O. Glehen - HIPEC in colorectal carcinomatosis

HIPEC in colorectal carcinomatosis

Glehen olivierSurgical Oncology

Hospices Civils de LyonCentre Hospitalier Lyon Sud

Management of peritoneal carcinomatosis: EVOLUTION

Before 1980PALLIATIVE TREATMENT

1980198019801980----95: HIPEC, 95: HIPEC, 95: HIPEC, 95: HIPEC, EPICEPICEPICEPIC

1995-2000: Cytoreductive surgery, phase II studies

2000-2011: Registration, randomized study, Development of expert centers

CURATIVE TREATMENT OF PC

Peritoneal carcinomatosis Peritoneal carcinomatosis Peritoneal carcinomatosis Peritoneal carcinomatosis

Locoregional diseaseLocoregional diseaseLocoregional diseaseLocoregional disease

Treatment of macroscopic disease

Cytoreductive surgery

Peritonectomy procedures

Treatment of microscopic disease

Intraperitoneal chemotherapy

Strong rational for locoregional treatment

Peritonectomy procedures

Organ resections

Rational for Hyperthermic Intraperitoneal Chemotherapy

1. Pharmacokinetic advantages of Intraperitoneal Chemotherapy

2. - Cytotoxicity of hyperthermia (42,5°C)

3. Synergistic effect « Hyperthermia -chemotherapy »

4. Following surgical procedures- Avoid « cancer cells entrapment » - BUT « single shot » treatment

Improved efficiency of systemic chemotherapyfro metastatic colorectal cancers

6

12 12

1415

18 18

21 21

24

0

5

10

15

20

25

BSC Bolus

5FU-LV

Xeloda LV5FU2 IFL Folfox Folfiri Folfox

puis IRI

Folfiri

puis oxali

Bevaciz +

sequentiel

5FU alone Sequentiel treatment

Combined treatment

Targeted therapy

Median survival

(months)

0%

23%

21%

36-59%

34-56%

60-72%

45-72%

Objective response

Author Year Journal IV Chemoregimen MFS (mths)

Median (mths)

Liver/Lung metastase

PC

Moertel 1989 JCO 5FU LV 6,2 14,7 ?

DeGramont 2000 JCO 5FU LV OXALIPLATINE

9,0 16,2 91% ?

Saltz 2000 NEJM 5FU LV IRINOTECAN 7,0 14,8 662/683 ?

Giachetti 2000 JCO 5FU chrono LV OXA 8,7 19,9 242/256 ?

Douillard 2000 Lancet 5FU IRINOTECAN 6,7 17,4 367/387 20 ?

Tournigand 2003 JCO FOLFIRI + FOLFOX 14,2 20,6 220/220 0

Kabbinavar 2003 JCO 5FU LV Avastin 9,0 21,5 35 ?

Hurwitz 2004 NEJM 5FU LV IRI Bevacizumab

10,6 20,3 813 ?

Goldberg 2006 JCO 5FU LV IRINOTECAN 9,7 19,0 305/305 0

Masi 2006 Ann Oncol

5FU LV OXA IRI 8,1 15,2 71/71 0

TOTAL >4000 < 20

METASTATIC COLORECTAL CANCER Systemic Chemotherapy

-Folprecht et al.Cancer Treat Res, 2007.

Retrospective study 3825 patients.-12% of peritoneal carcinomatosis-PC as strong prognostic factor-Patients with PC: median survival 7 to 18 months-Patients without PC: median survival 11 to 20 months

PC from colorectal origin Palliative systemic chemotherapy

PC from colorectal origin Palliative systemic chemotherapy

2095 patients

Median survival

•Patients with PC : 12.7 months

•Patients without PC : 17.6 months

Peritoneal carcinomatosis = metastatic diseaseBUT

Different natural history and response to systemic chemotherapy from liver or lung metastasis

5 months < median survival of colorectal PC ??< 24months

SYSTEMIC CHEMOTHERAPY

PERITONEAL CARCINOMATOSIS from COLORECTAL CANCER

Systemic chemotherapy should be considered as one important tool for the treatment of PC

Cytoreductive surgery+ HIPEC (MMC)

+ 5FU-Leucovorin

N=48

� Colorectal PC5-FU-Leucovorin

N=44

43% (HIPEC)

� 2-year survival

16% (control roup)

