Manlio Mencoboni

Regional pharmacokinetic selectivity of intrapleural cisplatin

The pharmacokinetics and toxicity of cisplatin were investigated in 3 patients affected by malignant mesothelioma who received 90 mg/m2 of the drug intrapleurally. The mean area under the pleural Pt concentration versus time curve (AUC) [12.83 (S.D. 4.06) mg.min/ml] was about 50 times greater than that detected in plasma [0.27 (0.03) mg.min/ml], indicating a clear pharmacological advantage for this route of administration. The mean plasma total Pt concentration was 1.1 micrograms/ml and the apparent total body clearance was 268 (101) ml/min. Platinum plasma pharmacokinetic data measured following intrapleural cisplatin administration (4 patients) were compared with those observed in 7 patients treated intravenously with the same dose of cisplatin (90 mg/m2) under the same modalities of hydration. Intrapleural administration of cisplatin resulted in significantly lower plasma total partial AUC (P less than 0.05) and prolonged plasma levels of filterable Pt compared with intravenous administration. No difference between the two routes of cisplatin administration in the renal clearance (S.D.) of filterable Pt [132 (64) ml/min and 122 (39) ml/min for intravenous and intrapleural cisplatin, respectively] were observed. None of the mesothelioma patients developed clinical symptoms or signs of pleural inflammation. The intrapleural treatment did not produce haemotoxicity and the emetic toxicity was lower compared with that observed in patients receiving cisplatin intravenously.

Dexamethazone-induced acute tumor lysis syndrome in a T-cell malignant lymphoma.

We report a case of steroid-induced acute tumor lysis syndrome and review the literature. A 60-year-old woman was started on steroid therapy for dyspnea due to bilateral pleural effusion and a large mass involving the anterior mediastinum. The final diagnosis was precursor T-lymphoblastic lymphoma-leukemia. Following steroid therapy, the patient developed acute renal failure and laboratory evidence of metabolic changes induced by massive cytolysis. She received vigorous hydration, diuretic and allopurinol therapy, and haemodialysis. Her diuresis, renal function and laboratory data returned to normal within 2 weeks. A review of the medical literature on T-cell lymphoma revealed only one similar case of steroid-induced acute tumor lysis syndrome, a life-threatening metabolic emergency. This risk should be kept into account in the management of patients with lymphoproliferative disorders.

Production of tumor necrosis factor and granulocyte colony stimulating factor by bone marrow accessory cells in myelodysplastic patients

Abstract:  This paper reports on the production of tumor necrosis factor (TNF) and granulocyte macrophage colony‐stimulating factor (GM‐CSF) by cultured mononuclear adherent cells derived from bone marrow of 25 patients affected by myelodysplastic syndrome (MDS) of different FAB subtypes. Mean production of GM‐CSF was much lower than in controls, without significant differences among different subtypes. Mean production of TNF was similar in MDS patients and in controls, but noteworthy differences were observed between patients with RA, RAEB and RAEB‐t and patients with RARS and CMML. Growth of bone marrow granulocyte macrophage and erythroid progenitors did not correlate with TNF and GM‐CSF production, although in MDS subtypes with higher GM‐CSF levels, colony growth was slightly higher than in subtypes with lower GM‐CSF production.

Studies on Hemotoxicity of Cyclophosphamide, Doxorubicin and Cis-Diamminodichloroplatinum Combined with Sodium-2-Mercaptoethane Sulfonate

The possible protective action of sodium-2-mercaptoethanesulfonate (mesna) on hemotoxicity induced by anticancer drugs was tested in normal mice. Mesna (100 mg/kg b.w.) was injected i.v. 1 h before the i.v. administration of cyclophosphamide (10, 120, and 200 mg/kg b.w.), doxorubicin (4.32, 7.2, and 12 mg/kg b.w.) and cis-diamminedichloroplatinum (5.4, 9, and 15 mg/kg b.w.). Results show that in this experimental model mesna does not seem to protect against toxicity of the tested anticancer drug on hemopoietic progenitor cells.

Protective effect on cisplatin hematotoxicity by procaine hydrochloride

The ability of procaine hydrochloride (P.HCl) to modulate the effects of cisplatin (DDP) on pluripotent (CFU-S) and committed (CFU-GM) murine hemopoietic stem cells was investigated. DBA/2NCrlBRF1 mice received DDP alone (10 and 16 mg/kg body wt. single i.p. injection) or in combination with P.HCl (40 mg/kg body wt. single i.p. injection). Hemopoietic progenitor cell (HPC) time survival curves were determined up to 14 days following treatment. The simultaneous administration of the lower DDP dose together with P.HCl greatly reduced the hemotoxicity of the antitumoral drug, while this protection was not significant with the higher DDP dose. These results support a role for P.HCl in protecting against DDP hematological toxicity.

