Craig E. Pfeifle

Cisplatin administered by the intracavitary route as treatment for malignant mesothelioma

Twenty‐one patients with malignant mesothelioma were treated with an experimental Intracavitary chemotherapy regimen of weekly intraperitoneal or intrapleural cisplatin (90–100 mg/m2) with simultaneous intravenous sodium thiosulfate delivered to protect against cisplatin‐induced nephrotoxicity. One of eight patients (12.5%) receiving intrapleural therapy and nine of 13 patients receiving intraperitoneal therapy demonstrated objective evidence of a clinical response, including three surgically defined major tumor regressions (23%). Patients receiving intrapleural treatment had more advanced disease prior to therapy than those receiving intraperitoneal therapy. It was concluded that intraperitoneal cisplatin is an active treatment program for intra‐abdominally localized mesothelioma. Additional investigation of intrapleural cisplatin should be undertaken in a patient population with less advanced disease or following surgical debulking. Cancer 58:18–21, 1986.

Intraperitoneal chemotherapy with melphalan.

We administered melphalan by the intraperitoneal route to investigate its toxicity and pharmacokinetics. The drug was instilled with 2 litres of fluid and allowed to dwell in the peritoneal cavity for 4 hours. No local toxicity was detected by clinical examination, laboratory tests, or histologic examination. The intraperitoneal route allowed the dose to be increased to approximately three times the maximum dose tolerated intravenously before drug leaking into the systemic circulation produced dose-limiting myelosuppression. The peak peritoneal concentration averaged 93-fold greater than the plasma concentration, and total drug exposure for the peritoneal cavity averaged 63-fold greater than that for plasma. Tumor regressions were observed in patients with ovarian carcinoma and gastrointestinal adenocarcinomas. This study shows that from the pharmacologic point of view, if any portion of the tumor can be reached by intraperitoneal instillation, then there is a very strong rationale for the administration of melphalan by the intraperitoneal route, rather than the oral or intravenous route, for the treatment of tumors confined to the peritoneal cavity.

Infectious peritonitis in patients receiving intraperitoneal chemotherapy

A total of 32 episodes of infectious peritonitis developed in 90 patients receiving intraperitoneal chemotherapy. Staphylococcus epidermidis was the organism most commonly cultured, accounting for 65 percent of isolates. Result of initial gram stain was positive in 35 percent of cases. The development of fever and abdominal pain as well as rising peripheral and peritoneal fluid white blood cell counts was helpful in the making of a diagnosis of infectious peritonitis. Seventy-five percent of patients were cured with antibiotic therapy alone whereas one quarter also required removal of the semi-permanent catheter. Patients treated with intraperitoneal chemotherapy delivered by dialysis exchange over several days exhibited significantly more episodes of infection than patients treated by a single-drug instillation each month. Although the development of bacterial peritonitis remains a problem during intracavitary chemotherapy, the use of subcutaneous ports and meticulous sterile technique during catheter manipulation will hopefully decrease the risk of occurrence of this potentially avoidable complication.

High‐dose intracavitary cisplatin with intravenous thiosulfate. Low incidence of serious neurotoxicity

Recent published reports have suggested that cisplatin administered in high doses or in certain combination chemotherapy can cause serious neurotoxicity in a large percentage of patients treated. In several highdose cisplatin‐based intracavitary chemotherapy trials with the simultaneous intravenous administration of sodium thiosulfate, the incidence of clinically relevant neurotoxicity has been extremely low. In addition, several patients with serious preexisting cisplatin‐induced neurologic dysfunction were treated without worsening of their clinical condition. It is suggested that thiosulfate might have been responsible for the low incidence of neurotoxicity in this patient population. Further experimental and clinical investigation of the potential of this agent to protect against cisplatin‐induced neuropathy appears warranted.

Effect of allopurinol on the toxicity of high‐dose 5‐fluorouracil administered by intermittent bolus injection

The effect of allopurinol pretreatment on the toxicity of 5‐fluorouracil (5‐FU) was examined in a clinical trial. Twenty‐three patients were given bolus infusions of 5‐FU every two weeks in doses that produced mild toxicity (0.8–1.9 g/m2). On alternate courses patients were pretreated with allopurinol either 300 mg two hours prior to and 10 hours after 5‐FU, or 300 mg every 8 hours for 4 doses starting 24 hours before 5‐FU. Seventeen and 20 pairs of courses were evaluable from the 2‐ and 24‐hour pretreatment groups, respectively. Allopurinol did not produce a significant degree of protection against 5‐FU‐induced myelosuppression or mucositis on either dose schedule. Neurotoxicity manifesting as both cerebellar and encephalopathic signs and symptoms was the most important toxicity encountered and was dose‐limiting for 5‐FU on this schedule. Mean oxipurinol serum concentrations at the time of 5‐FU administration were 24 uM and 104 uM for the 2‐ and 24‐hour allopurinol pretreatment schedules respectively. Allopurinol increased the T 1/2 of 5‐FU by a mean of 67% in three of the four patients studied. Pretreatment with allopurinol did not reduce the toxicity of 5‐FU administered as an intravenous bolus.

Uridine pharmacokinetics in cancer patients

SummaryThe availability of uridine can alter the sensitivity of tumor cells to antimetabolites such as N-phosphonacetyl-l-aspartic acid (PALA) and acivicin by virtue of the cells ability to salvage preformed metabolites from its environment. We investigated the pharmacokinetics of physiologically relevant amounts of uridine in cancer patients in a pilot study to further our understanding of uridine metabolism in the human body. Four cancer patients, two males and two females, were given an i.v. bolus of a trace amount of radiolabeled uridine. The nucleoside disappeared from the plasma in a triphasic manner, with initial half-lives of 0.57±0.28 and 1.79±0.62 min and a terminal half-life of 17.5±7.3 min. The volume of distribution was 481±70 ml/kg, and the plasma uridine clearance was calculated to be 1.70±0.42 l/min. Simultaneous plasma and bone marrow uridine concentrations were measured in a separate group of seven healthy volunteers. The uridine concentration in plasma was 2.32±0.58 μM, and that in the bone marrow plasma was 10.44±5.06 μM. These results suggest a very rapid turnover of uridine in the plasma when the nucleoside is present at physiologic concentrations, and that there is a locally high concentration of uridine available for salvage in the bone marrow.