Clinical pharmacokinetics of isolated pelvic perfusion.

The pharmacokinetic results of this study indicate that there is significant enhancement of pelvic drug levels with isolated pelvic perfusion, with the potential of increasing the therapeutic index and clinical efficacy. This system would seem to be ideal for evaluating fast-acting and highly toxic experimental drugs on human pelvic cancers having treatment protocols of limited clinical success. Pharmacokinetic modeling using empiric approximations for the kinetic rate constants is a convenient and novel way of fitting data using relatively simple mathematics and commercially available spreadsheets.

Pelvic perfusion for advanced colorectal cancers.

Isolated pelvic perfusion (IPP) is a form of intra-arterial local-regional treatment of tumor-bearing organs. IPP using a simplified balloon occlusion technique has shown promise in palliation of resectability of advanced rectal cancer in patients not amenable to treatment with conventional chemoradiation. This article reviews technique criteria and the response to IPP from seven literature studies of isolated pelvic perfusion with colorectal cancer. Current efforts should be directed to improving anti-tumor responses by optimizing chemotherapeutic protocols and modifying perfusion parameters, so that hopefully, this will lead to a more standardized and improved procedure for the isolated pelvic perfusion technique.

Isolated chemotherapeutic perfusion of pelvis as neoadjuvant or palliative therapy for advanced cancer of the rectum.

INTRODUCTION: Previously irradiated recurrent rectal cancer is a formidable patient threat with limited treatment options. Isolated pelvic perfusion (IPP) by the balloon-occlusion technique provides high-dose regional chemotherapy that may facilitate resection if appropriate or palliate pain and fungating tumor mass in the symptomatic patient. We currently report our results in 49 recurrent rectal cancer patients (26 had neoadjuvant IPP with intent to resect and 23 had IPP for palliation). METHODS: IPP was done for 1 hour with paclitaxel 30 mg/m(2), 5 fluorouracil 1500 mg/m(2), cisplatin/oxaliplatin 60-130 mg/m(2), and mitomycin C 10 to 15 mg/m(2) (the latter three achieving pelvic-to-systemic drug ratios of 6-9:1). RESULTS: Neoadjuvant perfusion in 26 patients achieved a response in 14 patients (made resectable). Seven had R0 resections (clear margins), six by abdominal sacral resection (ABSR), and one by an extended APR. Of seven other patients, one had a complete pathologic response negating planned resection, one had >50% tumor regression in pelvis (but developed distant metastases), and three refused ABSR. Planned ABSR in two patients was aborted because of complicating cardiovascular issues. A variety of medical and cancer issues precluded resection in the remaining 12 of these 26 neoadjuvant patients. Within the neoadjuvant group, median survival was 24 months in the responding (made resectable) group (14 patients) and it was 8 months in the non-resectable group (12 patients), p = 0.0001. In the responding (made resectable) group, seven patients had R0 resections (median survival 26 months) and seven patients were not resected (median survival 18 months), p = 0.0198. In the IPP group for palliation, 17 of 23 patients (74%) had significant relief of pain, and other tumor-related symptoms (mean survival 11 months). CONCLUSION: Isolated pelvic perfusion using a simplified balloon-occlusion technique has promise in palliation of or augmenting resectability of advanced rectal malignancy in patients not amenable to treatment with conventional modalities.

Isolated pelvic perfusion: plasma pharmacokinetics depend primarily on drug dosage and not the type of drug.

PURPOSE: Comparison of the pharmacokinetics of four drugs with the isolated pelvic perfusion protocol showed linear relationships between drug dosage and two isolated pelvic plasma parameters, mean AUC (pelvic exposure, microM min) and the mean maximum pelvic drug level (microM). It appears that the pharmacokinetics are sufficiently defined as to predict plasma distribution curves for an additional drug with this protocol. Recent FDA approval of oxaliplatin allowed an evaluation of this premise. METHODS: Linearity of drug dosage with maximum drug levels and exposure (AUC) in the isolated pelvic plasma yields initial estimates of these parameters for additional drugs. Use of an empirical, four-compartment pharmacokinetic model (Wanebo and Belliveau in Cancer Chemother. Pharmacol. 43:427, 1999) allowed the generation of predictive plasma distribution curves. These curves were established by optimizing the initial estimates of maximum drug levels and exposure along with estimates of two additional parameters (half-life of pelvic clearance and pelvic to systemic exposure ratio) from experimental data of the four drugs pharmacokinetically characterized. RESULTS: Calculated plasma distribution curves for oxaliplatin matched the experimental curves from the first three patients receiving oxaliplatin therapy, given the experimental ranges of pharmacokinetic parameters seen with the initial four drugs. CONCLUSION: These results give an overall picture for the plasma pharmacokinetics during the isolation period for the isolated pelvic perfusion protocol. Enough experimental data have been accumulated for five drugs to establish a simple pharmacokinetic model (Wanebo and Belliveau in Cancer Chemother Pharmacol 43:427, 1999) and interdrug relationships (i.e., this report) which can be used to predict reasonable plasma distribution curves for additional drugs with this protocol.