Vital Montpetit

Association of cisplatin nephrotoxicity with patient characteristics and cisplatin administration methods

Objective: To assess factors that affect cisplatin nephrotoxicity. Methods: In 425 patients treated with cisplatin, we assessed the effect of pretreatment factors and treatment conditions on the rise in serum creatinine with the first course of cisplatin, on the maximum rise in serum creatinine over the entire course of the cisplatin therapy, and on residual nephrotoxicity after the last cisplatin treatment ended. (Because of the nature of the relationship between serum creatinine and creatinine clearance, rise in serum creatinine was divided by pretreatment creatinine squared.) Patients were dichotomized into the upper quartile versus the lower three quartiles of degree of nephrotoxicity. Multivariate analyses were based on logistic regression, controlling for cisplatin dose per course. Results: Controlling for cisplatin dose per course, factors most closely associated with nephrotoxicity during the first course of cisplatin were: serum albumin and potassium, body surface area, and administration of cisplatin over 2–5 days per course vs 1 day (negative associations). Controlling for cisplatin dose per course, the single factor most closely associated with maximum life-time cisplatin nephrotoxicity was concurrent use of a vinca alkaloid (negative association). Controlling for cisplatin dose per course, factors most closely associated with residual nephrotoxicity after the end of cisplatin therapy were cumulative dose of cisplatin, concurrent use of metoclopramide (positive associations), uric acid and concurrent use of phenytoin and a vinca alkaloid (negative associations). The association of nephrotoxicity with uric acid and with body surface area was felt to be an artifact resulting from its positive association with pretreatment serum creatinine. Nephrotoxicity during the first course of cisplatin also correlated significantly with autopsy kidney cortex platinum concentrations in 77 evaluable patients. Conclusions: (1) While several factors correlated with cisplatin nephrotoxicity, most of the observed nephrotoxicity was not explained by the variables identified. (2) While most patients received intravenous hydration, patients receiving high hydration volumes did not have significantly less nephrotoxicity than patients receiving lower hydration volumes. (3) Of the variables identified, serum albumin, metoclopramide and phenytoin may have affected nephrotoxicity by altering cisplatin uptake into or distribution within the kidney.

Platinum concentrations in human autopsy tumor samples

Platinum concentrations were determined in autopsy tumor samples obtained from 27 patients who had received cisplatin 40–1,029 mg/m2 from 0 to 240 days antemortem. Liver metastases had significantly higher platinum concentrations than did tumors in other sites (p < 0.005). Platinum concentrations in liver metastases were similar to platinum concentrations in normal liver. Platinum concentrations in gliomas and brain metastases were similar to platinum concentrations in other extrahepatic tumors. Platinum concentration generally decreased with increasing distance into brain from tumor. By multiple stepwise linear regression analysis, the factors that were independently most closely associated with tumor platinum concentration were time from last cisplatin treatment, cumulative lifetime dose of cisplatin, route of cisplatin administration (intraarterial vs. other), and site of tumor deposit (liver vs. other) (r = 0.69, p < 0.001). Patients whose tumors had responded to cisplatin-containing regimens had mean tumor platinum concentrations that were higher than the mean tumor platinum concentrations in patients whose tumors had not responded to cisplatin (p < 0.05).

Penetration of VP-16 (etoposide) into human intracerebral and extracerebral tumors

SummaryVP-16 100 mg/m2 was given intravenously to 10 patients undergoing surgical resection of intracerebral tumors, and the drug was assayed in resected tumor using high pressure liquid chromatography. VP-16 concentrations varied from undetectable (<.1 µg/g) to 5.9 µg/g (mean, 1.4 µg/g). VP-16 concentrations in tumors were lower than concurrent plasma concentrations. In addition, intracerebral tumors had a lower concentration of VP-16 than did extracerebral tumors (mean VP-16 concentration, 3.9 µg/g) from 7 patients receiving VP-16 50–100 mg/m2 intravenously. Plasma pharmacokinetics of VP-16 were different in our patients with intracerebral tumors than in previously studied patients with extracerebral tumors and it is unclear what role this may have played invariability of tumor VP-16 concentrations. VP-16 concentrations were similar in glioblastomas and brain metastases. Specimens from patients with small cell undifferentiated carcinoma of the lung had the highest VP-16 concentrations. A patient who had both viable and necrotic tumor resected during an occipital lobectomy had a higher drug concentration in the necrotic than in the viable area of tumor. In addition, VP-16 concentration decreased as a function of distance into brain from the tumor. Based on our data, VP-16 might be expected to have less activity against intracerebral than against extracerebral human tumors.

Epithelioid hemangioma of the orbit.

