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1 Medicina Interna I, A.S.O. San Luigi, Regione Gonzole, 10, 10043 Orbassano, Italy2 Farmacologia, A.S.O. San Luigi, Regione Gonzole, 10, 10043 Orbassano, Italy3 Oncologia Medica, A.S.O. San Luigi, Regione Gonzole, 10, 10043 Orbassano, Italy4 Urologia, A.S.O. San Luigi, Regione Gonzole, 10, 10043 Orbassano, Italy5 Anatomia Patologica, A.S.O. San Luigi, Regione Gonzole, 10, 10043 Orbassano, Italy6 Dipartimento di Scienze Cliniche e Biologiche, Università di Torino and Laboratorio Analisi, A.S.O. San Luigi, Regione Gonzole, 10, 10043 Orbassano, Italy
(Correspondence should be addressed to M Terzolo; Email: terzolo{at}usa.net)
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Abstract |
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Introduction |
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The very recent demonstration that adjuvant treatment with mitotane was associated with beneficial effects on outcome in a large series of patients with ACC should renew interest in adjuvant mitotane therapy, notwithstanding bias inherent in a retrospective analysis (Terzolo et al. 2007). However, there is still limited information on the consequences of adjuvant mitotane treatment, since safety data of mitotane were mostly generated from series of patients with advanced ACC. Moreover, these data were largely obtained without monitoring mitotane concentrations, which is currently a standard of care (Allolio & Fassnacht 2006, Terzolo & Berruti 2008). Thus, the relationship between mitotane concentrations and the unwanted effects of the drug remains uncertain.
Therefore, we thought of interest to assess prospectively either the clinical or biochemical effects of chronic adjuvant mitotane treatment in a consecutive series of patients with ACC who have been rendered disease free by surgery. We focused on the first year of treatment, when mitotane concentrations are steeply increasing, and we assessed the unwanted effects of the drug in relationship with its circulating concentrations. The aim of the present study was not to evaluate the effects of mitotane on patient outcome but to address the safety and feasibility of adjunctive mitotane treatment, which may be questionable, given that mitotane is toxic and of complex use because of its narrow therapeutic index, the need of drug monitoring and steroid replacement (Lee 2007).
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Subjects and methods |
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Cases were drawn from a series of patients with ACC referred to and followed at our center. They were 17 consecutive patients (7 men and 10 women) aged 39.2±11.7 years who underwent radical resection of ACC from 1999 to 2005; follow-up for this report was closed in December 2007. Patients had to meet the following inclusion criteria: age 18 years or older, histologically confirmed diagnosis of ACC, complete tumor resection, availability of preoperative and postoperative computed tomography or magnetic resonance imaging. Exclusion criteria were macroscopically incomplete resection, incomplete staging, history of previous or concomitant malignancy, renal or liver insufficiency or any other severe acute or chronic medical or psychiatric condition, and previous or current treatment with chemotherapy or radiotherapy. Complete resection was defined as no evidence of macroscopic residual disease based on surgical and histopathology reports, as well as post-operative imaging. The Institutional Ethics Committee of the ‘Azienda Sanitaria Ospedaliera San Luigi’ approved the study. All participants volunteered for the study and provided written informed consent.
During the study period, adjuvant mitotane treatment aimed at reaching target serum concentrations of the drug (Haak et al. 1994, Baudin et al. 2001) has been standard of care at our institution following removal of ACC. In the absence of intolerability to mitotane, treatment was scheduled for at least 3 years, or longer in patients at perceived high risk of recurrence. Of 25 patients who were treated adjuvantly with mitotane after radical resection of ACC, 17 met all entry criteria and 8 patients were excluded: 5 had incomplete postoperative staging, 2 were on interferent medications (antiepilepsy drugs), and 1 had liver failure. All histological diagnoses were re-evaluated according to the Weiss criteria (nuclear atypia, atypical mitoses, frequent mitoses, small percentage of clear cells, diffuse architecture, necrosis, invasion of venous, sinusoidal, or capsular structures; Weiss 1984, Weiss et al. 1989) by an expert pathologist (M.V.). Staging at diagnosis was based on imaging studies and was corroborated by the findings at surgery. Staging was reported according to the McFarlane–Sullivan criteria (stage I: tumor 
5 cm, stage II: tumor >5 cm, stage III: tumor infiltration of neighboring structures or positive lymphnodes, stage IV: infiltration of neighboring structures and positive lymphnodes or distant metastases; MacFarlane 1958, Sullivan et al. 1978). Disease recurrence was defined as radiologic evidence of a new tumor lesion during follow-up.
