight pros and cons of the available therapeutic strategies including timing and sequence of treatments

Present recent practice-changing data and management options that may become standard of care in the near future

By answering to a number of key questions, this E-Learning module aims to:

Source

Number of

patients

Local

recurrences

5-year

disease-free

survival rate

Conventional technique

Arbman, et al.

1996 134 24% 50%

LSCO* 270 24% 40%

TME

Arbman, et al.

1996 125 8% 70%

Bjerkeset, et

al. 1996 81 4% 85%

Zaheer, et al.

1998 514 7% 79%

Heald, et al.

1998 405 3% 80%

HISTORICAL RATIONALE OF PERI-OPERATIVE

TREATMENT FOR LOCALLY ADVANCED RECTAL CANCER

High rates of local recurrence and overall poor survival

outcomes after curative resection of rectal cancer (especially

before the routine use of total mesorectal excision [TME])

Local recurrence is associated with a number of disabling

symptoms including:

◆ pain

◆ fistulation

◆ neurologic deficits

◆ ureteric obstruction

◆ infection

◆ lympho-vascular complications

*Lower Silesian Center of Oncology (own data)

ONCOLOGICAL OUTCOMES OF

STAGE II–III RECTAL CANCER

Patient outcomes remain poor despite routine adoption of TME

*Data from the control group of the Dutch TME trial.

van Gijn W, et al. Lancet Oncol 2011;12(6):575–82.

TNM stage

10-year

local recurrence

10-year

overall survival

I 3% 72%

II 8% 55%

III 19% 37%

Oncologic outcomes following TME surgery alone*

RANDOMISED TRIALS OF PERI-OPERATIVE THERAPY

BEFORE ROUTINE USE OF TME

Any peri-operative treatment (chemo-, radio- or chemoradiotherapy) either before or after

conventional (i.e., non-TME) surgery improves outcomes compared with surgery alone

Preoperative radiotherapy as adjuvant treatment in rectal cancer: Final results of a randomised study of the European Organisation for Research and Treatment of Cancer (EORTC)

• Gérard A, et al. Ann Surg 1988;208(5):606–14

Postoperative radiotherapy in Dukes’ B and C carcinoma of the rectum and rectosigmoid: A randomized multicenter study

• Balslev IB, et al. Cancer1986 1;58(1):22–8

Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: Results from NSABP Protocol R-01

• Fisher B, et al. J Natl Cancer Inst 1988;80(1):21–9

Prolongation of the disease-free interval in surgically treated rectal carcinoma

• Gastrointestinal Tumor Study Group. NEJM 1985;312:23

Preoperative irradiation for carcinoma of the rectum and rectosigmoid colon: Report of a National Veterans' Administration randomized study

• Roswit B, et al. Cancer 1975;35(6):1597–602

Post-op chemo: better DFS/OS Post-op RT: better local control

Post-op CRT: better DFS/OS Pre-op RT: better local control/OS

Pre-op RT: better local control Post-op RT: better local control (stage III)

Is peri-operative treatment still necessary

if high-quality TME surgery is performed?

Question 1

PRE-OPERATIVE RADIOTHERAPY IMPROVES LOCAL

CONTROL (BUT NO OVERALL SURVIVAL) EVEN IF

HIGH-QUALITY TME SURGERY IS PERFORMED

The Dutch TME trial

Reprinted from The Lancet Oncol, 12(6), van Gijn W, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the

multicentre, randomised controlled TME trial, 575–82. Copyright 2011 with permission from Elsevier; .Kapiteijn E, et al. N Engl J Med 2001;345:638–46.

Median follow-up 11.6 years

▪ 10-year local relapse: 5% vs. 11%; p<0.0001

▪ 10-year distant relapse: 25% vs. 28%; p=0.21

▪ 10-year OS: 48% vs. 49%; p=0.86

Years

Years

SCRT → TME

TMEN=1805

Clinically

resectable

(stage I-III)

RPrimary

endpoint:

local control

SCRT: 25 Gy in 5 fractions Overall survival

Local recurrence

X

While it may not improve overall survival,

delivering radiotherapy before surgery reduces

the risk of local recurrence (by approx. 60%)

Take home message

Should radiotherapy be

delivered before or after surgery?

Question 2

BETTER LOCAL CONTROL IF CHEMORADIOTHERAPY

IS DELIVERED BEFORE SURGERY

The German Rectal Cancer Study Group trial

Sauer R, et al. N Engl J Med 2004;351(17):1731–40; Sauer R, et al. J Clin Oncol 30 (16), 2012: 1926–33.

Reprinted with permission. © 2012 American Society of Clinical Oncology. All rights reserved.

CRT → TME

→ ACT

TME → CRT

→ ACT

N=799

Stage II-III


▪ 10-year local relapse: 7.1% vs 10.1%, HR 0.60; p=0.048

▪ 10-year distant relapse: 29.8% vs. 29.6%; HR 0.98; p=0.9

▪ 10-year OS: 59.6% vs. 59.9%; HR 0.98; p=0.85

CRT: 50.4 Gy (Pre-op) or 55.8 Gy (Post-op)

with 5FU 1000 mg/m2 ci d1-5 q28 x2

CT: FU 500 mg/m2 bolus d1-5 q28 x4

R

Primary

endpoint:

5-yr OS

LESS ACUTE AND LONG-TERM TOXICITY IF

CHEMORADIOTHERAPY IS DELIVERED BEFORE SURGERY

The German Rectal Cancer Study Group trial

Sauer R, et al. N Engl J Med 2004;351(17):1731–40.

Type of toxic effect

Preoperative

chemoradiotherapy

(n=399)

Postoperative

chemoradiotherapy

(n=237)

P-

value

Acute

Diarrhoea 12 18 0.04

Haematologic effects 6 8 0.27

Dermatologic effects 11 15 0.09

Any grade 3 or 4 toxic effect 27 40 0.001

Long-term

Gastrointestinal effects 9 15 0.07

Strictures at anastomotic site 4 12 0.003

Bladder problems 2 4 0.21

Any grade 3 or 4 toxic effect 14 24 0.01

CRT → TME

→ ACT

TME → CRT

→ ACT

N=799

Stage II-III

CRT: 50.4 Gy (Pre-op) or 55.8 Gy (Post-op)

with 5FU 1000 mg/m2 ci d1-5 q28 x2

CT: FU 500 mg/m2 bolus d1-5 q28 x4

R

Primary

endpoint:

