Forced diuresis to reduce nephrotoxicity of streptozotocin in the treatment of advanced metastatic insulinoma.

Abstract

Forced diuresis to reduce nephrotoxicity of streptozotocin in the treatment of advanced metastatic insulinoma Streptozotocin is a specific , cell toxin that was first used to treat malignant islet cell tumours in 1%8.' Enthusiasm for its use, however, has been tempered by the high risk of nephrotoxicity, which occurs in up to 100% of patients.2 We report on the successful management of a patient with a malignant insulinoma who sustained renal impairment when treated with streptozotocin alone but tolerated repeated administration of the drug without deterioration in renal function when a hydration technique was used to administer the drug. Case reportA 65 year old woman presented with a two year history of episodic abdominal pain, anorexia, and weight loss of about 19 kg. A gall bladder calculus was visualised on abdominal ultrasound, and a secretin-pancreozymin test showed impaired bicarbonate secretion. At laparotomy there was a large, unresectable tumour of the body of the pancreas fixed to retroperitoneal structures with multiple hepatic, omental, and mesenteric metastases. Despite this she remained well for 18 months but then developed Whipple's triad of hypoglycaemic symptoms after fasting and exercise, relieved by glucose. She had inappropriately high insulin concentrations with a mean insulin to glucose ratio of9-2, consistent with an insulin secreting tumour.Streptozotocin 500 mg/m2 (700 mg) was infused on three occasions on alternate days. Her symptoms responded, but her renal function steadily deteriorated with a creatinine clearance of only 30 ml/min (figure) and mild proteinuria (250 mg/24 h); further treatment was therefore suspended. Her symptoms recurred one year later, at which stage her renal function had recovered. Based on our experience with another nephrotoxic drug, cisplatin,3 we tried administering streptozotocin accompanied by hydration and diuresis to minimise the renal damage.We restarted streptozotocin at the same dose, but on each occasion the patient was prehydrated intravenously with two litres of normal saline hourly for two hours, and frusemide 40 mg was also given intravenously 30 minutes after the infusion was started. When a good diuresis was established streptozotocin was then given by a second infusion over 60 minutes and the saline infusion was titrated to maintain a total urine output of four to five litres throughout the procedure, which lasted roughly four hours. To date this method has been successfully used for eight treatment schedules, and her renal function has remained stable with a creatinine clearance of about 60 ml/min and normal findings on urine analysis (figure). CommentNinety percent of patients with malignant islet cell tumours have hepatic metastases at the time of diagnosis, so surgical treatment is usually fl~~~t ,, Creatinine clearance in relation to treatment with streptozotocin (500 mg/in2). Broken arrows represent administration using hydration technique.impracticable. Maintaining a high calorie intake or using diazoxide or long acting somatostatin an...

Streptozocin for treatment of pancreatic islet cell tumors in dogs: 17 cases (1989–1999)

“…In preclinical canine studies, 9 renal toxicoses were ameliorated by giving the drug as a 6-hour infusion rather than as a bolus, and in human patients that became azotemic after a single dose of streptozocin, concurrent diuresis with 0.9% NaCl allowed continued use of streptozocin without further deterioration of renal function. 18 In the present study, renal toxicosis developed after streptozocin treatment in only 1 dog. This dog had urinary granular casts prior to receiving streptozocin and, in retrospect, was not a good candidate for treatment.…”

“…Induction of diuresis through administration of 0.9% NaCl has been reported to ameliorate the renal toxic effects of streptozocin in human patients. 18 The mechanism of this protective effect has not been identified but may be attributable to protection of renal tubular macromolecules from the alkylating effects of streptozocin by reduced contact time between the drug and the renal tubular epithelium. 19 We have developed a similar diuresis protocol for administration of streptozocin to dogs.…”

Beta-Cell Neoplasia: Insulinoma

“…Fluid diuresis has been reported to ameliorate the renal toxicity of streptozotocin in humans, presumably as a result of less contact time between the drug and the renal tubular epithelium (Tobin et al, 1987;Kintzel, 2001). Fluid diuresis has been reported to ameliorate the renal toxicity of streptozotocin in humans, presumably as a result of less contact time between the drug and the renal tubular epithelium (Tobin et al, 1987;Kintzel, 2001).…”

A case of insulinoma effectively treated with low‐dose diazoxide

“…Streptozotocin is no longer used in the management of benign insulinoma due to it's nephrotoxicity and toxic effects on beta cells of the pancreas. 10 Everolimus is also used as an antitumor agent, but susceptibility to infection is easily caused by immunosuppression. 11 Due to the patient's steroid prescription, everolimus was considered suboptimal.…”

“…These medical options may include streptozotocin, everolimus, octreotide, and diazoxide, as described above. Streptozotocin is no longer used in the management of benign insulinoma due to it's nephrotoxicity and toxic effects on beta cells of the pancreas 10 . Everolimus is also used as an antitumor agent, but susceptibility to infection is easily caused by immunosuppression 11 .…”