Peritoneal dissection and

intraperitoneal chemotherapy under

hyperthermic conditions. If you select

the right patients long-term survival

can be achieved.

Chirurgia Avanzata Del Carcinoma Ovarico – Nuove Strategie A Confronto

Ovarian Cancer Advanced Surgery – New Strategies in Comparison

Bergamo, Italy

5-6 May 2011

Paul H. Sugarbaker, MD, FACS, FRCS

Program in Peritoneal Surface Malignancy

Washington Cancer Institute

Washington, DC, USA

Alternative Title:

Discussion regarding the poor long-term

results with CRS and HIPEC:

1. High PCI (concept of extent of disease)

2. Extensive prior surgery (concept of the

peritoneum as the first line of defense

against carcinomatosis)

3. Extensive prior systemic chemotherapy

(concept of natural or acquired drug

resistance)

Discussion regarding the poor long-term

results with CRS and HIPEC:

4. Inadequate perioperative hyperthermic

chemotherapy (concept of pharmacologic

drug selection).

5. Imperfect cytoreduction (concept of CRS

requiring visceral resections and

peritonectomy)

6. Lack of application to ovarian tumors of

low malignant potential (concept of

favorable tumor biology)

Bristow et al., 2007

Extent of disease and survival

Tentes et al., 2009

PCI <13 vs. >13

Are there modifications in patient

management that will result in a reduced

PCI at the time of CRS and HIPEC?

1. CRS + HIPEC as primary management

2. CRS + HIPEC after neoadjuvant

chemotherapy

3. ?

CONCEPT

The peritoneum is the first line of defense ofthe host against peritoneal dissemination ofcancer. If this barrier is disrupted in thepresence of cancer cells, fibrin entrapment atthe wounded site will cause progression deepto the peritoneum. Subsequent efforts totreat carcinomatosis by cytoreductive surgeryand peritonectomy with perioperativeintraperitoneal chemotherapy will bejeopardized.

Prior Surgical Score

Regions dissected

PSS-1 1

PSS-2 2-5

PSS-3 6-9

Tumor cell entrapment as seen on pelvic CT

Effect of prior systemic chemotherapy

Helm et al., 2010

Inadequate perioperative hyperthermic chemotherapy

requires pharmacologic engineering of drugs with

established cytotoxicity

Heat synergized chemotherapy:

Melphalan

Cyclophosphamide

Ifosfamide

Heat augmented chemotherapy:

Cisplatin, oxaliplatin

Doxorubicin

5-fluorouracil

Mitomycin C

Etoposide

No heat effects:

Paclitaxel

Docetaxel

Bidirectional chemotherapy (intraperitoneal

and intravenous)

Application to low malignant potential

(LMP) ovarian tumors with carcinomatosis

that have a less aggressive natural history

1. Low grade papillary serous

2. Mucinous ovarian

3. Granulosa cell

4. Gliomatosis peritonei

5. Pseudomyxoma from ruptured dermoid

cyst

Conclusions

1. The low perceived benefit from CRS

and HIPEC derives from poor patient

selection and suboptimal treatments.

2. Meticulous cytoreduction combined

with perioperative multidrug therapy

are needed in continuing phase II

explorations.

Cytoreductive Surgery and Perioperative

Intraperitoneal Chemotherapy for

Prevention and Treatment of Peritoneal

Surface Malignancy 2011

I. Basic Principles

II. Recent results of treatment

A. Appendiceal

B. Mesothelioma

C. Colorectal

D. Gastric

E. Ovarian

www.peritonealconference2012.com

Pharmacologic concept of bidirectional (IV and IP)

chemotherapy for peritoneal tumor nodules

Outer Layer

Inner core

Intraperitoneal 5-fluorouracil

Intravenous 5-fluorouracil Given in the

Operating Room

Intraperitoneal Gemcitabine

Intravenous Ifosfamide Given in the

Operating Room

Intraperitoneal Doxorubicin Given in the Operating

Room with Heat in Patients with Mucinous Cancer

0.01

0.1

1

10

100

Perit. Fluid

Plasma

Tumor nodules

0 15 30 45 60 90 120

Time (minutes)

Do

xo

rub

icin

(

g/m

L)

Area Under the Curve (IP/IV) for

Chemotherapy Agents Used for HIPEC

Drug Molecular Wt. (Da) AUC ratio

5-fluorouracil 130 250

Mitomycin C 334 75

Doxorubicin 580 230

Cisplatin 300 20

Paclitaxel 808 1000

Gemcitabine 263 500

Melphalan 305 93

Advantages of moderate hyperthermic

intraoperative intraperitoneal chemotherapy

General

Reversal of systemic hypothermia from long surgery

Normalization of blood clotting

Minimal toxicity for normal tissue (<43ºC)

Potentiation of other therapies

Stimulation of host immune system

With chemotherapy

Increased cytotoxicity of chemotherapeutic agents

Increased drug penetration into tissue by increasing membrane permeability

Inhibition of chemotherapy repair mechanisms

Reversal of drug resistance

With manual distribution

Mechanical debridement of cancer cells from tissue surfaces

Uniform treatment of hyperthermia and chemotherapy solution

Absence of unexposed surfaces

Absence of suture line recurrence

Credits and debits of two different technologies for hyperthermic intraperitoneal chemotherapy

