marien hospital h erne

Transcription

DEFINING A NEW ERA IN DIGESTIVE
DISEASE INTERVENTIONS
MARC A. REYMOND MD, MBA
PROFESSOR OF SURGERY
HEAD, SURGICAL ONCOLOGY
MARIEN HOSPITAL, HERNE
RUHR UNIVERSITY, BOCHUM
28.04.2015
28.04.2015
2
MARIEN HOSPITAL HERNE
Pressurized IntraPeritoneal Aerosol
Chemotherapy (PIPAC)
A new option in peritoneal cancer therapy
M.A. Reymond
Genolier Swiss Medical Network
New York-Presbyterian Hospital/ Well Cornell Medical Centre
Genolier, April 23rd, 2015
Disclosure
MAR is:
• Inventor and/or Holder of several patents and patent
applications on PIPAC and related technologies
• Consultant to Reger Medizintechnik, Villigendorf, Germany
• Shareholder of CAPNOMED GmbH, Villigendorf, Germany
Chemoresistance
To be most effective anticancer drugs must:
-
penetrate tissue efficiently
reaching all the cancer cells that comprise the target population
in a concentration sufficient to exert a therapeutic effect.
Most research into the resistance of cancers to
chemotherapy has concentrated on molecular
mechanisms of resistance
The role of limited drug distribution within tumors has
been neglected
Minchinton AI, Tannock IF. Drug penetration in solid tumors.
Nat Rev Cancer. 2006 Aug;6(8):583-92. Review
Background: PIPAC: Rationale
• Drug delivery system
• Intraperitoneal chemotherapy
• Poor distribution, Poor tissue penetration, High toxicity
• Takes advantage of physical laws
• Gas, Pressure
• (Electrostatic loading)
• Approved drugs (= systemic chemotherapy)
• Platin coumpounds
• Anthracyclines
• (Taxanes, Mitomycin C, Gemcitabin, …)
• Can be repeated
• Allows objective tumor response assessment
Reymond MA et al, Surg Endosc 1999
PIPAC: Technique
• Laparoscopic approach: 1 x 5 mm-Trocar, 1 x 10 mm Trocar, 12 mmHg IP pressure, 37 ºC
• Chemotherapy: CRC: Oxaliplatin 92 mg/m2 Others cancers: Doxorubicin 1,5 mg/m2 & Cisplatin
7.5 mg/m2 application for 30 min
• Device : MIP®, Reger Medizintechnik (CE-certified, class 2A)
• High-pressure injector: any industry-standard injector up to 20 bar
• Laminar air flow or filtered ventilation
Solass W et al, Surg Endosc 2012
PIPAC : Preclinical, blue stain, normal pig
• 5 German female landrace pigs,
45-60 kg
• Transvaginal cholecystectomy, 3
trocar technique
• 1x Lavage
– 6 L NaCl 0,9% solution w/ 20 ml
methylene blue.
– 1x inflow, 2x outflow
– Filling w/2 L, lavage 1 L/min for
15 min
• 4x Capnoperitoneum
•
– 10 ml NaCl 0.9% solution w/ 5 ml
methylene blue
– 30 min exposition time
Pressure-limited waste system
including valve and filter
PIPAC
IPC
PIPAC: Deeper tissue penetration
PIPAC
IPC
No staining
stained peritoneum (backside)
stained
capillar vessel
(properitoneal
fatty tissue)
PIPAC: ex vivo, Dbait, diseased human tissue
•
Therapeutic capnoperitoneum (12 mmHg) was established for 30 minutes in a
plastic box.
Solass W et al, Surg Endosc 2013b
• Dbaits (non-coding small
DNA fragments) were
coupled to cholesterol
molecules and to Cy5 (to
allow detection by
fluorescence)
• The gaseous phase was
consisting of CO2, the liquid
phase of microparticles of
Dbaits (100 ug/mL).
• 3 experiments:
– Nebulization w/ Dbaits
– Lavage w/ Dbaits
– Nebulization w/o Dbaits
Human sample of PC arising from
an endometrial adenocarcinoma
Penetration of therapeutic substance.
