A review of mitotane in the management of adrenocortical cancer
Jaydira Del Rivero*1.[D, Tobias Else2,OD, Julie Hallanger-Johnson3.(D, Katja Kiseljak-Vassiliades4,D, Nitya Raj5, Diane Reidy-Lagunes5.(D, Sandy Srinivas6, Jill Gilbert7, Anand Vaidya8,D, Emily Aboujaoude9, Irina Bancos*,10, [D, Antonio Tito Fojo*,11, [D
1Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States, 2Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48104, United States,
3Endocrine Oncology Program, H. Lee Moffitt Cancer Center, Tampa, FL 33612, United States,
4Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado School of Medicine at Colorado Anschutz Medical Campus Aurora, CO 80309, United States,
5Memorial Sloan Kettering Cancer Center, New York, NY 10065, United States,
6Stanford University School of Medicine, Stanford, CA 94305, United States,
7Division of Hematology and Oncology, Vanderbilt University School of Medicine, Nashville, TN 37203, United States,
8Center for Adrenal Disorders, Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, United States,
9Rutgers University, Piscataway, NJ 08854, United States,
10Division of Endocrinology, Diabetes, Metabolism and Nutrition and Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, United States,
11Columbia University, New York, NY 10027, United States
“Corresponding author: Jaydira Del Rivero, MD, Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA (jaydira.delrivero@nih.gov); Irina Bancos, MD, Division of Endocrinology, Diabetes, Metabolism and Nutrition and Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA (bancos.irina@mayo.edu); or, Antonio Tito Fojo, MD, PHD, Columbia University, New York, NY 10027, USA (atf2116@cumc.columbia.edu).
Abstract
Importance: Mitotane (Lysodren, o,p’-DDD [1-(o-chlorophenyl)-1-(p-chlorophenyl)-2,2-dichloroethane)] is currently the only United States Food and Drug Administration and European Medicines Agency-approved product for the treatment of adrenocortical carcinoma.
Observations: Mitotane is challenging to administer; however, its toxicities (specifically adrenal insufficiency) are well known, and the man- agement of adverse consequences has established approaches. While often viewed through the prism of a cytotoxic agent, it can also interfere with hormone production making it a valuable asset in managing functional ACC. A recently completed prospective trial has shed some light on its use in the adjuvant setting, but further clarity is needed. Many think mitotane has a role in the advanced or metastatic setting, although prospective data are lacking and retrospective analyses are often difficult to interpret.
Conclusions and relevance: When used carefully and thoughtfully, especially in patients with hormonal excess, mitotane is an important component of the treatment armamentarium for ACC.
Key words: mitotane; adrenocortical carcinoma; rare tumors.
Implications for practice
Mitotane [lysodren, o,p’-DDD (1-(o-chlorophenyl)-1-(p-chlorophenyl)-2,2-dichloroethane)] is currently the only United States Food and Drug Administration and European Medicines Agency-approved product for the treatment of adrenocortical carcinoma (ACC). Mitotane is challenging to administer. Often viewed through the prism of a cytotoxic agent, it can also interfere with hormone production making it a valuable asset in managing functional ACC. When used carefully and thoughtfully, especially in patients with hormonal excess, mitotane is an important component of the treatment armamentarium for ACC.
Introduction
Adrenocortical carcinoma (ACC) is a rare tumor with a SEER- estimated incidence of 0.72 per million populations per year and is responsible for 0.2% of all US cancer deaths.1 With a median age of diagnosis in the fifth to sixth decades,2 ACC often presents in advanced stages with large, locally invasive primary tumors or Cushing’s syndrome. It has a 75%-90% 5-year mortality with an average survival from diagnosis of 14.5 months.3 Most cases are sporadic, with rare cases asso- ciated with familial syndromes.
For primary ACCs and localized recurrences, open surgical resection offers the best chance for prolonged recurrence-free survival. Unfortunately, most patients eventually present with metastatic disease or recurrences incurable by surgery alone. Platinum-based therapies with 25%-30% response rates and mitotane are used in treating advanced ACC.4 This article examines the clinical experience and practical considerations with mitotane.
