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Objective: This study reports a six year experience with quinagolide (CV205-502) in the treatment of 40 patients with hyperprolactinemia or prolactinoma., Patients and Measurements: Forty patients with hyperprolactinemia were treated with quinagolide (CV 205-502, Norprolac) for 2-72 months (mean 31.6 months). The patient's ages ranged from 12 to 53 years and 90% were female. Seventeen had no radiologic evidence of tumor; 11 had microadenomas; and 12 had macroadenomas., Results: All patients had a reduction of the serum prolactin following quinagolide therapy with normalization in 82% with no tumor, 73% with microadenomas, and 67% with macroadenomas. Fifty-five percent of microadenoma and 75% of macroadenoma patients had a decrease in tumor size when assessed by a blinded reviewer. Ten of 38 female patients became pregnant while taking quinagolide. The dosage of quinagolide ranged from 75 to 400 [mgr]g/day with a median dose of 100[mgr]g/day. A comparison of side effects in a subgroup of 35 patients who had taken bromocriptine prior to quinagolide administration showed a greater than 75% reduction in nausea, vomiting, dizziness, and drowsiness during quinagolide administration., Conclusions: We conclude that quinagolide is a safe and effective long-term alternative to bromocriptine therapy, particularly in those individuals with bromocriptine intolerance.

Pentamethylmelamine (PMM) 80 mg/m2 was administered I.V. to 8 patients during surgical resection of intracerebral tumors. PMM concentrations in tumors were generally much higher than concurrent plasma concentrations, ranging from undetectable (less than .01 micrograms/g) to as high as 4.47 micrograms/g and were much higher in malignant melanoma samples than in astrocytoma samples. PMM was barely detectable or undetectable in most samples of edematous brain tissue adjacent to intracerebral tumor and in temporalis muscle. The PMM metabolites tetramethylmelamine (TeMM), trimethylmelamine (TrMM), and dimethylmelamine (DMM) were each detectable in tumor samples from one or two patients. Monomethylmelamine (MMM) was present in tumor samples from all except one patient. MMM was noted in samples of edematous brain tissue adjacent to tumor from 4 of 8 patients. It was the only PMM metabolite found in brain. TrMM, DMM, and MMM but not PMM, and TeMM were found in tumor cyst fluid from a patient with an intracerebral malignant melanoma. Two patients receiving therapeutic doses of PMM had biopsies taken of subcutaneous malignant melanoma deposits. PMM was undetectable in samples from one patient but reached high concentrations in the other patient. In both patients, MMM was the major metabolite. There was no indication that PMM penetrated into extracerebral tumors more readily than into intracerebral tumors Cerebrospinal fluid (CSF) samples were obtained from one patient without neurological toxicity who received low doses of PMM and from 4 patients receiving high doses of PMM who had developed neurological toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Methylglyoxal bis(guanylhydrazone) (MGBG; NSC 32946) is currently being reevaluated for its clinical antineoplastic activity against both hematological and solid tumors. MGBG (100 to 200 mg/sq m) was administered by slow infusion over 3 hr to six patients during surgical resection of intracerebral tumors. Excised tumor tissue and plasma were assayed for MGBG by high-pressure liquid chromatography. In all cases, MGBG penetrated rapidly into brain tumor tissue. Viable tumor tissue contained greater concentrations of MBGB than did necrotic tumor tissue. In two patients with glioblastoma multiforme, MBGB concentrations in brain tumor tissue were five- to 19-fold higher than concurrent plasma samples. However, MGBG did not penetrate well into the cerebrospinal fluid of two patients with Ommaya reservoirs given i.v. MGBG (200 mg/sq m). The highest MGBG concentration in cerebrospinal fluid reached only 22% of the concurrent plasma levels. These studies suggest that MGBG may be a useful agent in the treatment of intracerebral tumors but may not be effective against meningeal leukemia and meningeal carcinomatosis.

A phase I study of intracarotid cis-diamminedichloroplatinum was performed in 11 patients with intracerebral tumors (five glioblastoma, four melanoma, one meningeal sarcoma, and one lung carcinoma) progressing after radiation +/- chemotherapy. The internal carotid artery was temporarily cannulated by a percutaneous transfemoral approach. All patients received i.v. heparin, mannitol, and fluids; seven received dexamethasone, 50 mg i.v., twice the day before and the day of treatment. Intracarotid cis-diamminedichloroplatinum, 60 to 100 mg/sq m in 175 to 250 ml 0.45% NaCl solution with 1000 units heparin, was infused over 1 hr. Six patients received two or more courses (maximum of 6) at 2- to 8-week intervals. Gastrointestinal toxicity was mild to moderate. Ototoxicity was minor. Central nervous system (CNS) toxicity was focal, severe, permanent, and possibly due to embolus in one patient at 75 mg/sq m; focal and reversible in one patient at 100 mg/sq m; and generalized but reversible in one patient at 75 mg/sq m. Possible CNS toxicity was noted in two additional patients. Two patients with CNS toxicity developed permanent ipsilateral retinal toxicity, and one patients without CNS toxicity developed bilateral decreased visual and auditory acuity 2 weeks after his sixth treatment. Renal and hematological toxicity and orbital pain were mild. Response status included: early death, one; probable responses, six (2+ 4+, 6, 6+, 8, and 8+ months); stabilization, two (3+ and 4 months); and failure, two. We recommend cis-diamminedichloroplatinum (60 mg/sq m) every 2 to 4 weeks for Phase II studies. Severe CNS and retinal toxicity are possible.

