European Journal of Endocrinology (2012) 166 261–268 ISSN 0804-4643

CLINICAL STUDY High-dose mitotane strategy in : prospective analysis of plasma mitotane measurement during the first 3 months of follow-up Sophie Maucle`re-Denost1,2, Sophie Leboulleux1,2, Isabelle Borget5, Angelo Paci1,2, Jacques Young2,3,4,6, Abir Al Ghuzlan7, Desiree Deandreis1,2, Laurence Drouard1,2, Antoine Tabarin8, Philippe Chanson2,3,4,6, Martin Schlumberger1,2,3 and Eric Baudin1,2,4 1Department of Nuclear Medicine and Endocrine Tumors, Institut Gustave Roussy, Univ. Paris Sud, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France, 2Faculte´ de me´decine Paris-Sud, UMR-S693, Univ Paris-Sud, Le Kremlin-Biceˆtre, France, 3APHP Hoˆpitaux Universitaires Paris-Sud, Le Kremlin- Biceˆtre, France, 4Institut National de la Sante´ et de la Recherche Me´dicale U693, Le Kremlin-Biceˆtre, France, 5Department of Epidemiology, Institut Gustave Roussy, Villejuif, France, 6Department of Endocrinology, Le Kremlin Biceˆtre F-94276, France, 7Department of Pathology, Institut Gustave Roussy, Villejuif, France and 8Department of Endocrinology, Haut-Le´veˆque Hospital, Univ. Bordeaux, Avenue de Magellan, 33604 Pessac Cedex, France (Correspondence should be addressed to E Baudin at Department of Nuclear Medicine and Endocrine Tumors, Institut Gustave Roussy, Univ. Paris Sud; Email: [email protected])

Abstract 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 O14 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.

European Journal of Endocrinology 166 261–268

Introduction side-chain cleavage (17, 18). In 1994, Haak et al. (9) suggested that a plasma mitotane level above 14 mg/l Adrenocortical carcinoma (ACC) is a rare and aggres- was associated with a higher response rate and sive solid tumor characterized by a 5-year survival rate prolonged survival. Our own group has also been able of below 15% for metastatic disease (1–4). Mitotane to prospectively confirm these results in a separate study therapy continues to be a cornerstone of ACC treatment, (11). It is now standard in most European teams to as outlined by a recent consensus on adjuvant ACC monitor the plasma mitotane level in ACC patients, with therapy (5). The objective response rate for mitotane the aim of achieving a so-called ‘therapeutic plasma has been reported in prospective or retrospective studies mitotane level’ of above 14 mg/l. However, there are as between 10 and 33% (6–12), and it has been several factors that must be considered in mitotane suggested that mitotane has a prognostic impact for therapy. To begin with, the therapeutic window for patients with metastatic ACC (9, 13–16). Mitotane is a mitotane plasma concentrations is relatively narrow. As compound derived from the insecticide dichlorodiphe- noted earlier, a plasma mitotane concentration above nyldichloroethane and has been used to treat adrenal 14 mg/l elicits a higher rate of objective response; cancer since the late 1950s. It has potent adrenotoxic however, if the plasma mitotane level rises above effects and is able to block synthesis 20 mg/l, a higher rate of neurological adverse events by inhibiting 11b-hydroxylation and cholesterol is also reported (9, 11, 19). In addition, a significant

q 2012 European Society of Endocrinology DOI: 10.1530/EJE-11-0557 Online version via www.eje-online.org

Downloaded from Bioscientifica.com at 09/25/2021 03:00:01PM via free access 262 S Maucle`re-Denost and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2012) 166 number of patients fail to reach therapeutic plasma was based on imaging studies and findings at surgery mitotane levels at all, for reasons not yet known (9, 11, and were classified according to the ENSAT classification 15, 16). Finally, the long lag time from treatment (26). Mitotane therapy was given in an adjuvant setting start to peak levels is troublesome for advanced ACC in 13 patients (59%) and in a palliative setting in nine (11, 20). Indeed, in two earlier studies, it took a median patients (41%). interval of 3–5 months before therapeutic levels were obtained (11, 21). Research is ongoing to improve the management Study protocol and understanding of mitotane, including studies on its All patients were hospitalized during the first week of molecular targets, metabolism pathways, and the therapy and had signed an informed consent form. galenic form of the drug (22, 23). In 2006, we proposed Mitotane formulation was administered orally (Lyso- a high-dose mitotane