Background
Mitotane or o, p’-DDD (1-(o-chlorophenyl)-1-(p- chlorophenyl)-2,2-dichloroethane) (Figure 1; Supplementary Figure S1), is an isomer of DDD (Rothane), an analog of the insecticide dichlorodiphenyltrichloroethane (DDT). In 1949, Nelson and Woodward observed that oral administration of DDD to dogs induced necrosis of the zona fasciculata and zona reticularis of the adrenal cortex with a significant decrease in 17-hydroxycorticosteroids.5 Although early attempts to demonstrate a similar effect in humans were unsuccessful,6,7 observations that o,p’-DDD, a contami- nant of crude DDD, was an effective adrenocorticolytic agent led to further investigations.8-10 Bergenstal et al, the first to evaluate the effects of mitotane in ACC, reported objective regression of metastasis and suppression of steroid function.11
Originally approved in 1970 as an adrenal cytotoxic agent indicated for the treatment of inoperable, functional, or non- functional ACC, mitotane remains the only drug approved by the US Food and Drug Administration (USFDA) and the European Medicines Agency (EMA) for this rare cancer. Its mechanism of action is still unknown. Experimental findings suggest mitotane may alter the peripheral metabolism of ste- roids and suppress adrenal steroidogenesis via metabolites that can inhibit enzymes in the steroid synthesis pathway, including cholesterol side-chain cleavage enzymes, CYP11A1, and CYP11B1.12,13 (Supplementary Figure S2). Furthermore, anti-tumor activity has been reported in cultures of ACC cells, where cortisol secretion might be associated with enhanced mitotane sensitivity.14
Mitotane absorption, distribution, metabolism, and elimination following oral administration
Mitotane therapy remains as much art as a science requir- ing a physician experienced with mitotane and an informed patient. Formulated as 500 mg tablets, mitotane is admin- istered in 1-6 daily doses. Its oral bioavailability is variable and can be quite low and absorption can be enhanced with a high-fat meal, which increases its solubility. Following oral administration, 60% is excreted in the stool, with 40% con- centrated in the liver, brain, adipose, and adrenal tissues. Its
CI
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1
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DDT (Dichlorodiphenyltrichloroethane [1,1’-(2,2,2-Trichloroethane-1,1-diyl)bis(4-chlorobenzene)]
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DDD Dichlorodiphenyldichloroethane [(1-chloro-4-[2,2-dichloro-1-(4-chlorophenyl)ethyl]benzene]
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Mitotane
[1,1-(Dichlorodiphenyl)-2,2-dichloroethane; o,p’-DDD]
high volume of distribution indicates it extensively binds to tissues, particularly adipose tissue, due to its lipophilic nature, properties that delay attainment of a steady state, result in substantial variability in achieving desired blood levels and contributes to its long half-life.
Mitotane is metabolized in the liver, and while the exact metabolic pathways are not fully understood, it is known to be metabolized into several derivatives. The analytical method for measuring o,p’ — DDD in the plasma involves protein frac- tionation followed by HPLC and UV detection, a cumber- some assay done at a limited number of facilities.
Its elimination reflects its extensive tissue distribution and lipid solubility. As noted above, a large fraction of an ingested dose is eliminated in the feces, while excretion following
metabolism in the feces and urine, with a half-life that can range from days to weeks. Because of its long half-life and tissue storage, mitotane continues to be eliminated for a long time after treatment has stopped.
The above observations, supported by clinical experience and mitotane levels in individual patients is also supported by pharmacokinetic data from retrospectively collected samples of patients taking mitotane that allowed devel- opment of a population pharmacokinetics (PKs) model. A 2-compartment model with first-order absorption and elimination was reported as the best to describe the PK data of mitotane. The study further concluded that lean body weight and 3 genotypes-CYP2C19*2 (rs4244285), SLCO1B3 699A > G (rs7311358), and SLCO1B1 571T > C (rs4149057)-significantly affected mitotane clearance with fat amount significantly affecting its central distribution vol- ume.15 Furthermore, Allegra et al retrospectively analyzed sex-related PKs and reported that although female sex could be a risk factor for achieving therapeutic levels of mitotane, no difference in outcomes was observed.16
Approaches to mitotane initiation and titration vary. Some physicians start at 1 g/day and increase by 0.5 g every 3-7 days to a total dose of 3-4 g, followed by adjustments accord- ing to mitotane concentrations. With this approach, most patients tolerate a maximum daily dose of 6-8 g, eventually maintained at 3-4 g or less. An alternative fast-dosing mito- tane regimen starting at 1.5 g/day and increasing to 3, 4.5, and 6 g on days 2, 3, and 4 has been proposed but did not result in faster attainment of target mitotane levels.17 According to simulations, the time to reach a steady state is about 8 weeks and 6 months, respectively.18
Mitotane levels can be monitored at 4-week intervals until desired levels are reached and then every 4-12 weeks. Following mitotane loading, dose adjustments are usually made based on blood levels and side effects, but some physicians decide on dose based on tolerance and not concentrations.