Open abdomen manually distributed Closed abdomen

EfficiencyAllows continued cytoreduction of bowel and

mesenteric surfacesNo surgery possible during chemotherapy

Environmental hazard No aerosols detected Perception of increased safety

Distribution

Uniform distribution of heat and chemotherapy

solutions, tissues close to skin edge not

immersed

Possible poor distribution to dependent sites and

closed spaces

Pressure No increased intraabdominal pressureIncreased intraabdominal pressure may increase

chemotherapy penetration into tissue

PharmacologyAllows pharmacokinetic monitoring of tumor and

normal tissueTissue uptake of chemotherapy cannot be determined

Abdominal incision and suture lines Treated prior to performing the suturingRisk of recurrence in abdominal incision and suture

lines

Diaphragm perforation with

peritonectomy

Pleural space treated by hyperthermic chemotherapy

may prevent seeding of pleural space

Diaphragm closed prior to hyperthermic

intraperitoneal chemotherapy so pleural space

is not treated

Intestinal perforation Detected by observing immersed bowel loops Not detected

Hyperthermia Increased heat necessary to maintain 42°C Less heat required to maintain 42°C

The peritoneum is the “First Line of Defense” for

cancer spread in the abdomen and pelvis.

Surgical interventions in the presence of free

intraperitoneal cancer cells can promote deep

implantation and jeopardize benefit from CRS

(Cytoreductive Surgery) and PIC (Perioperative

Intraperitoneal Chemotherapy).

Survival by Histopathology in Appendiceal Cancer: DPAM vs. PMCA

All Patients – A; Patients with complete cytoreduction – B

Extent of Disease as Measured by the

Peritoneal Cancer Index

Survival by Peritoneal Cancer Index in Appendix Cancer:

1-20 vs. 20-39 -- DPAM and PMCA

Survival by Extent of Prior Surgery in Appendix Cancer:

DPAM and PMCA

Survival by Completeness of Cytoreduction:DPAM and PMCA

Cytoreductive surgery and hyperthermic intraperitoneal

chemotherapy for malignant peritoneal mesothelioma:

multi-institutional experience

Tristan D. Yan, Marcello Deraco, Dario Baratti, Shigeki Kusamura, Dominique Elias, Olivier

Glehen, Francois N. Gilly, Edward A. Levine, Perry Shen, Faheez Mohamed, Brendan J.

Moran, David L. Morris, Terence C. Chua, Pompiliu Piso, and Paul H. Sugarbaker

J Clin Oncol 27:6237-6242, 2009

Survival after CRS and HIPEC in 401

Patients with Peritoneal Mesothelioma

Peritoneal Colorectal Carcinomatosis Treated With

Surgery and Perioperative Intraperitoneal Chemotherapy:

Retrospective Analysis of 523 Patients From a

Multicentric French Study

Dominique Elias, François Gilly, Florent Boutitie, François Quenet, Jean-Marc Bereder,

Baudouin Mansvelt, Gérard Lorimier, Pierre Dubè, Olivier Glehen

J Clin Oncol 28:63-68, 2010

Peritoneal carcinomatosis from gastric

cancer: a multi-institutional study of 159

patients treated by cytoreductive

surgery combined with perioperative

intraperitoneal chemotherapy

Olivier Glehen, Francois Gilly, Catherine Arvieux, Eddy Cotte, et al.

Annals of Surgical Oncology (in press)

Survival and Disease-Free Survival of 159 Gastric

Cancer Patients with Carcinomatosis Treated with

CRS and HIPEC

Survival of Gastric Cancer Patients by

Completeness of Cytoreduction

Survival of Gastric Cancer Patients by

Peritoneal Cancer Index

A Systematic Review and Meta-

analysis of the Randomized

Controlled Trials on Adjuvant

Intraperitoneal Chemotherapy for

Resectable Gastric Cancer

Tristan D. Yan, Deborah Black, Paul H. Sugarbaker, Jacqui Zhu, et al.

Ann Surg Oncol,14:2702-2713, 2007

Forest Plot of Overall Survival at 3 Years

Hyperthermic intraperitoneal

chemotherapy in ovarian cancer.

First report of the HYPER-O Registry

Cyril W. Helm, Scott D. Richard, Jianmin Pan, David Bartlett, et al.

Int J Gynecol Oncol, 20:60-61, 2010

Kaplan-Meier Curve Survival Probability by

Platinum Response

Kaplan-Meier Curve Survival Probability by

CC Score

Kaplan-Meier Curve Survival Probability by

Time Point HIPEC Used

Conclusions

1. A strong rationale from tumor biology

and the pharmacologic advantages of

local-regional chemotherapy combine to

recommend treatments to manage

carcinomatosis.

2. When treatments are available at

experienced centers CRS and PIC are

reasonable treatment options for

appendiceal cancer, mesothelioma and

low volume carcinomatosis.

3. Adjuvant perioperative intraperitoneal

chemotherapy has been found beneficial

in numerous single institution phase III

trials.

4. The standard of care for peritoneal

surface malignancy varies greatly around

the globe form experimental to standard

of care.