strategy aimed at shortening the dren, 500 mg tablets, HRA-Pharma, Paris, France) time required to reach the therapeutic plasma level three times daily with a meal containing fat. Mitotane (24). We hoped that such a strategy would help, at least starting dose was 1.5 g/day and was rapidly increased partially, to overcome the poor and by 1.5 g/day until the highest dose was reached within lipophilic properties of the drug (16, 25).Ina the first 2 weeks (maximal daily dose 9 g/day). Clinical preliminary study, all three ACC patients who were tolerance (especially digestive tolerance) was used to given 3–9 g/day of mitotane reached therapeutic guide dose adjustment during these first 2 weeks of plasma mitotane levels by 6 weeks, with a manageable treatment. The aim after 2 weeks was to maintain the safety profile (24). highest tolerated dose over at least 4 weeks. To mitigate In order to confirm the benefit of this high-dose side effects, antiemetics and or loperamide were strategy, we expanded this single-center, prospective considered on a case-by-case basis. Of note, this high- study with two main objectives: to evaluate the dose strategy remained within the standard range of percentage of patients who reached a plasma mitotane routine prescription of mitotane in our center for years level above 14 mg/l during the first 3 months of (12). This strategy of prescription slightly differs with treatment (benefit) and to evaluate the unwanted effects the European Summary of Product Characteristics of this high-dose mitotane strategy (risk). (SPC) recommendation, available since 2004, which suggests that dosage should remain below or equal to 6 g/day. However, this strategy is in accordance with US Subjects and methods SPC, which recommend a starting dose of 6 g/day, increasing up to 9 or 10 g/day if tolerated. Substitutive All patients at the Institute of Gustave Roussy (IGR) adrenal therapy, i.e. 30–60 mg/day, was who were started on high-dose mitotane therapy for given immediately to all patients and fludrocortisone treatment of ACC between 2005 and 2009 were acetate (25–50 mg/day) was given within the first 2 enrolled in this prospective study. Patients were included weeks of therapy. Substitutive therapy was given in the study if their first-line high-dose mitotane alongside a normal salt diet and patient education by treatment was initiated and followed at IGR until the referring physician. progression and if a review of the ACC diagnosis including the assessment of Weiss criteria was carried Drug monitoring and toxicity evaluation out. Patients were excluded if they were participating in other studies such as the PK- Each patient attended follow-up visits at the IGR every Lysodren trial (ClinicalTrials.gov identifier: NCT00094497 monthly, which included a complete clinical evaluation whose main goal was to study the relationship between and routine biochemical tests. Plasma mitotane levels Lysodren dose and mitotane plasma concentrations were measured every 4 weeks or if severe adverse effects stratified for one of two pre-defined high-dose or low- developed. All treatments received before the initiation dose regimens), or if they underwent concomitant of mitotane were recorded. Mitotane therapy was treatment with or locoregional therapy managed by the physician and guided by clinical during the study. tolerance, biochemical test results, and plasma mitotane The definition of functional tumors was based on an concentration. Mitotane-related toxicity was graded increase in cortisol (assessed by measuring plasma and according to the National Cancer Institute (NCI) urinary excretion of cortisol), and/or androgen (assessed common toxicity criteria, version 3.0. In the event of by measuring plasma testosterone, androstenedione, grade 1–2 toxicity, the patients were allowed to reduce and DHEA sulfate), and/or estrogen (assessed by the daily dose by 1.5 g/day after 6 weeks. Before 6 measuring 17b-estradiol) levels. Plasma 17-hydroxy- weeks, patients were encouraged to maintain the and 11-deoxycortisol levels were also highest dose as long as possible. In the event of measured in all patients and and unacceptable toxicity (grade 3–4), the treatment was 11-desoxycorticosterone levels were measured to assess temporarily discontinued until recovery to grade 1 and function. Staging at the diagnosis then a lower daily dose (reduced by 1.5 g/day) was