Study protocol
Patient visits including imaging of both chest and abdomen were performed at our center at baseline (before introducing mitotane) and thereafter every 3 months until disease progression or end of the study period. At each visit, the patients underwent physical examination, routine laboratory evaluation, monitoring of mitotane concentrations and a hormonal work-up including determination of serum cortisol, aldosterone, 11-deoxycortisol, DHEAS, TSH, FT4, FT3, PRL, FSH, LH, total and free testosterone, ACTH, PRA, cortisol binding globulin (CBG), sex-hormone binding globulin (SHBG). Salivary cortisol was also measured since 2006, when an in-house assay was established at our center. Moreover, a careful interview of the patients was taken by the same physicians (Fulvia Daffara, Barbara Zaggia) to detect subjective symptoms that may have occurred during treatment. Adverse effects were retrieved by means of a questionnaire. Continuous counseling was offered to the patients and their primary care physicians by means of phone and e-mail contacts to cope with unwanted effects; additional visits were also performed when necessary. We report herein the results of the visits at baseline, +3,+6,+9,+12 months, and the last available follow-up for non-recurring patients. For patients who experienced ACC recurrence, the follow-up immediately preceding the detection of relapse was reported.
All the patients received the same mitotane formulation (Lysodren, 500 mg tablets) that was purchased by Bristol-Meyers Squibb, New York, NY, USA till 2003 and thereafter by Laboratoire HRA Pharma, Paris, France. Mitotane was administered orally at a starting dose of 1 g daily, with progressive weekly increments up to 4–6 g daily, or the highest tolerated dose, aiming to reach concentrations between 14–20 mg/l (Haak et al. 1994, Baudin et al. 2001). When such or even higher concentrations were attained, doses were tapered with further individual dose adjustments guided by the results of mitotane measurement and toxicity assessment. In the event of unacceptable side effects, the patients were allowed to return to a lower dose or discontinue temporarily restarting with a lower dose. All the patients received prophylactic glucocorticoid replacement (Cortisone acetate, 25 mg daily) when mitotane was commenced. Mitotane-related toxicity was graded using NCI CTCAE criteria (NCI 2003).
Assays
Blood samples were drawn between 0800 and 0900 h from an antecubital vein that was cannulated 30 min before after overnight fast and 24 hour discontinuation of any hormone replacement. Saliva was collected in commercially available devices using a cotton swab chewed for 2–3 min and inserted into a double-chamber plastic test tube. Salivary cortisol was measured with the same assay used for serum (Radim, Rome, Italy) with the analyte volume increased from 25 to 250 µl. The sensitivity of the method was 50 ng/dl (1.4 nmol/l). Routine clinical chemistry variables were determined using standard enzymatic methods. Hormone variables were measured in-house using commercially available reagents. The following hormones were measured with RIA: PRA and DHEAS (Sorin Biomedica, Saluggia, Italy), aldosterone and 11-deoxycortisol (Adaltis, Bologna, Italy), free testosterone (Radim), and CBG (Biosource, Torino, Belgium). ACTH was measured with IRMA (Nichols Institute, San Juan Capistrano, CA, USA) and PRL, LH, FSH, TSH, FT3, FT4, testosterone levels were determined using an automated chemiluminescence system (Architect ci8200, Abbott Laboratories); serum SHBG was determined using an automated chemiluminescence system (Immulite, Siemens Healthcare Diagnostics, Deerfield, IL, USA). All the samples for an individual subject were determined in the same laboratory and in duplicate. Intra- and inter-assay coefficients of variation for all hormone variables were less than 8 and 12%, respectively. Plasma mitotane was measured in-house by a HPLC assay, as described previously (De Francia et al. 2006).
