Presentation in Surgical Forum, Tel Aviv Medical Center, Israel M. Papoulas, MD

1. Prophylactic cytoreduction and
HIPEC in high risk patients for
peritoneal carcinomatosis
M. Papoulas
18.1.12

2. 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

3. Prophylactic cytoreduction and
HIPEC in high risk patients for
peritoneal carcinomatosis
• Peritoneum and Peritoneal Carcinomatosis
• Cytoreduction and HIPEC
• High Risk Patients and possible detecting modalities
• Second-Look Surgery

4. Peritoneum

5. 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

10. Peritoneal Carcinomatosis (PC)
3 Molecular Pathways
1.Dissemination from the primary tumor
2.Primary peritoneal tumor
3.Independent origins of primary tumor and
peritoneal implants

11. 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

12. Pathogenesis of peritoneal minimal residual disease

13. Rekhraj S, et al. Ann Surg Oncol 2008

16. 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.

17. Mechanisms of Peritoneal Dissemination
• Detachment of cells from the primary tumour
(spontaneous or as an adverse effect of treatment)
Rapid cell proliferation
Lack of effective drainage
Down regulation of intercellular adhesion molecules such as E-cadherin,

19. Mechanisms of Peritoneal Dissemination
• Peritoneal transport
Basic Forces
1. Gravity
2. Peristaltic Movement of GI tract
3. Negative Pressure by diaphragmatic muscle
movements

20. Mechanisms of Peritoneal Dissemination
• Mesothelial Adhesion
In the absence of mesothelial cells, interactions between cancer
cells and underlying extracellular matrix components is mainly
mediated by the β1 integrin subunit

21. Mechanisms of Peritoneal Dissemination
• Surgical trauma, inflammation, adhesion
(postoperative inflammation, wound healing, tumour growth)

22. 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

23. Mechanisms of Peritoneal Dissemination
• Invasion of submesothelial layers
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

25. 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

26. 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

27. Cytoreduction
State 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
exploration
CC-1 : tumor nodules persisting after cytoreduction
less than 2.5mm in diameter
CC-2 : tumor nodules between 2.5mm and 2.5cm
CC-3 : tumour nodules greater than 2.5cm or a
confluence of unresectable tumours
Sugarbaker PH, Lang Arch of Surg. 1999
Incomplete

28. • 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

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

32. High Risk Patients

33. 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
Eligibility
Consent for HIPEC
Cytology
Obstruction or perforation
Histopathology

34. FDG PET vs Second-Look surgery

35. • 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 laparotomy
RESULTS
• 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%.
CONCLUSION
The sensitivity of PET before second-look laparotomy for small-volume
persistent disease is low

36. Background
Challenging 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

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

40. 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

41. 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

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

46. Sugarbaker PH, Ann Surg Oncol 2008

47. Eligibility requirements:
1. Patients at high risk for recurrence
2. Symptomatic patients suggesting disease progression
3. Progressive rise in CEA

50. High Risk Patients for PC
Inclusion 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

51. 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.

53. 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% and
the 5-year disease-free
survival rate was 44%.

54. 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)

56. 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

59. 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?

60. Thank You!