A phase I, single-arm, open-label, dose escalation study of intraperitoneal cisplatin and doxorubicin in patients with recurrent ovarian cancer and peritoneal carcinomatosis

Tempfer, Clemens B.; Giger‐Pabst, Urs; Seebacher, Veronika; Petersen, Miriam; Doğan, Aşkın; Rezniczek, Günther A.

doi:10.1016/j.ygyno.2018.05.001

Cited by 80 publications

(76 citation statements)

References 25 publications

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“…Clinical used concentrations are constantly evolving. A dose escalation phase I study with a standard 3 þ 3 dose escalation design confirmed that cisplatin concentration could be increased up to 10.5 mg/m 2 (third step) with no dose limiting toxicity [29]. Nevertheless, a colon perforation occurred during surgical access and other reports suggest an over-risk of anastomotic leakage with PIPAC, suggesting that a clinically usable dose-limit exist for this technic [10,14,30].…”

Section: Discussionmentioning

confidence: 79%

PIPAC versus HIPEC: cisplatin spatial distribution and diffusion in a swine model

Davigo

Passot

Vassal

et al. 2020

International Journal of Hyperthermia

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Purpose: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel approach for delivering intraperitoneal chemotherapy and offers perspective in the treatment of peritoneal carcinomatosis. Concept is based on a 12 mmHg capnoperitoneum loaded with drug changed in microdoplets. It was postulated to guarantee a more homogeneous drug distribution and tissular uptake than hyperthermic intraperitoneal chemotherapy (HIPEC). The aim of this study was to compare cisplatin peritoneal distribution and pharmacokinetic between HIPEC and PIPAC procedures in a healthy swine model. Methods: Two groups of eight pigs underwent either HIPEC with cisplatin (70 mg/m 2) at 43 C for 60 min, or PIPAC with cisplatin (7.5 mg/m 2) for 30 min. Postoperatively, peritoneal areas were biopsied allowing peritoneal cavity cartography. Tissular and plasmatic cisplatin concentrations were analyzed. Results: Cisplatin distribution was heterogeneous in both the groups with higher concentrations obtained closed to the delivery sites. Median total platinum peritoneal concentration by pig was higher in the HIPEC group than in the PIPAC group (18.0 lg/g versus 4.3 lg/g, p < .001) but the yield was 2.2 times better with PIPAC. Platinum concentrations were higher in the HIPEC group in all stations. At each time-point, cisplatin plasmatic concentrations were higher in the HIPEC group (p < .001) but beneath the toxicity threshold. Conclusions: With doses used in clinical practice, HIPEC guaranteed a higher cisplatin peritoneal uptake than PIPAC in this swine model. Spatial drug distribution was heterogeneous with both technics, with hotspots closed to the drug delivery sites. Nevertheless, considering the dose ratio, IP drug uptake yield was better with PIPAC.

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Section: Discussionmentioning

confidence: 79%

PIPAC versus HIPEC: cisplatin spatial distribution and diffusion in a swine model

Davigo

Passot

Vassal

et al. 2020

International Journal of Hyperthermia

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“…Plasma concentrations of doxorubicin after PIPAC peaked at 4.0-6.2 ng/ml after 30 min with a fast plasma clearance of 2.6-6.0 mL/min, corresponding to 1% of the Area Under the Curve (AUC) measured after systemic application of a usual dose [58]. A formal Phase 1 dose escalation study confirmed that serum peaks of doxorubicin and cisplatin after PIPAC sharply increase and peak after 30-45 min with a subsequent sharp decline, and with the drugs being totally cleared from the circulation after 120 min to 24 h, again depending on the dosage level [70].…”

Section: Systemic Toxicitymentioning

confidence: 86%

“…All three components are now part of PIPAC [57]. Starting with the first preclinical experiments through technology development, first in-human use [58], Phase 1 [59][60][61] and Phase 2 [62][63][64][65][66][67] trials, PIPAC is currently being evaluated in randomized controlled trials [68][69][70][71][72] for palliative therapy of PM [73]. PIPAC ( Figure 3) is applied through laparoscopic access using two balloon trocars in an operating room equipped with laminar air flow.…”

Section: Pressurized Intraperitoneal Aerosol Chemotherapy (Pipac)mentioning

confidence: 99%

“…Since the dose applied is reduced by an order of magnitude (as compared to a usual systemic dose) [93] and due to the properties of the peritoneum-plasma barrier, the plasma concentration of the chemotherapeutic agent remains low [57] and, accordingly, the organ toxicity [70]. In addition, pressure enhances the pharmacokinetic advantage of regional delivery by reducing blood outflow from the abdomen over the liver and the abdominal wall during the uptake phase.…”

Section: Local Effect Vs Systemic Uptakementioning

confidence: 99%

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Overcoming Drug Resistance by Taking Advantage of Physical Principles: Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC)

