Stephen Cleary

Long-term survival of advanced refractory ovarian carcinoma patients with small-volume disease treated with intraperitoneal chemotherapy.

Ninety ovarian carcinoma patients failing primary intravenous (IV) combination chemotherapy were treated with cisplatin-based combination intraperitoneal therapy. Sixty-five patients had residual disease greater than 2 cm at the start of intraperitoneal therapy. Their median survival was 8 months. Twenty-five patients had disease less than 2 cm; their median survival was greater than 49 months, and the survival curve has an apparent plateau at 69%, with no relapses having occurred after 32 months. The median survival for all 90 patients was 15 months. The median duration of follow-up for all patients was 37 months. These results confirm the critical role of tumor bulk in determining the effectiveness of intraperitoneal therapy, and suggest a role for intraperitoneal salvage treatment in patients with small-volume disease.

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 high-dose cisplatin and cytosine arabinoside for refractory ovarian carcinoma and other malignancies principally involving the peritoneal cavity.

Sixty-two patients with refractory ovarian carcinoma or other malignancies principally confined to the peritoneal cavity were treated with an intraperitoneal combination chemotherapy regimen consisting of cisplatin (100 mg/m2 or 200 mg/m2) and cytosine arabinoside (4 X 10(-3) mol/L or 10(-2) mol/L). Sodium thiosulfate was simultaneously administered intravenously (IV) to protect against cisplatin-induced nephrotoxicity. Sixteen of 52 evaluable patients demonstrated evidence of a clinical response including 14 (36%) of 39 with refractory ovarian carcinoma. Systemic toxicity was not severe except for cisplatin-induced emesis and a single episode of major renal insufficiency. Dose-limiting toxicity was bone marrow suppression with cytosine arabinoside administered at 10(-2) mol/L. We conclude that combination intraperitoneal therapy with high-dose cisplatin and cytosine arbinoside can be safely administered with objective tumor responses observed in patients with ovarian carcinoma refractory to front-line chemotherapy and in occassional individuals with other malignancies principally confined to the peritoneal cavity.

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.

Selective intraperitoneal biochemical modulation of methotrexate by dipyridamole.

Dipyridamole increases the toxicity of methotrexate in a concentration-dependent manner. We hypothesized that concurrent intraperitoneal administration of both drugs would result in high peritoneal concentrations with much lower plasma concentrations, permitting a selective increase in the activity of methotrexate against intraperitoneal tumors without enhancing systemic toxicity. Initially, 2.16 mg/m2/d methotrexate and 12 mg/m2/d dipyridamole were delivered together as a constant intraperitoneal infusion for 48 hours. With escalation of chemotherapy, eventually 4.32 mg/m2/d methotrexate was administered for 168 hours. Forty-seven courses were administered to 18 patients. The mean peritoneal to plasma concentration ratios of methotrexate and non-protein bound dipyridamole were 71.6 +/- 34.8 and over 2,300, respectively. Chemical peritonitis was the dose-limiting toxicity. Three patients had some evidence of a response (two with decreasing tumor markers, and the third with a reduction in ascites). We conclude that the drug concentrations are in an appropriate range for selective intraperitoneal biochemical modulation of methotrexate, and that it is feasible to expose tumors confined to the peritoneal cavity to these drugs for long periods of time.

Phase I trial of combination therapy of cancer with N-phosphanacetyl-L-aspartic acid and dipyridamole

SummaryWhile N-phosphonacetyl-L-aspartic acid (PALA), an inhibitor of de novo pyrimidine biosynthesis, demonstrated a unique spectrum of activity during preclinical drug evaluation, multiple clinical trials have shown it to possess minimal clinical activity. One explanation for the disappointing results is the possibility that tumor cells are able to utilize circulating uridine in the synthesis of pyrimidines (salvage pathway). Dipyridamole, an inhibitor of nucleoside transport, has been demonstrated experimentally to potentiate the cytotoxicity of PALA significantly. In addition, this agent has a long safety record when used clinically in man. A phase I trial of this two-drug combination was therefore conducted, with a fixed oral dose of dipyridamole (50 mg/m2 every 6 h) and an escalating i. v. dose of PALA administered every 3 weeks. The dose-limiting toxicity with this schedule was diarrhea and abdominal cramping pain at a PALA dose of 3900–4200 mg/m2. Among the 65 patients participating in this trial 4 objective responses (2 partial, 2 minimal) were observed. Because of the potential for unique clinical synergy between PALA and dipyridamole further investigation should be considered.

Hypomagnesemia following high-dose intracavitary cisplatin with systemically administered sodium thiosulfate.

Seventy-one patients receiving a minimum of two courses of high-dose intracavitary cisplatin (100–200 mg/m2/course) with i.v. thiosulfate administered to protect against cisplatin-induced renal insufficiency were retrospectively evaluated to examine the influence of thiosulfate and large cumulative doses of cisplatin on the incidence of hypomagnesemia. Only 8% of 50 patients who had normal serum magnesium levels prior to the initiation of the experimental program became hypomagnesemic during the therapeutic trial. Similarly, while 67% of the 21 patients with low initial serum magnesium levels remained hypomagnesemic, 33% had normal serum levels at the completion of therapy. It is suggested that the intravenous administration of thiosulfate might have been responsible for the strikingly low incidence of hypomagnesemia in this patient population. A prospective evaluation of the utility of sodium thiosulfate in preventing cisplatin-induced renal magnesium wasting appears indicated.

Phase I/pharmacokinetic study of thioguanine administered as a 48-hour continuous intraperitoneal infusion.

Thioguanine (TG) is an antimetabolite with established antileukemic activity. The most pharmacologically rational manner of TG administration is continuous infusion. Intraperitoneal (IP) delivery of TG provides the opportunity to definitively test the concept of high-dose, long-term antimetabolite administration. The high systemic clearance and in vitro activity of TG against ovarian carcinoma suggested that it would be an excellent candidate for IP administration as a prolonged infusion. TG was administered as a 48-hour continuous IP infusion in this phase I/pharmacokinetic study. TG infusions were administered using a portable, programmable pump (Pancretec Provider Model 2000; Pancretec, Inc, San Diego). Twenty-five patients were treated. At a dose of 900 mg/m2/48 h, TG produced unacceptably severe myelosuppression. The dose-limiting toxicity was granulo-cytopenia. Other toxicities were mild: emesis, alopecia, skin rashes, and photosensitivity reactions. IP TG did not produce chemical peritonitis, hepatotoxicity, or mucositis. The pharmacokinetics of IP TG were determined in 16 patients. TG levels were measured by reverse-phase high-performance liquid chromatography (HPLC). At steady state, the mean peritoneal to plasma TG ratio was 1,800 at the maximum tolerated dose (MTD). Steady-state TG levels in the peritoneal cavity and plasma were 2 mmol/L and 1.1 mumol/L, respectively, at a dose of 744 mg/m2. The elimination half-life of TG from the peritoneal cavity was one hour. TG exhibited linear pharmacokinetics over the dosage range investigated. Encouraging clinical activity was seen with IP TG. There was one partial response (PR) and four minor responses (MR). TG can be safely administered by the IP route. The recommended dose for phase II testing is 744 mg/m2/48 h. IP TG has a favorable pharmacokinetic advantage and has demonstrated encouraging clinical activity. Further studies of IP TG infusions are warranted.