pressureised intraperitoneal aerosol chemotherapy

1. Pressurized Intra Peritoneal Aerosol
Chemotherapy (PIPAC)
Dr. Girish Saini

2. OUTLINE
• Introduction
• Indication
• Method
• Outcome and Comparison
• Complication
• Message

3. INTRODUCTION
• Pressurized Intra Peritoneal Aerosol Chemotherapy (PIPAC) is a minimally-
invasive therapy distributing chemotherapy as a pressurized aerosol into the
abdominal cavity during laparoscopy.
• PIPAC is a drug delivery technique with superior pharmacological properties
for treating peritoneal metastasis.

4. • PIPAC is a relatively new method to alleviate symptoms, in particular to
control ascites and to induce regression of peritoneal metastasis, leading to a
better quality of life (QoL).

5. ePIPAC
• Adding electrostatic loading (electrostatic precipitation PIPAC, ePIPAC) as
an adjunct to aerosol form and artificial hydrostatic pressure improved tissue
uptake in the preclinical model.
• Low-dose PIPAC with cisplatin 7.5 mg/m2 and doxorubicin 1.5 mg/m2 was
applied intraperitoneally at a pressure of 12 mmHg and a temperature of
37°C for 30 minutes (off-label use of approved drugs).
• Additionally, a voltage 7500-9500 V and a current ≤ 10 µA were applied over
a stainless steel brush electrode emitting a stream of electrons

6. • The first ePIPAC use in three human patients with histologically proved
peritoneal metastasis of hepatobiliary-pancreatic (HBP) origin.
• ePIPAC was technically feasible and easy to perform.
• The therapeutic aerosol vanished within 30 seconds after electrostatic
activation

7. INDICATION
• Carcinoma ovary
• Carcinoma stomach
• Colorectal carcinoma
• Carcinoma unknown primary
• Hepatobiliariy Pancreatic
Carcinoma
• Appendiceal tumors
• Mesothelioma
• Others

8. • Systemic chemotherapy resistant peritoneal metastasis
• Patients with PM who have no indication for cytoreductive surgery (CRS)
and hyperthermic intraperitoneal chemoperfusion (HIPEC)
• Further tumor manifestations, such as distant hematogenous metastases, are
to be ruled out
• The peritoneal carcinomatosis index (PCI) (usually higher than 8–10)

9. • Patients with progressive disease during systemic chemotherapy and patients
with distant metastases other than PM were not eligible for PIPAC.
• Precondition to undergo surgery is an Eastern Cooperative Oncology Group
(ECOG) performance status of 2 or better, which was re-evaluated before
each repeated procedure at intervals of about 6 week

10. METHOD
• PIPAC procedures is performed laparoscopically under general anesthesia.
• The standardized pre-therapeutic diagnostic laparoscopy is video-
documented.
• Both diagnostic laparoscopy and PIPAC should strictly follow our internal
standardized operational procedures and adhered to the surgical safety
checklists.

11. • A pneumo-peritoneum of 12 mmHg is induced by an open mini-incision (1
cm) with a 12 mm-trocar inserted consecutively under video-optic guidance.
• An additional 5 mm trocar is placed into the abdominal cavity under direct
visualization.
• If ascites is present, it was completely evacuated by suction and quantified
(in mL).
• The accessibility to the abdomen should described (“access” vs. “non-
access”)

12. • The adhesion score is assessed and documented if patients have previous
surgeries or adhesions due to tumor manifestation, according to the modified
method of Coccolini et al.
• PCI is evaluated and verified by a second surgeon.
• A localized peritonectomy of the best accessible areas of the 4 abdominal
quadrants is carried out according to our protocol, and the samples are sent
for pathological analysis.
• The micro-pump is installed into the 12 mm-trocar and fixed under direct
vision.

14. • The injection pump is connected
• All the staff leave the operating room.
• The chemo-distribution of aerosol is initiated and controlled from a
footswitch in the preparation room, separated by a closed window from the
operating room.
• This allowed the monitoring of the laparoscopy tower, the injection pump,
and the anesthesia condition of the patients by all the responsible persons.

15. • First, cisplatin at a dosage of 7.5 mg/m2 in 150 mL NaCl 0.9%, then
doxorubicin at 1.5 mg/m2 body surface in 50 mL NaCl 0.9% are insufflated.
• The injection pump delivered the chemotherapy at a maximum pressure of
200 psi and a flow rate of 0.5 mL/min to the micro-pump.
• Here, the fluid is transformed to aerosol and applied to the abdomen.

16. • A constant pressure of 12 mmHg with a zero flow of CO2 ensure that the
patient is relaxed and that the aerosol does not escape from the abdomen.
• After this phase of application, the aerosol is kept in the abdominal cavity
for 30 minutes.
• Finally, the situs are controlled for bleeding and the pump was removed
under direct vision.
• While the rest of the aerosol and CO2 are transferred into the central
ventilation system of the clinic (in analogy to the vent of anesthetic gases)
through a closed system.

17. • The procedure is finalized by removing the trocars (without abdominal
drainage) and closing the fascia and the skin.
• All single-use products and the micropump are disposed, and the multiple-
use instruments are cleaned and sterilized
• PIPAC is repeated every 5th week, and seems to stabilize or improve quality
of life, and might improve survival
• Histopathological regression is examined in patients undergoing at least 2
PIPAC procedures. The relative tumor cell covering areas of each biopsy are
analyzed (in %) by 2 experienced gastrointestinal pathologists.

