Cette présentation faite le 27 Avril 2017 à l'Hôpital Saint Joseph organisée par le Dr Vincent de Parades fait le point sur les nouvelles approches multidisciplinaires dans la prise en charge des cancers colorectaux en insistant sur la prise en charge de la maladie métastatique hépatique et de la carcinome péritonéale pour terminer sur les nouvelles approches par immunothérapie. Cette EPU a connu un large succès d'audience avec plus de 60 participants. Merci à toutes et tous.

1. Place des nouveaux traitements dans
les cancers colorectaux
Prof Eric Raymond
Chef de service d’oncologie médicale
Hôpital Paris Saint-Joseph
Paris 14ème

3. Nouveaux traitements oncologiques des
cancers colorectaux
• Prise en charge de la maladie métastatique hépatique
• Le tandem Chimiothérapie +/- thérapie ciblée + Chirurgie
• Traitement intra-artériels hépatiques
• Chimiothérapies intra-artérielles
• Radio-embolisation hépatique à lY90
• Billes chargées à l’irinotecan (Debiri)
• Traitements de la carcinose péritonéale
• IPAC
• PIPAC
• Immunothérapie des cancers colorectaux

4. Le foie
Nouveaux traitements oncologiques des cancers colorectaux

5. Colorectal cancer: a typical example where liver
metastases are potentially curable
• 50% of patients with colorectal
cancer will eventually develop liver
metastases during the natural
course of the disease
• 25% of patients present with liver
metastases at the time of diagnosis
Ruers T, Bleichrodt RP. Treatment of liver metastases, an update on
the possibilities and results. Eur J Cancer 2002;38:1023-1033

6. Improved survival across time for
metastatic colorectal cancer
1980 1985 1990 1995 2000 2005 2010
Best supportive care
Median OS
5-FU
Irinotecan
Capecitabine
Oxaliplatin
Cetuximab
Bevacizumab
Panitumumab
OS(Mos)
30
20
10
0
1980 1985 1990 1995 2000 2005
Yr
2010
Ziv-aflibercept
Regorafenib

7. Allongement de la survie médiane

8. 80405: OS in Patients Rendered Disease
Free With SystemicTherapy + Surgery
N (Events) mOS, Mos (95% CI)
124 (34) 66.3 (59.8-NA)
Venook AP, et al. ASCO 2014. Abstract LBA3.
0
12 24 36 48 60 72
80
100
60
40
0
OS(%)
20
84
Mos
>25% long term survival

9. Resectable
Borderline
Resectable
Unresectable
10-30%
70%
Distribution of liver metastases

10. Resectable
Borderline
Resectable
Unresectable
10-15%
70%
Distribution of liver metastases
and principle of systemic therapy
PREOPERATIVE DOUBLET
(followed by a post-operative
3 month doublet)
-Short-term duration (£6 months)
SYSTEMIC DOUBLETS
-Long-term duration (≥6 months)
-Response rate 40-50%
- Optimal tolerance
10-15%

11. Improve progression-free survival
(Improve survival)
Surgery
Preoperative
Chemotherapy
(FOLFOX)
3 months
Postoperative
Chemotherapy
(FOLFOX)
3 months

12. Overall median survival following
liver resection: 3.6 years (1.7-7.3)
>1 liver metastases
>3 cm tumor diameter
Synchronous
Elevated CEA
Poor tumor grade
Positive margins
Solitary nodule
<5 cm diameter
Metachronous
Nordlinger et al, Ann Surg 2012
Kanas et al, Clinical Epidemiol 2012
Adam et al, Ann Surg 2010
Prognostic factors of survival
Role of systemic therapy+++
Role of chemotherapy +/-
Interval of relapse
Age, performance status