5-yr OS

Grade 3 or 4 acute toxic effects of chemoradiotherapy


▪ 10-year local relapse: 7.1% vs. 10.1%, HR 0.60; p=0.048

▪ 10-year distant relapse: 29.8% vs. 29.6%; HR 0.98; p=0.9

▪ 10-year OS: 59.6% vs. 59.9%; HR 0.98; p=0.85

SELECTIVE USE OF POST-OPERATIVE RADIOTHERAPY

INCREASES THE RISK OF TUMOUR RECURRENCE

The MRC-07 trial

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

Primary

endpoint:

local

recurrence

▪ CRM+ tumours: 10% in pre-op RT arm and 12% in post-op RT arm

▪ 60/77 (78%) of patients with CRM+ tumours received post-op (C)RT

▪ 86% of specimens in the mesorectal or intramesorectal plane

3-yr LR rate:

4.4% vs 10.6%

3-yr DFS rate:

77.5% vs 71.5%

SCRT: 25 Gy in 5 fractions

CRT: 45 Gy + 5FU 200mg/m2/day (or 300 mg/m2 q1w + FA)

ACT: 5FU 370-425 mg/m2 + FA d1-5 q28 or q1w

TME + CRT (if

CRM+) ± ACT

SCRT → TME

± ACTN=1350

Resectable

tumours

R

Radiotherapy is more effective and

less toxic when delivered before surgery

Take home message

What are the standard pre-operative treatment

regimens (before ASCO 2020)?

Question 3

25 Gy in

5 fractionsSurgery

50.4-–54 Gy in

28–30 fractions with

concurrent 5FU

or capecitabine

Surgery

STANDARD PRE-OPERATIVE TREATMENT REGIMENS

FOR LOCALLY ADVANCED RECTAL CANCER (BEFORE ASCO 2020)

Long-course chemoradiotherapy (CRT) and short-course radiotherapy (SCRT)

Short-course radiotherapy (SCRT)

and immediate surgery

6–8 weeks

<1 week

25 Gy in

5 fractionsSurgery

Short-course radiotherapy (SCRT)

and delayed surgery

4–8 weeks

Long-course chemoradiotherapy

(CRT) and delayed surgery

THE TRANS-TASMAN ROGT 01.04 AND POLISH TRIALS

Long-course chemoradiotherapy and short-course radiotherapy + surgery within

1 week are equivalent in terms of local tumour control

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

2. Reproduced from: Bulko K, et al. Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer.

Br J Surg 2006;93(10):1215-23, by permission of John Wiley and Sons Ltd., Copyright © 2013 British Journal of Surgery Society Ltd.

CRT → Surg

→ ACT

SCRT → Surg

→ ACT

N=323

T3, N any

3-yr LR: 7.5% vs 4.4%; p=0.24

4-yr LR: 10.6% vs 15.6%; p=0.21

CRT → Surg

SCRT → SurgN=312

T3-4, N any,

mid-low

LOCAL RECURRENCE

R R


LCRT: 50.4 Gy + 5FU 225mg/m2/day

ACT: 5FU 425 mg/m2 + FA d1-5 q28 x4 (SCRT) or x6 (CRT)

Primary

endpoint:

3-yr LR


LCRT: 50.4 Gy + 5FU 325mg/m2 +FA d1-5 q28 x2

Primary

endpoint:

Sphincter

preservation

5-yr OS: 67.2% vs 66.2%, HR 1.01; p=0.965-yr OS: 74% vs 70%, HR 1.12; p=0.62

OVERALL SURVIVAL

CRT → Surg

→ ACT

SCRT → Surg

→ ACT

N=323

T3, N any

CRT → Surg

SCRT → SurgN=312

T3-4, N any,

mid-low R R




Primary

endpoint:

3-yr LR



Primary

endpoint:

Sphincter

preservation



1 week are equivalent in terms of overall survival

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

2. Reproduced from: Bulko K, et al. Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer.

Br J Surg 2006;93(10):1215-23, by permission of John Wiley and Sons Ltd., Copyright © 2013 British Journal of Surgery Society Ltd.

Severe late AEs

Short-course radiotherapy (n=138)

Chemoradiation (n=141)

Small/large intestine† 7 (5.1) 2 (1.4)

Urinary bladder 2 (1.4) 1 (0.7)

Skin (non-healing perineal wound) 0 4 (2.8)

Urether 1 (0.7) 1 (0.7)

Nerves: motor function 3 (2.2) 2 (1.4)

Nerves: sensory function 1 (0.7) 1 (0.7)

Nerves: pain 0 1 (0.7)

Postoperative hernia requiring surgery 1 (0.7) 1 (0.7)

Fracture of femoral neck 1 (0.7) 0

Total complications 16 in 14 patients 13 in 10 patients1. Ngan SY, et al. J Clin Oncol 2012;30(31):3827–33;

2. Bujko K, et al. Br J Surg 2006;93(10):1215–23

SAFETYGrade ≥3 late AEs

Late RT toxicity type

SC (n=155) LC (n=158)

Grade 3 Grade 4 Grade 3 Grade 4

Skin, pelvic 0 1 0 1

Subcutaneous tissue 0 1 0 1

Small or large intestine 2 3 6 2

Bladder 3 0 2 0

Other* 2 1 3 0

Any toxicity 6 3 10 3

CRT → Surg

→ ACT

SCRT → Surg

→ ACT

N=323

T3, N any

CRT → Surg

SCRT → SurgN=312

T3-4, N any,

mid-low R R




Primary

endpoint:

3-yr LR



Primary

endpoint:

Sphincter

preservation



1 week are equivalent in terms of late adverse events

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

2. Bujko K, et al. Br J Surg 2006;93(10):1215–23

Treatment pCR Downstaging

SCRT 1% 28%

CRT 15% 45%

Treatment pCR R1 resection

SCRT 1% 13%

CRT 16% 4%

Long-course CRT is the preferred option when tumour downstaging is needed

CRT → Surg

→ ACT

SCRT → Surg

→ ACT

N=323

T3, N any

CRT → Surg

SCRT → SurgN=312

T3-4, N any,

mid-low R R




Primary

endpoint:

3-yr LR



Primary

endpoint:

Sphincter

preservation


Long-course chemoradiotherapy is associated with higher rates of tumour

downstaging and pCR than short-course radiotherapy + surgery within 1 week

Reprinted from The Lancet Oncol, 18(3), Erlandsson J, et al. Optimal fractionation of preoperative radiotherapy and timing to surgery

for rectal cancer (Stockholm III): a multicentre, randomised, non-blinded, phase 3, non-inferiority trial, 336–46 Copyright 2017, with

permission from Elsevier; Pettersson D, et al. Br J Surg 2015;102(8):972–8.

