Peritoneal metastases fromcolorectal and gastric cancers

Glehen olivierSurgical Oncology

Hospices Civils de LyonCentre Hospitalier Lyon Sud

Colorectal carcinomatosis

Is There a Possibility of a Cure in Patients With Col orectal Peritoneal Carcinomatosis?Goere et al. Ann Surg 2012

107 patients treated with completecytoreductive surgery and Intraperitoneal Chemotherapy

Follow-up for all patients more than 5 years surgical procedures

16% of patients were considered curedwith 5-year or more of disease-freeinterval

YES

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

PERITONEAL CARCINOMATOSIS from COLORECTAL CANCER

-Franko 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

PERITONEAL CARCINOMATOSIS from COLORECTAL CANCER

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

recommandations

� Pseudomyxoma Peritonei.� Peritoneal Mesothelioma.

� PC from colorectal , smallbowel 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 ???

2 2 2 2 Registries: 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

2 2 2 2 Registres: national and international

�Identification of 2 principal prognostic factors

�Completeness of cytoreductive surgery

�Extent of carcinomatosis

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

CC-0

Quantitative toolPeritoneal Cancer Index (Sugarbaker) : PCI

PCI from 0 to 39

Consensus Milan 2006

CC-0

Colorectal carcinomatosis

Carcinomatosis ExtentCarcinomatosis ExtentCarcinomatosis ExtentCarcinomatosis Extent

Is synchronous liver

metastasis a

contraindication for

curative treatment of

carcinomatosis?

Questions

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

� Liver metastasis does not constitute 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

What about systemic

chemotherapy?

Questions

Improved efficiency of systemic chemotherapyfor 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

PC from colorectal origin Palliative systemic chemotherapy

2095 patients

Median survival

•Patients with PC : 12.7 months

•Patients without PC : 17.6 months

French registry colorectal PCMultivariate analysis

Variable p Relative risk

PCI <0.0001 1.052

CC-Score 0.05 1.398

Lymph node + 0.02 1.534

Adjuvant Chemotherapy 0.002 0.578

Peritoneal carcinomatosis has a different naturalhistory and response to systemic chemotherapy than

liver or lung metastasisBUT

50 to 75% of patient with peritonealcarcinomatosis will develop extra-peritoneal

diseaseRole of adjuvant systemic chemotherapy into registries

SYSTEMIC CHEMOTHERAPY

PERITONEAL CARCINOMATOSIS from COLORECTAL CANCER

Systemic chemotherapy should be consideredas one important tool in the multidisciplinary

management of PC

Systemic chemotherapy

should be used before,

after, both ?

Unresolved Questions

P = 0.042

Ann Surg 2012

120 patients

Patients with progressive but resectable disease had median survival more than 30 months

P = NSAnn Surg 2012

� Progression with neoadjuvant systemic chemotherapy does not constitute 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 extraperitonealdisease

Colorectal carcinomatosis and neoadjuvant chemotherapy

Ann Surg 2012

What is the exact role of

HIPEC into therapeutic

management ?

Unresolved Questions

There was not significant difference between:

� Median OS ox alone 41 months , (95%CI 29–61)

� Median OS ox-iri 47 months , (95%CI 32-61)(p=0.94)

What is the specific role of HIPEC ?

PRODIGE 7 (F Quenet)RANDOMIZED FRENCH STUDY

No HIPEC

Complete cytoreductive surgery

RANDOMIZATION

HIPEC oxaliplatin

Colorectal carcinomatosis

Perioperative systemic chemotherapy for 6 months

RANDOMIZATION

Interest of 2nd look for

patients at risk of

carcinomatosis

development?

Prevention

� 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:• Minimal macroscopic PC completely resected• Ovarian metastases ,• Perforation of primary tumour.

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

50% of patients had carcinomatosis

HIPEC was an the only independantprognostic factor

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

Gastric carcinomatosis

Results

Overall survival according to etiology

Cancer 2010

� Feb. 1989 – Aug. 2007

� 159 patients

� 15 centers

� M: 83 F: 76

� Mean age 53,4 ± 12,8

� PC Synchronous : 44%

� PC Metachronous : 66%

� HIPEC : 154 cases (94%)

• Closed abdomen :

142 cases (54%)

• Open abdomen : 46%

� EPIC : 12 cases (7,5%)

� Mitomycin C : 83%

Intraperitoneal chemotherapy

Gastric carcinomatosis AFC

� Mortality: 10 cases (6,5%)� Morbidity grade 3-4: 38 cases

(27,8%)• Digestive fistula : 16%• Reoperation: 14%• Mean post-operative stay :