Staining reveals fluorescence up to 1 mm in the therapeutic capnoperitoneum sample (a),
no tissue penetration uptake in the lavage sample (b), and no staining in the control
sample (c).
Cryosection of human peritoneum, red CoDbaitCy5 staining, blue dapi (nucleus). (a) after nebulization of Dbaits; (b) after
lavage with Dbaits; (c) after nebulization without Dbaits.
Scale bar 0.01 cm
Biological activity.
Preffered intranuclear phosphorylation of H2AX is observed in the peritoneal
carcinomatosis nodule, in particular at the invasion front.
Cryosection of human peritoneum. Detection of early Dbait activity marker = Phosphorylated H2AX. red CoDbaitCy5 staining, blue dapi
(nucleus), green GH2AX.
PIPAC vs. HIPEC : In vitro, CRC, Oxaliplatin
Models:
a) Drug exposition in 3-dimensional xenograft model with CT26 and LS174
colorectal cancer cell lines
b) Transmembraneous outflow model using normal human peritoneum
(hernia surgery) and retroperitoneal liquid circulation
Outcome:
1) Depth of tissue penetration (immunofluorescence)
2) Tissue drug concentration (ICP mass spectrometry)
3) Degree of apoptosis (TUNEL)
4) Peritoneal passage (AUC lavage solution)
Direct comparison HIPEC vs PIPAC:
i) Hyperthermia vs. normothermia
ii) 30 min vs. 40 min exposition time
iii) 0.14 mg/ml vs. 0.028 mg/ml (460 mg/m2 body surface vs 92 mg/m2)
Haidara A, M. Sc. Thesis, UMR INSERM U965 (Marc Pocard),2015
CT26 cell line
LS 174 cell line
In both cell lines (CT26 and LS174) degree of apoptosis PIPAC > HIPEC, although:
- dosis PIPAC < HIPEC (1/5)
- no hyperthermia in the PIPAC group
PIPAC vs. HIPEC: In vitro, CRC, Oxaliplatin
Degree of oxaliplatin penetration into tumor nodes
Oxaliplatin tissue uptake PIPAC > HIPEC
Systemic exposure to oxaliplatin
Transperitoneal uptake PIPAC < HIPEC
(HIPEC dose = 5x PIPAC Dose)
• Both HIPEC and PIPAC with oxaliplatin induce
apoptosis in vitro in this 3D-CRC cell line model
• Efficacy PIPAC > HIPEC in vitro
• Tissue penetration into nodules PIPAC > HIPEC in vitro
• Less « systemic » release after PIPAC than HIPEC
This is the first independent confirmation
of the pharmacological results obtained at RUB (with DOX
and Dbait)
PIPAC: tissue penetration in-human (DOX)
Normal Peritoneum
Tumor nodule
After PIPAC: presence of doxorubicin in the nucleus throughout the whole peritoneal
surface up into the retroperitoneal fatty tissue.
• Highest concentration between 100 and 200 µm (from the surface).
• concentration in tumor nodules reach high levels (up to 4,1 µmol/g),
= up to 200x DOX concentration reported after HIPEC
Fluorescence microscope: red: doxorubicin-coloration; green: picogreen nuclear staining. Arrow: surface and penetration
direction. Line: doxorubicin-penetration barrier.
Solass W et al, Ann Surg Oncol 2013
PIPAC: DOX+CIS, mechanism of action
Microscopic analysis of peritoneal metastasis from a platin-resistant ovarian cancer. Histological
appearance before (a1) and 6 weeks after PIPAC therapy (b1) with cisplatin and doxorubicin showing
encirclement of the tumor node by fibrosis (nodular sclerosis). Panels a2 and b2 show apoptotic cells as
determined by TUNEL analysis: after PIPAC therapy, apoptosis can be demonstrated at the outer limit of
the tumor node (tumor invasion front).
Solass W et al, Frontiers in Anticancer
Drug Discovery (in press)
PIPAC: Low systemic uptake (in-human: DOX)
Pharmacocinetic profile in peripherous venous blood (typical profile) after PIPAC
with Doxorubicin [DOX] 1,5 mg/m2 body surface for 30 min. with i. -abd. Pressure
of 12 mmHg. Peak doxorubicin plasma concentrations are low (4.0 – 6.2 ng/ml,
around 1% systemic delivery). High bioavailability. Clearance (Cl/F) between 2,66,0 ml/min.