N=840

Resectable


RT: 50 Gy in 25 fractions

SCRT → Surg (4–8 wk)

RT → Surg (4–8 wk)

Primary

endpoint:

Time to LR

(non-inferiority)

SCRT → Surg (<1 wk)

THE STOCKHOLM III TRIAL

Delaying surgery up to 4–8 weeks after short-course

radiotherapy is another option and increases

pathologic tumour regression

Time to recurrence 33.4 vs. 19.3 (NS)

5-yr RFS: 65% vs. 68%

5-yr OS: 76% vs. 77% %

Years

Patholical outcomes SRT(n=234)

SRT-delay(n=228)

P-value¶

Tumour stage 0.001

yp0 4 (1.7) 27 (11.8)

ypI 69 (29.5) 76 (33.3)

ypII 71 (30.3) 53 (23.2)

ypIII 74 (31.6) 55 (24.1)

ypIV 5 (2.1) 6 (2.6)

ypx† 11 (4.7) 11 (4.8)

Tumour category <0.001

ypT0 5 (2.1) 27 (11.8)

ypT1 12 (5.1) 27 (11.8)

ypT2 74 (31.6) 60 (26.3)

ypT3‡

ypT3ab 88 (37.6) 67 (29.4)

ypT3cd 41 (17.5) 26 (11.4)

ypT3x 3 (1.3) 1 (0.4)

ypT4

ypT4a 1 (0.4) 5 (2.2)

ypT4b 3 (1.3) 3 (1.3)

ypTx† 5 (2.1) 5 (2.2)

Node category 0.059

ypN0 149 (63.7) 163 (71.5)

ypN1 52 (22.2) 41 (18.0)

ypN2 28 (12.0) 19 (8.3)

ypNx† 5 (2.1) 5 (2.2)

Tumour regression* <0.001

Grade 0 17 (7.3) 15 (6.6)

Grade 1 165 (70.5) 104 (45.6)

Grade 2 41 (17.5) 64 (28.1)

Grade 3 2 (0.9) 11 (4.8)

Grade 4 4 (1.7) 23 (10.1)

Grade x† 5 (2.1) 11 (4.8)

Circumferential resection margin§ n=170 n=150 1.000#

Positive (≤1 mm) 11 9

Negative (>1 mm) 159 141

R

*Dworak regression grading system; †Not included in statistical analysis; ‡subcategorization not used in statistical analysis; §142 patients with missing

data excluded from analysis; ¶Mann–Whitney U test, except #Fisher's exact test

Long-course, fluoropyrimidine-based,

chemoradiotherapy and short-course radiotherapy

have been standard pre-operative treatment

regimens with largely equivalent results

(before ASCO 2020)

Take home message

What is the best timing of surgery

after long-course chemoradiotherapy?

Question 4

f

DATA FROM NATIONAL REGISTRY STUDIES

Retrospective studies suggest that delaying surgery up to 60 days after

chemoradiotherapy may increase pathologic tumour regression rates

1. Reproduced from: Sloothaak DAM, et al. Optimal time interval between neoadjuvant chemoradiotherapy and surgery for rectal cancer. Br J Surg 2013;100(7):933-9, by permission of

John Wiley and Sons Ltd., Copyright © 2013 British Journal of Surgery Society Ltd.; 2.; Huntington C, et al. Ann Surg Oncol 2016;23(3):877–87.

Dutch Surgical Colorectal Audit Database (n=1593)1

Time interval between CRT and surgery was an

independent predictive factor for pCR (HR 1.63; p=0.002) Intervals >60 days associated with higher rates of positive surgical margins

(6.7 vs. 4.8 %, p=0.009) and lower rates of sphincter-preserving surgery

(64.9 vs. 68.9 %, p=0.007) and worse survival (HR 1.31; p<0.001)

US National Cancer Database (n=6397)2

TME after 8–12 weeks

TME after 4–8 weeks327 stage II-III

patients

candidates for

CRT TME after 12–14 weeks

TME after 6–8 weeks237 patients

receiving CRT for

high-risk

tumours

Primary endpoint: pCR Primary endpoint: tumour downstaging

pCR: 10.0% vs 18.6%; p=0.027

No difference in surgical quality

or morbidity between groups

pCR: 9% vs 20%; p<0.05

ypT0: 7% vs 20%; p<0.05

ypT0: 42% vs 55%; p<0.05

No difference in surgical quality

or morbidity between groups

THE TURKISH AND UK TRIALS

Clinical trials supporting the contention that delaying surgery after


Akgun E, et al. Br J Surg 2018;105(11):1417–25; Evans J, et al. Presented at ESMO 2016; abstract 4520.

R R

THE GRECCAR-6 TRIAL

Clinical trials confuting the contention that delaying surgery after


Lefevre JH, et al. J Clin Oncol, 34 (31), 2016: 3773–80. Reprinted with permission. © 2016 American Society of Clinical Oncology. All rights reserved.

TME after 11 weeks

TME after 7 weeksN=253

CRT-treated

Stage II-III

mid-low

CRT: 45 to 50 Gy with either 5FU or capecitabine

Primary endpoint: pCR

▪ ypCR in the ITT population: 15.0% vs. 17.4% (p=0.60)

▪ ypCR in the PP population: 17.2% vs. 15.7% (p=0.78)

▪ Sphincter-preserving surgery: 90.4% vs. 89.1% (p=0.73)

▪ Overall post-operative morbidity: 32.0% vs. 44.5% (p=0.04)

▪ Incomplete mesorectal excision: 10% vs. 21.3% (p=0.012) !

R

If long-course chemoradiotherapy is delivered,

surgery should be carried out 6 to 8 weeks after

pre-operative treatment completion

Take home message

Is there any role for adjuvant chemotherapy

after pre-operative treatment?

Question 5

1. Sainato A, et al. Radiot Oncol 2014;113(2):223-9; 2. Bosset J-F, et al. N Engl J Med 2006;355(11):1114–23; 3. Breugom AJ, et al. Ann Oncol 2015;26(4):696–701;

4. Glynne-Jones R, et al. Ann Oncol 2014;25(7):1356–62.

Study Period Accrual

Staging

modality Adj CT regimen

Primary

hypothesis

Starting

Adj CT

Completing

Adj CT

5-yr

DFS (%)

5-yr

OS (%)

I-CNR-RT

(n=634)1

1992–

2003

100% DRE, rigid rectoscopy, CT AP,

chest X-ray, (ERUS optional)

Obs

vs.

bolus 5-FU-LV

+10% in

5-yr OS 91.4% <58.4%62.8^

HR 0.98

65.3^

70.0^

HR 1.04

69.1^

EORTC 22921

(n=1011)2

1993–

2003

100% DRE, rigid rectoscopy, CT AP,

chest X-ray, (ERUS optional)

Obs

vs.

bolus 5-FU-LV

+10% in

5-yr OS 73.1% 42.9%52.2

HR 0.87

58.2

63.2

HR 0.85

67.2

PROCTOR/

SCRIPT

(n=437)3

2000–

2013

52% NA

(inclusion after surgery)

Obs vs. bolus

5-FU-LV/

Nordic/Cape

+10% in

5-yr OS 94.5% 73.6%55.4

HR 0.80

62.7

79.2

HR 0.93

80.4

CHRONICLE

(n=113)4

2004–

2008

14% NA

(inclusion after surgery)

CT TAP before Adj CT

Obs

vs.

