Localized colorectal cancer

Dr. Julien Taieb, Université Paris

Descartes, Paris, France
 Disclosures
•Honoraria for speaker or advisory role for : AMGEN, BMS, HallioDx,
Merck, MSD, Novartis, Pierre Fabre, Roche, Sanofi, Servier
Neoadjuvant Chemotherapy with Oxaliplatin and
Capecitabine Versus Chemoradiation with
Capecitabine for Locally Advanced Rectal Cancer
with Uninvolved Mesorectal Fascia (CONVERT) :
Initial Results of A Multicenter Randomised, Open-
label, Phase III Trial
P.-R. Ding1, X.-Z. Wang2, Y.-F. Li3, Y.-M. Sun4, C.-K. Yang5, Z.-G. Wu6, R. Zhang7, W.
Wang8, Y. Li9, Y.-Z. Zhuang10, J. Lei11, X.-B. Wan12, Y.-K. Ren13, Y. Cheng14, W.-L. Li15,
Z.-Q. Wang16, Z.-Z. Pan1, Y.-H. Gao17, Z.-F. Zeng17, W.-W. Xiao17, D.-S. Wan1
1Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China, 2General surgery, Shantou Central Hospital（Affiliated Shantou
Hospital Of Sun Yat-sen University）, Shantou, China, 3Colorectal Surgery, Yunnan Cancer Hospital/The Third Affiliated Hospital of Kunming Medical
University, Kunming, China, 4Colorectal Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China, 5Gastrointestinal Surgical
Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, China, 6Department of Gastrointestinal Surgery, Meizhou
Peopleʼs Hospital, Meizhou, China, 7Colorectal Surgery, Liaoning cancer hospital, Shenyang, China, 8Department of Gastrointestinal Surgery,
Guangdong Provincial Hospital of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China,
9Gastrointestinal surgery, Guangdong provincial people`s hospital, Guangzhou, China, 10Abdominal Surgery, Cancer Hospital of Shantou University

Medical college, Shantou, China, 11Gastroenterology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China, 12Department of
General Surgery, Henan Cancer Hospital&The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China, 13Department of Surgery, The
Affiliated Cancer Hospital of Zhengzhou University, Henan Provincial Cancer Hospital, Zhengzhou, China, 14Department of Gastrointestinal Surgery, The
First Affiliated Hospital of ChongQing Medical University, Chongqing, China, 15Surgical oncology, First Affiliated hospital of Kunming Medical University,
Kunming, China, 16Department of Gastrointestinal Surgery, West China Hospital of Sichuan University, Sichuan, China, 17Department of Radiotherapy,
Sun Yat-sen University Cancer Center, Guangzhou, China
 Rectal cancer treatment from the 1990’s

1990’s Surgery Post-op radiotherapy

2000’s TME
Pre-op radiotherapy
Surgery

TNT:
Pre-op radiotherapy and TME
2020’s RAPIDO
Pre-op chemotherapy Surgery
PRODIGE 23
STELLAR
TME
2030’s
Pre-op chemotherapy
Without radiotherapy
Surgery

WW
strategy
?
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 Treatment and disease stage
Low-risk High-risk

T2 T3a-b / Nx T3c-d T4/ Nx

< 4 cm Lateral LN+
EMVI+
CRM < 1mm
Up-front TME
Oragan preservation
? TNT
CRT Survival without
metastases

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 Treatment and disease stage
Low-risk Intermediate-risk High-risk

T2 T3a-b / Nx > 4 cm T3c-d T4/ Nx

< 4 cm T2 T3/ Nx Lateral LN+
CRM > 2mm EMVI+
CRM < 1mm
Up-front TME
Oragan preservation TNT
? RT-free strategy? TNT
CRT CT alone Survival without
metastases

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Has this been done already?

• Phase III trial: FOWARC

n =165 pts/arm

Not powered for non inferiority

CRT (5FU) - TME FOLFOX - TME

Résection R0 91% 89% ns
ypCR 14% 7% < 0,05
3-years LR* 8% 8% ns
3-years DFS* 73% 73.5% ns
3-years OS* 91% 91% ns
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J Clin Oncol 2017, *J Clin Oncol 2019
Neoadjuvant Chemotherapy with Oxaliplatin and Capecitabine Versus Chemoradiation with
Capecitabine for Locally Advanced Rectal Cancer with Uninvolved Mesorectal Fascia
(CONVERT) : Initial Results of A Multicenter Randomised, Open-label, Phase III Trial
Ding et al.
F
4 cycles of CapeOx * 4 cycles of CapeOx *
⚫ Locally advanced rectal cancer nCT O
(capecitabine and S (capecitabine and
⚫ Stage II/III & uninvolved MRF group L
oxaliplatin) U
R
oxaliplatin) L
⚫ 5-12 cm （anal verge）before April 1: 1 G O
2019; <12 cm after April 2019 R E
RT 50 Gy /5wks + R 6 cycles of CapeOx * W
⚫ Aged from 18-75 years nCRT Y -
Capecitabine 825mg/m2 po (capecitabine and
⚫ ECOG ≤ 1 group bid 5 days/7 †
U
oxaliplatin) P