Solass W et al, Ann Surg Oncol 2013
PIPAC: low liver toxicity (DOX + CIS)
Minimal hepatotoxicity with significant gGT increase (ANOVA, p < 0,05), GOT & GPT
remaining WNR. No effect of PIPAC on liver function and metabolism.
Blanco A et al. Ann Surg Oncol
2013;20:2311-6
PIPAC: no acute or cumulative renal toxicity
(CIS + DOX)
No acute renal toxicity, and no cumulative toxicity
Blanco A et al. Ann Surg Oncol
2013;20:2311-6
PIPAC: Indications
5.11.2011 to 21.1.2015: 636 PIPAC + 11 PITAC in 328 patients
752 procedures (intention to treat)
1%
8%
5%
5%
3%
0%
44%
15%
19%
Ovarian
Gastric
Colon
CUP
Appendix, PMP
Mesotheliom
HBP
Breast
Palliative indication in pretreated, platin-resistant peritoneal
carcinomatosis, primary CRS and HIPEC not indicated
Therapy within the framework of regulatory studies PIPAC-OV1 (NCT01809379) and PIPAC-GA1
(NCT01854255) as well of as off-label use according to German AMG.
All patients had previous guideline-based therapy with approval of the IRB. All patients were presented at
the tumor board of the Comprehensive Cancer Center, Marien Hospital, Ruhr-University Bochum.
Indication 1: PIPAC as salvage therapy
• In patients not eligible for CRS & HIPEC:
– What are you proposing to these patients ?
– Why not applying PIPAC q6w until disease progression ?
• ¾ objective tumor regression (histology) in platin-resistant PC of
ovarian, gastric, colorectal cancers and mesothelioma ?
• Low risk, minimal invasive procedure
• Improvement of QoL
PIPAC: Objective tumor response assessment
a1
a2
a3
b1
b2
b3
c1
c2
c3
PIPAC: CRC: OX: Tumor response
Platin-resistant 3rd line „salvage“ situation
24%
35%
major
partial
no response
N/A
12%
29%
Clinical Benefit Rate (Σ histological CR +
PR) is 84% (11 objective tumor regressions
in 13 patients with ≥ 2 PIPAC) or 64% (out
of all 17 patients).
Semi-quantitative analysis of regression
grading after 1 PIPAC shows a significant
drop of median TRG 5 à 2, p= 0.005)
Demtröder et al, Colorectal Dis, in press
29
Crude survival after first PIPAC
Colorectal cancer with PC, palliative 3rd line „salvage“ situation
Observed actuarial survival of 17 consecutive patients with PC of CRC (mean PCI = 16) after
PIPAC salvage therapy with oxaliplatin.
Patients had previously received 2 lines of palliative systemic chemotherapy (median, min-max 1-3). All patients had previous surgery.
Most patients received combined systemic palliative chemotherapy with PIPAC. One-year survival is 70%, 14/17 patients are alive after a
mean follow-up of 237 days. Median survival has not been reached yet (dotted line). X-axis: survival in days. Y-axis: cumulated survival.
EORTC-QLQ30 symptom scores
expected
under PIPAC
Left panel: in 91 peritoneal carcinomatosis patients classified according to their
survival at time of assessments; Right panel: in a subgroup of 48 of those patients
having received at least 2 PIPAC at 6 weeks intervals
Odendahl et al, Eur J Surg Oncol, in press
Indication 2: „neoadjuvant“ PIPAC
• In patients not eligible for CRS & HIPEC:
– Why not applying repeated PIPAC until major tumor
regression in order to perform secondary CRS and
HIPEC ?
• Around 1/4 complete tumor response in platin-resistant
PC of ovarian, colorectal, gastric cancer and
mesothelioma
• Secondary CRS and HIPEC possible in a significant number of
patients
– Colorectal cancer
– Gastric cancer (incl. signet-ring)
– Mesothelioma
– Others ?