Mitotane efficacy
Multiple studies have provided insight into the efficacy of mitotane (Table 1 and Supplementary Table S1). This section highlights relevant literature in the adjuvant and metastatic settings and reports of the relevance of therapeutic dosing lev- els to support clinical effects.
Indications for mitotane therapy
Adjuvant setting
Currently, there is a fairly unanimous consensus on using mitotane as adjuvant therapy for patients with moder- ate to high risk for recurrence of their ACC. For exam- ple, the European Society of Endocrinology recommends adjuvant mitotane for patients with a high risk of recur- rence,26 including those with (1) intraoperative tumor- cell spillage; (2) any large low-grade tumor with vascular and capsular invasion; and (3) high-grade disease defined as a Ki67 > 10% or more than 20 mitotic figures per 50 high-power field regardless of tumor size.19,27 However, according to the National Comprehensive Cancer Network (NCCN), the use of adjuvant mitotane following the resec- tion of localized disease is a category 3 recommendation meaning there is disagreement if the intervention can be deemed appropriate.20
A lack of complete unanimity is understandable if one examines the limited evidence provided by retrospective anal- yses of non-randomized data. This data includes a 2007 ret- rospective study of patients with stages I to III ACC who had undergone radical surgery with curative intent. The analysis included 102 and 75 patients from the Italian and German ACC registries, respectively.21,22 This retrospective study helped affirm but did not provide the needed proof that adju- vant mitotane may delay disease recurrence in patients with completely resected ACC. The study’s retrospective nature and disparate outcomes amongst the Italian and German reg- istries are concerning and suggest a bias in mitotane admin- istration. Another large retrospective single-center trial also supports the efficacy of mitotane in prolonging recurrence- free survival.23 However, not all studies support the use of mitotane as an adjuvant therapy, including a report of 53 patients who underwent complete resections.24 In the latter, while 7 received adjuvant mitotane, mean disease-free inter- vals for those who did and did not receive adjuvant therapy were equivalent at 2.4 years. Finally, in a separate report, dis- ease recurrence within 1 year was recorded in 8 of 11 patients who received mitotane as adjuvant therapy despite having plasma levels > 14 µg/mL in 6 of those.28
In addition to the challenge of analyzing clinical data retro- spectively, assessing the value of adjuvant mitotane is further complicated by the knowledge that the risk of recurrence can vary greatly given disease heterogeneity, a variable not uni- formly addressed in most studies and even in registry data. The first ADIUVO trial, “Examining the Efficacy of Adjuvant Mitotane Treatment” (NCT00777244), enrolled patients with a diagnosis of ACC at low risk of recurrence after surgery, a cohort that represented a minority of patients and reported a better-than-expected prognosis with a 5-year RFS rate of approximately 75%.25 Forty-five patients were randomized to mitotane and 46 to observation, with HRs in the observation arm compared to the treatment arm of 1.321 (95%CI, 0.55- 3.32, P = . 54) for recurrence and 2.171 (95%CI, 0.52-12.12, P = . 29) for death, leading the authors to recommend against routine use of adjuvant mitotane in this subset of patients thus avoiding a potentially toxic treatment.29 Currently, ADIUVO-2 is enrolling patients who have undergone com- plete surgical resection and have high-risk ACC defined as stages I-III with a Ki67 > 10% (NCT03583710). However, with a primary objective of comparing the efficacy of adju- vant mitotane ± etoposide and cisplatin on recurrence-free survival, it lacks a no mitotane control and thus will not address the value of mitotane compared to no mitotane. Study recruitment to ADIUVO-2 is expected to be completed in 2025.
