Rationale supporting the use of vasoconstrictors for intraperitoneal chemotherapy with platinum derivatives

Intraperitoneal (i.p.) chemotherapy is a promising therapeutic method to improve the effectiveness of cisplatin in patients with ovarian cancer and peritoneum involvement. Intraperitoneal treatment can be intraoperatively performed just after a complete surgical resection of peritoneal tumor nodules. However, little is known regarding the pharmacokinetics of platinum during intraoperative i.p. chemotherapy (IIC). Serum and i.p. measurements of total and ultrafilterable platinum were performed to determined pharmacokinetic parameters in 11 consecutive patients who received a 2-h IIC with 50 mg/m cisplatin. Protein concentrations were determined in serum and peritoneal liquid at the same times. The cisplatin concentration required to kill OVCAR-3 human ovarian cancer cells and evaluation of cisplatin binding to proteins were determined in vitro. Platinum i.p. concentration decreased rapidly and quickly came under the cytotoxicity threshold (10 mg for 2 h). About 85% of i.p. and serum cisplatin was ultrafilterable during IIC. Platinum concentrations were closely related to protein concentrations. Due to the very low level of serum protein (almost 25 g/l), serum cisplatin binding during chemotherapy was very low (almost 25%), but increased with protein concentration recovery. These pharmacokinetic data show that a sufficient concentration to kill human ovarian cancer is not reached with a single i.p. bath containing 50 mg/m cisplatin for 2 h. A new protocol with a renewed bath and a higher cisplatin concentration is under investigation.

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“…Also, the ratio between i.p. and serum platinum concentrations is at the lower end of the ranges previously described [12,14,20].…”

Section: Discussionmentioning

confidence: 71%

“…cisplatin treatments showed that the ratios in terms of exposure or peak concentrations are 12 and 20, respectively [12,13]. The relationship between concentration/exposure and efficacy is well established, and supports the interest for local administration [13,14].…”

Section: Introductionmentioning

confidence: 62%

Serum and intraperitoneal pharmacokinetics of cisplatin within intraoperative intraperitoneal chemotherapy: influence of protein binding

Royer¹,

Guardiola

Polycarpe

et al. 2005

Anti-Cancer Drugs

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“…Enhanced drug accumulation in the subperitoneal peritoneal space and subsequently in the tumour can be achieved by simultaneous intraperitoneal administration of vasoconstrictors such as epinephrine, which will reduce drug loss through the peritoneal and tumoural vascular networks from the subperitoneal space to the systemic compartment [22][23][24], simultaneous administration of intravenous chemotherapy and absorption of the intraperitoneally delivered drug to the systemic compartment ( Figure 1) [3,18].…”

Section: Pharmacodynamic Aspects Of Intraperitoneal Chemotherapymentioning

confidence: 99%

Pharmacological principles of intraperitoneal and bidirectional chemotherapy

Bree

Michelakis

Stamatiou

et al. 2017

Pleura and Peritoneum

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Intraperitoneal chemotherapy is associated with a significant pharmacokinetic and pharmacodynamic benefit and can, alone or in combination with systemic chemotherapy (bidirectional chemotherapy), be used for treating primary and secondary peritoneal surface malignancies. Due to the peritoneal-plasma barrier, high intraperitoneal drug concentration can be achieved by intraperitoneal chemotherapy, whereas systemic concentration remains low. Bidirectional chemotherapy may provide in addition adequate drug concentrations from the side of the subperitoneal space to the peritoneal tumour nodules. Major pharmacological problems of intraperitoneal chemotherapy are limited tissue penetration and poor homogeneity of drug distribution to the entire seroperitoneal surface. Significant pharmacological determinants of intraperitoneal chemotherapy are choice of drug, drug dosage, solution volume, carrier solution, intra-abdominal pressure, temperature, duration, mode of administration, extent of peritonectomy and interindividual variability. Drugs most commonly applied for intraperitoneal chemotherapy include mitomycin C, cisplatin, carboplatin, oxaliplatin, irinotecan, 5-fluoruracil, gemcitabine, paclitaxel, docetaxel, doxorubicin, premetrexed and melphalan. The drugs and their doses that are used vary widely among centres. While the adequate drug choice for intraperitoneal and bidirectional chemotherapy is essential, randomized clinical trials to determine the most optimal drug or drug combination are lacking, and only eight retrospective comparative clinical studies are available. Further clinical pharmacological studies are required to determine the most effective drug regimen for intraperitoneal and bidirectional chemotherapy in various indications. In the future, reliable drug sensitivity testing and genetic profiling of peritoneal metastases will be needed for enabling patient-specific therapy.

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“…General statements regarding the effects of vasoactive agents are confusing and sometimes contradictory, due to the variety of experimental systems, complex interactions of local-regional and systemic effects of vasopressive agents, and large differences between the neovasculature of tumor nodules and normal capillaries. Both intravenous and intraperitoneal administration of vasoactive molecules in combination with chemotherapeutic drugs has been explored [36,62,63] . A preclinical study of the use of an intraperitoneal epinephrine plus intraperitoneal cisplatin in a rat model with PC, showed a direct correlation between the intraperitoneal epinephrine concentration and cisplatin accumulation in rat peritoneal tumor nodules [64] .…”

Section: Vasoactive Agentsmentioning

confidence: 99%

Pharmacologic rationale for treatments of peritoneal surface malignancy from colorectal cancer

Sugarbaker

Speeten²,

Stuart³

2010

WJGO

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Rationale supporting the use of vasoconstrictors for intraperitoneal chemotherapy with platinum derivatives

Cited by 25 publications

References 10 publications

Serum and intraperitoneal pharmacokinetics of cisplatin within intraoperative intraperitoneal chemotherapy: influence of protein binding

Serum and intraperitoneal pharmacokinetics of cisplatin within intraoperative intraperitoneal chemotherapy: influence of protein binding

Pharmacological principles of intraperitoneal and bidirectional chemotherapy

Pharmacologic rationale for treatments of peritoneal surface malignancy from colorectal cancer

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