A case report of neurological adverse events caused by short-term and low-dose treatment of mitotane: The role of therapeutic drug monitoring.

RATIONALE: Low-dose mitotane has been widely used for many decades in patients with advanced adrenocortical carcinoma (ACC), which exhibited good safety profiles compared with the high-dose regimen. The clinical efficacy and toxicity of mitotane are closely related to its plasma concentration, and therapeutic drug monitoring (TDM) is recommended. Until now, no severe adverse drug reaction (ADR) related to the toxic plasma level after a short-term treatment of low-dose mitotane has been published. PATIENT CONCERNS: A 50-year-old Chinese female presented with severe neurological adverse events related to a toxic plasma levels of 42.8 mg/L after 4 months treatment of low-dose mitotane. DIAGNOSES: During the course of therapy, no other medication could cause neurological adverse events. Therefore, we suspected a high sensitivity to the side effect of mitotane related to a toxic plasma level. INTERVENTIONS: Treatment of mitotane was stopped. OUTCOMES: The trough plasma concentration of mitotane decreased to 18.7 mg/mL after one and a half months, and the neurological symptoms gradually improved after drug discontinuance. LESSONS: The present case provides the first report of severe neurological adverse events induced by the short-term use of low-dose mitotane for adjuvant treatment in a patient with ACC, indicating that potentially severe ADR can also occur when using low-dose regimen in the early stage of treatment. TDM and early recognition could result in a favorable outcome.

A simplified method for therapeutic drug monitoring of mitotane by gas chromatography-electron ionization-mass spectrometry.

Mitotane is a key drug for the treatment of adrenal cortical carcinoma. Due to its narrow therapeutic window, 14-20 µg/mL, monitoring its concentration is crucially important. In this study, a simplified method for measuring mitotane in plasma using gas chromatography-electron ionization-mass spectrometry (GC-EI-MS) was developed. Through deproteination and liquid-liquid extraction, mitotane and an internal standard (IS) were extracted from plasma samples. GC-EI-MS yielded retention times of 8.2 and 8.7 min, for mitotane and the IS, respectively, with a total run time of 12 min. Selectivity and intra-/inter-batch accuracy and precision analyses provided a lower limit of quantification of 0.25 µg/mL, and a calibration curve between 0.25 and 40 µg/mL had good linearity (coefficient of determination = 0.992). The matrix effect factor and percent recovery of the method had good precision. Additionally, long-term sample stability was observed below 4°C. In a clinical setting, mitotane levels in plasma from an adrenal cortical carcinoma patient were within calibration range. Therefore, this simplified method can be applied to routine therapeutic drug monitoring of mitotane, which may contribute to improved treatment of adrenal cortical carcinoma.

A method for the minimally invasive drug monitoring of mitotane by means of volumetric absorptive microsampling for a home-based therapeutic drug monitoring.

Mitotane is the only currently approved treatment for adrenocortical carcinoma (ACC), a rare endocrine malignancy. Plasma levels within the range of 14 to 20 mg L-1 are correlated with higher clinical efficacy and manageable toxicity. Because of this narrow therapeutic index and slow pharmacokinetics, therapeutic drug monitoring is an essential element of mitotane therapy. A small step towards the therapeutic drug monitoring (TDM) by volumetric absorptive microsampling (VAMS) was made with this work. A simple method enabling the patient to collect capillary blood at home for the control of mitotane blood concentration was developed and characterized using MITRA™ VAMS 20 µL microsampler. Dried blood samples were extracted prior to HPLC-UV analysis. Mitotane and the internal standard dicofol (DIC) were detected at 230 nm by ultra-violet detection after separation on a C8 reversed phase column. The assay was validated in the range of 1 to 50 mg L-1. Dried samples were stable at room temperature and at 2-8 °C for 1 week. At 37 °C, a substantial amount of the analyte was lost probably due to evaporation. Hematocrit bias, a common problem of conventional dried blood techniques, was acceptable in the tested range. However, a significant difference in recovery from spiked and authentic patient blood was detected. Comparison of mitotane concentration in dried blood samples (CDBS) by VAMS with venous plasma in patients on mitotane therapy demonstrated poor correlation of CDBS with the concentration in plasma (CP). In conclusion, application of VAMS in clinical routine for mitotane TDM appears to be of limited value in the absence of a method-specific target range.