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Downloaded from Bioscientifica.com at 09/25/2021 03:00:01PM via free access EUROPEAN JOURNAL OF ENDOCRINOLOGY (2012) 166 High-dose mitotane strategy in ACC 263 resumed. When plasma concentrations O30 mg/l were notfollowedatIGR.Twopatientswereexcluded reached, mitotane treatment was temporarily inter- because additional therapies were administered during rupted for 7 days or more depending on the presence the first 3 months. Five patients were excluded because and severity of adverse effects and then resumed at a they were enrolled in the PK Lysodren protocol. lower dose. Twenty-two consecutive ACC patients entered the Every 3 months, patients underwent hormonal study (eight males and 14 females; median age, 59 and morphologic evaluation, including a computed years; range 25–73 years; Table 1). All patients tomography scan and FDG-PET. Tumor recurrences and underwent surgery, including 12 patients (54%) who responses are not described in this paper. underwent nephrectomy. Before surgery, 15 tumors (68%) were functioning and eight patients (36%) were Plasma mitotane measurements graded 1 according to the WHO performance status. The median time between initial surgery and the Plasma mitotane level was measured in the morning on initiation of mitotane therapy was 3.5 months (range: an empty stomach and 12 h after the previous dose 7 days to 3 years). The median time between the every month for the first 3 months. Mitotane measure- initiation of mitotane therapy and the initiation of ments were performed using an HPLC method at IGR another therapeutic modality was 6 months (3–31 before 2008 (11) and then by PAREXEL (rZ0.98 months). At 6, 9, and 12 months, 12, 8, and 6 patients, between the two methods, as assessed in 45 consecutive respectively, were still receiving mitotane as a single patients in 2007) after 2008. Intra-assay coefficients of therapy. According to the ENSAT classification, disease variation were 20% at low values and 15% at high stages at the diagnosis were II, III, and IV in 27, 50, values. We defined a therapeutic plasma mitotane range and 23% of patients respectively. of between 14 and 20 mg/l, a pretoxic mitotane level of between 20 and 30 mg/l, and a toxic mitotane level when concentrations exceed 30 mg/l. Mitotane dose and plasma mitotane levels Among the 22 patients, three patients (14%) tolerated Statistical analysis a maximum daily mitotane dose of 9 g, four patients (18%) tolerated a maximum daily mitotane dose of Early therapeutic plasma mitotane level was defined 7.5 g, six patients (27%) tolerated a maximum daily as above: 14 mg/l at 1 month after the initiation of mitotane dose of 6 g, eight patients (36%) tolerated a mitotane therapy. A correlation was sought between maximum daily mitotane dose of 4.5 g, and one patient several parameters and achievement of early thera- (5%) tolerated a maximum daily mitotane dose of 4 g. peutic plasma mitotane level. The following parameters The median maximum daily dose administered within were analyzed: age (median threshold 59 years), body the first 2 weeks was 6 g/day (range: 4–9 g/day). The 2 mass index (BMI; median threshold 25 kg/m ), tumor highest starting doses of 7.5–9 g/day achieved in seven weight and size (median threshold 600 g and 14 cm), hormone secretion (cortisol or androgen, yes or no), Table 1 Patient characteristics. ENSAT Staging (stage II vs III–IV), clinical setting (adjuvant or palliative), and the mitotane dose at 2 Characteristics n (%) patients weeks (above the median threshold 6 g/day, yes or no). n 22 The results are reported as odds ratios. A correlation Age (years); median, range 59 (25–73) was also sought between the total cumulative mitotane Male/female 8 (36%)/14 (64%) dose and the plasma mitotane level, using the Pearson BMI (kg/m2); median, range 23.5 (19–31) correlation coefficient (significance was set at 5%). Weiss score 2 R3 22 (100%) Categorical data was evaluated using c and continued %6 10 (45%) variables were compared using Student’s t-test. All O6 12 (55%) analyses were performed using SAS software, version Median, range 7 (4–9) 9.1 (Cary, NC, USA). A P value !0.1 was considered Follow-up under mitotane alone (months) significant at univariate analysis. Median, range 6 (3–31) ENSAT Stage II 6 (27%) III 11 (50%) IV 5 (23%) Results Hormonal secretion 15 (68%) Cortisol 4 (27%) Patients Androgen 2 (13%) CortisolCandrogen 8 (53%) Forty-seven ACC patients were referred to our insti- 11DOC 1 (6%) tution and were treated with adjuvant or palliative Aldosterone 0% Adjuvant mitotane treatment 13 (59%) mitotane. Eighteen patients were excluded because the Palliative mitotane treatment 9 (41%) high-dose mitotane strategy was either not started or

