Present and Future of Present and Future of Hyperthermic Hyperthermic intraperitoneal chemo intraperitoneal chemo (HIPEC) in Colorectal (HIPEC) in Colorectal Peritoneal MetastasesPeritoneal Metastases

Dominique ELIAS

Cancer Campus, Grand-Paris

Stages IV treated with Chemo: Stages IV treated with Chemo: PC PC have a poorer prognosis than have a poorer prognosis than other sitesother sites

From the phase III trials N9741 and N9841 (Folfox / Folfiri)From the phase III trials N9741 and N9841 (Folfox / Folfiri)

NbNb Median OSMedian OS

Without PCWithout PC 17311731 17.6 months17.6 months

p< 0.01p< 0.01

With PCWith PC 364364 12.7 months12.7 months

Conclusion: Conclusion: - Shorter OS and DFS when PC- Shorter OS and DFS when PC

- - 5-y survival with Folfox (all pts:5-y survival with Folfox (all pts: 4%)4%)

(Franko J et al. ASCO 2011)

Is it possible to obtain Is it possible to obtain definitive cure with CCRS + definitive cure with CCRS + HIPEC ?HIPEC ?

•Prospective study of our patients treated between January 1995 and December 2005 (n=93).

•Learning curve = worst results.

The Cure = no recurrence during a minimal delay of 5 years

(Goéré et al. Ann Surg 2013, on line)

Median follow-up: 99 months Median follow-up: 99 months Median Survival : 34 monthsMedian Survival : 34 months Overall 5-year survival : 32%Overall 5-year survival : 32%

Absolute cure at 5 years:17/107 pts = 16%

125815273341648993234710141616244993

0.000.100.200.300.400.500.600.700.800.901.00

0 12 24 36 48 60 72 84 96 108 120Months

Overall Survival

Disease-freeSurvival

At risk

At 10 years:102/612 pts =16,7%

At 5 years without rec.24/148 pts =16%

At last……

1) Hepatectomy for PM or HIPEC for PM: overall survival and definitive cure rates are the same.

2) Peritoneum can be considered as an organ, a site of metastasis, similarly to the liver .

Current survival rate of 146 colorectal PC Current survival rate of 146 colorectal PC treated with CCRS + HIPEC: treated with CCRS + HIPEC: Prospective bi-centric study (Paris/ Montpellier)Prospective bi-centric study (Paris/ Montpellier)

(Quenet, Elias et al, Ann Surg 2011; 254: 294-301)

Median survival:41 months

5-year survival:

48%

Is there a benefit to Is there a benefit to use surgery alone ?use surgery alone ?

Surgery Surgery versusversus No Surgery No Surgery

Is there a trial comparing ?Is there a trial comparing ?

SurgerySurgery

Similar patientsSimilar patients ®®No SurgeryNo Surgery

Answer is: NOAnswer is: NO

Complete resection alone of Complete resection alone of PC ?PC ?

NbNb Selection Median OS 5-Y Selection Median OS 5-Y SurvivalSurvival

Mulsow 2011Mulsow 2011 3131 IP <10IP <10 25 months 25 months 22%22%(Erlangen)(Erlangen)

Cashin 2012Cashin 2012 5757 + SPIC* 25 months+ SPIC* 25 months 18%18% (Uppsala)(Uppsala)

Evrard 2012Evrard 2012 3030 IP <10IP <10 30 months 30 months 25%25%(Bordeaux)(Bordeaux)

*SPIC = Sequential postop. intraperitoneal chemo.*SPIC = Sequential postop. intraperitoneal chemo.

Différence entre les moyennes de survie restreinte

CHIP

Chimio

Retrospective comparative studyIn the control group: 3.4 lines of chemoMedian survivals: 25 months vs 60 months

(Elias et al. J Clin Oncol 2009; 27:681-5)

Conclusion:Conclusion:

No clear difference between resection and no resection.

When it is possible to easily resect the PC: probably it is useful for the patient.

If you do it, median survival will be at least 25-30 months.