Time Until Partial Response in Metastatic Adrenocortical Carcinoma Long-Term Survivors.

A partial response (PR) has been proposed as a surrogate for overall survival in advanced adrenocortical carcinoma (ACC). The primary endpoint of the study was to characterize the time until a PR in patients with metastatic ACC treated with a standard therapy is achieved. Long-term survivors were selected to allow evaluation of delayed tumor response to mitotane. Records from patients with metastatic ACC that survived for > 24 months were retrieved. Tumor response was analyzed according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Time until a tumor response, after treatment initiation or therapeutic plasma mitotane level, was analyzed. Sixty-eight patients were analyzed. The first-line systemic therapy was mitotane as a monotherapy (M) (n = 57) or cytotoxic polychemotherapy plus/minus mitotane (PC ± M) (n = 11). The second-line therapy was M (n = 2) or PC ± M (n = 41). Thirty-two PRs occurred in 30/68 patients (44.1%): this was obtained for 13 (40.6%) during M and during PC ± M for 19/32 responders (59.4%). PRs were observed within 6 months of starting M or PC ± M in 76.9 and 94.7% of responses, respectively, within 6 months of therapeutic plasma mitotane being first observed in 88.9% of responses with M and in 53.3% of responses with PC ± M. All PRs (but one) occurred within 1 year after initiating treatment. To conclude, Most patients with metastatic ACC and long survival times had PRs within the first 6 months of standard systemic therapy, and almost all within the first year. The absence of response after that period could be considered as a treatment failure. Maintenance of mitotane therapy in non-responders after 1 year should be questioned in future randomized trials.

Effects of mitotane on the hypothalamic-pituitary-adrenal axis in patients with adrenocortical carcinoma.

OBJECTIVE: Mitotane, a drug used to treat adrenocortical cancer (ACC), inhibits multiple enzymatic steps of adrenocortical steroid biosynthesis, potentially causing adrenal insufficiency. Recent studies in vitro have also documented a direct inhibitory effect of mitotane at the pituitary level. The present study was aimed to assess the hypothalamic-pituitary-adrenal axis in patients with ACC receiving mitotane. DESIGN AND METHODS: We prospectively enrolled 16 patients on adjuvant treatment with mitotane after radical surgical resection of ACC, who underwent standard hormone evaluation and h-CRH stimulation. A group of 10 patients with primary adrenal insufficiency (PAI) served as controls for the CRH test. RESULTS: We demonstrated a close correlation between cortisol-binding globulin (CBG) and plasma mitotane levels, and a non-significant trend between mitotane dose and either serum or salivary cortisol in ACC patients. We did not find any correlation between the dose of cortisone acetate and either ACTH or cortisol levels. ACTH levels were significantly higher in patients with PAI than that in patients with ACC, both in baseline conditions (88.99 (11.04-275.00) vs 24.53 (6.16-121.88) pmol/L, P = 0.031) and following CRH (158.40 (34.32-275.00) vs 67.43 (8.8-179.52) pmol/L P = 0.016). CONCLUSIONS: The observation of lower ACTH levels in patients with ACC than that in patients with PAI, both in basal conditions and after CRH stimulation, suggests that mitotane may play an inhibitory effect on ACTH secretion at the pituitary levels. In conclusion, the present study shows that mitotane affects the HPA axis at multiple levels and no single biomarker may be used for the assessment of adrenal insufficiency.

Therapeutic drug monitoring of mitotane: Analytical assay and patient follow-up.