CAPOX

+10.5% in

3-yr DFS 92.6% 48.1%71.3*

HR 0.80

77.5*

87.8*

HR 1.18

88.8*

Poor

accrual

Old studies,

long recruitment

period

Inadequate staging modalities

Sub-optimal

chemo regimens

Poor compliance

with chemotherapy

Unrealistic statistical

hypothesis

^Survival outcomes in the

resected population

*3-yr survival rates

RESULTS AND CAVEATS OF PHASE III TRIALS OF

ADJUVANT CHEMOTHERAPY VS. OBSERVATION

FOLLOWING PRE-OPERATIVE (CHEMO) RADIOTHERAPY

SINGLE AGENT FLUOROPYRIMIDINE VS

OXALIPLATIN-BASED ADJUVANT CHEMOTHERAPY

The ADORE trial

Reprinted from The Lancet Oncol, 15(11), Hong YS, et al. Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and leucovorin as adjuvant chemotherapy for locally advanced

rectal cancer after preoperative chemoradiotherapy (ADORE): an open-label, multicentre, phase 2, randomised controlled trial, 1245–53. Copyright 2014, with permission from Elsevier.

Primary endpoint:

3-yr DFS

321 eligible pts

R0 surgery for

ypT3/4 and/or

ypN+ after CRT FOLFOX x8

FUFA x4

ypStage II patients

ypStage III patients

All patients

R

RECOMMENDATIONS FOR ADJUVANT THERAPY

AFTER PRE-OPERATIVE SHORT- OR LONG-COURSE

RADIOTHERAPY

Bregni G, et al. Cancer Treat Rev 2020;83:101948

The role of adjuvant chemotherapy following

pre-operative treatment is still uncertain, and pros

and cons should be regularly discussed with patients

Take home message

What is the rationale of intensifying

pre-operative therapy, and what type of intensified

treatment strategies have been investigated?

Question 6

van Gijn W, et al. Lancet Oncol 2011;12(6):575–82; Sauer R, et al. J Clin Oncol 2012;30(16):1926–33; Gérard J-P, et al. J Clin Oncol 2012;30(36):4558–65; Allegra C, et al. J Natl

Cancer Inst 2015;107(11):djv248; Rödel C, et al. Lancet Oncol 2015;16(8):979–89; Schmoll H-J, et al. Presented at ASCO 2018; abstract 3500.

0

20

40

60

80

100

Dutch TME CAO/ARO/AIO-94 NASBP-R04 CAO/ARO/AIO-04

0

10

20

30

40

Dutch TME CAO/ARO/AIO-94 NASBP-R04 PETACC-6 CAO/ARO/AIO-04

0

2

4

6

8

10

Dutch TME CAO/ARO/AIO-94

ACCORD12/0405

NASBP-R04 PETACC-6 CAO/ARO/AIO-04

0

5

10

15

20

25

CAO/ARO/AIO-94 ACCORD12/0405

NASBP-R04 PETACC-6 CAO/ARO/AIO-04

RECTAL CANCER OUTCOMES WITH PRE-OPERATIVE

(CHEMO)RADIOTHERAPY AND TME

Distant recurrence is the main cause of treatment failure

pCR: 8–21%

Local recurrence: 4–8%

5-yr OS: 64–80%

Distant recurrence: 19–30%

Trial N Treatment Primary endpoint ypCR 3/5-yr DFS 3/5-yr OS

STAR 7475FU + RT

5FU-Ox60 + RT 5-yr OS

16%

16%

66.3%

69.2%

77.6%

80.4%

ACCORD PRODIGE 2 598Cape + 45 Gy

Cape-Ox50 + 50 GyypCR

13.9%

19.2%

67.9%

72.7%

76.4%

81.9%

NSABP-R04 16085FU/Cape + RT

5FU/Cape-Ox50 + RT3-yr local control

17.8%

19.5%

64.2%

69.2%

79.0%

81.3%

CAO/ARO/AIO-04 12655FU + RT

5FU-Ox50 + RT 3-yr DFS

13.0%†

17.0%†

71.2%†

75.9%†

88.0%

88.7%

PETACC-6 1094Cape + RT

Cape-Ox50 + RT3-yr DFS

11.3%

13.3%

71.3%

70.5%

83.1%

80.1%

FOWARC 3125FUFA + RT

mFOLFOX6 + RT3-yr DFS

14.0%†

27.5%†

76.4%

77.8%

93.7%

92.0%†Statistically significant

ADDING LOW DOSE OXALIPLATIN TO STANDARD

CHEMORADIOTHERAPY DOES NOT IMPROVE OUTCOMES

Aschele C, et al. J Clin Oncol 2011;29(20):2773–80; Aschele C, et al. Presented at ASCO 2016; abstract 3521; Gerard J-P, et al. J Clin Oncol 201028(10):1638–44;

Gérard J-P, et al. J Clin Oncol 2012;30(36):4558–65; Allegra C, et al. J Natl Cancer Inst 2015;107(11):djv248; Rödel C, et al. Lancet Oncol 2012;13(7):679–87; Rödel C, et al. Lancet

Oncol 2015;16(8):979–89; Schmoll H-J, et al. Presented at ASCO 2014; abstract 3501; Schmoll H-J, et al. Presented at ASCO 2018; abstract 3500; Deng, J Clin Oncol 2016; Deng Y,

et al. Presented at ASCO 2018; abstract 3502.

CAPOX →

CRT → TME

CRT → TME

→ CAPOXN=108

High-risk

tumours*

* MRF involved/threatened, T4, T3 low tumours, N+,

CRT: 50.4 Gy with Capecitabine 1650 mg/m2/day

and oxaliplatin 50 mg/m2 1q8 x5

Primary

endpoint:

pCR

Neoadjuvant CT Adjuvant CT P-value

G3/4 tox 19% 54% 0.0004

Max N cycles 0.0001

0 0% 25%

≤2 2% 14%

3 4% 4%

4 94% 57%

Mean RDI

Capecitabine 0.91 0.67 <0.0001

Oxaliplatin 0.94 0.73 <0.0001

THE GRUPO CÁNCER DE RECTO 3 STUDY

Systemic chemotherapy has higher compliance and better safety profile

when given before than after surgery

Fernández-Martos C, et al. J Clin Oncol 2010;28(5):859–65; Fernández-Martos C, et al. Ann Oncol 2015;26(8):1722–8.