Cisplatin-based first-line treatment of elderly patients with advanced non-small-cell lung cancer: Joint analysis of MILES-3 and MILES-4 phase III trials

Purpose To test the efficacy of adding cisplatin to first-line treatment for elderly patients with advanced non-small-cell lung cancer (NSCLC) within a combined analysis of two parallel phase III trials, MILES-3 and MILES-4. Patients and Methods Patients with advanced NSCLC who were older than age 70 years with Eastern Cooperative Oncology Group performance status 0 to 1 were randomly assigned to gemcitabine or pemetrexed, without or with cisplatin. In each trial, 382 events were required to detect a hazard ratio (HR) of death of 0.75, with 80% power and two-tailed α of .05. Trials were closed prematurely because of slow accrual, but the joint database allowed us to analyze the efficacy of cisplatin on the basis of intention-to-treat and adjusted by trial, histotype, non-platinum companion drug, stage, performance status, sex, age, and size of the study center. Results From March 2011 to August 2016, 531 patients (MILES-3, 299; MILES-4, 232) were assigned to gemcitabine or pemetrexed without (n = 268) or with cisplatin (n = 263). Median age was 75 years, 79% were male, and 70% had nonsquamous histology. At a median 2-year follow-up, 384 deaths and 448 progression-free survival events were recorded. Overall survival was not significantly prolonged with cisplatin (HR, 0.86; 95% CI, 0.70 to 1.05; P = .14) and global health status score of quality of life was not improved, whereas progression-free survival (HR, 0.76; 95% CI, 0.63 to 0.92; P = .005) and objective response rate (15.5% v 8.5%; P = .02) were significantly better. Significantly more severe hematologic toxicity, fatigue, and anorexia were found with cisplatin. Conclusion The addition of cisplatin to single-agent chemotherapy does not significantly prolong overall survival, and it does not improve global health status score of quality of life in elderly patients with advanced NSCLC.

Cisplatin inhibits erythroid committed progenitor (BFU‐E) mobilization in peripheral blood

Abstract: Circulating myeloid (CFU–GM) and erythroid (BFU–E) progenitor levels were evaluated weekly throughout 3 courses of treatment with vinorelbine (VNB) ifosfamide (IFO) and filgrastim (G‐CSF) with or without addition of cisplatin (DDP) in 20 stage IIIB or IV non small‐cell lung cancer patients. In IFO, VNB, DDP‐treated patients, BFU‐E mobilization in peripheral blood following chemotherapy and G‐CSF was completely lacking, in contrast with the patients treated with IFO, VNB plus G–CSF. CFU–GM release, however, was of the same order in the 2 groups of patients. Further investigations are needed to explain why presence of DDP in this chemotherapeutic protocol hinders erythroid progenitor release in peripheral blood.

Pharmacokinetic Evaluation of Intrapleural Carboplatin in Patients with Malignant Pleural Effusion

SummaryCarboplatin 360 mg/m2 was administered intrapleurally to 4 patients with malignant pleural effusion. Simultaneous pleural fluid and plasma samples were collected at various times after treatment to measure the total and filterable levels of platinum. The pleural area under the concentration versus time curve (AUC) for filterable platinum was 26- to 98-fold greater than the corresponding plasma AUC, plasma levels remaining in the range of 3 to 18 μmol/L. The concentrations of platinum in plasma were compared with those observed in 7 additional patients receiving the same dose of carboplatin intravenously. The comparative intrapleural and intravenous therapy led to peak concentrations of platinum 6 to 7 times lower after intrapleural than after intravenous treatment, in significantly lower partial AUCs, and in prolonged levels of filterable platinum following intrapleural treatment. No significant difference, either for total or for filterable platinum, was noted comparing the overall plasma exposure. Systemic clearance and mean residence time values for filterable platinum in plasma were about 1.8 times lower and 2 times higher, respectively, after intrapleural treatment than after intravenous administration. Both the cumulative urinary excretion and renal clearance, as well as the apparent volume of distribution at steady-state for filterable platinum, were comparable with the values obtained after intravenous carboplatin. The observed differences in plasma pharmacokinetics between the 2 routes of administration mainly reflect the delayed absorption of carboplatin into the systemic circulation after intrapleural treatment. The locoregional treatment was well tolerated by all patients, and no symptoms of thoracic discomfort or acute toxicity were noted.

Diltiatem does not increase the in vivo sensitivity of murine hemopoietic progenitor cells to doxorubicin

The effect of doxorubicin and the calcium antagonist, diltiazem, on murine hemopoietic progenitor cells was studied in vivo. Dose-survival curves of murine bone marrow colony forming units (CFU)--spleen and granulocyte macrophage--were determined by in vivo and in vitro methods in DBA/2NCr/BR mice treated with doxorubicin alone or by simultaneous administration of doxorubicin (DX) and diltiazem (DTZ). Time response of bone marrow hematopoietic progenitor cells (HPC) was followed in mice similarly treated. Combination of DTZ with DX did not change the toxic effect of the latter on hemopoietic cells, either in the dose-survival model or in the time-related experiment.