Adrenocortical carcinoma (ACC) is an aggressive malignancy of the adrenal gland. Mitotane (o,p'-DDD) is the most effective chemotherapy for ACC. According to the literature, mitotane plasma trough concentrations within 14-20 mg L-1 are correlated with a higher response rate with acceptable toxicity. Therapeutic drug monitoring (TDM) of mitotane is therefore recommended. The aim of this study was to propose a robust and simple method for mitotane quantification in plasma. The validation procedures were based on international guidelines. Sample preparation consisted of a single protein precipitation with methanol using 100 µL of plasma. The supernatant was submitted to liquid chromatography coupled with ultra-violet detection at 230 nm. Mitotane retention time was 7.1 min. The limit of detection was 0.1 mg L-1 and the limit of quantification was 0.78 mg L-1 . The assay demonstrated a linear range of 0.78-25 mg L-1 with correlation coefficients (r2 ) at 0.999. Inter- and intra-assay precision was <4.85%. Evaluation of accuracy showed a deviation <13.69% from target concentration at each quality control level. This method proved easy and rapid to perform mitotane TDM and required a small volume of sample. It was successfully applied to routine TDM in our laboratory.

Contribution of Therapeutic Monitoring in the Assessment of Toxic Adverse Effects of Mitotane: a Case Report.

Mitotane provided serious side effects and low doses seemed to be tolerated. Determination of mitotane concentration in plasma is recommended. We report the case of toxic plasma levels with low doses of mitotane in a 47-year-old man with adrenocortical cancer.

Lipoprotein-Free Mitotane Exerts High Cytotoxic Activity in Adrenocortical Carcinoma.

CONTEXT: Mitotane (o,p'-DDD), the only approved drug for advanced adrenocortical carcinoma (ACC), is a lipophilic agent that accumulates into circulating lipoprotein fractions and high-lipid-containing tissues. OBJECTIVE: The aim of our study was to evaluate the in vivo and in vitro biological implication of serum lipoproteins on pharmacological action of mitotane. Distribution and concentration of mitotane were studied in plasma and adrenal tissue samples from mitotane-treated patients. The effect of lipoprotein-bound or lipoprotein-free (LP-F) mitotane was analyzed on proliferation and apoptosis of human adrenocortical H295R cells. A retrospective study of patients with ACC treated or not with statins was also performed. RESULTS: o,p'-DDD distribution among very low-density lipoprotein, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and LP-F fractions obtained after plasma ultracentrifugation of 23 of mitotane-treated patients was widely distributed in each subfraction. A positive correlation was observed between mitotane levels in plasma and in LDL, HDL, but also LP-F compartment. Intratumor o,p'-DDD concentrations in five ACC samples of mitotane-treated patients were found to be independent of cholesterol transporter expression, scavenger receptors, and LDL receptors. In vitro studies showed significant higher antiproliferative and proapoptotic effects and higher cell and mitochondrial uptake of mitotane when H295R cells were grown in LP-F medium. Finally, retrospective study of an ACC cohort of 26 mitotane-treated patients revealed that statin therapy was significantly associated with a higher rate of tumor control. CONCLUSIONS: Altogether, our in vitro and in vivo studies provided compelling evidence for a greater efficacy of LP-F mitotane. Patients with ACC may thus benefit from therapeutic strategies that aim to increase LP-F mitotane fraction.

Short-term variation in plasma mitotane levels confirms the importance of trough level monitoring.

OBJECTIVE: Mitotane is the drug of choice in patients with adrenocortical carcinoma. The anti-neoplastic effect is correlated with mitotane plasma levels, which render it crucial to reach and maintain the concentration above 14 mg/l. However, mitotane pharmacokinetics is poorly understood. The aim of this study was to investigate the variation in plasma mitotane levels during the day and the influence of a single morning dose. DESIGN: A prospective case-control study was conducted to investigate the variation in plasma mitotane levels. METHODS: Patients who had been treated for at least 24 weeks and had reached the therapeutic plasma level (14 mg/l) at least once were eligible. In the first group, mitotane levels were determined hourly for the duration of 8 h after administration of a single morning dose. In the second group, mitotane levels were assessed similarly without administration of a morning dose. RESULTS: Ten patients were included in this study, and three patients participated in both groups. Median plasma level at baseline was 16.2 mg/l (range 11.3-23.3 mg/l) in the first group (n=7) and 17.0 mg/l (13.7-23.8) in the second group (n=6). Plasma levels displayed a median increase compared with baseline of 24% (range 6-42%) at t=4 after morning dose and a change of 13% (range -14 to 33%) at t=4 without morning dose (P=0.02). CONCLUSION: A substantial increase in mitotane plasma levels was observed in steady-state patients within a period of 8 h after morning dosing. Without morning dose, mitotane curves showed a variable profile throughout the day. This implies that random sampling could yield incidentally high levels. For this reason, we recommend early-morning trough sampling as standard management in monitoring mitotane treatment.