OBJECTIVE To describe the histopathologic features of two cases of epithelioid hemangioma occurring in the orbit and to distinguish this condition from Kimuras disease and from other vascular lesions of proliferated endothelium. DESIGN Two interventional case reports. INTERVENTION Treatment consisted of orbitotomy with excision of the tumor. MAIN OUTCOME MEASURES Histopathologic examination including light microscopy, immunohistochemistry, and electron microscopy and clinical follow-up. RESULTS In one case, there was no local recurrence after 2 years of follow-up. In the other case, local recurrence required re-excision 2 years after surgery with no apparent recurrence 16 years later. Histopathologic examination of both tumors disclosed an epithelioid hemangioma. A characteristic finding was the presence of peculiar plump vacuolated endothelial cells lining the vascular lumina. CONCLUSIONS Epithelioid hemangioma is an uncommon benign vascular tumor that can occur in the orbit, and surgical excision is usually required. It is the same condition as angiolymphoid hyperplasia with eosinophilia. There are distinct clinical and histopathologic characteristics to distinguish epithelioid hemangioma from Kimuras disease and from other vascular tumors.

Human central nervous system and plasma pharmacology of mitoxantrone

Mitoxantrone 5–6 mg/m2 was administered IV to 10 consenting patients prior to surgical resection of an intracerebral tumor. Plasma pharmacokinetic parameters were calculated and concentration of mitoxantrone in intracerebral tumors was determined. Concentrations of mitoxantrone were also determined in autopsy tissues of one of the patients who expired 192 days after receiving the drug. The plasma pharmacokinetics were best described by a 3 compartment model, with a t1/2γ of 4.74±5.53 h. Mitoxantrone concentrations in the intracerebral tumors were potentially cytotoxic and ranged from 4 to 322 ng/g. In all but one case, mitoxantrone concentration was higher in tumor than in concurrent plasma samples. There was no obvious relation between tumor mitoxantrone concentration and peak plasma mitoxantrone concentration or time from mitoxantrone administration to tumor removal. Low grade gliomas and viable tumors tended to have lower mitoxantrone concentrations than did other tumor types and necrotic tumors. In the patient undergoing autopsy, highest mitoxantrone concentrations were found in liver, thyroid and heart.

Cisplatin and radiation in the treatment of tumors of the central nervous system: pharmacological considerations and results of early studies

PURPOSE To review the human central nervous system pharmacology of cisplatin, factors that affect cisplatin uptake in tumors, and use alone and with radiation for the treatment of primary brain tumors. METHODS AND MATERIALS The authors review their own prior published and unpublished experience and data published by other groups on the above issues. RESULTS Cisplatin is one of the most active chemotherapy drugs available for the treatment of solid tumors. It is synergistic with several other agents, including radiation. While it attains only low concentrations in the normal central nervous system, concentrations and plasma-tissue transfer constants for human intracerebral tumors are comparable to those in extracerebral tumors. Tumor type appears to be a more important determinant of platinum concentration than is tumor location, and gliomas do achieve lower concentrations than do other intracerebral or extracerebral tumors. Several other factors have also been identified that correlate with concentrations of cisplatin achieved in human tumors. While cisplatin alone and in combination with other drugs does have some degree of efficacy against primary brain tumors, combining it with cranial irradiation has generally not resulted in any substantial improvement in outcome to date, although some individual studies have been somewhat encouraging. New approaches are currently under investigation. CONCLUSION Human pharmacology studies provide a rationale for use of cisplatin in the treatment of human brain tumors, and human and in vitro studies suggest some manipulations that might potentially further augment tumor platinum concentrations. While clinical studies suggest that cisplatin combinations may be of some value vs. human primary brain tumors and brain metastases, and while in vitro studies suggest that cisplatin potentiates radiation efficacy, no combination of cisplatin plus radiation yet tested has appeared to be superior to radiation alone.

Factors affecting human autopsy kidney-cortex and kidney-medulla platinum concentrations after cisplatin administration