Verwaal et al. J Clin Oncol 2003, Ann Surg Oncol 2008

COLORECTAL PCRandomized study

P=0.001

-Elias et al.J Clin Oncol 2008

Retrospective study.-48 Cytoreductions + HIPEC (oxaliplatin) versus 48 « modern » systemic chemotherapy alone-Median follow-up > 63 months-Better results for patients treated with HIPEC

-51% of 5 year survival vs 13% (p<0,05)-Median survival of 62 months vs 24 months

Cytoreduction with HIPEC


-Franco et al.Cancer 2010

Prospective study.-67 Cytoreductions + HIPEC versus 38 « modern » systemic chemotherapy alone-Some patients had liver metastasis

-Better results for patients treated with HIPEC-Median survival of 35 months vs 17 months

Cytoreduction with HIPEC


2 2 2 2 Registres: national and international

�> 500 patients�1990 - 2007�75 to 86 % : HIPEC�54 to 85% de complete cytoreduction�Mortality: 3 to 4% Morbidity:25 to 30%�Median survival > 30 months�5 year survival > 30%

J Clin Oncol 2004 and 2010

COLORECTAL CARCINOMATOSIS

Cytoreductive surgery and intraperitoneal chemotherapy

Colorectal carcinomatosis

Completeness of cytoreductive surgery

J Clin Oncol 2010

CC-0

CC-1

CC-2 ou 3

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Carcinomatosis ExtentCarcinomatosis ExtentCarcinomatosis ExtentCarcinomatosis Extent

Is synchronous liver

metastasis a

contraindication for

curative treatment of

carcinomatosis?

Unresolved Questions

Survival according to the presence of associated Liver Metastases (n= 65) (p= NS)

� Liver metastasis does not contitute an absolute contraindication for curative approach of carcinomatosis• Liver metastasis should be controlled by systemic chemotherapy

• Extensive liver surgery combined to extensive peritoneal surgery should be avoided

Colorectal carcinomatosis and synchronous liver metastasis

Response to neoadjuvant

systemic chemotherapy

should be used for patient’s

selection ?


Survival according to the use of neoadjuvant chemotherapy (n= 120 patients)

P = 0.042

Ann Surg 2012

Survival according to response to neoadjuvant chemotherapy (n= 120) (p= NS)

P = NSAnn Surg 2012

� Progression with neoadjuvant systemic chemotherapy does not contitute an absolute contraindication for curative approach of carcinomatosis• Median survival more of 30 months may be obtained

� The use of neoadjuvant systemic chemotherapy is important to exclude patients who will develop extraperitoneal disease

Colorectal carcinomatosis and neoadjuvant chemotherapy

Ann Surg 2012

2012 : Treatment of Peritoneal carcinomatosis :When and how to treat ? French national

recommandations

� Pseudomyxoma Peritonei.� Peritoneal Mesothelioma.� PC from colorectal, small bowel

adenocarcinoma and appendiceal cancers.

Patient in good general statusWhen optimal cytoreductive surgery (R0 – R1) is achievable.

Strict patient selection.Experienced multidisciplinary

center.

� PC from gastric cancer.� PC from ovarian cancer.

PC from pancreas, bile duct,gallblader, breast, ….

Highly recommendedUnder evaluation

Ongoing trial inclusion

Probably not ???

PERITONEAL CARCINOMATOSIS

RECOMMENDATIONS TO GENERAL SURGEONS AND ONCOLOGISTS

For current practice

Curative treatment of peritoneal

carcinomatosis must be

considered at the time of

diagnosis

1ST Message

Not after failure of palliative treatment (surgery –systemic chemotherapy)

AN AGGRESSIVE THERAPEUTIC

APPROACH

Mortality 4%Morbidity 34%

Evaluation of general status

How to select patients for treatment with curative intent?

Which PATIENTS ??

How to manage patients for treatment with curative intent?

Cytoreductive surgery and perioperative intraperitoneal chemotherapy should be performed in expert centers in peritoneal surface malignancy

� Complex, costly, long procedures

� Better patients selection

� Lower complications rates

� Higher rate of complete cytoreduction

Smeenk, Br J Surg 2007

AFC 2008

WHERE ???