PIPAC: OX: colorectal: tumor response (RECIST)
a
b
58 y.o. patient with metachronous peritoneal carcinomatosis of colorectal cancer 27 months after diagnosis and after
systemic chemotherapy (XELOX, then capecitabin alone due to side-effects) (a) Abdominal CT-scan before PIPAC-therapy
with extensive peritoneal carcinomatosis (arrows) (b) Complete radiological response according to RECIST criteria after 3
cycles of Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) q6w with oxaliplatin 92 mg/m2 at a pressure of 12
mmHg and a temperature of 37 °C for 30 minutes, combined with systemic chemotherapy (FOLFIRI). Patient is alive 18
months after PIPAC #1 with excellent quality of life.
PIPAC: OX: colorectal: tumor response
a
b1
+
b2
#
&
The patient underwent complete cytoreductive surgery (CC-0) and Hyperthermic IntraPeritoneal Chemotherapy (HIPEC) 7 months after
PIPAC #1. (a) Macroscopy of the left upper abdomen showing limited PC (Peritoneal Carcinomatosis Index = 3) with diffuse scarring.
(b1) Four suspect millimetric nodes on the surface of the small bowel were resected, all of them were tumor-free(+). (b2) Vital tumor
cells (arrows) were found in 3/9 peritoneal biopsies and in the omentum, together with extensive fibrosis (#) and large mucous areas (&)
as a sign of tumor regression.
PIPAC: sclerosis of the invasion front
Macroscopy of the great omentum of a 64 y.o. colorectal cancer patient after repeated
PIPAC with oxaliplatin 92 mg/m2 body surface. Complete secondary cytoreductive surgery
(CC-0) and HIPEC was possible. A fibrotic capsule of 2-3 mm thickness (arrows) had
developed in the periphery/ at the outer invasion front of the tumor mass (8,4 x 7,4 x 4,6
cm). Patient is alive 11 months after salvage therapy with PIPAC with excellent quality of
life.
Reymond et al. In: Levine, Ceelen (Eds)
Intraperitoneal chemotherapy (in press)
3
5
PIPAC: effect on vascularisation
Same patient: Effect of PIPAC application on the vascularisation of a centimetric
peritoneal metastasis. Panels a1 and b1 show CT-scan of a bulky disease involving
the omentum. Contrast enhancement is clearly reduced after PIPAC therapy (arrows),
documenting a loss of vascularization of the tumor node.
Reymond et al. In: Levine, Ceelen (Eds)
Intraperitoneal chemotherapy (in press)
3
6
PIPAC: mechanism of action
Peritoneal metastasis initially associate with and grow
preferentially along pre-existing mesenteric vessels.
In tumors this angiogenic activity is located within a few hundred
micrometers from the tumor rim
Repeated PIPAC induces tumor regression by apoptosis
Tumor tissue is replaced by fibrosis
Neovessels are interrupted/ destroyed
Example after 5x PIPAC with CIS + DOX. Panels a and b : same
patient, same time point. PIPAC effect appears to be (relatively)
selective on tumor tissue
PIPAC will evidence HIPEC
• Choice of drugs in CRS & HIPEC is poorly
evidenced
– Study design difficult because of methodological barriers
• PIPAC can help HIPEC for determining the right
drug in a particular indication
– Comparative studies comparing drug A vs .drug B in various
cancer types and histologies possible
– Favourable methodological framework conditions
• Objective response assessment
• Procedure standardized
– Results could be largely extrapolated to HIPEC
References
1. Demtröder et al. Colorectal Diseases (in press)
2. Khalili-Harbia N. Endoscopy (in press)
3. Odendahl K et al. Eur J Surg Oncol (in press)
4. Giger-Pabst U et al. Anticancer Res. 2015 Apr;35(4):2309-14.
5. Tempfer CB et al. Gynecol Oncol. 2015 Feb 18. [Epub ahead of print]
6. Sabaila A et al. Gynecol Obstet Fertil. 2015 Jan;43(1):66-7..
7. Tempfer CB et al. Wien Med Wochenschr. 2014 Dec;164(23-24)
8. Oyais A et al. Zentralbl Chir. 2014 Feb 4. [Epub ahead of print]
9. Tempfer CB, et al. Gynecol Oncol. 2014 Feb;132(2):307-11.
10.Solass W et al. Ann Surg Oncol. 2014 Feb;21(2):553-9.