Who is it interesting to Who is it interesting to resect, and how to resect, and how to resect ?resect ?

Multicentric retrospective study (15 years), Multicentric retrospective study (15 years), Including the leaning curves of all the centres =

the worst results Complete cytoreductive surgery (CC0) in Complete cytoreductive surgery (CC0) in 85%85% of of

the casesthe cases

Postoperative deaths: Postoperative deaths: 3%3% Morbidity (grade 3-4): Morbidity (grade 3-4): 30%30% Mean hospital staying: Mean hospital staying: 22,5 days22,5 days

(Elias et al. J Clin Oncol 2009; 27: 681-685)

French registry: 523French registry: 523 colorectal PC treated colorectal PC treated with cytoreductive surgery + with cytoreductive surgery + intraperitoneal chemo treated in 23 intraperitoneal chemo treated in 23 centres.centres.

Overall Survival of the 523 Overall Survival of the 523 patientspatients

Median survival: 30 months 5-years survival: 27%

Survival according to the Survival according to the Radicality Radicality of the Surgery (p< of the Surgery (p< 0.0001)0.0001)Look at the median survivals….Look at the median survivals….

The Peritoneal The Peritoneal carcinomatosis Index (PCI) carcinomatosis Index (PCI) (Ranging from 1 to 39)(Ranging from 1 to 39)

Survival according to the Survival according to the ExtentExtent of the of the Péritoneal Carcinomatosis (p< 0.0001)Péritoneal Carcinomatosis (p< 0.0001)

PC with associated LM ? PC with associated LM ? IGR’series:IGR’series:

61 HIPEC alone 61 HIPEC alone vsvs 37 HIPEC37 HIPEC + LM+ LM

Retrospective study issued from a prospective Retrospective study issued from a prospective data base.data base.

Selection of similar patientsSelection of similar patients (61 and 37): (61 and 37): Age, Sex, Status of the primary, Age, Sex, Status of the primary, PCI (mean was PCI (mean was

13),13), radicality, systemic chemotherapy. radicality, systemic chemotherapy.

Except for LMExcept for LM

Mortality: 4%; Morbidity: 54%Mortality: 4%; Morbidity: 54%

(Maggiori L et al. Ann Surg 2013)

Higher Survival rate (p=0.04) Higher Survival rate (p=0.04) when no LMwhen no LM

PCI<12 without LM : 76 months

PCI<12 + LM <3: 40 months

PCI≥12 or LM ≥3: 27 months

Overall Survivals according to Overall Survivals according to the the

extent of the diseaseextent of the disease

What patients to resect ?

Those with a PCI < 20Those with a PCI < 20

Those with a good general statusThose with a good general status

LM are not a contraindication if LM are not a contraindication if resectable without major riskresectable without major risk

Is it useful to add Is it useful to add HIPEC ?HIPEC ?

Principle of HIPEC: Principle of HIPEC: A combined treatmentA combined treatment

1.1. Surgery to treat the visible disease (> 1 mm)Surgery to treat the visible disease (> 1 mm)

2.2. HIPEC to treat the remaining non visible HIPEC to treat the remaining non visible disease.disease.

The strong The strong beliefbelief of surgeons in the efficacy of surgeons in the efficacy of this « package » encourages them to of this « package » encourages them to devote a lot of time and a lot of energy to devote a lot of time and a lot of energy to resect all visible disease (+++).resect all visible disease (+++).

Impact of Impact of HIPEC aloneHIPEC alone: : experimental dataexperimental data

60 rats with colorectal PC were randomized in 3 arms.Hipec: 90 min, close procedure, inflow temperature at 42°C.

CRS CRS + HIPEC CRS + HIPEC

Mito 15 mg/m² Mito 35 mg/m²

Nb 20 20 20R2 6 4 4Med. Surv 43d 75d 97dP 0.003 < 0.001

Conclusion: Efficacy of HIPEC and efficacy of increasing dosage.

(Klaver Y et al. Br J Surg 2010; 97: 1874-80)

Complete surgery (CS) Complete surgery (CS) alone alone versusversus CS plus HIPEC ? CS plus HIPEC ?