Expert center should be contacted at the time of diagnosis

Indications

• Patients with no extraabdominal disease

� Body-scan

� Pet-scan

• POSSIBILITY of COMPLETE CYTOREDUCTIVE SURGERY +++

� Preoperative assessment: CT-scan, MRI

� Peroperative assessment ++++

• Laparoscopy

• Detailed operative report

How to select patients for treatment with curative intent?

WHICH carcinomatosis ???


Precise description of

carcinomatosis distribution and

extension must be performed

SECOND Message

• POSSIBILITY of COMPLETE CYTOREDUCTIVE SURGERY +++

• PRECISE ASSESSMENT OF CARCINOMATOSIS EXTENT ++++

�Description of small bowel, hepatic pedicula, bladder involvement

�Photos or films

How to manage patients for treatment with curative intent?

IN ALL CASES

Help expert centers for selection

Avoid useless explorative laparotomy

Precise description during laparotomy or laparoscop y of carcinomatosis that are not evaluable on

morphologic exams

Mesenteric retraction Diffuse small tumoral nodules


Respect peritoneum !!

Respect parietal wall!!

THIRD Message

�Peritoneum is the first-line of defense

� “Cancer cells entrapment”

�Curative procedure more complex and less efficient

Respect peritoneum and parietal wall

No extensive peritonectomies or cytoreductive surgery without perioperative intraperitoneal chemotherapy

Clinical situations: carcinomatosis suspected on

preoperative exams

• Explorative laparoscopy (trocarts on middle line)

• Diagnostic biopsy



Clinical situations: Carcinomatosis is

discovered peroperatively

�No resection of primary tumor

• Rectosigmoïd tumors (ureters)

�Stomia for occlusive tumor

�Exception for hemorrhagi tumors

�Avoiding drainage into flank


The prognosis depend on the treatment of the metastatic disease and not on the primary tumor

� What should we do with scars or intraperitoneal nodules or anastomoses

following previous surgery?

� More extensive will be previous surgery, more difficult, extensive and

less curative will be the curative treatment


What is the exact role of

HIPEC into therapeutic

management ?


PRODIGE 7 (F Quenet)RANDOMIZED FRENCH STUDY

No HIPEC

Complete cytoreductive surgery

RANDOMIZATION

HIPEC oxaliplatin


Perioperative systemic chemotherapy for 6 months

RANDOMIZATION

Interest of 2nd look for

patients at risk of

carcinomatosis

development?

Prevention

Patients et Methods (1)� From 1999 to 2009, 47 patients with a high risk to develop a PC

(without clinical, radiologic or biologic symptoms) , underwent asecond look, 12 months after their first surgery.

� Selected: 3 groups of high-risk patients:• 28 who presented a minimal macroscopic PC synchronous to the

primary (and which was completely resected during the same session)• 8 who presented synchronous ovarian metastases ,• 11 who presented a perforation of their primary tumour.

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

Patients et Methods (2)� Careful exploration of the whole abdominal cavity� Mean duration of surgery: 6 hours

47 patients

23 with PC (49%) 24 without PC (51%)23 Cytoreduc Surg + HIPECMean peritoneal index: 7 No HIPEC = 6 (PC- H-)

(PC+ H+) HIPEC = 18 (PC- H+)

Follow-up: 45 months (mean)Nb Recurrence IP recurrence Died

PC+ H+ 23 12 (52%) 6 3 (13%)

PC - H + 18 2 (11%) 1 0

PC – H - 6 4 (75%) 3 3 (50%)

Only one prognostic factor: HIPEC (p = 0.02)

Among the 41 pts with HIPEC: only 7 (17%) presented a peritoneal recurrence

Conclusion (1)

� A second-look, performed 1 year after the resection of the primary,in a selected high-risk group of patients, allowed to found and treatan early and minimal PC in 50% of the patients.

� This new therapeutical approach seems benefit for the patientswho initialy presented a minimal PC or ovarian metastasis.

� These encouraging preliminary results lead to initiate a prospectiverandomized trial, with the aim to definitely prove this benefit.

French randomized multicentric study (Prophylochip)

Patients at risk of carcinomatosis development

(Perforated tumors, localized carcinomatosis removed, isolated ovarian metastasis)

Adjuvant FOLFOX (6 months)

or systemic chemotherapy

(Negative workshop)

Randomization 8 months)

Follow-up2nd look and

prophylactic HIPEC

Health & Medicine

O. Glehen - HIPEC in colorectal carcinomatosis