Because Cisplatin potentiates the effect of radiotherapy in animal tumor systems and because Cisplatin is capable of causing regressions of human malignant melanomas, a study was initiated in patients with malignant melanoma metastatic to brain to investigate the feasibility of administering Cisplatin once a week during cranial irradiation. Cisplatin 40 mg/m2/week (three doses) was given I.V. to 18 patients during whole brain irradiation, 3 000 rads in 12 fractions over 21/2 weeks. Eleven patients also received Cisplatin 120 mg/m2 every three weeks, starting three weeks after cranial irradiation. Median survival was ten weeks, and only one of 13 patients whose brain metastases had not been resected experienced neurological and CT scan improvement. Thirteen patients have died, and brain metastases were a major cause. No regression of extracerebral tumor was seen in 15 patients with evaluable extracerebral lesions. During weekly low-dose Cisplatin administration, nausea and vomiting were moderate to severe. No granulocytopenia was noted, although three courses were associated with mild thrombocytopenia. Mucositis, peri orbital swelling, vertigo, and headache were each noted in two of 51 courses of treatment and seizures, ototoxicity, pancreatitis, and hiccups were each noted in one course. Renal toxicity and ototoxicity each developed in three of the 11 patients receiving Cisplatin 120 mg/m2, and nausea and vomiting were severe.

Eighty-seven adult patients who had achieved bone marrow remission of leukemia developed one or more episodes of meningeal leukemia. Multiple patient characteristics were examined for their effect on probability of achieving complete remission from meningeal disease and for their effect on duration of meningeal remission. Presence of obtundation (P less than 0.01) or other symptoms of meningeal disease (P = 0.02) were associated with a low remission induction rate. Other factors which tended (P = 0.06-0.20) to be associated with low remission induction rates included high cerebrospinal fluid (CSF) opening pressure, absence of splenomegaly at initial diagnosis, high peripheral blood leukocyte count (WBC) at the episode of marrow disease most recently preceding the meningeal disease, and use of only one as opposed to two or more intrathecal drugs as treatment. Factors associated with long duration of meningeal remissions included diagnosis (AML greater than acute undifferentiated leukemia greater than ALL, P = 0.05), absence of symptoms (P = 0.04), low CSF WBC (P = 0.01), rapid attainment of meningeal remission (P = 0.01), rapid attainment of initial bone marrow remission (P = 0.02), and long duration of initial bone marrow remission (P less than 0.01). Absence of cranial or peripheral neuropathies, low CSF protein and opening pressure, and short time interval between diagnosis of marrow and meningeal disease also tended (P = 0.06-0.20) to be associated with long meningeal remissions. Patients treated according to an intensive protocol utilizing cranial irradiation and triple drug treatment via an Ommaya reservoir had substantially longer meningeal remissions than did patients treated with less intensive therapy (P = 0.01). Relapse-free survival curves suggest that some patients are cured of their meningeal disease.

The antitumor agent 3-deazauridine (DAU) was administered rapidly to four patients before surgical removal of intracerebral tumor. Tumor, adjacent brain tissue, and temporalis muscle were assayed for DAU by high-pressure liquid chromatography. DAU penetrated comparably into tumor, brain, and muscle; in one patient, tissue concentrations were higher than concurrent plasma concentrations. The active metabolite 3-deazauridine 5'-triphosphate was quantitated in one tumor sample and greatly exceeded its Ki for cytidine 5'-triphosphate synthetase. DAU was also present in autopsy brain specimens from two patients treated shortly antemortem. Cerebrospinal fluid concentrations were 22.1 and 59.0%, respectively, of concurrent plasma concentrations during continuous infusion of DAU in two patients. Cerebrospinal fluid concentration was 3.1 microgram/ml 2 hr after a 30-min infusion of 1.5 g of drug per sq m and fell to 1.9 microgram/ml at 16 hr. Thus, DAU is capable of penetrating into intracerebral tumor, brain, and cerebrospinal fluid and is worthy of investigation in the treatment of intracerebral and meningeal neoplasms.

