Prophylactic cytoreduction and HIPEC in high risk patients for

peritoneal carcinomatosis

M. Papoulas 18.1.12

To open the peritoneal cavity is a relatively simple act. Similarly, abdominal closure is not, as a rule, a difficult procedure. Yet it is a matter far from simple to be certain, after this space has been opened and closed, that in the tense interval of the operation everything has been correctly done to serve the best interests of the patient …It is an axiom that the abdominal surgeon must enter the peritoneal cavity “prepared for anything and everything”

EM Livingston, 1932

• Peritoneum and Peritoneal Carcinomatosis• Cytoreduction and HIPEC• High Risk Patients and possible detecting modalities• Second-Look Surgery

Prophylactic cytoreduction and HIPEC in high risk patients for

peritoneal carcinomatosis

Peritoneum

Peritoneum and Carcinomatosis

• Complex structure• Specific functions • First line of defense in host resistance to

peritoneal carcinomatosis• Can it be considered as an organ? • Weak points (lymphoid aggregates- milky spots,

lacunae subdiaphragmatic, raw surfaces )

Sugarbaker PH, J Surg Oncol 2007

Peritoneal Carcinomatosis (PC)

3 Molecular Pathways

1.Dissemination from the primary tumor2.Primary peritoneal tumor3.Independent origins of primary tumor and

peritoneal implants

PC develops roughly in• 4% to 19% of patients after curative surgery•44% of patients with recurrent colorectal cancer who need re-laparotomy•40% to 80% of patients who die from the disease

Pathogenesis of peritoneal minimal residual disease

Rekhraj S, et al. Ann Surg Oncol 2008

Considerations

• Weak point: none reported on the accuracy of free peritoneal cancer cell detection in predicting recurrence within each cancer stage

• Further work should include large patient numbers with early stage disease (stages I and II, where there is maximum clinical and therapeutic benefit to be gained)

• Further studies should also investigate the effect of free peritoneal cancer cell detection on peritoneal recurrence, after perioperative intraperitoneal chemotherapy.

Mechanisms of Peritoneal Dissemination

• Detachment of cells from the primary tumour (spontaneous or as an adverse effect of treatment)

Rapid cell proliferationLack of effective drainageDown regulation of intercellular adhesion molecules such as E-cadherin,

• Peritoneal transportBasic Forces

1. Gravity

2. Peristaltic Movement of GI tract

3. Negative Pressure by diaphragmatic muscle movements

Mechanisms of Peritoneal Dissemination

• Mesothelial Adhesion

Mechanisms of Peritoneal Dissemination

In the absence of mesothelial cells, interactions between cancer cells and underlying extracellular matrix components is mainly mediated by the β1 integrin subunit

• Surgical trauma, inflammation, adhesion (postoperative inflammation, wound healing, tumour growth)

Mechanisms of Peritoneal Dissemination

Exudating wounds on peritoneal surface might promote tumour growth by the entrapment of malignant cells by fibrin clots via cell surface integrin and non-integrin (VE- cadherin, ICAM1, P-selectin) receptors

• Invasion of submesothelial layers

Mechanisms of Peritoneal Dissemination

I. Mouse gastric cancer model (MKN-45-P)- Inhibition of MMP7 by specific antisense oligonucleotide suppressed peritoneal invasion without changing cellular proliferation.

Yonemura Y, J Exp Clin Cancer Res 2001

II. RT- PCR based detection of MMP-7 and peritoneal lavage cytology from patients with gastric Ca is an independent predictor of peritoneal dissemination.

Yonemura Y, Clin Cancer Res 2001

Changing our minds…Introduction to cytoreduction and HIPEC

• In the past: PC from GI malignancies was lethal condition, with a short survival and poor quality of life

• In the present: prevention of PC is possible, cure of selected patients is a reality, strategies for improved palliation become standard of care

3 Basic Observations

1. Pattern of cancer dissemination, ordered pathophysiology

2. ‘Metastatic inefficiency’ Weis L. Cancer Rev 1986

Cancer cells contained within the vascular system and bone marrow are not likely to progress. On the contrary, cancer cells in the coelomic cavity have a profound capability to implant, progress and disrupt function.

