Human Pharmacokinetic Study of Heated Intraperitoneal Oxaliplatin in Increasingly Hypotonic Solutions after Complete Resection of Peritoneal Carcinomatosis

Abstract

Purpose: We studied the pharmacokinetics of heated intraoperative intraperitoneal (i.p.) oxaliplatin (LOHP) solution and its safety profile in increasingly hypotonic solutions. This is the first clinical study of i.p. chemohyperthermia with hypotonic solutions. Methods: Patients with peritoneal carcinomatosis (PC) underwent complete cytoreductive surgery followed by intraoperative i.p. chemohyperthermia (IPCH) with successive dextrose solutions of 300, 200, 150 and 100 mosm/l. LOHP (460 mg/m²) was administered in 2 liters of solution/m² at an i.p. temperature of 42–44°C for 30 min. IPCH was performed using an open procedure (skin pulled upwards) with a continuous closed circuit. Patients received intravenous leucovorin (20 mg/m²) and 5-fluorouracil (400 mg/m²) just before IPCH to maximize the effect of LOHP. i.p. plasma and tissue samples were analyzed by means of atomic absorption spectrophotometry. Sixteen consecutive patients with PC of either gastrointestinal or peritoneal origin were treated. The safety of the procedure was studied. Results: Pharmacokinetics: The mean duration of the entire procedure was 7.7 ± 2.6 h. Half the LOHP dose was absorbed within 30 min at all dose levels. Absorption was not higher with hypotonic solutions than with isotonic solutions. The area under the curve of LOHP in plasma did not increase with decreasing osmolarity of the i.p. solutions. Intratumoral LOHP penetration was high; it was similar to that at the peritoneal surface, and about 18 times higher than that in nonbathed tissues. LOHP penetration was not significantly increased by using hypotonic solutions. Safety: There was a very high incidence of unexplained postoperative peritoneal bleeding (50%) and unusually severe thrombocytopenia in the 150 and 100 mosm/l groups. Conclusion: Contrary to experimental studies, this clinical study showed no increase in tumoral or systemic penetration of LOHP with i.p. hypotonic solutions (200, 150 or 100 mosm/l) during IPCH. A high incidence of i.p. hemorrhage and thrombocytopenia was observed.

Treatment-related post-operative mortality after cytoreductive surgery and perioperative intraperitoneal chemotherapy

“…Post-operative bleeding has also been a major problem after HIPEC with oxaliplatin, but we have seen little of this probably because of the lower dose used. 37 Our results also show that many of the postoperative complications are associated with post-operative mortality such as infection, bleeding, pneumonia, fistula, collection, and pancreatic leak. As most of the patients in the mortality group suffered from multiple postoperative complications, it is important to note that these complications are intertwined, prolonging the length of hospital stay and increasing the likelihood of patients returning to theatre.…”

Pharmacological principles of intraperitoneal and bidirectional chemotherapy

“…The use of hypotonic solutions has resulted in higher drug accumulation in tumour cells and increased cytotoxicity in experimental studies [46][47][48]. In contrast to these findings, in a clinical study [49], absorption and intratumoural oxaliplatin were not notably higher for hypotonic than for isotonic solutions. Noteworthy, in the group of patients with a hypotonic carrier solution, unexplained abdominal bleeding and severe thrombocytopenia were frequently observed.…”

Progression of Pseudomyxoma Peritonei after Combined Modality Treatment: Management and Outcome

“…1 Aggressive cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment strategy for PMP with promising survival results. [2][3][4][5] The peritonectomy procedures are a useful tool to optimize resection of macroscopic peritoneal implants. HIPEC seems to reduce the recurrence or progression rate significantly by the cytotoxic effect on (microscopic) tumor residue, especially in patients with low-grade pathology and complete cytoreduction.…”

“…HIPEC seems to reduce the recurrence or progression rate significantly by the cytotoxic effect on (microscopic) tumor residue, especially in patients with low-grade pathology and complete cytoreduction. 3,[5][6][7] Recurrent or progressive disease after this combined modality treatment is however, still a problem. Treatment approaches for recurrent or progressive PMP are not well described, although surgery seems to be the most common option.…”