13. Figure 2. Pathologic response classification methods: (a) tumor regression grade (TRG) scoring system (black area: tumor cells, grey area: necrotic area; fibrils; fibrosis) [31] (b)
representative photomicrographs of metastases demonstrating complete, major and minor pathologic response [32]. (a) Rubbia-Brandt L et al. Importance of histological tumour
response assessment in predicting the outcome in patients with colorectal liver metastases treated with neoadjuvant chemotherapy followed by liver surgery. Ann Oncol 2007;
18(2):299e304; by permission of Oxford University Press. (b) Reprinted with permission. Ó 2008 American Society of Clinical Oncology. All rights reserved. Blazer, DG III et al.: J Clin
Oncol 26(33), 2008:5344e51.
T. Gruenberger et al. / Surgical Oncology 21 (2012) 309e315 311
resulted in response
Clinically significan
increasingly being r
erative chemothera
therapy has been as
injury and subsequ
study by Kishi et al.
the combination of b
a significantly lower
FOLFOX alone both
cycles: 5% vs 46%, re
respectively; p ¼ 0
related nodular rege
combination of bev
alone in 274 patients
In a second retro
oxaliplatin (5-FU/O
compared with 5-F
p ¼ 0.02) in 105 pat
0 12 24 36 48 60
1.0
0.8
0.6
0.4
0.2
Time (months)
MjHR
PHR
NHR
Log rank p < 0.005
0 2 4 6 8 10
0.8
0.6
0.4
0.2
Time (years)
Overall survival (probability)
Complete vs
major response p = 0.037
Major vs
minor response p = 0.028
Complete response
Major response
Minor response
1.0
b
Figure 3. a. Overall survival of 106 patients with complete clinical follow-up and
major, partial, or no histologic tumor response in CLM treated with neoadjuvant
chemotherapy and surgery [31]. b. Overall survival by the degree of pathologic
response to neoadjuvant chemotherapy with or without bevacizumab [32]. (a) Rubbia-
Brandt L et al. Importance of histological tumour response assessment in predicting the
outcome in patients with colorectal liver metastases treated with neoadjuvant
chemotherapy followed by liver surgery. Ann Oncol 2007; 18(2):299e304; by
permission of Oxford University Press. MjHR Major histologic tumor response; PHR
Table 1
Overview of published pa
Blazer et al. 2008a
[32]
5-FU þ oxaliplatin (n
5-FU þ oxaliplatin þ
bevacizumab (n ¼ 50
Kishi et al. 2010a
[35]
FOLFOX (n ¼ 117)
FOLFOX þ bevacizum
(n ¼ 102)
Ribero et al. 2007b
[36]
5-FU þ oxaliplatin (n
5-FU þ oxaliplatin þ
bevacizumab (n ¼ 62
Klinger et al. 2010c
[37
FOLFOX (n ¼ 50)
FOLFOX þ bevacizum
(n ¼ 50)
Major/complete pathological response is predictive
of better survival outcome in patient receiving
preoperative CT followed by liver surgery
Gruenberger et al, Surg Oncol 2012

14. The goal for the team!
No viable tumor cell
visible !

15. Resectable
Borderline
Resectable
Unresectable
10-15%
70%
Role of medical oncology: optimize
the quality of response
PREOPERATIVE TRIPLETS
(followed by post-operative
3 months doublets)
-Short-term duration (£6 months)
-High response rate (60-70%)
SYSTEMIC DOUBLETS
-Long-term duration (≥6 months)
-Response rate 40-50%
- Optimal tolerance
10-15%

16. Selection of targeted agent according
to K-Ras status
1st line
triplet
FOLFOX/FOLFIRI
+
Targeted agent VEGF inhibitor
(Avastin®
Bevacizumab)
EGFR Inhibitor
(Erbitux®
cetuximab)
KRas Wild Type
(no mutation)
KRas mutated

17. Downstage tumor lesions
to allow resection
and …Improve survival
Surgery
Preoperative
Chemotherapy
(triplets)
3 months (<6 months)
Postoperative
Chemotherapy
(FOLFOX)
3 months
• Progression at first evaluation is
associated with disease
aggressiveness, poor outcome
• The value and safety of resection
becomes questionable (delay further
chemo)
• FOLFOX is the only
chemotherapy validated in
adjuvant setting
• Irinotecan and targeted
therapies have never been
validated in this setting