11.Solass W et al. Ann Surg Oncol. 2013 Oct;20(11):3504-11.
12.Blanco A et al. Ann Surg Oncol. 2013 Jul;20(7):2311-6.
13.Solass W et al. Surg Endosc. 2012 Jul;26(7):1849-55
14.Solass W et al. Surg Endosc. 2012 Mar;26(3):847-52
15.Reymond MA et al. Surg Endosc. 2000 Jan;14(1):51-5.
PIPAC: Clinical studies
• Phase-2 study. Intraperitoneal Aerosol High-pressure
Chemotherapy for Women With Recurrent Ovarian Cancer (PIPACOV1). NCT01809379. http://www.clinicaltrials.gov. Study
completed.
• Phase-2 study. Intraperitoneal Aerosol Chemotherapy in Gastric
Cancer (PIPAC-GA01). NCT01854255. http://www.clinicaltrials.gov.
Recruiting.
• Phase-2 study. Treating Peritoneal Carcinomatosis With PIPAC.
NCT02320448. http://www.clinicaltrials.gov. Recruiting.
• A phase I, open-label, three step dose escalation study with CIS
and DOX applied as pressurized intraperitoneal aerosol
chemotherapy (PIPAC) in patients with recurrent ovarian cancer
and peritoneal carcinomatosis. EudraCT: 2014-001034-28. Under
regulatory review.
PIPAC: PIPAC-OV1
• Prospective, phase II trial
• Target accrual: n=50 (Simon 2 stage design for phase II studies)
• rPROC after at least 2 chemotherapy lines
• Treatment: 3 x PIPAC q 28-42 days;
cisplatin 7.5 mg/m2 & doxorubicin 1.5 mg/m2
at 12 mmHg, 37 °C for 30 min
• Approval by national drug agency (BfARM; 613910-4039261),
Ethics Committee RUB (4515-12 FF)
• EudraCT 2012-004397-26
• NCT01809379
PIPAC: PIPAC-OV1
• PIPAC has a CBR of 60% in women with
rPROC (peritoneal carcinomnatosis, salvage
situation, 3rd-line)
• Objective tumor regression =79% after 3
PIPAC
• PIPAC positively affects QoL
• PIPAC is safe with CTCAE grade 3 events in
8/64 women and no event grade ≥4
• PIPAC in rPROC should be investigated in
randomized phase II/phase III trials
Tempfer CB et al. Gynecol Oncol. 2015 Feb 18. [Epub ahead of print]
PIPAC : Ideal intraperitoneal chemotherapy ?
Minimally invasive procedure
X
Procedure can be repeated
(X)
Homogeneous drug distribution within the body cavity
(X)
Effective/deep drug penetration into tumor nodes
X
Low systemic drug uptake, low systemic toxicity
X
Low dose of drug, low local toxicity
X
No need for previous cytoreductive surgery
(X)
Efficacy in the presence of diffuse small bowel invasion
X
Objective and early assessment of tumor response
X
Simultaneous administration with systemic chemotherapy possible
(X)
Administration of a large range of active substances (drugs,
antibodies, genes, nanomolecules)
(X)
Conclusions
• PIPAC can induce regression of platin-resistant peritoneal
metastasis: ovarian, gastric, CRC, mesothelioma, …
• Pharmacological superiority over systemic chemotherapy
and HIPEC is already proven
• PIPAC can be proposed to many patients ineligible for CRS &
HIPEC
• PIPAC (as of today) should not be combined with CRS
• PIPAC might be a „neoadjuvant“ therapy before CRS and
HIPEC
• PIPAC might be an adjuvant therapy for patients at risk
• PIPAC will provide high-level scientific evidence on
intraperitoneal chemotherapy
Thank you
PIPAC is giving biology access to the
operating field
PIPAC empowers surgeons with novel
possibilities to improve outcome of
surgery by steering ist environment
PIPAC Hospitals: Europe (Feb.2015)
active
trained
to be trained
PIPAC Hospitals: Worldwide
active
trained
to be trained

marien hospital h erne

Transcription

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