▪ pCR: 13.5% vs. 14.3%; p=0.94

▪ R0 resection: 87% vs. 86%; p=0.40

▪ 5-yr DFS: 64% vs. 62%; p=0.85

R

Reprinted from The Lancet Oncol, 16 (8), Garcia-Aguilar J, et al. Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2

trial, 957–66. Copyright 2015, with permission from Elsevier.

Mean interval from CRT to surgery: 8.5 weeks




259 stage II-III patients enrolled into 4 sequential Phase 2 study groups

THE MSKCC 12-201 TRIAL

More cycles of systemic chemotherapy after chemoradiotherapy and longer radiotherapy

to surgery interval may increase pathologic tumour regression





THE MSKCC 12-201 TRIAL

More cycles of systemic chemotherapy after chemoradiotherapy and longer radiotherapy

to surgery interval may increase pathologic tumour regression

Reprinted from The Lancet Oncol, 16 (8), Garcia-Aguilar J, et al. Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2

trial , 957–66. Copyright 2015, with permission from Elsevier.

THE CAO/ARO/AIO-12 TRIAL

Systemic chemotherapy may be more effective if given after than

before long-course chemoradiotherapy

Fokas E, et al. J Clin Oncol 2019;37(34):3212–22.

Stage II-III

rectal cancer*

N=306

* T3c/d needed for T3N0 middle rectal tumours

** Oxaliplatin-based CRT

Primary endpoint:

pCR (pic-the-winner

design)

Treatment pCR p value

FOLFOX → CRT 17% 0.201

CRT→ FOLFOX 25% <0.001

Only the CRT → FOLFOX arm

met the predefined hypothesis

against historical controls

Either treatment (FOLFOX or CRT) had better

compliance and lower toxicity when used first

R

FOLFOX x3 CRT** Surgery

CRT** FOLFOX x3 Surgery

Distant recurrence represents the main cause

of treatment failure and death, and could be better

addressed by the early (i.e., pre-operative)

delivery of systemic chemotherapy

Take home message

What are the new standard pre-operative

treatment regimens (after ASCO 2020)?

Question 7

THE PRODIGE 23 TRIAL

3 months of induction mFOLFIRINOX followed by chemoradiotherapy is superior than

chemoradiotherapy alone

Conroy T, et al. J Clin Oncol 2020;38(suppl 15):4007. Presented at ASCO 2020. With permission from Dr Thierry Conroy.

Stage II-III

rectal cancer

N=461

Primary

endpoint:

3-year DFS

Treatment pCR P-value

Standard 12.1%<0.001

Experimental 27.8%

Reduced risk of post-operative

complications with TNT

No difference in QoL

CRT SurgerymFOLFOX x12

or Cape x8

mFOLFIRINOX x6 CRT Surgery

R

mFOLFOX x6

or Cape x4

THE RAPIDO TRIAL

Short-course radiotherapy followed by 4 months of oxaliplatin-based

chemotherapy is superior than chemoradiotherapy alone

Reprinted from Lancet Oncol, 22(1), Bahadoer RR, et al. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy,

TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial, 29-42, Copyright 2021, with permission from Elsevier.

CRT SurgeryHigh-risk

rectal

cancer*

N=885

Optional CAPOX x8

or FOLFOX x12

SCRTCAPOX x6

or FOLFOX x9Surgery

*≥1 high-risk features: CRM+, T4, N2, lateral N+, EMVI

Primary endpoint:

3-year disease-related

treatment failure

Treatment pCR p value

Standard 14.3%<0.001

Experimental 28.4%

No difference in post-operative

complications and QoL

R

30.4%

23.7%

Induction mFOLFIRINOX followed by long-course

chemoradiotherapy, and short-course radiotherapy

followed by oxaliplatin-based chemotherapy improve

survival outcomes and pCR rate compared

with chemoradiotherapy alone, and will likely

become new standards of care

Take home message

Do all stage II-III tumours have the same

recurrence risk? Are there additional

risk factors that could help to refine patient

stratification and inform treatment decisions?

Question 8

Study Pts (n) Period F-up (m) Outcome ≤ mm >4 mm P-value

Yoshida, 2008 100 1996-2000 NR 5-year DFS 86.7% 60.6% NR

Akagi, 2012 463 (IIA) 1995-1999 86 5-year RFS 86.6% 71.3% 0.00015

86Akagi, 2012 422 (IIIB) 1995-1999 5-year RFS 68.7% 49.1% <0.0001

Study N pts Period F-up (m) Outcome ≤5 mm >5 mm P-value

Merckel, 2001 514 1981-1997 80 5-year CRS 85.4% 54.1% <0.0001

Merckel, 2001 371 1984-1986 61 5-year CRS 71.0% 55.0% 0.0014

Shin, 2012 291 (91 CRT) 2003-2009 43.8 5-year DFS 77.6% 55.2% <0.0001

Study N pts Period F-up (m) Outcome <6 mm ≥6 mm P-value

Miyoshi, 2006 247 1960-1969 140 5-year OS 59.0 37.0 <0.01

Miyoshi, 2006 196 1980-1997 77 5-year OS 71.0 50.0 <0.01

BEYOND TNM CLASSIFICATION: ADDITIONAL,

MRI-ASSESSABLE, RISK FACTORS TO CONSIDER IN

THE DECISION-MAKING PROCESS

Nougaret S, Reinhold C, Mikhael H W, et al. The use of MR imaging in treatment planning for patients with rectal carcinoma: Have you checked the “DISTANCE”? Radiology

2013;268:330–44. Reproduced with permission © RSNA, 2013.

Depth of mesorectal invasion (i.e., sub-classification of T3 into T3a, T3b, T3c and T3d)

Oncological outcomes based on the pathological depth of mesorectal invasion




Nagtegaal ID, Quirke P. J Clin Oncol, 26(2), 2008: 303–12. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.

LOCAL RECURRENCE DISTANT RECURRENCECircumferential

resection margin (CRM)

involvement (i.e., tumour

within 1 mm from the

mesorectal fascia)




Kapiteijn E, et al. N Engl J Med 2001;345(9):638–46; Nagtegaal ID, et al. Am J Surg Pathol 2002;26(3):350–7.

Image from Horvat N, et al. MRI of Rectal Cancer: Tumor Staging, Imaging Techniques, and Management. RadioGraphics 2019;39:367–87. Copyright 2019 RSNA.