We have not yet the answerWe have not yet the answer

French French Prodige 7Prodige 7 trial is on going trial is on going

Complete cytoreductive surgeryComplete cytoreductive surgery

®®

HIPEC No HIPECOxali, 30 min, 43°COxali, 30 min, 43°C+5-FU and Leuco IV+5-FU and Leuco IV

Already 250 randomized patients among the 280…

Equivalence between LM Equivalence between LM and PMand PM

287 hepatectomy287 hepatectomy 119 CCRS+HIPEC119 CCRS+HIPEC Exclusion of [Hepatec + CCRS-HIPEC] (n=37)Exclusion of [Hepatec + CCRS-HIPEC] (n=37)

Subgroups according to the global tumor Subgroups according to the global tumor load:load:– LM in 2 groups: ≤ 10 LM, and > 10 LMLM in 2 groups: ≤ 10 LM, and > 10 LM– PM in 3 groups: PCI 1-5, 6-15, > 15PM in 3 groups: PCI 1-5, 6-15, > 15

Same overall global Same overall global survivalsurvival

Overall survival for the 2 Overall survival for the 2 gps of LMgps of LM

Overall Survival for the 3 Overall Survival for the 3 gps of PMgps of PM

Equivalence of prognosis Equivalence of prognosis between LM and PMbetween LM and PM

Application and extension of this Application and extension of this therapeutical concept:therapeutical concept:

Introduction to the concept of a Introduction to the concept of a Second-LookSecond-Look Surgery in patients Surgery in patients at at high riskhigh risk of developing colorectal of developing colorectal peritoneal metas. at the moment of peritoneal metas. at the moment of the resection of the primarythe resection of the primary

(Elias et al. Ann Surg 2008; 247: 445-450)

Rational of the second-lookRational of the second-look

HIPEC is all the more « light » and all the HIPEC is all the more « light » and all the more efficient that the PC is minimal.more efficient that the PC is minimal. But to But to detect early minimal PC is possible neither with clinic detect early minimal PC is possible neither with clinic

neither with imaging.neither with imaging.

It is the reason why it is logical to propose a systematic second-look to asymptomatic patients presenting high risks to develop a PC, with the aim to treat PC at an early stage.

Definition of High-risk patients

Review of the literature Review of the literature (6522 articles)(6522 articles)

No real high-risk:– Occlusive tumorsOcclusive tumors– Bleeding tumorsBleeding tumors– T4T4– Positive cytologyPositive cytology– Positive lymph nodesPositive lymph nodes– Rignet-cell tumorsRignet-cell tumors– Mucinous tumorsMucinous tumors

Real high-risk:- Perforated tumors- Peritoneal metastases- Ovarian metastases

(Honoré C. et al. Ann Surg Oncol 2013; 20: 183)

Risk between 35% and 80%Risk ≤ 20%

Patients et MethodsPatients et Methods

Patients with a high risk to develop a PC: we selected 3 gps:– With minimal macroscopic PC (which was completely resected (which was completely resected

during surgery)during surgery)

– With ovarian metastases – With perforation of their primary tumour of their primary tumour

All these patients received the adjuvant standard treatment after the first surgery: 6 months of systemic chemotherapy (Folfox or Folfiri)

12 months after their first surgery, if a complete work-up was negative, , we proposed a second look + HIPEC

(Elias et al. Ann surg 2011; 254: 289-293)

Results (1)Results (1)

Between 1999 and 2009– 41 patients included

– Median follow-up: 30 months [range: 9-109]

Macroscopic PC at « 2Macroscopic PC at « 2ndnd look » : look » : 56% (23/41) (mean PCI 8 (23/41) (mean PCI 8 ++ 6) 6)

100% HIPEC Mortality : 2% (1/41)Morbidity : 9,7% (4/41)

Results (2)Results (2)

Minimal synchronous PC resected with the primary Minimal synchronous PC resected with the primary tumourtumour– Peritoneal recurrence rate Peritoneal recurrence rate 60%60% (15/25) (15/25)– Mean PCI : Mean PCI : 9±69±6

