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2014 Onkologische Fortbildung, LUKS
Cytoreductive surgery (CRS) and
Hyperthermic intraperitoneal
Chemotherapy (HIPEC)
Kuno Lehmann
Klinik für Viszeral- und Transplantationschirurgie
UniversitätsSpital Zürich
Agenda
1. Principles of Cytoreductive Surgery (CRS) and
Hyperthermic intraperitoneal Chemotherapy (HIPEC)
Appendix tumors: Pseudomyxoma
2. Morbidity and Mortality: success of the team
3. Outcome and survival:
CRS/HIPEC yes or no for colorectal cancer
4. Where will we go: PIPAC, Innovations
Fortbildung Onkologie LUKS 2014
CRS/HIPEC = Curative Intention
Cytoreductive surgery
→ complete removal of all macroscopic tumor
HIPEC
→ eradication of remnant or floating – microscopic - cells
«It is what you don‘t see
that kills your patient»
P. Sugarbaker
Fortbildung Onkologie LUKS 2014
Indications for CRS/HIPEC
Appendiceal tumors
Colorectal cancer
Primary peritoneal mesothelioma
Gastric cancer
Pancreas
Biliary tumors
Breast cancer
Recurrent Ovarian
cancer
Fortbildung Onkologie LUKS 2014
CRS/HIPEC
„Pseudomyxoma“
• Low malignant
Colorectal Carcinomatosis
• Various (high) grades
• Indolent course
• Bad outomes
• Surgery only teratment
• Limitations for surgery!!
• No chemo possible
• Systemic treatment
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Pseudomyxoma peritonei
APPENDIX TUMORS
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CRS/HIPEC for PMP
10 years
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Classification of Peritoneal Mucinous Carcinomatosis
DPAM
PMCA
Disseminated Peritoneal
Adenomucinosis
Peritoneal Mucinous
Carcinomatosis
Hybrid
Moderate to abundant
extracellular mucin
with proliferative
epithelium
DPAM with less than
5% PMCA
Abundant extracellular
mucin,single layer of
cells
Ronnet Am J Surg Pathol 1995
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DPAM vs. PMCA after CRS/HIPEC
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Malignant appendix Tumors (all stages)
NET
Goblet cell
AdenoCA
muc
AdenoCA
Signetring
Cancer 2002
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Prognostic Factor – Prior Surgical Score (PSS)
Pseudomyxoma peritonei (385 patients)
PSS 0 – 2 :
25 % improved survival compared with PSS 3
Sugarbaker et al., Ann Surg, Oncol., 1999
Mesothelioma (33 patients)
PSS 0 – 2 :
median survival 41 months
PSS
median survival 13 months
3:
Sebbag et al, BJS, 2000
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Technical aspects
CYTOREDUCTIVE SURGERY
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Fluid movements in
the peritoneal cavity
• gravity
• respiration
• Intestinal
peristalsis
• Parietal Peritoneum
• Visceral Peritoneum
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Douglas’ pouch / Excavatio rectovesicalis
Urologic procedures
Blader reconstruction
CAVE: Patients with high
grade carcinomatosis
(signet ring)
Honoré. Ann Surg 2012
Lehmann, Hepatogastroenterology 2014
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The liver sulci
• Bursa omentalis (stomach, pancreas)
• Liver hilus, insertion of the falciform ligament
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Hyperthermic intraperitoneal Chemotherapy
HIPEC
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Phase I: Preparation
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Hyperthermia and chemotherapy
Drug
TER (40-42OC)
TER (42-45OC)
Cisplatin
1.48-3.9
1.39-4.6
Doxorubicin
1.0
1.0
Mitomycin C
1.00
2.8
TER = thermal enhancement ratio
Urano et al., Int J Hyperthermia 1999
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Pharmacokinetics of intraperitoneal Mitomycin C
Mitomycin in 3 Doses
Van Ruth et al, Surg Oncol Clin N Am (2003)
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HIPEC
• Effective: Multivariant analyses, PRODIGE 7
• ?? Best drug(s)
• Oxaliplatin (cave: side effects) (Elias, JCO 2009)
• Mitomycin C / Doxorubicin (Sugarbaker, 1995)
• ?? Optimal concentrations are unknown
• Temperature: 90’ at 42° or 30’ at 43°
• Dose and volume are calculated according to body
surface area (side effects)
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HIPEC ≠ systemic Cx
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Peritoneal carcinomatosis in mice
before HIPEC
• syngeneic tumor
cells (MC38)
7 days
14 days
• 100% of animals
• rapid progression
(14days)
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HIPEC in mice
Lehmann K et al. Annals of Surgery 2013
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Intracellular ROS: another approach
O2-∙
Superodide
Dismutase
Antabus
(Disulfirame)
H 2O 2
Catalase
H2O+O2
Diethyldithiocarbamate
DDC
Lehmann K et al. Annals of Surgery 2013
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MORBIDITY AND MORTALITY
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Ann Surg 2009
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Safety and Standards to minimize morbidity
Bruchoperation aus Caspar Stromayr´s Practica copiosa, illustrierte Handelsschrift 1559,
Stadtbibiliothek Lindau
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Perioperative Safety and Standards
Nursing Team
i.v. Hydration, bowel
preparation, stoma placement
OR Team
positioning
Cardio-Technician
pump
Anesthesia
Intensive Care
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Guidelines
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Quality of life after CRS and HIPEC
Full recovery after 3-6+ months
Main problems
• Depression
• Pain
• Disturbed digestion
• Ileostomy
Justified in
Stage IV
cancer?