18. • Treatment related toxicity is evaluated after 2 weeks. Response is evaluated
histologically by the Peritoneal Regression Grading Score (PRGS) and
cytologically by analysis of the lavage fluid.
• The biopsy with the maximum tumor cell area is used to evaluate peritoneal
regression. Briefly, biopsies are fixed in 4% buffered formalin, embedded in
paraffin, cut to 4 µm sections, and stained with hematoxylin and eosin
(H&E) using an automated slide strainer.

19. OUTCOME
• Karnowsky-Index increased significantly
• It can induce regression of peritoneal carcinomatosis in end-stage, multi
resistant tumors.
• It is easy to use, and is well tolerated, a decisive feature in patients with
limited life expectancy.
• Can be repeated up to 8 times in the same patient
• Median postoperative hospital stay was 3 days.

20. • Abdominal access is the critical step of the procedure. PIPAC does not
induce chemical bowel perforations.
• PIPAC is safe and surgical complications are rare

21. COMPARISON
• Plasma concentration-time profile analysis after PIPAC indicated superior
ratio between dose, systemic and local drug concentration: PIPAC required
only 1/10th of the doxorubicin dose to achieve higher tumor concentrations
(0.03-4.1 µmol/g) as reported for HIPEC (0.02 µmol/g).
• In contrast, systemic availability of PIPAC and HIPEC were equal as
indicated by the approximately 10-times lower maximal plasma
concentrations after PIPAC.
• Liver and renal tests showed neither acute nor cumulative toxicity

22. COMPLICATION
• Adhesions
• Bowel perforations
• Parietal hematoma
• Hospital mortality (0.3%)
• Peritonitis (0.15%)
• Tumor lysis syndrome (0.15%)
• Repeated PIPAC with oxaliplatin can lead to SPS.(Severe Peritoneal Sclerosis)

23. Take home message
• Peritoneal metastasis and the presence of ascites, is a feature of poor
prognosis for patients with stage IV disease
• Symptom control and the maintenance of QoL remain the major treatment
objectives in the management of patients with stage IV disease.
• Options beyond palliative chemotherapy are limited in patients with stage IV
disease and peritoneal metastasis.

24. • Hence, PIPAC might enrich the portfolio of palliative treatment options with
the overall goal of symptomatic improvement and alleviation of QoL-
reducing parameters.
• Due to its minimal-invasive applicability, low operative risk, and short post-
operative in-hospital stay with a good overall tolerability, this additional
option in systemic therapy seems acceptable in critically ill patient
• In conclusions, PIPAC is not toxic and may nead symptom-oriented
optimization with regard to ascites reduction, (partial) macroscopic and
histopathologic regression of PM and better QoL.

25. • PIPAC has the potential — due to its restricted invasiveness, limited surgical
side-effects and risks, and its lack of systemic toxicity — to be used for
symptom control in Gastric Cancer patients with disseminated Peritoneal
metastasis, in addition to systemic therapy.
• However, the predictors of response and the optimum intervals of PIPAC
within systemic therapy concepts are yet to be identified in on-going further
studies.
• Thus, we are not too optimistic that PIPAC will become standard treatment
in Gastric Cancer patients with Peritoneal metastasis in the near future.

26. Source and Reference
1. Indications and surgical results of Pressurized IntraPeritoneal Aerosol Chemotherapy
(PIPAC) for palliative therapy of peritoneal metastasis after 748 consecutive
procedures(Marc A Reymond, MD, Cedric Demtroder, MD, Jurgen Zieren, MD, Urs Giger-
Pabst, MD, Dirk Strumberg, MD, Clemens B Tempfer, MD. Ruhr-University Bochum)
2. Intraperitoneal Chemotherapy of Peritoneal Carcinomatosis using Pressurized Aerosol
as an Alternative to Liquid Solution: First Evidence for Efficacy and Tolerability
(Wiebke Solass, MD, Urs Pabst-Giger, MD, Thomas Murdter, PhD, Reinhold Kerb, MD,
Matthias Schwab, MD, Jurgen Zieren, MD, Marc A Reymond, MD, MBA. Ruhr-University
Bochum, Germany)
3. Electrostatic Precipitation Pressurized IntraPeritoneal Aerosol Chemotherapy
(ePIPAC): first in-human application(Marc A Reymond. Ruhr-University Bochum)

27. • Gockel I, Jansen-Winkeln B, Haase L, et al. Pressurized Intraperitoneal
Aerosol Chemotherapy (PIPAC) in Gastric Cancer Patients with Peritoneal
Metastasis (PM): Results of a Single-Center Experience and Register Study. J
Gastric Cancer. 2018;18(4):379–391. doi:10.5230/jgc.2018.18.e37
• Jansen-Winkeln B, Thieme R, Haase L, Niebisch S, Pommer C, Lyros O, et
al. Perioperative safety of intraperitoneal aerosol chemotherapy: analysis of
our first 111 pressurized intraperitoneal aerosol chemotherapy (PIPAC)
procedures. Chirurg. 2018 doi: 10.1007/s00104-018-0667-5.

28. • Severe peritoneal sclerosis after repeated pressurized intraperitoneal
aerosol chemotherapy with oxaliplatin (PIPAC OX): report of two
cases and literature survey.(Graversen M1,2, Detlefsen S3,4, Pfeiffer P3,5,
Lundell L6,7, Mortensen MB6,3) Clin Exp Metastasis. 2018 Mar;35(3):103-108.
doi: 10.1007/s10585-018-9895-9. Epub 2018 Apr 28

29. Thank You

30. 8

31. 9

32. 19