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Downloaded from Bioscientifica.com at 09/25/2021 03:00:01PM via free access 264 S Maucle`re-Denost and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2012) 166 patients were maintained over a median time of only of 4 mg/l at 1 month and 11 mg/l at 2 months was 4 days (range: 1–45 days) while the 4–6 g starting daily measured in the subgroup of patients who achieved doses achieved in 15 patients were maintained over a a therapeutic level at 3 months. Four other patients median time of 25 days (range: 2–330 days). The 22 reached therapeutic mitotane levels after 3 months patients had received a median cumulative mitotane (months 5 and 14) but before alternative therapeutic dose of 142 g (range: 66–270) after 1 month, 272 g options were given. Finally, two patients reached the (range: 112–405) after 2 months, and 405 g (range: therapeutic levels at the time of combined mitotane and 157–546) after 3 months. chemotherapy (months 6 and 27; Fig. 1B). Toxic A therapeutic plasma mitotane level of 14 mg/l or mitotane levels were reached in two patients (9%) at over was reached at least once during the first 3 months month 2 and month 6 respectively. Pretoxic levels were of therapy by 10/22 patients (45%). Therapeutic levels reached in one (4.5%) patient at month 2. were measured in six patients (27%) at 1 month, in seven patients (32%) at 2 months, and in seven patients Parameters correlated with the early (32%) at 3 months (Fig. 1A). A minimum mitotane level therapeutic plasma mitotane level No correlation was found between the parameters listed A 35 and early achievement of a therapeutic plasma level. The median cumulative mitotane dose in patients who reached a therapeutic mitotane level was 276 g 28 (range: 87–741). No significant correlation was found between the cumulative mitotane dose and the plasma mitotane level. 21 Tolerance of the high-dose mitotane strategy 14 Treatment toxicities are detailed in Table 2. The most frequent adverse event was digestive toxicity (grade 1 or 2). Onset of digestive toxicity was not related to plasma 7 mitotane level. Mitotane was transiently discontinued in 11/22 patients (50%) due to toxicity, for a median time of 7 days (range: 7–180), after a median time of 2.5 0 months (range: 1–11 months). At the time of with- M1 M2 M3 drawal, the median plasma mitotane level was 20 mg/l Months (range: 2.6–31) and 5/11 patients (45%) had a plasma Mitotane plasma level >14 mg/ml never reached mitotane level !14 mg/l. None of the patients Mitotane plasma level >14 mg/ml reached once permanently discontinued mitotane due to toxicity. Mitotane plasma level >14 mg/ml reached twice least The 11 patients who transiently discontinued mitotane treatment experienced grade 1 or 2 digestive toxicity B (73% anorexia, 73% , 64% , 36% , and 9% abdominal pain). Furthermore, 30 cholestasis was observed in eight patients (73%) and grade 1 cytolysis in one patient (9%). Only three of these 20 11 patients had reached a plasma level O30 mg/l. Two 14 of these three patients also experienced neurological toxicity: grade 3 ataxia in one (plasma mitotane level Mitotane level (mg/l) Mitotane level of 34 mg/l) and grade 3 disabling vertigo in the other M1 M2 M3 / M5 M6 / M14 / M27 patient (plasma mitotane level of 36 mg/l). The Months remaining patient did not experience any neurological With mitotane in monochemotherapy toxicity despite a plasma mitotane level at 31 mg/l. One Combined mitotane and chemotherapy patient experienced grade 4 anemia due to erythro- blastopenia, but the plasma mitotane level remained Figure 1 (A) Results of plasma mitotane levels at 1, 2, and 3 months at 6.7 mg/l. All toxic effects were reversible. of therapy assigned in three subgroups according to the number of Four patients (18%) permanently discontinued plasma mitotane level values O14 mg/l attained. (B) Date of the first mitotane treatment after a median time of 12 months therapeutic plasma mitotane level reached as a function of time: (range: 7–24 months) because of tumor progression. At 14 patients reached a therapeutic level at the time of mitotane monochemotherapy and two patients at the time of combined that time, the median plasma mitotane level was 5 mg/l polychemotherapy. (range: 2.6–15.5).