The objective of this study was to determine factors that affect cisplatin concentrations in human kidney cortex. We used flameless atomic absorption spectrophotometry to assay platinum in autopsy specimens of kidney cortex obtained from 83 cisplatin-treated patients. Concentrations were correlated with pretreatment factors and treatment conditions using univariate nonparametric statistics. Hierarchical stepwise multiple regression analyses of transformed (to normalize) data were then used to assess which factors were most important, controlling for other factors. Kidney-cortex platinum concentrations varied from 0 to 14.8 μg/g (median, 2.04 μg/g). The cumulative lifetime dose of cisplatin ranged from 10 to 1120 mg/m2 (median, 112 mg/m2). The time from the last cisplatin dose to death was <1–609 days (median, 38 days). According to univariate statistics, factors that correlated (P<0.05) with kidney-cortex platinum concentrations were the cisplatin dose per course, the pretreatment serum urea level, metoclopramide use (positive correlations), the time from the last cisplatin treatment to death, and the pretreatment serum albumin value (negative correlations). Factors that approached significance (0.05≤P≤0.10) were a history of hypertension, hyperbilirubinemia (positive), the serum calcium level, and phenytoin use (negative). In the multiple regression analysis, after controlling for the cisplatin dose per course and the time from the last treatment to death, only concurrent metoclopramide and phenytoin use entered the model. The hydration volume did not affect corrected kidney-cortex or kidney-medulla platinum concentrations. The following conclusions were reached: (1) it may be feasible to use lower hydration volumes than those used routinely, (2) any effect of hydration volume on cisplatin nephrotoxicity may not be mediated via a reduction in kidney-cortex platinum concentrations, (3) higher cisplatin doses might be tolerated with new 5-hydroxytryptamine-3 (5HT-3) antiemetics than were tolerated with metoclopramide, and (4) phenytoin should be tested for its ability to reduce cisplatin nephrotoxicity.

Penetration of teniposide (VM-26) into human intracerebral tumors

Thirty-four consenting patients received VM-26 50–100 mg/m2 I.V. before surgical resection of intracerebral tumor, and drug was measured using a high pressure liquid chromatographic technique. Sufficient tumor for analysis was obtained from 29 patients. Brain metastases (13 patients) had higher concentrations of V M-26 than did gliomas (13 patients). Concentrations were comparable in brain metastases and meningiomas (3 patients). Prolonged (24 h) infusion of V M-26 did not appear to result in higher tumor drug concentrations in 5 patients than did rapid (1 h) infusion in 24 patients. Pretreatment with Amphotericin-B 10 mg/m2 12 h and 1 h before VM-26 did not appear to have any effect on VM-26 uptake into 4 intracerebral tumors, although data were limited, and VM-26 concentrations were very high in 1 metastasis. Pretreatment with oral glycerol 500 mg/kg 18 h, 12 h, 6 h, and immediately before I.V. VM-26 may have resulted in increased penetration of VM-26 into 9 tumors, although confirmation is required. Amphotericin-B, glycerol, and operative conditions did not appear to alter VM-26 plasma pharmacokinetics.

Human central nervous system pharmacology of tiazofurin

A nontoxic dose of the new antineoplastic antimetabolite tiazofurin was given IV to 16 patients prior to or during surgical resection of malignant intracerebral tumors. The drug was readily detectable in 15 of the 16 tumors. Uptake into tumor was rapid, although tiazofurin concentrations in brain tumors were generally (but not always) lower than concentrations in plasma, muscle and brain. Tumor cyst fluid drug concentrations were comparable to drug concentrations found in tumor. Cerebrospinal fluid drug concentrations were measured in 2 patients and were high in one patient and low in the other.

Human autopsy-tissue distribution of menogaril and its metabolites

Autopsy-tissues were obtained from eight patients who had last received menogaril (total cumulative dose, 175–1080 mg/m2) intravenously (one patient) or orally (seven patients) from 1 to 285 days prior to death. Tissue samples were assayed for menogaril and its metabolities by high-pressure liquid chromatography. Unchanged menogaril was found only in a single lung-tissue sample from a patient who had died < 24 h after receiving his last treatment.N-Demethylmenogaril was found in two lung-tissue samples and in single samples of the thyroid, lymph node, pancreas, cerebellum, and tumor. The major menogaril metabolite found in human autopsy-tissues was 7-deoxynogarol. The highest 7-deoxynogarol concentrations were found in the large bowel (median, 201 ng/g), liver (median, 183 ng/g), and lung (median, 177 ng/g). The heart ranked as the 9th of 18 organs in median 7-deoxynogarol concentration, after the large bowel, liver, lung, tumor, thyroid, skeletal muscle, adrenal gland, and kidney. The lowest concentrations were detected in brain tissue. Our results suggest that the low degree of cardiac toxicity and the possible pulmonary toxicity of menogaril may be related to relative tissue concentrations of menogaril metabolites. Tumor 7-deoxynogarol concentrations were comparable with those in normal tissues, except that concentrations in intracerebral tumors were higher than those in the normal brain. Tissue 7-deoxynogarol concentrations appeared to be directly related to the cumulative dose and inversely related to the time from the last treatment to death; the value obtained by dividing dose by time correlated (P<0.05) with tissue 7-deoxynogarol concentrations.