18. 12 Cycles Folfiri + cetuximab
Borderline metastases
Major tumor response

19. sected.
ficienttoallowacurative
quesaimedatincreasing
before surgery in cases of
planned hepatectomy.21
could be combined with
r few contralateral, unre-
hird,whenmultinodular
ected by a single proce-
ablation, two-stage hep-
ns within 2 months after
g to the classification by
rease in serum bilirubin
rothrombin time to less
ses was not a contraindi-
en, resection of extrahe-
s the hepatectomy. For
was generally delayed for
ing the time interval to
examination, serum tu-
9), and abdominal ultra-
the remaining 5% of patients.
0
No. of patients at risk
Overall survival 161 78 41 25 18 14
Disease-free survival 96 45 31 22 17 12
SurvivalProbability
Time (years)
1.0
0.8
0.6
0.4
0.2
1 2 3 4 5 6 7 8 9 10
Overall survival (n = 184)
Disease-free survival (n = 184)
33%
19%
27%
15%
Fig 1. Overall and disease-free survival curves of patients with initially unre-
sectable disease who underwent resection after downsizing chemotherapy.Adam, J Clin Oncol 2009
This multidisciplinary strategy benefits to patients
in terms of overall survival (curability)

20. Improve survival
Avoid unnecessary toxicities
Systemic Chemotherapy
(5FU-based doublets)
≥6 months

21. Management of 1st line therapy according
to evaluation @ 3 months
1st line
Doublets
(FOLFOX or
FOLFIRI) Switch to
other doublet
(Discuss targeted
therapy)
Maintain same
regimen
for 3 months
Objective Response
or Stable Disease
(70-75%)
Progressive
Disease (25-30%)

22. Improvement of liver-disease control
(disease mainly/exclusively limited to the liver)
Potential indications for liver-
directed therapies
- Acquired resistance after systemic chemotherapy (after
1-1.5 year of controlled disease)
- Major preoperative dowstaging for borderline lesions in
combination to systemic therapy
- Adjuvant treatment after resection of multiple lesions
with limited response to previous systemic
chemotherapy

26. Conclusions
• Resectable: Perioperative FOLFOX is
mainstay (3+3, no proved added value of
optimizing response)
• Borderline: Preoperative triplets (with a
targeted agent) optimizes the quality of
response before surgery (then adjuvant
FOLFOX)
• Never resectable: Long term disease
control is key and liver targeted therapy
should be discussed

27. Le Péritoine
Nouveaux traitements oncologiques des cancers colorectaux

28. Do we know the spontaneous survival of
patients with isolated PC?
Not well reported in the literature
<6 months for CRC
<4 months for gastric cancer
<3 months for pancreatic cancer
EVOCAPE study (370 patients with PC of GI origin, only 26% treated with CT
ü Median OS: 5.2, 3.1, and 1.5 months for CRC, gastric, and pancreas respectively
ü Impact of tumor burden: OS ranging from 9.8 months (small stage I granulations
<5mm) to 3.7 months (large stade IV masses > 2cm)
Sadeghi et al, Cancer 2000

29. Peritoneal carcinomatosis (PC) is one way of
dissemination among others for malignancies
- 65-90% of colorectal cancers, 60% of gastric cancers
- Distant visceral metastasis require systemic chemotherapy to
ensure global disease control
- PC is a rising problem since systemic chemotherapy has
improved patients’ survival >6 months
Visceral metastasis are the more frequent site of
dissemination for recurrent malignancies

30. PIPAC

31. L’immunothérapie
Nouveaux traitements oncologiques des cancers colorectaux

33. MHC
PD-L1
PD-1
PD-1
T-cell
receptor
PD-L2
T cell
NFκB
Other
PI3K
Tumor cell
IFNγ
IFNγR
Shp-2
Antibodies
Immune Checkpoint antibodies
1. Topalian SL, et al. N Engl J Med. 2012;366:2443-2454

40. Conclusion
• Le traitement des métastases hépatiques des cancers colorectaux
requière l’accès à un plateau de soins pluridisciplinaire pour
augmenter les chances de guérison
• De nouvelles approches médico-chirurgicales sont en cours
d’évaluation pour le traitement de la carcinose péritonéale
• L’immunothérapie est une approche prometteuse dont la place est en
cours d’évaluation dans les cancers colorectaux avancés ou
métastatiques