Reduction of the body burden of PCBs and DDE by dietary intervention in a randomized trial.

Serum polychlorinated biphenyls (PCBs) in Anniston, AL, residents have been associated with hypertension and diabetes. There have been no systematic interventions to reduce PCB body burdens in Anniston or other populations. Our objective was to determine the efficacy of 15 g/day of dietary olestra to reduce PCBs in Anniston residents. Blood PCBs and 1,1-bis-(4-chlorophenyl)-2,2-dichloroethene were measured at baseline and 4-month intervals in a double-blind, placebo-controlled, 1-year trial. Participants with elevated serum PCBs were randomized into two groups of 14 and received potato crisps made with olestra or vegetable oil (VO). Elimination rates during the study period were compared with 5-year prestudy rates. Eleven participants in the olestra group and 12 in the VO group completed the study. Except for one participant in the VO group, reasons for dropout were unrelated to treatments. The elimination rate of 37 non-coplanar PCB congeners during the 1-year trial was faster during olestra consumption compared to the pretrial period (-0.0829 ± 0.0357 and -0.00864 ± 0.0116 year(-1), respectively; P=.04), but not during VO consumption (-0.0413 ± 0.0408 and -0.0283 ± 0.0096 year(-1), respectively; P=.27). The concentration of PCBs in two olestra group participants decreased by 27% and 25% during the trial. There was no significant time by group interaction in change from baseline. However, group main effects for total PCBs and PCB 153 were of borderline significance. This pilot study has demonstrated that olestra can safely reduce body burdens of PCBs and supports a larger intervention trial that may also determine whether reduction in PCBs will reduce the risk of hypertension and diabetes.

PCB concentrations and dioxin-like activity in blood samples from Danish school children and their mothers living in urban and rural areas.

Human exposure to persistent organic pollutants (POPs) is of major concern due to a diversity of adverse effects from prolonged exposure and bioaccumulation. Manufacturing of polychlorinated biphenyls (PCBs), a subgroup of POPs, has been prohibited for many decades; however, human exposure still occurs due to the persistent nature of the chemicals. The concentrations of the dioxin-like PCB congeners 105, 118 and 156 and the non-dioxin-like PCB congeners 28, 52, 101, 138, 153 and 180, p,p'-DDE, p,p'-DDT, o,p'-DDE, o,p'-DDT, HCB and ß-HCH as well as the dioxin-like activity using the AhR transactivity assay were analysed in blood samples from Danish schoolchildren and their mothers in the European framework of the DEMOCOPHES/COPHES projects. The participants were selected from an urban and a rural area, respectively. The PCB concentrations and the AhR-TEQ (TCDD toxic equivalent) were significantly higher in schoolchildren living in the urban area compared with the rural, and for AhR-TEQ, a strong correlation between the mothers and children was observed. We found a significant negative correlation between BMI and PCB concentrations in the children. Finally, in the mothers, there was a positive association between age and PCB concentration. These results show that both PCBs and dioxin-like activity can be measured as biomarkers of exposure and effects in blood samples from children and women. The results indicate that people living in urban areas may be exposed to higher concentrations of PCBs, dioxins and dioxin-like chemicals, which may lead to a greater risk of adverse effects for urban populations.