Hill, Ann Surg Oncol 2011
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COLORECTAL CARCINOMATOSIS
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With or without?
Level of evidence?
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Median OS 6
EVOCAPE 1 study
months for CRC
125 patients with PC from colorectal cancer (95-97)
Risk factors for survival (median OS)
localized,small
diffuse, small
larger (2cm)
cake
Sadeghi, Cancer 2000
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Metastatic colorectal cancer
Multimodal therapy concepts
Author/Trial
n
N with
PER
Regimen
mOS
5yS
Crystal
2x599
?
Folfiri
+/- Cetuximab
19.9
20% at 3y
2x700
Ascites=
Folfox
exclusion! +/- Bev
21.3
NR
2x368
?
Xelox, Bev
+/-Cet
20.3
NR
FOLFOX4, +/panitumumab
26
10%
VanCutsem, 2009
N016966
Saltz, 2008
Cairo-2
Tol, 2009
PRIME
Douillard 2013
639
Cunningham, Lancet 2010
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Peritoneal carcinomatosis
PC: peritoneal
carcinomatosis
NON-PC Metastases
+ PC Metastases
mOS
12.7 vs. 17.6 months
N=2095
Franko, J Clin Oncol 2012
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Only one randomized trial
Problem
• Inadequate CRS
31/45 pts with
residual disease
• Control: 5-FU only
Verwaal, J Clin Oncol 2003
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Matched controls
75% of controls had
a laparatomy
SELECTION BIAS
Elias, J Clin Oncol 2009
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Selection
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CRC: Selection criteria for CRS/HIPEC
Current limits
− Extraabdominal disease
exception: few small liver metastases (wedge)
− synchronous PC Biology of the disease
− High PCI (peritoneal cancer index)
Differentation! signet ring
small bowel involvement
→ no complete (CC-0) resection possible
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Peritoneal Cancer Index (PCI)
Peritoneal Cancer Index
(PCI 0 - 39)
Esquivel &
Sugarbaker, 1998
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Peritoneal Cancer Index (PCI)
N=523, multicentric, colorectal cancer
Elias et al., JCO, 2010
Elias et al., Ann Surg 2014
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CRC: Less is more: PCI limit < 15
Elias, Ann Surg, 2014
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Completeness of Cytoreduction (CRC)
N=523, multicentric, colorectal cancer
Elias et al., J Clin Oncol, 2010
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No indication for
palliative CRS/HIPEC
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• Preoperative/“neoadjuvant“ systemic treatment
• Planned second look
• PIPAC
FUTURE ISSUES
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Chemotherapy prior to CRS/HIPEC
Laparo
scopy!
Metachronous
• 21% progression on chemotherapy
• No prolonged chemotherapy
Passot et al. Ann Surg 2012
Synchronous
• Biology of the disease (synchronous tumors)
• Disease control: N+
• Avoid CRS in patients with rapid progressive disease
• Improved outcome if response
• No avastin!
Lehmann et al. Ann Surg 2012
Elias et al. J Clin Oncol 2009
Passot Ann Surg Oncol 2014
Eveno, Ann Surg Oncol 2014
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Second look for high risk patients
Minimal PC
Ovarian metastasis
Perforated tumor (T4)
6x FOLFOX/FOLFIRI
+ 6 months
Relaparotomy
CRS/HIPEC or HIPEC only
Elias et al., AnnSurg, 2008
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Second look for high risk patients?
Minimal disease
Ovarian metastases
Tumor perforation
(pT4)
Carcinomatosis in 23 of
41 (56%) patients
PROPHYLOCHIP
Elias et al., AnnSurg, 2011
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Need for new ideas
• Synchronous PC
• CRC and PCI around 15 or higher
• Signet ring
• Stomach cancer
• Local palliation
7x FOLFIRI/Cet
Bild heizmann
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PIPAC (Pressurized IntraPeritoneal Aerosol Chemotherapy)
• Low morbidity
• No surgery
• +/- 4
applications
• Together with
sCx
• 10% dose of
HIPEC
Solass, Reymond, Ann Surg Oncol (2014)
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PIPAC (Pressurized IntraPeritoneal Aerosol Chemotherapy)
Solass, Reymond, Ann Surg Oncol (2014)
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Conclusions
Cytoreductive Surgery / HIPEC
• Has a curative intent
• can be performed safely
• requires dedicated teamwork and standards
• Treat wise (limitations!), in a team (interdisciplinary),
and treat early (low PCI)
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Danke für Ihre Aufmerksamkeit
Fortbildung Onkologie LUKS 2014