Primary endpoints: 3-year local regional failure free survival

Staging: MRI Secondary endpoints: DFS, OS, pCR rate, TRG, R0 resection rate, safety, compliance, and preventive diverting
ileostomy rate.

Initial results only Non-inferiority margin: 1.6 ???

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CONSORT
Refused surgery, 17
Protocol violation,
5CCR, 2
M1 diseases, 2
Died from SAE, 2
nCT group nCRT group
Randomized n=663
(n = 331) (n = 332)

Eligible (mITT) , n (%) 327 (100) 330 (100)

Starting nCT or nCRT (PP), n (%) 300 (91.7) 289 (87.6)

Receving surgery, n (%) 272 (83.2) 261 (79.1)

Starting adjuvant chemotherapy, n (%) 235 (71.9) 222 (67.3)

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CONSORT
Refused surgery, 17
Protocol violation,
5CCR, 2
M1 diseases, 2
Died from SAE, 2
nCT group nCRT group
Randomized n=663
(n = 331) (n = 332)

Eligible (mITT) , n (%) 327 (100) 330 (100)

Starting nCT or nCRT (PP), n (%) 300 (91.7) 289 (87.6)

Receving surgery, n (%) 272 (83.2) 261 (79.1)

Starting adjuvant chemotherapy, n (%) 235 (71.9) 222 (67.3)

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Surgical & pathological results (PP population)

All
patients

Low
LARC

*Peri-operative metastasis: metastases identified before or during surgery

More pathological responses / TRG 0-1 with nCRT (38.6% vs 24%, p<0.001) but also
More preventive diverting ileostomy with nCRT (63.6 vs 52.2%, p=0.008)

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Conclusion
• nCT with CapeOx alone achieved similar pCR, cCR, and good downstaging (ypstage 0-1) rate compared to
nCRT.

• nCT with CapeOx alone reduced the peri-operative distant metastases and preventive ileostomy rate.

• Overall safety were similar in two arms; nCRT associated with lower compliance in adjuvant phase.

• CapeOx regimen could serve as a potential alternative to CRT in LARC with uninvolved MRF.

• Long-term follow-up is needed to confirm these results.

Julien TAIEB, Paris

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Conclusion
• nCT with CapeOx alone achieved But
similar pCR, cCR,
numerically and for
better good downstaging (ypstage 0-1) rate compared to
nCRT
nCRT.

• nCT with CapeOx alone reduced the peri-operative distant metastases and preventive ileostomy rate.

• Overall safety were similar in two arms; nCRT associated with lower compliance in adjuvant phase.

• CapeOx regimen could serve as a potential alternative to CRT in LARC with uninvolved MRF.

• Long-term follow-up is needed to confirm these results.

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Conclusion
• nCT with CapeOx alone achieved But
similar pCR, cCR,
numerically and for
better good downstaging (ypstage 0-1) rate compared to
nCRT
nCRT.

• nCT with CapeOx alone reduced the peri-operative

OK distant metastases and preventive ileostomy rate.

• Overall safety were similar in two arms; nCRT associated with lower compliance in adjuvant phase.

• CapeOx regimen could serve as a potential alternative to CRT in LARC with uninvolved MRF.

• Long-term follow-up is needed to confirm these results.

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Conclusion
• nCT with CapeOx alone achieved But
similar pCR, cCR,
numerically and for
better good downstaging (ypstage 0-1) rate compared to
nCRT
nCRT.

• nCT with CapeOx alone reduced the peri-operative

OK distant metastases and preventive ileostomy rate.

• Overall safety were similar in twoaarms;

nCT remains nCRT
bit more associated
toxic with
with 12.3% vs lower compliance
8.3% of grade 3-4 in adjuvant phase.
events

• CapeOx regimen could serve as a potential alternative to CRT in LARC with uninvolved MRF.

• Long-term follow-up is needed to confirm these results.

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Conclusion
• nCT with CapeOx alone achieved But
similar pCR, cCR,
numerically and for
better good downstaging (ypstage 0-1) rate compared to
nCRT
nCRT.