Generally tritiated homoharringtonine ([3H]HHT, 150 microCi, 430 micrograms) was administered intravenously to seven patients at varying times before surgical resection of malignant brain tumor. Plasma, urine, cerebrospinal fluid (CSF), and tumor specimens were obtained during surgery, and the concentrations of HHT, its major metabolite, and [3H]HHT equivalent were determined chromatographically and radiochemically. For [3H]HHT equivalent, the concentration in tumor ranged from 0.6 to 4.3 ng/g and the ratio of tumor to plasma concentration from 0.5 to 1.8. In one patient who had CSF available for drug determination, the CSF to plasma ratio of total [3H]HHT was 0.3 at 45 minutes after drug administration and less than 0.2 ng/ml was unchanged HHT. For unchanged HHT, drug concentration in tumor ranged from undetectable (4 patients) to 1.8 ng/g. A major metabolite of HHT was detectable in the tumor specimens of all the patients. These results indicate that homoharringtonine can penetrate into brain tumors; in 3 patients with brain tumors, the ratios of HHT concentration in the tumor to that in the concurrent plasma were greater than one.

Radiolabelled Baker's Antifolate (BAF) was administered to 6 patients undergoing surgical resection of intracerebral tumors. Levels of radioactivity in resected tumor and edematous brain adjacent to tumor were generally higher than levels in concurrent plasma samples and were generally comparable to levels in temporalis muscle. Levels in tumor cyst fluid were far lower than concurrent plasma levels and levels in surrounding tumor. Chromatography was performed on tumor from 2 patients and revealed that only a small proportion of the radioactivity represented unchanged BAF. The major metabolite present in tissues was 1 000 times less potent as an inhibitor of dihydrofolate reductase than was BAF. Five patients had cerebrospinal fluid (CSF) sampled following administration of tracer doses of radiolabelled BAF. Radioactivity levels were far lower in CSF than in plasma. Levels of radioactivity in the CSF were also far lower than levels in tumor and brain samples from other patients and were slightly lower than tumor cyst fluid levels. Two patients had CSF collected after they received therapeutic doses of BAF. In these patients, both CSF and plasma were assayed using a dihydrofolate reductase inhibition assay. As with tracer dose studies, CSF concentrations of BAF were substantially lower than were concurrent plasma concentrations. Thus it appears that only very low concentrations of BAF are attainable in human CSF and intracerebral tumor, although a metabolite which is a very weak inhibitor of dihydrofolate reductase attains high concentrations in tumor.

A pilot study was performed combining cis-diamminedichloroplatinum (CDDP) and radiation therapy to treat patients with high-grade astrocytomas. CDDP at a dose of 40 mg/m2/week intravenously was given during the course of cranial irradiation. Following irradiation, CDDP was given every three weeks on a schedule of 35-40 mg/m2/day for three days until toxicity became unacceptable or until tumor progression occurred. Radiation therapy consisted of 6 000 rads over a seven week period or 5 000 rads followed by an additional 1 500 rads to the tumor site. Patients were followed by computerized axial tomography (CT) scan and neurologic examination. Thirty patients were entered onto the study; 22 were considered evaluable. The median survival was 53 weeks and the median time to progression was 21 weeks. Toxicity was generally tolerable; however, ototoxicity may be enhanced by this treatment. CDDP combined with cranial irradiation is tolerable and feasible, although close follow-up is recommended in case CDDP has to be temporarily interrupted.

Cerebrospinal fluid (CSF) was obtained from five patients by lumbar puncture and from two patients by Ommaya reservoir tap after the i.v. administration of the antitumor agent N-(phosphonacetyl)-L-aspartate (PALA). PALA was quantified enzymatically by inhibition of the target enzyme, aspartate carbamoyltransferase. After a 1-hr infusion of PALA, its CSF concentration steadily rose until the eighth hr, at which time it was 12 to 40% of concurrent plasma concentration. PALA concentration then declined more gradually in CSF than in plasma, and CSF concentrations exceeded plasma concentrations by 24 hr. PALA concentration X time product in CSF was 12 to 25% of that in plasma. PALA was infused i.v. for 30 to 60 min into eight patients undergoing surgical resection if intracerebral tumors. Its concentration in intracerebral tumor was greater than or comparable to concentration in temporalis muscle in four of six patients from whom muscle was obtained. The PALA concentration in edematous brain tissue was consistently lower than the concentration in tumor or muscle. In a patient undergoing occipital lobectomy, the PALA concentration in brain was inversely proportional to the distance from the tumor. PALA reached concentrations in intracerebral tumor that appeared to be similar to concentrations reported previously in s.c. tumors, although biopsy techniques and conditions differed.