Mitotane levels predict the outcome of patients with adrenocortical carcinoma treated adjuvantly following radical resection.

CONTEXT: Mitotane plasma concentrations ≥ 14 mg/l have been shown to predict tumor response and better survival in patients with advanced adrenocortical carcinoma (ACC). A correlation between mitotane concentrations and patient outcome has not been demonstrated in an adjuvant setting. OBJECTIVE: To compare recurrence-free survival (RFS) in patients who reached and maintained mitotane concentrations ≥ 1 4 mg/l vs patients who did not. DESIGN AND SETTING: Retrospective analysis at six referral European centers. PATIENTS: Patients with ACC who were radically resected between 1995 and 2009 and were treated adjuvantly with mitotane targeting concentrations of 14-20 mg/l. MAIN OUTCOME MEASURES: RFS (primary) and overall survival (secondary). RESULTS: Of the 122 patients included, 63 patients (52%) reached and maintained during a median follow-up of 36 months the target mitotane concentrations (group 1) and 59 patients (48%) did not (group 2). ACC recurrence was observed in 22 patients of group 1 (35%) and 36 patients in group 2 (61%). In multivariable analysis, the maintenance of target mitotane concentrations was associated with a significantly prolonged RFS (hazard ratio (HR) of recurrence: 0.418, 0.22-0.79; P=0.007), while the risk of death was not significantly altered (HR: 0.59, 0.26-1.34; P=0.20). Grades 3-4 toxicity was observed in 11 patients (9%) and was managed with temporary mitotane discontinuation. None of the patients discontinued mitotane definitively for toxicity. CONCLUSIONS: Mitotane concentrations ≥ 14 mg/l predict response to adjuvant treatment being associated with a prolonged RFS. A monitored adjuvant mitotane treatment may benefit patients after radical removal of ACC.

Influence of the CYP2B6 polymorphism on the pharmacokinetics of mitotane.

OBJECTIVE: The aim of this study was to assess the potential impact of the pharmacogenetic variability of CYP2B6 and ABCB1 genes on the pharmacokinetics of mitotane. METHODS: A retrospective analysis was carried out on 27 patients with adrenocortical carcinoma on postoperative adjunctive mitotane. CYP2B6 and ABCB1 polymorphisms were genotyped and tested for an association with plasma trough concentration after 3, 6, 9, and 12 months of therapy. RESULTS: Patients with the GT/TT genotype had higher mitotane plasma concentrations compared with patients with GG at 3 months (14.80 vs. 8.01 µg/ml; P=0.008) and 6 months (17.70 vs. 9.75 µg/ml; P=0.015). Multivariate logistic regression analysis showed that only the CYP2B6 rs3745274GT/TT genotype (odds ratio=10.7; P=0.017) was a predictor of mitotane plasma concentrations of at least 14 µg/ml after 3 months of treatment. Mitotane concentrations were not influenced by the polymorphisms of the ABCB1 gene. CONCLUSION: Evaluation of the CYP2B6 polymorphism enabled prediction of the individual response to adjuvant mitotane treatment.

Simultaneous analysis of mitotane and its main metabolites in human blood and urine samples by SPE-HPLC technique.

Adrenocortical carcinoma (ACC) is a rare malignancy with an incompletely understood pathogenesis and a poor prognosis. The adrenalytic activity of mitotane has made it the most important single drug in the treatment of ACC. Unfortunately, the exact mechanism of mitotane action is still unknown. It is believed that mitotane belongs to the class of drugs that require metabolic transformation by cytochrome P450 for therapeutic action; therefore determination of plasma levels of not only mitotane but also its metabolites would help in carrying out the treatment. The objective of this work was to develop and validate an SPE-HPLC method for simultaneous determination of mitotane and its metabolites in different biological fluids. The sample preparation consisted of a solid-phase extraction on a Discovery DSC(18) cartridge, while analysis of extracts was performed on a Symmetry C(18) column. The usefulness of the proposed method was confirmed by analysis of plasma, red cell and urine samples from patient chronically treated with 1.5 g of mitotane. The patient involved in this study had a high plasma concentration of mitotane and none of the investigated metabolites were found. In order to investigate whether the polymorphism of CYP2C9 and CYP2C19 enzymes could be related to the metabolism of mitotane, RT-PCR analysis was performed.