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Table 2 Mitotane toxicity graded according to the National Cancer a median of 4 weeks. A higher dose (above 6 g/day) Institute (NCI) criteria (NCI. NCTAE version 3). could only be maintained for a few days and should, therefore, not be recommended on a routine basis. Grade Five studies have provided data on patient tolerance Toxicity 1234to mitotane either as a single drug (7, 9, 12, 28) or in combination with chemotherapy (29). It is interesting Hematologic Anemia 4 – – 1 to note that single agent mitotane could be adminis- Leukopenia 3 – – – tered at higher doses (median 6 g/day (7) or 4–8 g/day Hepatic (9, 12)) than when combined with chemotherapy Cholestasis 7 3 – – (1–4 g/day (29)). Cytolysis 1 – – – In addition to our previous reports, only a few Constitutional symptoms Asthenia 3 1 – – studies analyzed the potential relationships between Gastrointestinal the mitotane dose and plasma levels during the first Anorexia 4 4 – – month of treatment (11, 20, 24, 28). In one study, all Diarrhea 2 2 – – eight patients treated with 1–3 g/day and all patients Nausea 2 6 – – Vomiting 4 3 – – who ingested at least 283 g of mitotane achieved Abdominal pain 1 – – – therapeutic plasma mitotane levels within a median Neurology time of 3–5 months (20). In another study on 17 Confusion 1 – – – patients treated with a median daily dose of 4 g (28), all Ataxia – 1 1 – patients achieved a therapeutic plasma mitotane level Dysarthria 1 – – – Vertigo/dizziness 2 – 1 – after a maximum of 9 months, and 47% achieved Vision trouble 1 – – – therapeutic plasma levels at 3 months. In this study, Memory trouble – 1 – – using a 6 g/day median mitotane dose, we report similar Other results at 3 months. However, only 64% of the patients Skin 5 – – – 3 1 – – reached a therapeutic plasma mitotane level after the ingestion of a median cumulative mitotane dose of 405 g, a percentage that is similar to that obtained in our previous study (12). Of note, this inability to reach Discussion the therapeutic plasma mitotane level in some patients has already been reported in previous studies (9, 15). There is no consensus regarding the optimal strategy for Indeed, digestive absorption of the drug is only 40% of initiating mitotane therapy in ACC patients. In addition, the ingested dose, and changes in the galenic presen- no randomized study is planned to solve this issue. tation of the drug may also affect its bioavailability (25). Therefore, comparison of historical studies and Therefore, our study does not provide firm evidence of implementation of prospective studies like this study or the superiority of a high-dose mitotane regimen during the ongoing stratified PK-Lysodren trial provides the the first 3 months of therapy. However, a high-dose best evidence possible. To date, plasma mitotane level strategy defined as dosage above or equal to 4 g/day is the only confirmed predictor of tumor response to could still be beneficial in shortening the treatment mitotane therapy (27). The free-of-charge Lysosafe interval required to achieve a therapeutic plasma service allows the centralization of plasma mitotane measurement, and thus recommendations based on this Initiation 4–6 g/day endpoint are easily applicable in Europe. To the best of Early adjustment based on our knowledge, this study in ACC patients is the first digestive tolerance to provide monthly mitotane measurements during the first 3 months of therapy. Adverse effects (AE) In our study, 45% of ACC patients (ten out of 22) Plasma level at month 1–2 reached a plasma mitotane level in the therapeutic range within the first 3 months with high-dose - AE Grade <3 and plasma level >4mg/l - AE Grade ≥ 3 : mitotane discontinuation mitotane strategy. Therapeutic mitotane levels were at month 1 or >11mg/l at month 2: until recovery grade 1 (minor mitotane maintained for at least two measurements during the maintain the high-dose strategy dose: 1–1.5 g/day) - In case of plasma level >30mg/l: stop - Plasma level <4mg/l at month 1 or <11 first 3 months of therapy in 32% of ACC patients. In at least 7 days or resume when toxicity mg/l at month 2: reconsider low dose has recovered (–1.5g/day) strategy (1–4g/day) in case of Grade 1–2 total, 64% of ACC patients (14 out of 22) reached the side effects therapeutic plasma level before another therapeutic - Consider other antitumor options - Consider other antitumor options depending on tumor progression and or depending on tumor progression and or option was initiated, at a median time of 2 months anatomical presentation anatomical presentation (range 1–14 months) after the initiation of treatment. A median dose of 6 g/day was given during the first 2 Figure 2 Recommendation for mitotane initiation high-dose weeks of treatment and 68% of patients who were given strategy during the first 2 months of treatment: algorithm of Gustave 4–6 g/day were able to maintain the same dose for Roussy Institute.