UPPER RECTUM (30%)

CRM + 16.5%†

2-yr local recurrence: 3.8%*

MIDDLE RECTUM (41%)

CRM + 13.2%†

2-yr local recurrence: 10.1%*

LOWER RECTUM (29%)

CRM + 25.9%†

2-yr local recurrence: 10%*

† CRM involvement in Dutch patients treated with surgery alone in the Dutch TME trial

* Local recurrence in the group of patients treated with surgery alone regardless of the CRM status

Location of the

primary tumour(i.e., high, mid and low

rectal cancers)

BEYOND TNM CLASSIFICATION

Additional, MRI-assessable, risk factors to consider in the decision-making process

1. Koh D-M, et al. Clin Med Oncol 2008;2:267-73. Reproduced under the terms of the Creative Commons Attribution 3.0 License (available at:

http://www.creativecommons.org/licenses/by/3.0/; accessed Nov 2020); 2. Reprinted from Ann Oncol, 25(4), Chand M, et al. EMVI-positive stage II rectal cancer has similar clinical

outcomes as stage III disease following pre-operative chemoradiotherapy, 858–63. Copyright 2014 European Society for Medical Oncology, with permission from Elsevier.

Extramural venous

invasion (EMVI)1

N=478 stage II–III patients treated

with surgery +/- pre-operative CRT2

3-year DFS

EMVI−/N− 79%

EMVI+/N− 59%

EMVI−/N+ 63%

EMVI+/N+ 50%

Multicentre observational study

N=122 good-prognosis patients treated with surgery alone

SURGERY ALONE FOR GOOD-PROGNOSIS TUMOURS –

THE MERCURY STUDY

A risk-adapted pre-operative treatment approach is feasible and may

spare good-prognosis patients from unnecessary toxicity

Taylor FGM, et al. Ann Surg 2011;253(4):711–9.

MRI feature Good prognosis Poor prognosis

CRM >1 mm clear <1 mm involved

Low rectal <5 cm Intersphincteric plane clear of tumour Intersphincteric plane involved by tumour

T stage T1/2, T3a/b T3c/d, T4

EMVI Negative Positive

N stage Any Any

Outcomes (median follow-up 61.5 months)

◆ 5-yr local relapse: 3.3%

◆ 5-yr DFS 68.2% (95% CI: 60.3-77.0%)

◆ 5-yr OS: 84.7% (95% CI :76.0-90.4%)

Group of patients for whom the

risk-benefit ratio of neoadjuvant

therapy may not be favourable

TOTAL NEOADJUVANT THERAPY (RAPIDO/PRODIGE-23

APPROACH) FOR POOR-PROGNOSIS TUMOURS

A risk-adapted pre-operative treatment approach is feasible and may

improve oncological outcome of poor-prognosis patients

Modified from Taylor FGM, et al. Ann Surg 2011;253(4):711–9.

MRI feature Good prognosis Poor prognosis

CRM >1 mm clear <1 mm involved

Low rectal <5 cm Intersphincteric plane clear of tumour Intersphincteric plane involved by tumour

T stage T1/2, T3a/b T3c/d, T4

EMVI Negative Positive

N stage Any N2 or lateral N+

Group of patients most likely to benefit from neoadjuvant treatment,

especially according to the principle of “total neoadjuvant therapy”

Distance from the anal verge, depth of mesorectal

invasion, extramural venous invasion and

threatening/involvement of the mesorectal

fascia are high-risk factors to consider when

making decisions regarding de-escalation or

intensification of pre-operative therapy

Take home message

Is radiotherapy an essential component of the

pre-operative treatment? Could it be omitted?

Question 9

PRE-OPERATIVE RADIOTHERAPY IMPROVES LOCAL

CONTROL (BUT NO OVERALL SURVIVAL) EVEN IF

HIGH-QUALITY TME SURGERY IS PERFORMED

The Dutch TME trial

Reprinted from The Lancet Oncol, 12(6), van Gijn W, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the

multicentre, randomised controlled TME trial, 575–82. Copyright 2011 with permission from Elsevier; .Kapiteijn E, et al. N Engl J Med 2001;345:638–46.


▪ 10-year local relapse: 5% vs. 11%; p<0.0001

▪ 10-year distant relapse: 25% vs. 28%; p=0.21

▪ 10-year OS: 48% vs. 49%; p=0.86

Years

Years

SCRT → TME

TMEN=1805

Clinically

resectable

(stage I-III)

RPrimary

endpoint:

local control

SCRT: 25 Gy in 5 fractions Overall survival

Local recurrence

X

Peeters KCMJ, et al. J Clin Oncol, 23 (25), 2005: 6199-206. Reprinted with permission © 2005 American Society of Clinical Oncology. All rights reserved.

LATE TOXICITIES OF PRE-OPERATIVE RADIOTHERAPY

FOR RECTAL CANCER

Bowel function

*Patients without a stoma

Incontinence

at day

Incontinence

at night

Anal mucus

loss

Anal blood

loss

Use of pads%

of p

atie

nts

with

dys

func

tion

N=597, alive and disease-free

(33% of the Dutch TME trial population)

Median follow-up: 5.1 years

SCRT → TME

TMEClinically

resectable(stage I-III)

R

Marijnenet CAM, et al. J Clin Oncol ,23 (9), 2005: 1847–58. Reprinted with permission © 2005 American Society of Clinical Oncology. All rights reserved.

0

10

20

30

40

50

60

70

80

90

100

3 6 12 18 24

No RT

Preop RT

.01 .002 .48 .11 .06P-value

Sex

ual

ly a

ctiv

e p

atie

nts

(%

)

Months since surgery

0

10

20

30

40

50

60

70

80

90

100

3 6 12 18 24

No RT

Preop RT

.25 .19 .02 .09 .01

Months since surgery

Females Males

N=990, alive and

disease-free

(55% of the Dutch

TME trial population)

SCRT → TME

TME

Clinically

resectable

(stage I-III)


FOR RECTAL CANCER

Sexual activity

R

Birgisson H, et al. J Clin Oncol, 23(25), 2005: 6126–31. Reprinted with permission. © 2005 American Society of Clinical Oncology. All rights reserved.

No RTPreop RT Within/adjacent to the RT volume 25 11 1.98

Outside RT volume 23 15 1.33

RT+ RT- RR

RT-

RT+

Pooled analysis of the Uppsala and Swedish trials N=1599

SCRT → Surgery

Surgery → RT

(stage II-III)Clinically

resectable

tumours

SCRT→ Surgery

Surgery

Clinically

resectable

tumours

Uppsala trial

Swedish trial


FOR RECTAL CANCER

Second cancers

R

R

Primary endpoint

3-year DFS

- mFOLFOX6-RT vs.

deGramont-RT

- mFOLFOX6 vs.

deGramont-RT

THE FOWARC TRIAL

Omitting radiotherapy appears to be feasible without any detrimental effect on long-term

survival outcomes

Deng Y, et al. J Clin Oncol, 37 (34), 2019: 3223–33. Reprinted with permission. © 2019 American Society of Clinical Oncology. All rights reserved.

