Colorectal Peritoneal CarcinomatosisPatient selection for CRS+HIPEC

A D’Hoore MD PhD, AM Wolthuis MD PhD, G.Bislenghi MDE Van Cutsem, S Tejpar, J Dekervel

RC Dresen, V Vandecaveye

Department of Abdominal Surgery, Digestive Oncology and Radiology

No related disclosures

Franko J et al. Lancet Oncology 2016

Oligometastasis in spectrum concept

- Unique group of patientslimited burden of metastatic disease

- Ablative therapy of the metastases in combination with systemic therapycould lead to

prolonged disease - free survival and even cure

Treatment strategy

Limited peritoneal spread eligible for locoregional treatment in combination with systemictreatment

Two components

HIPEC

Complete cytoreductiveSurgery

Prodige 7 : patients’ outcome depends on our capacity to obtain a macroscopically complete resection

Prospective comparative trial

Elias D etal. J Clin Oncol 2008; 27

Median survival : 23.9 mo (standard) vs 62.7 mo (HIPEC) p<.055 year overall survival rates : 13% (standard) vs 51% (HIPEC)

No ∆ systemic CHT : mean 2.3 lines

A systematic review and meta-analysisCRS + HIPEC

Huang CQ-Oncotarget 2017

15 controlled studies 76 HIPEC related studies

Cytoreductive surgery = standardised- Extraperitoneal resection

- Diaphragma stripping

- Radical omentectomy

- …

HIPEC modalities: heterogeneity in protocols- Different chemotherapeutic drugs

Mitomycin C – Oxaliplatin

- Carrier solution- Perfusate Volume- Open versus closed technique- Duration of the perfusion

Impact on Pk and Pd of the drug

Leuven prospective HIPEC database

Selection

Resectability : complete cytoreductive surgery ?- accuracy whole-body DW MRI

Role of ‘neoadjuvant’ systemic chemotherapy- improve patient selection for CRS- borderline resectable/unresectable disease

Systemic disease a (relative) contra-indication

Quantitative intra-operative assessmentPeritoneal Carcinomatosis Index (P Sugarbaker)

Simplified PCI 7-region count(Dutch Cancer Institute) (Dutch Cancer Institute)

Jacquet P. et al. Cancer treat Res 1996; 82:359-74Verwaal VJ et al. Br J Surg 2004; 91:739-746

extent of disease relates toability of obtaining complete cytoreduction

Eur J Surg Oncol 2008

Median survival (mo)

0

5

10

15

20

25

30

35

40

45

50

Loggie Glehen Verwaal Yan

CC-0

CC-1

CC-2

Optimised Chemomedian survival : 2

extensive disease : radix infiltration apparently limited disease

Role of laparoscopy-Obviate unnecessary laparotomy (20%)

- extensive small bowel involvement- extensive diaphragm involvement

-Understages Resectable disease

- coeliac axis and hepatic pedicle- retroperitoneal extension

-Hampered by previous laparotomy/adhesions

Whole-body DW MRI for operability assessment

DresenRC et al. Cancer Imaging 2019

97.8% sensitivity to detect PC

88.9% PPV; 98.7% NPV

Exclude patients with extensive small bowel disease

Retroportal N+

N+P+

P+

Primary

Kruckenberg

Leuven data (60 patients)

distant/nodal metastases : 18 of patients had unresectable distant metastases WB-DWI detected in 17 of 18 (94%).

Correct assessment of operability in 54 of 60 patients (90%)

Understaging extent disease 6 ptsNo overestimation of PCI

Only laparoscopy in 16 patients

Whole body MR-DWI based PCI versus PCI at laparotomy

N = 42Linear correlation : R2 = 0,84p < 0.0001

* WB-DWI - 5 underestimated3 evaluated by laparoscopy2 Futile attempt of surgery

* No erroneous overestimation of disease

22

2

1 2

2

0

0

0

0 2

0PCI = 11Operable

0

Patient 56 years old.

3.5 years after primary treatment of T3N1 SigmoidCa

Treated with neo-adjuvant chemotherapyfor peritoneal carcinomatosis

FDG-PET CT shows excellent response withregression of peritoneal metastasesand no distant metastases

CEA level significantly decreased

Eligible for HIPEC?

33

2

1

2

2

21

1

3 3

11PCI = 24Inoperable

Resectability (complete cytoreductive )

T biology

Adapted from ESMO guidelines , Ann of Oncol 2016.

Bad

Good

easy difficult

PCI < 12Limited small

bowelWell,mod

differentiation, Node -

PCI > 15Extensive small bowel involvementHepatic hilum involvement

Non-differentiatedSignet-cellExtensive nodal diseaseRapid progression under systemic therapyBRAF mutation

patient-relatedBiological age - significant comorbidity

overall median survival = 29 mo

P<.001

multivariate analysis of overall survival

HR 95%CI p

Well/moderate differentiation 4.011 1.024- 8.826 0.045

Complete cytoreduction 5.152 1.185-10.179 0.023

Yan TD et al. Ann Surg 2008; 248:829-835

Prognosis of metastatic colorectal cancer is affectedboth by number of disease sites and presence of peritoneal involvement

liver M+ and PC : median survival 5 moa more aggressive strategy for selected patients ?

Thomassen I. et al.Dis Colon Rectum 2013

PC and limited resectable liver M+ ?any better than systemic chemotherapy ?

PDSS peritoneal disease severity score

Ann Surg Oncol 2016

COMPASS nomogram

PDSS COMPASS

External validation of COMPASS

Demey K, Wolthuis A, de Buck van Overstraeten A, Fieuws S, Vandecaveye V, Van Cutsem E, D'Hoore A.Ann Surg Oncol. 2017 Nov;24(12):3604-3608

RAS Mutation Decreases Overall Survival After Optimal Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy of Colorectal Peritoneal Metastasis: A Modification Proposal of the Peritoneal Surface Disease Severity ScoreAnn Surg Oncol 2019

Ongoing Clinical Research

1. Role of prophylactic HIPEC in high risk advanced CR cancerpT4aperforated tumorsKrukenberg

2. Induction chemotherapy before debulking surgery

Risk for PC in deep serosal involvement and T4a

159 T4 colorectal cancer patients

Synchronous PC n=29

Synchronous distant

metastases, other than PC:

n=11

No Synchronous PC n=130

Metachronous PC n=30

Disease (recurrence)

other than PC at time of

diagnosis of PC: n=18

Peritoneal disease T3 (<1mm) T4aAt the time of surgery

9.3% 22% 0.076

Subsequent 13% 28% 0.069

p T4a

pT3 ≤ 1 mm

Klaver C et al. Ann of Surg Oncology 2018

Advantages of induction systemic treatment

- 50 % systemic relapse

- further selection

progression under chemo/beva : excludes CRS + HIPEC

- Increase resectability ?

Role of ‘neoadjuvant’ chemotherapy in unresectable disease

Pilot study

N = 10 patients

laparoscopic mapping (7 regions)

start systemic chemotherapy : Folfox + Beva

results : 1 pt. developped small bowel perforation : palliative treatment

7 pts. progressive disease

only 2 : stable diseasemedian overall survival 8.3 mo (1.4-16.8)

Hompes D. et al. Colorectal Dis 2014

Conclusion

Patients with limited PC from colorectal origin shouldundergo complete cytoreductive surgery (+ HIPEC)

but HIPEC protocol needs standardisation

pT4a (and deep serosal invasion) tumours need intensifiedfollow-up (Whole Body-DW MRI)

prophylactic HIPEC = investigational