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Negative-balance isolated pelvic perfusion in patients with incurable symptomatic rectal cancer: results and drug dose correlation to adverse events

Background Drug leakage and lack of a drug-removal system have prevented clinical application of isolated pelvic perfusion (IPP). These barriers were overcome with negative-balance IPP (NIPP) in experimental pig models. Here, a phase 1 clinical study of NIPP was performed in patients with incurable symptomatic rectal cancer. Purpose To establish a safe regimen of high-dose regional chemotherapy with NIPP using cisplatin in patients with incurable rectal cancer. Material and Methods Between June 2004 and January 2007, NIPP therapy was performed for 23 patients (11 women, 12 men; mean age, 58 years). NIPP was routinely performed twice over a 4-week interval. Dose-limiting toxicities (DLTs) were defined using a 5 + 3 design, and cisplatin doses were escalated from 170 mg/m2, with a fixed 5-fluorouracil dose of 1000 mg/m2. The grade of adverse events (AEs) at the first and second sessions of NIPP therapy, pharmacokinetics, and antitumor response were evaluated. Results No DLTs were observed during the first session of NIPP. However, at the second session, two patients experienced the DLT of neuropathy after administration of 200 mg/m2 cisplatin. Therefore, 190 mg/m2 cisplatin was indicated as the maximum tolerated dose (MTD). The plasma pelvic-to-systemic exposure ratio was 18.4 based on the maximum concentration and 19.0 based on the concentration-time curve. Solid tumor responses included complete response in two patients, partial response in five patients, stable disease in 15 patients, and progressive disease in one patient. Conclusion NIPP may offer the safe delivery of high-dose regional chemotherapy (MTD of 190 mg/m2 cisplatin) with negligible AEs and effective control of tumor growth in patients with incurable rectal cancer.