3. Peritoneal space- plasma barrier locoregional

treatment with minimal systemic toxicity

CytoreductionState of the art, the surgeon’s role

• Resection of all macroscopic lesions• Completeness of cytoreduction (CC) score CC-0 : No peritoneal seeding exposed after complete

explorationCC-1 : tumor nodules persisting after cytoreduction less than 2.5mm in diameterCC-2 : tumor nodules between 2.5mm and 2.5cmCC-3 : tumour nodules greater than 2.5cm or a confluence of unresectable tumours

Sugarbaker PH, Lang Arch of Surg. 1999

Incom

plete

• 5-year survival: 50% for PCI<10, 20% for 11-20 and 0% for PCI>20• PCI >20, palliation is the goal of treatment, relative contraindication for

elective intervention for colon cancer. Elias D. Cancer 2001

HIPEC

• Why hyperthermic? I. Destruction of cancer cells II. Augmentation of cytotoxicity III. Increased penetration

High Risk Patients

High Risk Patient’s Prespective• Ideal management plan for improving survival and quality of

life: Cytoreduction + HIPEC at the time of primary colorectal cancer resection

BUT Lack of expertise centers

EligibilityConsent for HIPEC

Cytology Obstruction or perforation

Histopathology

FDG PET vs Second-Look surgery

• 22 patients with advanced stage ovarian (n=17) or peritoneal (n=5) carcinoma• Six cycles of chemotherapy (platinum based)• Complete clinical and radiological remission, normal CA-125• FDG-PET performance, correlation with Second-Look laparotomyRESULTS • Persistent disease was found in 13 of the 22 patients (59%)• Only one of nine sites with macroscopic and none of four with microscopic

disease were accurately predicted• Sensitivity was only 10% and the specificity 42%.CONCLUSIONThe sensitivity of PET before second-look laparotomy for small-volume

persistent disease is low

BackgroundChallenging problem: Patients without imageable disease in the

presence of an increasing CEA level

- 60%- 90% of these patients will have recurrent disease at laparotomy

- 50% will have resectable disease - May benefit from a 5-year survival rate of as high as 40%

Libutti SK, et al. Ann Surg Oncol 2001

On a per patient basis, FDG-PET performed admirably. On a per lesion basis, the value of FDG-PET was not as obvious.

Short history of second look surgery• Wangensteed OH (1949), new idea “Surgery is the most effective tool by wich to cure primary GI cancer;

therefore, additional surgery could be used to extirpate isolated sites of disease progression improving survival” Systematic plan of reoperation of patients with lymph node positive disease

Gilbertsen VA, Wangensteed OH, Surg Gynecol Obstet, 1962

Second-look surgery

• Identify high risk patients for peritoneal carcinomatosis• Early diagnosis of PC• Convert a positive second-look patient to a long-term

survivor• Peritoneal carcinomatosis is present and diagnosed

during second- look surgery in 55% of patients at high risk for PC

• Projected survival of patients with positive second look converted to disease free status is 50% at 5 years

Distant metastasis alone are uncommon (8%)Local failure or regional lymph node metastasis occur in 48% as the only siteIn 92%, local failure occurs alone or in combination with distant metastasis

Sugarbaker PH, Ann Surg Oncol 2008

Eligibility requirements: 1. Patients at high risk for recurrence2. Symptomatic patients suggesting disease progression3. Progressive rise in CEA

High Risk Patients for PCInclusion criteria

• Curative Resection for CRC presented with: (1) Minimal PC completely excised at the time of primary operation (2) ovarian metastasis synchronous with the primary tumour (3) Perforation into the peritoneal cavity

• Disease free, no sign of recurrence , stable serum CEA one month before second-look surgery

• Good general status (WHO performance status < 2)

Elias et al, Ann Surg 2011

Design of the Study

• Adjuvant chemotherapy (5FU plus oxaliplatin or irinotecan) over 6 months

• 6 months after the end of chemotherapy, re-evaluation of the patient- if the work-up was negative, then a second look surgery was performed

• HIPEC (oxaliplatin with IV 5FU + Leukovorin) was systematically performed after cytoreduction in patients who had macroscopic PC.

Results• PC was found and treated with complete surgery plus HIPEC

in 23 of the 41 (56%) patients. Median follow-up was 30 (9–109) months. PCI low (9 +/-6)

• One patient died postoperatively• In the univariate analysis no patient or tumour characteristics

were predictive of macroscopic PC

5-year overall survival rate was 90% andthe 5-year disease-free survival rate was 44%.

Follow up

• In the PC+ group, 12 of 23 patients (52%) relapsed and 3 (13%) died

Recurrences: n= 1 peritoneum, n= 5 liver + lung + peritoneum n= 6 diffuse but not in peritoneum• In the PC0 group, 2 out of 18 relapsed and all are alive Recurrences: n= 1 peritoneum n= 1 colonic Macroscopic PC is a significant risk factor for recurrence

(p=0.006)

Weak Points…

• FDG-PET was not systematically performed preoperatively• Second-look surgery performed 1 year after resection of

the primary tumour• Not clear if omentectomy and oophorectomy was

performed in patients without macroscopic PC• Difficulty of canceling a decision during surgery• Number of patients• Wider selection criteria for high risk patients

Considerations

• Clear guidelines for reoperative surgery Patients characteristics, tumour, imaging• Can a second look surgery add a reasonable length of

good-quality of life?• Timing, early or late? • Credit vs Debit?

Conversion of second-look-positive patient to a long term survivor

Morbidity, mortality

• HIPEC on the primary surgery if possible?

Thank You!