Statistical analysis
Database management and all statistical analyses were performed by using the ‘Statistica’ for Windows software package (Statsoft Inc., Tulsa, OK, USA). Rates and proportions were calculated for categorical data, and median, ranges and percentiles for continuous data. Normality of data was assessed by the Wilk–Shapiro's test and since data were not normally distributed, two-tailed non-parametric tests were used. Differences for a given variable at different follow-up times were analyzed by means of the. Correlation analyses were determined by calculating the Spearman's R coefficient. A matrix of simple correlations was calculated between concentrations of mitotane and the other biochemical variables measured at baseline and every 3 months for one year. Bonferroni adjustment for multiple comparisons was performed. Missing data were dealt with by excluding patients from particular analyses if their files did not contain data for the required variables. Levels of statistical significance were set at P<0.05.
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Results |
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glutamyl transpeptidase (GT), which was observed in all patients, but transaminases were elevated only in few patients (Table 2). Constitutional and gastrointestinal symptoms were more frequently observed in the first 3–6 months of therapy and in most cases resolved completely, or improved consistently, after institution of palliative therapy and increase of glucocorticoid replacement. No clear correlation between mitotane concentrations and patient complaints was evident. Gastrointestinal symptoms relapsed at any increment in mitotane dose.
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Discussion |
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TopAbstractIntroductionSubjects and methodsResultsDiscussionDeclaration of interestReferences |
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The present study demonstrates that adverse effects are to be expected in patients treated adjuvantly with mitotane; however, toxicity is manageable and compliance to treatment can be attained proven that a close patient–physician relationship is established to induce and maintain motivation to treatment and provide counseling to cope with unwanted effects. The use of rather low doses of mitotane (up to 6 g daily) may explain why mitotane-related toxicity was acceptable (Kasperlik-Zaluska et al. 1995, Dickstein et al. 1998), while severe and disabling toxicity was reported in the studies where high, rapidly increasing, daily doses of mitotane were employed (Vassilopoulou-Sellin et al. 1993, Schulick & Brennan 1999). In our series, all the patients experienced elevation of aPH and GT and most patients reported also gastrointestinal symptoms, but gastrointestinal and hepatic toxicities were of grade 1 in most cases. Adverse manifestations occurred early in the course of treatment but usually subsided afterwards and did not require discontinuation of the drug in most patients. Interestingly, gastrointestinal symptoms were particularly evident at the beginning of treatment and relapsed at any increment in mitotane dose. It is possible to speculate that the patients may develop tolerance to the gradual effects of mitotane and indeed temporary mitotane withdrawal was necessary in only three cases; however, such patients were then able to resume treatment and to attain elevated drug levels without new episodes of toxicity. We disclose the limitation of a possible underreporting of mild adverse effects since the view that mitotane is a toxic drug may have definitively influenced our approach of retrieving side effects. In particular, neurological toxicity (Haak et al. 1994) should have been assessed with specific neuropsychological examinations to detect subtle disturbances of memory, language, and mental performance.
It is likely that the monitoring of plasma mitotane levels to guide dose adjustments has been a key factor to predict and limit unwanted effects attaining better tolerance. Previously, mitotane monitoring has been used in an adjunctive setting only by Haak et al. (1994) and Baudin et al. (2001). We confirm our previous observation that a low-dose mitotane regimen is able to consistently provide elevated mitotane levels (Terzolo et al. 2000), but the time lag necessary for attaining mitotane levels greater than 14 mg/l was particularly long in some patients, because we were very cautious in dose escalation, even if all patients eventually reached such concentrations. The present findings may suggest the importance of attaining elevated mitotane concentrations, since 3 out of 5 patients who reached the target levels after 6 months suffered a relapse of ACC, while recurrent disease was observed in only 3 out of 12 patients who reached those levels within 6 months. High-dose regimens offer the advantage of providing higher concentrations in less time but the trade-off may be less tolerability and greater toxicity (Faggiano et al. 2006). During follow-up, most of the patients maintained elevated mitotane concentrations despite tapering of the drug.