Reduced tumour downstaging

and pCR without radiotherapy

Better safety profile and long-term

QoL without radiotherapymFOLFOX→ TME → mFOLFOX

deGramont-RT → TME → deGramont

Stage II-III

tumours R mFOLFOX-RT → TME → mFOLFOX

THE PROSPECT TRIAL

Other clinical trials of pre-operative systemic chemotherapy without

radiotherapy are ongoing

Schrag D, et al. Clin Trials 2019;16(2):165–75.

TME

TME

TME

Phase 2/3 trial (n=1060)

Primary endpoints

R0 resection/Time to LR (Ph 2)

Time to LR and DFS (Ph 3)

Sponsor: Alliance for Clinical Trials in Oncology

Collaborator: National Cancer Institute

Main inclusion criteria

- High and mid

tumours (5-12 cm)

- T2N1, T3N0,

T3N1 (EUS or MRI)

- CRM safe (>3mm)

While results from preliminary studies are

promising, confirmatory data are needed before

routinely omitting pre-operative radiotherapy,

especially for high-risk tumours (generally

excluded/underrepresented in clinical studies)

Take home message

Is there any role for organ-sparing

management strategies?

Question 10

THE ACOSOG Z6041 TRIAL

Local excision after chemoradiotherapy may be a safe alternative to TME, and ensure organ

preservation and good QoL for selected patients with T2 tumours

Reprinted from The Lancet Oncol, 16 (15), Garcia-Aguilar J, et al. Organ preservation for clinical T2N0 distal rectal cancer using neoadjuvant chemoradiotherapy and local excision

(ACOSOG Z6041): results of an open-label, single-arm, multi-institutional, phase 2 trial, 1537–46, Copyright 2015, with permission from Elsevier.

CRT*

T2N0, <4 cm,

<40% of the circumference,

within 8 cm of the a.v.

N=79

Local excision**

* Oxaliplatin-based CRT

** Transanal excision or transanal endoscopic microsurgery

Primary endpoint:

3-year DFS

Pathological findings

ypT0/Tis: 49%

ypT1: 14%

ypT2: 31%

ypT3: 4%

Disease-free survival Incontinence and QoL

Reprinted from The Lancet, 390(10093), Rullier E, et al. Organ preservation for rectal cancer (GRECCAR 2): a prospective, randomised, open-label, multicentre, phase 3 trial, 469–79.

Copyright 2017, with permission from Elsevier.

THE GRECCAR 2 TRIAL

Local excision after chemoradiotherapy may be a safe alternative to TME, and ensure organ

preservation and good QoL for selected patients with T2 tumours

Primary endpoint: composite

outcome with 4 components:

death, recurrence, major

surgical morbidity, and severe

complications (i.e., definitive

colostomy, anal incontinence,

or impotence) at 2 years

n=81* n=61*

n=43* n=38*

n=28*

* Per-protocol population

ypN+ after TME in 7/89 (8%) cases:

0/30 in ypT0

0/13 in ypT1

3/36 (8%) in ypT2

4/10 (40%) in ypT3

2/28 had ypN+

1/28 had residual

Disease in the bowel

Local excision was not superior to TME

but it was oncologically safe.

3 years after local excision alone:

- local recurrence = 9%

- alive and disease-free = 70%

Reprinted from The Lancet Oncol, 11(9), Maas M, et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of

individual patient data, 835–44. Copyright 2010, with permission from Elsevier.

5-yr DFS

pCR: 83.3%

No pCR: 65.6%

5-yr local recurrence

pCR: 2.8%

No pCR: 9.7%

5-yr DMFS

pCR: 88.8%

No pCR: 74.9%

5-yr OS

pCR: 87.6%

No pCR: 76.4%

PATIENTS ACHIEVING PATHOLOGICAL

COMPLETE RESPONSE AFTER PRE-OPERATIVE

TREATMENT AND SURGERY HAVE A BETTER PROGNOSIS

MRI AND ENDOSCOPY ALLOW ASSESSMENT OF TUMOUR

REGRESSION AND IDENTIFICATION OF COMPLETE RESPONSE

AFTER PRE-OPERATIVE TREATMENT

1. Patel UB, et al. J Clin Oncol, 29(I28), 2011: 3753–60. Reprinted with permission. © 2011 American Society of Clinical Oncology. All rights reserved; 2. Maas M, et al. Ann Surg Oncol 2015;22:3873–80.

Reproduced under the terms of the Creative Commons Attribution 4.0 International License (available at: http://creativecommons.org/licenses/by/4.0/; accessed Nov 2020).

mrTRG 4

persistent intermediate

signal intensity with minimal

low signal fibrosis

mrTRG 5

no/little tumour regression

mrTRG 1

absence of any

tumour signal

mrTRG 2

predominant scar signal

intensity with minimal

residual tumour

mrTRG 3

mixed areas of low signal

fibrosis and intermediate

signal intensity

Absence of residual

ulceration, stenosis, or

mass during digital

rectal examination,

endoscopic examination

and pelvic MRI

Imaging and endoscopic aspect of clinical complete response

PROPOSED CRITERIA FOR THE ASSESSMENT OF

TUMOUR RESPONSE IF A WATCH & WAIT APPROACH

IS CONSIDERED

DRE, digital rectal exam.

Modified from Smith JJ, et al. BMC Cancer 2015;15:767.

Incomplete Response Near Complete Response Complete Response

Endoscopy Visible tumour

Irregular mucosa, small mucosal nodules or

minor mucosal abnormality, superficial

ulceration, mild persisting erythema of the scar

Flat white scar telangiectasia,

no ulcer, no nodularity

DRE Palpable tumourSmooth induration or

minor mucosal abnormalitiesNormal

MRI-T2W

More intermediate than dark T2 signal,

no T2 scar AND/OR no regression

of lymph nodes

Mostly dark T2 signal, some remaining

intermediate signal AND/OR partial regression

of lymph nodes

Only dark T2 signal, no intermediate

T2 signal AND no visible lymph nodes

MRI-DW

Insignificant regression of signal on B800-B1000

AND/OR obvious low

signal on ADC map

Significant regression of signal on B800-B1000

AND/OR minimal or low

residual signal on ADC map

No visible tumour on B800-B1000

AND/OR lack of or low

signal on ADC map

International Watch & Wait Database. Available at: http://www.iwwd.org/; accessed Nov 2020.

“Our aim is to inform the public of the developments in the field of organ preservation in rectal cancer

management and to promote a network of international health care professionals to foster evidence-

based medical information and recommendation dissemination to ensure the maximal spread of “core

treatment quality standards” to the appropriate audiences for a maximised benefit of rectal cancer care”.