Nadiradze

Horvath

Sautkin

et al. 2019

Cancers

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Theoretical considerations as well as comprehensive preclinical and clinical data suggest that optimizing physical parameters of intraperitoneal drug delivery might help to circumvent initial or acquired resistance of peritoneal metastasis (PM) to chemotherapy. Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is a novel minimally invasive drug delivery system systematically addressing the current limitations of intraperitoneal chemotherapy. The rationale behind PIPAC is: (1) optimizing homogeneity of drug distribution by applying an aerosol rather than a liquid solution; (2) applying increased intraperitoneal hydrostatic pressure to counteract elevated intratumoral interstitial fluid pressure; (3) limiting blood outflow during drug application; (4) steering environmental parameters (temperature, pH, electrostatic charge etc.) in the peritoneal cavity for best tissue target effect. In addition, PIPAC allows repeated application and objective assessment of tumor response by comparing biopsies between chemotherapy cycles. Although incompletely understood, the reasons that allow PIPAC to overcome established chemoresistance are probably linked to local dose intensification. All pharmacological data published so far show a superior therapeutic ratio (tissue concentration/dose applied) of PIPAC vs. systemic administration, of PIPAC vs. intraperitoneal liquid chemotherapy, of PIPAC vs. Hyperthermic Intraperitoneal Chemotherapy (HIPEC) or PIPAC vs. laparoscopic HIPEC. In the initial introduction phase, PIPAC has been used in patients who were quite ill and had already failed multiple treatment regimes, but it may not be limited to that group of patients in the future. Rapid diffusion of PIPAC in clinical practice worldwide supports its potential to become a game changer in the treatment of chemoresistant isolated PM of various origins.

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“…Further, a substantial number of patients received bi-directional treatment which makes it impossible to separate treatment response to ePIPAC and systemic chemotherapy. Patients were treated with oxaliplatin or lowdose cisplatin and doxorubicin despite the recently published doseescalation study on cisplatin and doxorubicin [24], but since the entire procedure and setup (apart from the 1 min electrostatic precipitation) should resemble the setup in the PIPAC-OPC1 study, the same dose of chemotherapy was used.…”

Section: Patientmentioning

confidence: 99%

Pressurized IntraPeritoneal Aerosol Chemotherapy with one minute of electrostatic precipitation (ePIPAC) is feasible, but the histological tumor response in peritoneal metastasis is insufficient

Graversen

Detlefsen

Ellebæk

et al. 2020

European Journal of Surgical Oncology

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Introduction: Electrostatic precipitation Pressurized IntraPeritoneal Aerosol Chemotherapy (ePIPAC) has shown superior penetration depth and tissue uptake compared to standard PIPAC. We investigated the feasibility and objective tumor response to ePIPAC with 1 min of precipitation in patients with peritoneal metastasis (PM). Materials and methods: Patients with PM from various abdominal cancers were included in an amendment to the ongoing prospective PIPAC-OPC2 trial. Colorectal and appendiceal PM were treated with oxaliplatin, patients with PM from other primaries were treated with a combination of cisplatin and doxorubicin. Three ePIPAC procedures were planned in each patient including repeated peritoneal biopsies for response evaluation. After emission to the peritoneal cavity, the aerosolized chemotherapeutics were precipitated for 1 min followed by immediate exsufflation and abdominal closure. Histological regression from the first to the third ePIPAC was evaluated according to the Peritoneal Regression Grading Score (PRGS) and compared to data from the PIPAC-OPC1 trial. Complications and toxicities were recorded according to Dindo-Clavien and CTCAE. Results: Sixty-five ePIPAC procedures were performed in 33 patients (median 2, range 1e6). Ten patients were eligible for response evaluation based on biopsies from the first and third ePIPAC procedure. Four patients had disease progression, four patients had regressive disease, and two patients had stable disease according to PRGS. No life threatening adverse reactions and no mortality was observed following ePIPAC. Conclusion: One minute ePIPAC was feasible and safe, but the histological tumor response was insufficient compared to standard PIPAC directed therapy with 30 min passive diffusion time.

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A phase I, single-arm, open-label, dose escalation study of intraperitoneal cisplatin and doxorubicin in patients with recurrent ovarian cancer and peritoneal carcinomatosis

Cited by 80 publications

References 25 publications

PIPAC versus HIPEC: cisplatin spatial distribution and diffusion in a swine model

PIPAC versus HIPEC: cisplatin spatial distribution and diffusion in a swine model

Overcoming Drug Resistance by Taking Advantage of Physical Principles: Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC)

Pressurized IntraPeritoneal Aerosol Chemotherapy with one minute of electrostatic precipitation (ePIPAC) is feasible, but the histological tumor response in peritoneal metastasis is insufficient

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