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Downloaded from Bioscientifica.com at 09/25/2021 03:00:01PM via free access 266 S Maucle`re-Denost and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2012) 166 mitotane levels (23). Indeed, 27% of the patients in this 4 or 11 mg/l was reached at month 1 or 2 in all patients study achieved a therapeutic plasma level of mitotane who achieved the therapeutic plasma mitotane level at 1 month. at 3 months. In contrast, 50% (6/12) or only 8% (1/12) Grade 3 or 4 adverse events were observed in 13% of of patients unable to achieve the therapeutic plasma patients and the drug was temporarily discontinued due mitotane level during the first 3 months experienced to toxicity in 50% of patients. Although 22% of patients plasma mitotane level above 4 or 11 mg/l at month 1 or permanently discontinued mitotane in one old study 2 respectively. Therefore, we recommend that a high- (7), results similar to ours of only transient discontinu- dose strategy defined by a mitotane dose initiation ation have also been reported by another team (28). between 4 and 6 g/day could be given during the first 6 This suggests that the management of mitotane therapy weeks of therapy and could only be maintained if the could benefit both from experienced physicians and toxicity profile is acceptable and if minimum plasma from constant mitotane monitoring. To the best of our mitotane levels of 4 or 11 mg/l are obtained during the knowledge, mitotane-induced erythroblastopenia is first or second month of therapy. Such cut-off values described for the first time in this study. As the require confirmation in larger prospective studies. In erythroblastopenia event recovered after mitotane was case of consistently low plasma levels of mitotane and stopped and also recurred early after mitotane therapy advanced ACC, the place of a combined cytotoxic was resumed, we consider this side effect to be directly chemotherapy should be discussed, as has been recently related to mitotane administration. Mainly digestive proposed (33). Additional parameters like prognostic toxicity was observed, even when plasma mitotane parameters, the rate of tumor progression, and levels remained below 14 mg/l (50% of cases). Three anatomical locations of tumors may also be charac- patients (13.6%) exhibited toxic mitotane levels, among terized to refine the best strategy. Other options like whom two (9%) experienced grade 3–4 neurological locoregional therapies may represent interesting toxicity. These results are in accordance with two alternatives in the case of favorable prognostic par- previous studies in which such toxicities were observed ameters and appropriate tumor presentation (1, 34). in 41 and 12% of patients treated with a lower dose of Based on these results, an expert opinion in the mitotane (21, 28). We therefore consider that side management of mitotane treatment is presented effects related to the high-dose mitotane strategy in Fig. 2. appeared sooner in our study but are still manageable In conclusion, a high-dose strategy defined as a with the help of plasma mitotane measurements. median dose of 6 g/day of mitotane over 6 weeks In a previous study, we found that the mitotane dose allowed 27% of ACC patients to reach the 14 mg/l could explain 38% of plasma mitotane levels, which therapeutic plasma mitotane level within 1 month, and suggests that other factors are involved in regulating 45% of patients within 3 months. If this strategy is plasma levels of mitotane (11). No relationship between adopted, we suggest that mitotane dose is readjusted plasma mitotane level and the mitotane dose was found according to plasma mitotane levels at 1 or/and 2 in this study, suggesting that the dose is only one of the months and patient tolerance. parameters that may affect mitotane plasma level. Our hypothesis is that the benefits of a high-dose mitotane Declaration of interest strategy may be restricted to a subgroup of patients We declare that E Baudin is coinvestigator of the PK Lysodren trial characterized by their capacity to absorb, metabolize, and received grants from HRA. and store mitotane in an efficient manner. However, such mechanisms remain to be elucidated. For instance, mitotane is bound to lipoproteins in the plasma (30, 31) Funding and access to target tissue such as the brain is This research did not receive any specific grant from any funding dependent on lipoprotein profiles (32). Furthermore, agency in the public, commercial, or not-for-profit sector. mitotane has been shown to affect lipoprotein profiles by increasing low-density lipoprotein and high-density Acknowledgements lipoproteins (28). However, the relationship between mitotane access to target tissues and the lipoprotein Thanks to Lorna Saint-Ange for editing. profile has yet to be analyzed. Interestingly, 86% (6/7) of the patients who were within the therapeutic plasma mitotane range at 3 References months had already reached the level at 1 or 2 months. In addition, they represent 43% (6/14) of patients who 1 Assie G, Antoni G, Tissier F, Caillou B, Abiven G, Gicquel C, reached the therapeutic plasma mitotane level during Leboulleux S, Travagli JP, Dromain C, Bertagna X, Bertherat J, the entire study. Therefore, another potential interest of Schlumberger M & Baudin E. Prognostic parameters of metastatic adrenocortical carcinoma. 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