Hypoadrenalism was an expected consequence of mitotane treatment that occurred in almost all patients in the first 12 months. Inhibition of cortisol secretion became more evident while continuing the drug. Serum cortisol showed some variability but salivary cortisol, which is an accurate index of free, biologically active cortisol, unaffected by CBG levels (Riad-Fahmy et al. 1982), was more consistently reduced. Adrenal replacement therapy was monitored best with careful clinical assessment and measurement of electrolytes, since assessment of serum cortisol was confounded by current steroid supplementation and mitotane-induced increase in CBG. Monitoring of ACTH levels was also of little help because of a great scattering of values among different subjects. Elevated ACTH concentrations may imply insufficient glucocorticoid replacement even if we did not observe any clear correlation between the dose of cortisone acetate and ACTH levels, which were little modified by any further increment in the substitution dose.
We confirm that glucocorticoid replacement at higher doses than those currently used in Addison's disease is necessary (Dackiw et al. 2001, Schteingart et al. 2005, Allolio & Fassnacht 2006, Libè et al. 2007) and doses as high as 50–75 mg cortisone acetate daily had to be used and were of benefit in reducing gastrointestinal and constitutional symptoms. The reportedly increased metabolic clearance rate of glucocorticoids (Hague et al. 1989, Haak et al. 1994, Kasperlik-Zaluska et al. 1995, Allolio & Fassnacht 2006) and the remarkable increment in CBG induced by mitotane (Van Seters & Moolenaar 1991), which we have confirmed in the present series, may contribute to the increased demand of steroid supplementation.
We recorded an increase in 11-deoxycortisol levels that became significant when calculating the 11-deoxycortisol to cortisol ratio to take into consideration the remarkable decrease in cortisol levels. This finding supports the view that mitotane is able to inhibit CYP11B1 activity, as previously observed in vitro (Brown et al. 1973, Lindhe et al. 2002). Interestingly, metabolic activation of o,p'-DDD is partially dependent on CYP11B1 and this biotransformation may be critical to determine the activity of the drug (Hahner & Fassnacht 2005, Schteingart 2007). In our study, mitotane treatment decreased DHEAS levels in parallel with cortisol while changes in aldosterone and PRA were less evident. These findings are in line with the result of autoradiography studies showing that irreversible binding of o,p'-[14C]DDD was confined to both zona fasciculata and zona reticularis in normal human cortex (Lindhe et al. 2002), thus supporting the view that the zona glomerulosa is relatively spared by the cytotoxic effect of mitotane (Hahner & Fassnacht 2005). As a matter of fact, mineralocorticoid supplementation was not necessary in all patients and was of limited benefit in some patients who later discontinued it.
We have observed a marked reduction in FT4 levels that were inversely correlated with mitotane concentrations and dropped in the hypothyroid range in most evaluable patients; conversely, TSH did not change accordingly. Mitotane treatment was previously found to increase thyroxine-binding globulin (Van Seters & Moolenaar 1991) and to compete with thyroxine for thyroxine-binding globulin sites (Marshall & Tompkins 1968). However, these mechanisms may hardly account for a pattern characterized by low FT4, with roughly normal FT3 and TSH levels. These findings mimic central hypothyroidism and some patients with reduced FT4 levels were put on thyroxine. An alternative explanation may imply that mitotane affect deiodase activity, thus changing the FT4 to FT3 ratio. Scanty information on free thyroid hormone concentrations during mitotane treatment is available; anyway, it was already reported that in some patients thyroxine replacement may become necessary (Allolio et al. 2004). However, the clinical benefit of thyroxine replacement in our patients was uncertain.