24,2±19 days

Mortality-Morbidity1344 procedures

� Mortality : 4,1%

� Morbidity gr. 3-4:

33,8%

• Dig. fistula : 9,6%

• Reoperation: 14%

• Mean post-

operative stay :

24,1±18 days

Gastric carcinomatosis AFC

Gastric carcinomatosisPrognostic factors

Institutions

P<0,001

Gastric carcinomatosisPrognostic factors

Treatment with neoadjuvant systemic chemotherapy

P=0,018

Gastric carcinomatosisPrognostic factors

Completeness of cytoreductive surgery

Patients CC-0:

•Median 15 months

•5 year survival:25%

Patients CC-2 or 3

•Median 4 months

•2 years survival:0%

P<0,001

Gastric carcinomatosisPrognostic factors

Influence of disease extension in patients treated by complete cytoreductive surgery

No patient alive at 2 years for PCI > 13

P=0,038

No patient alive at 1 year for PCI > 19

PHASE III STUDY in Gastric CancerYang et al. Ann Surg Oncol 2011

Cytoreductive surgery

RANDOMISATION

Cytoreductive surgery + HIPEC with CDDP

and MMC

Gastric Carcinomatosis

Systemic chemotherapy ?? Perioperative or adjuvant??

RANDOMISATION

PHASE III STUDY in Gastric CancerYang et al. Ann Surg Oncol 2011

HIPEC did not improve mortality and morbidity rates

PHASE III STUDY in Gastric CancerYang et al. Ann Surg Oncol 2011

HIPEC improved survival (p=0.046)

Synchronous PC++

Conclusions

� Cytoreductive surgery and HIPEC are the onlyway to obtain long-term survivors

� 5-year survival rates of 20% may be obtainedinto expert centers

� Strict selection necessary

� Which patients?• Patients with perfect general status (< 70

years)� High Mortality et Morbidity rates� Quality of life ++++

• Complete cytoreductive surgery� Strongest prognotic factor

• Limited PC (PCI < 19 ou 12)

LIMITED NUMBER OF PATIENTS

Conclusions

Conclusions

� How to improve selection?

• Neoadjuvant systemic chemotherapy� Gold standard in Europe� Exclusion of patients with metastatic progression

• Neoadjuvant intraperitoneal chemotherapy

Neoadjuvant intraperitoneal systemic chemotherapy (NIPS) Yonemura

Neoadjuvant intraperitoneal systemic chemotherapy (NIPS) Yonemura

Increases the rate complete cytoreductive surgery by increasing downstaging

Phase I-II in Europe

Conclusions� How to improve

selection?

• Laparoscopy as soon as possible +++++

� Exclusion of patients diffuse disease

� Diagnosis of limited PC

Gastric cancers and preventive management

� Recurrences following curative treatment

Recurrences > 50%• 1/3 of peritoneal carcinomatosis• 1/3 of locoregional recurrence

CANCER that HAVE THE MOST IMPORTANT RATE of LOCOREGIONAL RELAPSE

Yoo Br J Surg 2000

Peritoneal recurrence and gastric cancer

� Factors associated with peritoneal recurrence• Linitis or poorly differentiated tumors

(independant cancer cells)• Lymph node involvement• Serosal involvement• Positive cytology+++

Maehara Br J surg 2000

Ceelen Br J Surg 2000

Bonenkamp N Engl J Med 1999

Honore Eur J Surg Oncol 2013

Meta-analysis of postoperative intraperitoneal chemotherapy in gastric cancer

Yan et al Ann Sug Oncol 2007

GASTRICHIP (PHRC 2012)Randomized multicentric phase III

Curative gastrectomy

Peroperative systemic chemotherapy recommended

Peroperative

RANDOMIZATION

Curative gastrectomy + HIPEC oxaliplatin

Gastric adenocarcinoma T3-T4 and/or N+ and/or cyto + (laparoscopy and ultrasound

endoscopy)

Postoperative adjuvant treatment

Peroperative

RANDOMIZATION

Indication of curative gastrectomy

Inform consent

Take Home Messages

•Cytoreduction and HIPEC should be considered for many colorectal PC and some gastric PC

•The 2 most important prognostic factors are

COMPLETENESS OF CYTOREDUCTIVE SURGERY

PCI

•Multidisciplinary management including systemic chemotherapy isvery important and should be more evaluated

•HIPEC for prevention and prophylactic approach should beconsidered