Synchronous ovarian metastases resected with the Synchronous ovarian metastases resected with the primary tumourprimary tumour– Peritoneal recurrence rate Peritoneal recurrence rate 62%62% (5/8) (5/8)– Mean PCI Mean PCI : 7±5: 7±5

Perforated primary tumourPerforated primary tumour– Peritoneal recurrence rate Peritoneal recurrence rate 37%37% (3/8) (3/8)– Mean PCI : Mean PCI : 5±25±2

Results (3)Results (3)

9111 218192 43 14 1

4468111 53 44 1

0 ,0 0

0 ,1 0

0 ,2 0

0 ,3 0

0 ,4 0

0 ,5 0

0 ,6 0

0 ,7 0

0 ,8 0

0 ,9 0

1 ,0 0

0 1 0 2 0 3 0 4 0 5 0 6 0 7 0

M o n th s

O v e ra l l s u rv iv a lD is e a s e fr e e s u rv iv a l

P a tie n ts a t r is k

Peritoneal recurrence : 17% (7/41) 6 after PC at 2nd look (26%)1 after no PC at 2nd look (6%)

5-y overall survival 90%

5-y disease free survival 44%

PC at 2nd look = risk factor for Peritoneal recurrence

« ProphyloCHIP » trial « ProphyloCHIP » trial (Prodige (Prodige 15)15)

Nb of patients = 130 Nb of patients = 130 (75 patients already randomized) 11stst endpoint : 3-y Disease Free Survival endpoint : 3-y Disease Free Survival

« high risk » patients

Standard arm

Experimental arm

6 months IV Folfox IV

SurveillanceSystematic 2nd

look plus HIPEC

Randomization

Negative work-up

Dans la vraie vie: que faire quand Dans la vraie vie: que faire quand vous découvrez fortuitement une CP vous découvrez fortuitement une CP ??

L’idéalL’idéal L’acceptableL’acceptable L’innaceptableL’innaceptable

ConclusionConclusion

The treatment of PC has dramatically changed during the The treatment of PC has dramatically changed during the last 10 years.last 10 years.

Now it is possible to definitely cure some PC (like liver Now it is possible to definitely cure some PC (like liver metastasis)metastasis)

The impact of a complete surgery is major (+++).The impact of a complete surgery is major (+++).

The impact of HIPEC is not clear enough.The impact of HIPEC is not clear enough.

The second-look + HIPEC approach is promising as early The second-look + HIPEC approach is promising as early treatment of early peritoneal metastases for high-risk treatment of early peritoneal metastases for high-risk patients.patients.

To progress more rapidly: please, include your patients in To progress more rapidly: please, include your patients in trials !trials !

Thank youThank you

Cox regression analysisCox regression analysis

Overall SurvivalOverall Survival Odds-Ratio Odds-Ratio (95%) (95%)

pp

PCI ≥ 12PCI ≥ 12 4.6 (2.5-8.5)4.6 (2.5-8.5) <0.001<0.001

pN+ primary tumourpN+ primary tumour 3.3 (1.3-8.9)3.3 (1.3-8.9) 0.0160.016

no postoperative no postoperative chemotherapychemotherapy

3.0 (1.5-6.2)3.0 (1.5-6.2) 0.0020.002

synchronous resection of PC synchronous resection of PC & LM& LM

2.0 (1.1-3.7)2.0 (1.1-3.7) 0.0220.022

Independent factors for poor overall survival :

Cox regression analysisCox regression analysis

Disease-free SurvivalDisease-free Survival Odds-Ratio Odds-Ratio (95%)(95%)

pp

PCI ≥ 12PCI ≥ 12 1.6 1.6 ((1.01-2.71.01-2.7)) 0.0480.048

synchronous resection of PC synchronous resection of PC & LM& LM

1.9 (1.2-3.2)1.9 (1.2-3.2) 0.0070.007

Independent factors for poor disease-free survival