Maurie Markman

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.

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.

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.

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.

Mediastinal Fibrosis Simulating Residual Hodgkin’s Disease

A 28-year-old male with nodular sclerosing Hodgkins disease and massive mediastinal adenopathy was treated with combination chemotherapy and radiotherapy. Following 1,300 rads and six cycles of chemotherapy the patient was felt, on the basis of chest x-ray and CT scan, to have extensive residual mediastinal and intrapericardial involvement with tumor. At thoracotomy he was found to have markedly enlarged mediastinal lymph nodes with the normal tissue being replaced by dense sclerotic material without tumor. In Hodgkins disease, CT scanning has proved to be an extremely valuable tool in assisting in staging and treatment planning. This case emphasizes, however, that one must be cautious in the interpretation of persistent abnormalities following curative therapy. Carefully selected patient information obtained from exploratory thoracotomy continues to be helpful in defining disease status.

Intraperitoneal chemotherapy: Principles and results of clinical trials

While the intraperitoneal administration of chemotherapeutic agents for their cytotoxic rather than sclerosing properties is not a new idea [1,2], recent modelling studies, suggesting a pharmacokinetic rationale for this method of drug delivery to tumors principally confined to the peritoneal cavity, has renewed interest in this idea [3]. In this review the basic principles of intraperitoneal chemotherapy will be presented along with a discussion of the theoretical and practical problems associated with the technique. Finally, a summary of recent single agent and combination intraperitoneal chemotherapy trials will be presented as well as a brief discussion of other innovative approaches utilizing the intraperitoneal route.

NO INCREASE IN ALLERGIC REACTIONS WITH INTRACAVITARY ADMINISTRATION OF CISPLATIN

tablet per day. 11 of the 122 women (9%) had an NAPAP-positive urine test-ie, they had taken at least one tablet containing phenacetin or paracetamol in the 12 h before the test. 3 of the 11 NAPAP-positive women denied having taken any analgesic medication, and 6 reported taking only analgesics which contained neither phenacetin nor paracetamol (see figure). Thus only 2 women with positive tests reported taking such analgesics. Comparison of the stated phenacetin or paracetamol intake and NAPAP concentration in urine showed a significant negative correlation (Spearman rank correlation coefficient, r= -0.77, p 0-0001). In other words, the higher the NAPAP concentration in urine, the lower the reported drug intake. These findings suggest that analgesic users tend either to deny drug intake or to give incorrect information about the kind and extent of their analgesic intake.

Human histocompatibility antigens and survival in acute myelocytic leukemia

Several previous reports have suggested an association between human histocompatibility antigens (HLA) and survival in acute myelocytic leukemia (AML). The authors have retrospectively analyzed the records of 104 consecutive newly diagnosed patients with AML treated on the Leukemia Service of the Johns Hopkins Oncology Center from March 1978 through May 1982 who had HLA typing performed to further evaluate this point. The authors have been unable to demonstrate a statistically significant association of HLA phenotype with the ability to achieve a complete response (CR), length of CR, survival of the total group of treated patients, or survival of only those patients achieving a CR (P < 0.05). The available evidence does not strongly support a significant influence of HLA on survival in AML.