• nCT with CapeOx alone reduced the peri-operative

OK distant metastases and preventive ileostomy rate.

• Overall safety were similar in twoaarms;

nCT remains nCRT
bit more associated
toxic with
with 12.3% vs lower compliance
8.3% of grade 3-4 in adjuvant phase.
events

• CapeOx regimen could serve

If CRTasis acontra-indicated
potential alternative
and iftoNICRT in LARC
is proven with uninvolved MRF.
in-fine

• Long-term follow-up is needed to confirm these results.

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Conclusion
• nCT with CapeOx alone achieved But
similar pCR, cCR,
numerically and for
better good downstaging (ypstage 0-1) rate compared to
nCRT
nCRT.

• nCT with CapeOx alone reduced the peri-operative

OK distant metastases and preventive ileostomy rate.

• Overall safety were similar in twoaarms;

nCT remains nCRT
bit more associated
toxic with
with 12.3% vs lower compliance
8.3% of grade 3-4 in adjuvant phase.
events

• CapeOx regimen could serve

If CRTasis acontra-indicated
potential alternative
and iftoNICRT in LARC
is proven with uninvolved MRF.
in-fine

• Long-termLong-term
follow-up oncologic
is neededoutcomes
to confirm(DFS
these results.
and OS) and confirmatory studies in western patients

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How to integrate this « radiotherapy free » approach
in the new context
CONVERT RAPIDO PRODIGE 23 STELLAR

M+ before 0.7% 1% 1% ?
surgery

pCR 13.8% 28.4% 27.8% 16%

Local R ? 8.7% 4.8% 8.5%

3y DFS ? 76.3% 76% 64%

3y OS ? 89% 90.7% 86%

• Can we imagine that nCT will perform as good as a TNT strategy for
intermediate risk rectal cancer patients?

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My conclusion on CONVERT
Preop CapeOX without RT is :

• Feasible and safe = YES

• Innovative = YES

• Practice Changing = NOT YET

• Pending questions: what is the impact of skipping nCRT on LARS and global QoL?

=> Confirmation on long-term oncologic outcomes and on western patients are now needed

Julien TAIEB, Paris

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 LBA22

Tumor budding, an important prognostic factor in

stage III colon cancer patients treated with
oxaliplatin-based chemotherapy: a post-hoc analysis
of the IDEA France Prodige-GERCOR study

Debora Basile, Chloé Broudin, Jean-Francois Emile, Antoine Falcoz, Laurent Mineur,
Jaafar Bennouna, Christophe Louvet, Jérôme Desrame, Serge Fratte, Thierry
André, Julien Taieb, Magali Svrcek

A#4290 Mini oral

 Introducion
Tumor budding: single cancer cells or cluster comprising <5 cells, Surrogate of dynamic process of EMT,
a prognostic marker in stage I and II CC but never well studied in stage III disease
Primary objective:
• to assess the prognosic role of tumor budding in order to better stratify stage III CC patients
TB1 (0-4: low) TB2 (5-9: intermediate) TB3 (≥10: high)

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 Patient’s characteristics
Results
Flow chart

1000+ patients studied

Bd linked to tumor perforation and VELIPI status

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Results
• Disease-free survival • Overall survival

Tumor Budding is an independent

prognostic factor in stage III colon
cancer patients 5-years OS for TB1: 89.15% IC95% (85.61-91.87)
5-years OS for TB2: 81.62% IC95% (76.53-85.71)
3-years DFS for TB1: 79.44% IC95% (75.13-83.09) 5-years OS for TB3: 80.17% IC95% (75.50-84.05)
3-years DFS for TB2: 69.33% IC95% (63.60-74.34)
3-years DFS for TB3: 65.39% IC95% (60.12-70.14)

Adjustment was done on :

Age / Gender / ECOG PS
T stage / N stage / T grade/
Tumor deposits / VELIPI
Obstruction / Perforation
Immunoscore / Ttt duration

3-years DFS for TB1: 79.44% IC95% (75.13-83.09) adjHR: 1.41 (1.12-1.77, p= 0.003) 5-years OS for TB1: 89.15% IC95% (85.61-91.87)
5-years OS for TB2-3: 80.83% IC95% (77.48-83.73)
3-years DFS for TB2-3: 67.17% IC95% (63.35-70.69)

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Results: Disease-free survival
• Kaplan-Meier according to TN and TB subgroups • Kaplan-Meier according to chemotherapy duration and TB subgroups

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To summarize

• In this large series from a randomized phase III trial, TB is an independent prognostic factor for OS and
DFS in stage III CC patients treated with oxaliplatin-based standard adjuvant chemotherapy.