High-dose mitotane strategy in adrenocortical carcinoma: prospective analysis of plasma mitotane measurement during the first 3 months of follow-up.

BACKGROUND: The benefit-to-risk ratio of a high-dose strategy at the initiation of mitotane treatment of adrenocortical carcinoma (ACC) remains unknown. METHODS: To evaluate the performance of a high-dose strategy, defined as the highest tolerated dose administered within 2 weeks and maintenance therapy over 4 weeks, we conducted a single-center, prospective study with two main objectives: to evaluate the percentage of patients who achieve a plasma mitotane level above 14 mg/l and to evaluate the tolerance of mitotane within the first 3 months of treatment. Plasma mitotane levels were measured monthly using HPLC. RESULTS: Twenty-two patients with ACC were prospectively enrolled. The high-dose mitotane strategy (4 g/day or more in all patients, with a median of 6 g/day within 2 weeks) enabled to reach the therapeutic threshold of >14 mg/l at 1, 2, or 3 months in 6/22 patients (27%), 7/22 patients (32%), and 7/22 patients (32%) respectively. In total, a therapeutic plasma mitotane level was reached in 14 out of 22 patients (63.6%) during the first 3 months in ten patients, and after 3 months in four patients. Grade 3-4 neurological or hematological toxicities were observed in three patients (13.6%). CONCLUSION: Employing a high-dose strategy at the time of mitotane initiation enabled therapeutic plasma levels of mitotane to be reached within 1 month in 27% of the total group of patients. If this strategy is adopted, we suggest that mitotane dose is readjusted according to plasma mitotane levels at 1 or/and 2 months and patient tolerance.

[Adrenocortical carcinomas: therapeutic advances in 2011]. / Corticosurrénalomes: actualités thérapeutiques.

Adrenocortical cancer (ACC) is a rare aggressive malignancy with a poor prognosis (5-year survival: 45 %). Their management requires multidisciplinary expertise. Complete resection by an expert surgeon is the only curative treatment. Very few adjuvant treatments are available and their efficacy is not fully proved. Adjuvant mitotane therapy increases the disease-free survival in the majority of patients after surgery but further studies are needed to determine patients in whom this treatment is the more beneficial. Blood concentrations of mitotane between 14 and 20mg/l are necessary to have a full efficiency but this therapeutic window may cause side effects difficult to control. When aggressive parameters are present, radiotherapy is proposed. In case of residual or unresectable disease, combination of chemotherapy and mitotane is conventionally proposed. FIRM-ACT study establishes that EDP (etoposide, doxorubicine et cisplatine) is the most effective chemotherapy for progressive ACC. The first results of treatment with tyrosine kinase inhibitors, in patients with progressive disease despite one or two lines of chemotherapy are disappointing but this may be partly explained by the interaction with mitotane which reduces the plasma concentrations of sunitinib in particular. Clinical trials are underway to assess the effectiveness of other targeted therapies, including treatments acting on the IGF-1 receptor.

[Mitotane as possible cause of acute intermittent porphyria]. / Mitotan som mulig årsag til akut intermitterende porfyri.

A 54 year-old woman with acute intermittent porphyria (AIP) developed an attack of porphyria after 156 days of treatment with mitotane following a non-radical adrenalectomy for adrenocortical carcinoma. Mitotane therapy was discontinued but the attack of porphyria persisted for more than four months and included episodes with severe metabolic and neurologic toxicities. Mitotane is probably porphyrinogenic for patients with AIP.

A simple HPLC method for plasma level monitoring of mitotane and its two main metabolites in adrenocortical cancer patients.