We observed a clinical picture suggestive of hypogonadism in most of our male patients and, at the last available follow-up, 4 out of 7 men were replaced with testosterone. Overall, the replacement was followed by an improvement in strength, mood and sexual drive but worsened gynecomastia in 2 patients. The endocrine pattern was puzzling being characterized by a progressive decline in free testosterone concentrations, that were inversely correlated with mitotane concentrations, while total testosterone increased in the short time to decrease thereafter being gonadotropin mostly unchanged. These findings may be explained by a complex effect of mitotane, including inhibition of testosterone secretion by the testes and induction of SHBG synthesis, which was confirmed in the present study. The increase in liver release of binding proteins is likely more rapid than inhibition of testicular steroidogenesis thus explaining the particular time course of total testosterone concentrations. Because of the similarity between adrenocortical and testicular tissue, mitotane could be expected to cause testicular damage; however, there is a sparse support for this in the literature (Sparagana 1987). In a recent study, Nader et al. (2006) reported that after more than 6 months of treatment with mitotane total and free testosterone concentrations were reduced while hepatic production of SHBG was stimulated by an estrogen receptor-dependent mechanism. The lack of LH increase following decrease in free testosterone suggests that mitotane may also have an effect at the pituitary level, possibly through its estrogen-like activity. In our female patients, gonadal function was mostly preserved and this may be explained by the fact that mitotane has only a weak estrogen-like activity that may likely explain the slight hyperprolactinemia observed in some patients. As a matter of fact, mitotane showed a 1000-fold lower binding affinity than 17β-estradiol for recombinant human estrogen receptor 
(Chen et al. 1997). In the literature, there are scanty data on the effects of mitotane on female sexual function suggesting that mitotane does not interfere with gonadal steroidogenesis (Ojima et al. 1988).
It has been already reported that mitotane increases serum cholesterol mainly by increasing the LDL component (Maher et al. 1992, Terzolo et al. 2000, Allolio et al. 2004). In the present study, we confirmed the increase in total cholesterol but the new finding was the observation of a marked increase in HDL cholesterol, which was also directly correlated with serum mitotane concentrations and may be possibly related to the estrogen-like activity of the drug.
To summarize, a low-dose monitored mitotane regimen is able to provide target serum concentrations of the drug with an acceptable toxicity in an adjuvant setting. The variability in mitotane levels between different patients seems to depend more on individual factors than on the amount of drug administered. Strengths of the present investigation include the prospective nature, assessment of a rather homogeneous cohort of consecutive patients and use of a monitored mitotane treatment according to a predefined protocol. In our view, patients who are rendered disease-free by surgery and are submitted to adjunctive mitotane treatment are the best model to assess the clinical and biochemical alterations associated with mitotane use without confounding due to the systemic and endocrine effects of the tumor. Conversely, most of the previous studies were retrospective and included patients with advanced ACC, who frequently had a poor performance status or suffered the consequences of concomitant therapies (i.e. other steroid synthesis inhibitors or antineoplastic treatments), thus explaining the poor safety profile of mitotane that was often observed (Pommier & Brennan 1992, Wajchenberg et al. 2000, Dackiw et al. 2001, Schteingart et al. 2005, Allolio & Fassnacht 2006, Libè et al. 2007, Terzolo & Berruti 2008). We acknowledge the limitation of a rather small cohort of patients owing to the rarity of ACC, thus the relationship between mitotane concentrations and patient outcome should be investigated in larger studies.
Side effects occurred frequently but well-informed and motivated patients are able to cope with them without discontinuing permanently mitotane, proven that a careful tailoring of the mitotane schedule is done. Patient well-being is improved by an accurate monitoring and adjustment of hormone replacement, that is difficult to do depending mostly on a clinician's judgement since hormone measurement is of little value apart from determination of salivary cortisol and free testosterone, which may reflect more accurately the impact of mitotane on adrenal and testicular steroidogenesis. These aspects add to the complexity of adjunctive mitotane treatment. However, the complexity of treatment should not argue against its use because we have demonstrated that chronic mitotane administration is feasible and rather well tolerated whenever ACC patients are managed by physicians with specific expertise.
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Declaration of interest |
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Funding |
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Acknowledgements |
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References |
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TopAbstractIntroductionSubjects and methodsResultsDiscussionDeclaration of interestReferences |
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  M. Terzolo, M. Fassnacht, G. Ciccone, B. Allolio, and A. Berruti Adjuvant Mitotane for Adrenocortical Cancer--Working through Uncertainty J. Clin. Endocrinol. Metab., June 1, 2009; 94(6): 1879 - 1880. [Full Text] [PDF]
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and 25–75th percentile (P=0.001 at Friedman's ANOVA for repeated measurements).