• Tumor budding seems to improve prognostication over T and N stage risk groups

• High TB may benefit from 6 mo of adjuvant treatment

• TB seems prognostic in patients with low Immunoscore® but not in those with high IS®
(attacker/defender theory)

 TB should now be mandatory in every pathology report concerning patients resected

from a stage III CC.

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Risk of bowel obstruction in patients undergoing
neoadjuvant chemotherapy for high-risk colon
cancer: A nested case-control matched analysis of
an international, multi-centre, randomised controlled
trial (FOxTROT)
James Glasbey et al., ESMO® 2021, Abs #389MO

Mini oral
FOxTROT : neoadjuvant FOLFOX in stage III colon cancer

N=1053
Adult patients with high-risk colonic cancer randomised in the FOxTROT trial

N=354 (33.6%)
Patients randomised to
standard adjuvant
chemotherapy only

N=699 (66.4%)
Patients randomised to short course neoadjuvant chemotherapy (NAC) and standard
adjuvant chemotherapy

N=1 (0.1%)
Patient
withdrawal

Bowel obstruction = 4.3% N=698 (66.4%)

Included in analyses

Linked to post-op mortality

and poor survival N=30 (4.3%)
Patients that developed
colonic obstruction during
N=668 (95.7%)
Patients that did not
develop obstruction during
NAC
NAC (cases)
dMMR = 2 (6.7%)
pMMR = 26 (86.7%)
Unknown = 2 (6.7%) N=90
Risk factors for obstruction? Patients age- and sex-
matched to obstructed
cases (controls)
dMMR = 12 (13.3%)
pMMR = 67 (74.4%)
Unknown = 11 (12.2%)
 FOxTROT : neoadjuvant FOLFOX in stage III colon cancer
Localisation tumorale
Colon Ascending
flexures Transverse Colon rectosigmoid
colon
0,4% 0,0% 0,0% 0,6%
Non obstructive in
(0,0% à 1,3%) (0,0% à 0,0%) (0,0% à 0,0%) (0,0% à 1,8%)
endoscopy
n=223 n=15 n=19 n=167
3,3% 6,8% 0,0% 2,5%
Stricture (radiology and
(0,0% à 9,5%) (0,0% à 19,2%) (0,0% à 0,0%) (0,0% à 7,4%)
endoscopy)
n=31 n=16 n=13 n=41
9,9% 4,5% 0,0% 2,1%
Obstructive in endoscopy (0,0% à 27,4%) (0,0% à 13,0%) (0,0% à 0,0%) (0,0% à 6,1%)
n=11 n=23 n=6 n=49

Both stricture and 19,8% 67,8% 31,4% 7,6%

obstructive lesion in (0,0% à 42,2%) (34,3% à 93,8%) (9,2% à 53,6%) (0,0% à 15,5%)
endoscopy n=12 n=12 n=17 n=43

• J. Glasbey et al., ESMO® 2021, Abs #389MO 63,4% (443/698) 30,7% (214/698) 5,9% (41/698)
Low risk (<1%) medium risk (1-10%) High risk (>10%)
Neoadjuvant pembrolizumab in localized/locally
advanced solid tumors with mismatch repair
deficiency

Kaysia Ludford, et al., ESMO® 2021, Abs #1758O

 Neoadjuvant pembrolizumab in localized/locally advanced
solid tumors with mismatch repair deficiency
N= 35
• 19 colon
• 8 rectum
• 2 duodenum
• 2 pancreas surgery Objective I :
• 4 others • pCR
Clinical benefit • tolerability
Evaluation
Pembro x 6 cycles Objectives II:
Inclusion
• RR
Pembrolizumab Or 1 year of treatment • OS, DFS
• Locally advanced Néo-adjuvant Evaluation • Organ presevation
Tumors
X 2 cycles • ctDNA (baseline & 3 weeks)
• MSI
• N = 35 No clinical
benefit
Treatment stop

Clinical benefit
• OR (CR or PR)
• SD (-1% to -29%)
• SD (+1% à +19%) + ctDNA stable or decreased
• Clinical benefit
 Waterfall plot RECIST v 1.1 (n=32)
40
resected

% Meilleur changement par rapport à la

20 Not resected

Main results: 0

-20

baseline
-40
ORR: 75% (CR: 25%, PR : 50%) -60

SD: 22% -80

PD: 3% -100

-120

12 complete responses + 2 major

responses in endoscopy
pCR
pCR: 69% in those resected Non-CR
(n=15) 31%
69%
pCR

11% : not resected and not relapsing

 THANK YOU

Cytotoxic LT

Cancer cell