Mitotane (o,p'-DDD or (1,1-dichloro-2-[o-chlorophenyl]-2-[p-chlorophenyl]ethane, DDD) is the drug of choice for non-resectable and metastatic adrenocortical carcinomas (ACC). Measurement of mitotane and metabolites, o,p'-DDE (1,1-dichloro-2-[p-chlorophenyl]-2-[o-chlorophenyl]ethene, DDE) and o,p'-DDA (1,1-[o,p'-dichlorodiphenyl] acetic acid, DDA) provides a better understanding of mitotane pharmacokinetics and pharmacodynamics. We have developed a simple, robust and efficient high performance liquid chromatography (HPLC) method to measure mitotane and its two main metabolites, DDE and DDA. The method involves a single ethanol extraction of mitotane, DDE, DDA, and an internal standard (int std) p,p'-DDD (1,1-dichloro-2,2-bis(p-chlorophenyl)ethane) with an extraction efficiency of 77-88%. All compounds are measured simultaneously using a reversed-phase phenyl HPLC column with an isocratic elution of mobile phase at a flow rate of 0.6 ml/min followed by UV detection at λ 226 nm. Inter and intra-day validation demonstrates good reproducibility and accuracy. Limits of quantitation are 0.2 µg/ml for mitotane and DDE, and 0.5 µg/ml for DDA. The method has been evaluated in plasma from 23 patients on mitotane therapy, revealing DDA concentrations 1-18 times higher than the parent compound.

Plasma concentrations of o,p'DDD, o,p'DDA, and o,p'DDE as predictors of tumor response to mitotane in adrenocortical carcinoma: results of a retrospective ENS@T multicenter study.

CONTEXT: In patients with adrenocortical carcinoma (ACC) mitotane activity has been suggested to depend on plasma levels 14 mg/liter or greater and metabolite formation. OBJECTIVE: The study was performed to confirm the correlation of the currently used mitotane (o,p'DDD) threshold of 14 mg/liter with tumor response and to evaluate the additional value of 1,1-(o,p'-dichlorodiphenyl) acetic acid (o,p'DDA) and o,p'DDE (1,1-(o,p'-dichlorodiphenyl)-2,2 dichloroethene) levels for predicting tumor response. SUBJECTS/METHODS: Plasma samples collected within 3 months of best response from 91 patients on mitotane therapy for advanced ACC were analyzed retrospectively. O,p'DDD and metabolites were assessed and related to tumor response and survival. Receiver operating characteristic curves were used. Sensitivity and specificity were calculated for different cutoff levels of o,p'DDD and metabolites. RESULTS: Objective tumor response was observed in 19% of patients. Median o,p'DDD level was higher in responders (P = 0.03). More responders were found among patients achieving o,p'DDD levels 14 mg/liter or greater (P = 0.02). Univariate and multivariate analysis showed significantly longer survival for patients with o,p'DDD levels 14 mg/liter or greater (hazard ratio 0.52, P = 0.04, hazard ratio 0.46, P = 0.03). An o,p'DDD cutoff value of 14 mg/liter was associated with a sensitivity of 65% and specificity 69%. An o,p'DDD level 20 mg/liter or greater or 14 mg/liter or greater combined with o,p'DDA level 92 mg/liter or greater was associated with a specificity of 90 and 92%, respectively. CONCLUSIONS: Our data confirm the value of o,p'DDD plasma monitoring as well as targeting the 14 mg/liter cutoff level in the therapeutic management of ACC patients. Furthermore, our results suggest additional benefit of higher levels of o,p'DDD and combined measurement of o,p'DDD and o,p'DDA.

[Mitotane in the treatment of adrenal carcinoma]. / Mitotaani lisämunuaissyövän hoidossa.

Mitotane has been used for 50 years as the first-line drug in the treatment of disseminated adrenocortical carcinoma. It reduces local recurrence of the disease and development of metastases even after a seemingly total surgical removal of the tumor. The use of mitotane has been hampered by its copious adverse effects. Its use requires knowledge of the properties and biological effects of the product. Determination of plasma levels of mitotane will help in carrying out the treatment. The dosage can be optimized and the drug's adverse effects avoided by monitoring the plasma level.