THE INTERNATIONAL WATCH & WAIT DATABASE

Given the poor acceptance of randomisation between surgery and Watch & Wait,

large observational studies represent the best available evidence In this setting

Chadi SA, et al. Lancet Gastroenterol Hepatol 2018;3(12):825–36; Renehan AG, et al. Lancet Oncol 2016;17(2):174–83; van der Valk M, et al. Lancet 2018;391(10139):2537–45;

Smith JJ, et al. JAMA Oncol 2019;5(4):e185896.


Results of main observational studies and meta-analyses of Watch & Wait

following clinical complete response to PRE-operative therapy


Assessment

methods for cCR

Median

follow-up

(years)

2-yr local

regrowth

(%)

Salvage surgery

for local

regrowth

3-yr distant

metastases

(%)

5-yr disease-

specific

survival (%)

5-yr

OS (%)

InterCoRe

meta-

analysis

1990–

2017602 NA 3.1 21

89%

(R0 in 98%)9.1 NA 87

OnCoRe2011–

2013129 MRI (100%) 2.8 33

76%

(R0 in 97%)NA NA

96*

(3-year OS)

IWWD2015-

2017880

Endoscopy (90%)

MRI (71%)

Biopsy (42%)

3.3 25.278%

(R0 in 88%)8.1 93.8 84.7

MSKCC2006–

2015113 NA 3.6 <20

100%

(R0 in 95%)8 90 73

* Survival estimate on 109 study patients

Chadi SA, et al. Lancet Gastroenterol Hepatol 2018;3(12):825–36; Renehan AG, et al. Lancet Oncol 2016;17(2):174–83; van der Valk M, et al. Lancet 2018;391(10139):2537–45;

Smith JJ, et al. JAMA Oncol 2019;5(4):e185896.


Assessment

methods for cCR

Median

follow-up

(years)

2-yr local

regrowth

(%)

Salvage surgery

for local

regrowth

3-yr distant

metastases

(%)

5-yr disease-

specific

survival (%)

5-yr

OS (%)

InterCoRe

meta-

analysis

1990–

2017602 NA 3.1 21

89%

(R0 in 98%)9.1 NA 87

OnCoRe2011–

2013129 MRI (100%) 2.8 33

76%

(R0 in 97%)NA NA

96*

(3-year OS)

IWWD2015-

2017880

Endoscopy (90%)

MRI (71%)

Biopsy (42%)

3.3 25.278%

(R0 in 88%)8.1 93.8 84.7

MSKCC2006–

2015113 NA 3.6 <20

100%

(R0 in 95%)8% 90 73

* Survival estimate on 109 study patientsNeed for intensive follow-up strategies to rule out local

regrowth, especially in the first 2 years after cCR


Results of main observational studies and meta-analyses of Watch & Wait

following clinical complete response to PRE-operative therapy

MY PROPOSED FOLLOW-UP PROTOCOL FOR PATIENTS

WHO ARE MANAGED WITH A WATCH & WAIT APPROACH

3 m 6 m 9 m 12 m 15 m 18 m 21 m 24 m

DRE x x x x x x x x

CEA x x x x x x x x

Flexi-sigmoidoscopy x x x x x

Colonoscopy x

MRI pelvis x x x x x x

CT scan thorax-abdomen x x

30 m 36 m 42 m 48 m 54 m 60 m

DRE x x x x x x

CEA x x x x x x

Flexi-sigmoidoscopy x x x

Colonoscopy x

MRI pelvis x x x

CT scan thorax-abdomen x

Duration induction/consolidation chemotherapy: 4 months

Primary objective: to compare survival outcome of TNT-treated patients

versus conventionally treated patients (historical control)

THE OPRA TRIAL – PRELIMINARY RESULTS

Organ preservation is more likely to be achieved with consolidation rather than with

induction chemotherapy

Garcia-Aguilar J, et al. J Cin Oncol 2020;38(Suppl 15):4008. Presented at ASCO 2020. With permission from Dr Julio Garcia-Aguilar.

Secondary endpoint: to compare organ preservation in induction- versus

consolidation-chemotherapy-treated patients

Patients who receive

consolidation

chemotherapy are

more likely to be

managed with an

organ-preservation

approach

Similar survival

outcome for

patients treated

with TNT and

selective organ

preservation and

historical controls

DELIVERING HIGHER DOSE OF RADIOTHERAPY MAY

INCREASE THE PROPORTION OF PATIENTS WHO

COULD BE SUITABLE FOR WATCH & WAIT

Reprinted from The Lancet Oncol, 16 (8), Appelt AI, et al. High-dose chemoradiotherapy and watchful waiting for distal rectal cancer: a prospective observational study, 919–27,

Copyright 2015, with permission from Elsevier.

1-yr LR rate: 15.5%

2-yr LR rate: 25.9%

Patient-scored faecal incontinence

Bearing in mind the small

numbers and short follow-up,

patient-reported functional

outcomes were encouraging

◆ 51 patients with cT2/3, N0/1 distal tumours treated with 60 Gy + 5 Gy brachytherapy boost + continuous UFT

◆ 40/51 (78.5%) had cCR and were managed with Watch & Wait

◆ After a median follow-up of 23.9 months, 9/40 (22.5%) had local recurrence, all treated with salvage surgery

◆ 58% had local control at 2 years with chemoradiotherapy alone, 7.5% had distant metastases

Organ preservation with either local excision or

Watch & Wait cannot be considered yet a standard of

care, but it could be considered for selected patients

who are managed in highly specialised centres

Take home message

SUMMARY OF CLINICAL RECOMMENDATIONS

Low-risk disease

T3a/b high-mid tumours,

N0, EMVI-, CRM-

Intermediate-risk disease

T3 low tumours, T3c/d high-mid

tumours, N1, EMVI-, CRM-

High-risk disease

T4, N2, lateral N+, EMVI+,

CRM+, levator muscles

threatened/involved

TME

SCRT, CRT,

RT → FOLFOX,

or mFOLFIRINOX→ CRT

RT → FOLFOX

or mFOLFIRINOX→ CRT

(SCRT or CRT if not suitable for

systemic chemotherapy)

TME TMELocal excision (if ycT1)

or W&W (if cCR) based

on patient preferences

and only in highly

specialised centres

Local excision (if <ycT1)

or W&W (if cCR) based

on patient preferences

and only in highly

specialised centres

HOW THE RISK-ADAPTED ALGORITHM FOR THE

PRE-OPERATIVE TREATMENT OF STAGE II-III RECTAL

CANCER MAY LOOK LIKE IN THE NEAR FUTURE

THANK YOU!For any queries, please contact

[email protected]

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