Advanced/metastatic setting
Again, given the rarity of ACC, only limited evidence supports the conclusion that single agent mitotane has measurable anti-tumor activity in the advanced/metastatic setting. One report of 13 patients receiving single agent mitotane described objective responses in 4/13 patients (31%; 95% CI, 18%- 44%), including one complete radiographic response and 3 hormonal responses. The durations of response were 10, 11, and 33 months for the 3 patients with hormonal responses and 48 months for the patient who scored a complete radio- graphic response. The authors noted that 4 responses were observed among the 6 patients with plasma mitotane lev- els > 14 µg/mL, whereas no response was observed among the
| Report | Subjects | Results | Comment |
|---|---|---|---|
| Mitotane efficacy-single agent mitotane in the adjuvant setting Terzolo, 200719 · Retrospective analysis of patients with stages I to Berruti, 201720 III ACC who had undergone radical surgery with curative intent | |||
| Recurrence rates [HRs compared to Italian Registry adjuvant mitotane] | · Helped affirm but not prove strong bias that in patients with completely resected ACC adjuvant mitotane may delay disease recurrence, with uncer- tain survival benefit | ||
| . Italian ACC Registry: 102 patients-47 treated with adjuvant mitotane; 55 did not receive mito- tane [control] | · 47 Italian Registry treated with adjuvant mitotane: 48.9% | · Retrospective analysis always a concern and more so with difference between control groups in risk of death, that although attributed to better prognostic factors and more aggressive treatment of recur- rences in Germany likely reflects bias in administra- tion of mitotane to better candidates in Italy driving better outcomes amongst mitotane-treated and worse in the control | |
| · German ACC Registry: all 75 did not receive mito- tane [control] | . 55 Italian Registry mitotane not administered. [control]: 90.9% HR = 2.98; 95% CI, 1.75-5.09; p, 0.0001 · 75 German Registry mitotane not administered [control]: 73.3% HR = 2.61; 95%CI, 1.56-4.36; p, 0.0001 Risk of death [HRs compared to Italian Registry adjuvant mitotane] . 55 Italian Registry Control Group: HR = 2.03; 95%CI 1.17-3.51; p = 0.011 · 75 German Registry Control Group: HR 1.60; 95%CI, 0.94-2.74; P = . 083 | ||
| Else, 201421 | · Data from 391 adult patients with a diagnosis of adrenocortical cancer were collected in a retrospec- tive single-center study | · Mitotane therapy but not RT significantly improved recurrence-free survival (HR 0.7, P <. 05) | · Authors concluded "Adjuvant therapy, particularly mitotane therapy in conjunction with radiation, should be considered to delay tumor recurrence." |
| . Integrated all available patients in 2 Cox regression models, containing either of the adjuvant treatment modalities-mitotane or radiation therapy (RT)- to estimate HRs for death and recurrence | · When both mitotane and RT were integrated into one model, there was a significant interaction between mitotane therapy and radiation therapy (HR 0.4, P < . 05), suggesting an additional benefit. · Both therapies failed to attain a significant effect on overall survival. However, data suggest an interaction of both treatments for overall survival, albeit not statistically significant. | ||
| Pommier, 199222 | · Retrospective analysis of 73 patients with ACC including 20 whose disease was unresectable and 53 who underwent complete resections | · Amongst 53 with complete resections, 7 had adju- vant mitotane | · Retrospective analysis always a concern, but no benefit ascribed to adjuvant mitotane |
| · Recurrence in all 10 patients receiving adjuvant therapy. | |||
| · Disease-free interval: 2.4 years in adjuvant group vs. 2.5 years in non-adjuvant therapy following complete resection. | |||
| Report | Subjects | Results | Comment |
|---|---|---|---|
| Baudin, 200123 | · Adjuvant mitotane given to 11 patients referred to Institut Gustave Roussy | Disease recurrence within 1 year recorded in 8/11 patients who received mitotane as adjuvant ther- apy despite plasma levels > 14 mg/L in 6/8 | · Adjuvant mitotane not recommended |
| Terzolo, 202124 [ADIUVO 1 TRIAL, NCT00777244] | · Enrolled patients with a diagnosis of ACC at low to intermediate risk of recurrence after surgery (a cohort that represents a minority of patients) · 45 patients randomized to mitotane and 46 to observation | · Better-than-expected prognosis with a 5-year RFS rate of ~75%. · Recurrence rate in observation arm: HR 1.321, 95%CI, 0.55-3.32, P = 0.54 · Death rate in observation arm: HR 2.171, 95% CI, 0.52-12.12, P = 0.29 | · Authors recommend against routine use of adjuvant mitotane in this subset of patients, who may thus avoid a potentially toxic treatment |
| Mitotane Efficacy-Single Agent Mitotane in the Advanced/Metastatic Setting | |||
| Report | Subjects | Results | Comment |
| Baudin, 200123 | · Mitotane given to 13 patients with metastatic disease referred to Institut Gustave Roussy | · Reported "objective tumor responses" in 4/13 (31%) patients with metastatic lesions, but only one a complete radiographic response while 3 were objective hormonal responses . Duration of response 10, 11, and 33 months for 3 patients with hormonal response and 48 months for a patient with CR. · Responses observed amongst 6 patients with plasma o,p'-DDD levels >14 mg/; no response observed among 7 with "consistently low" plasma levels | · Emphasizes the importance of discriminating radiographic tumor reductions from reduction in hormone levels. Both are valuable but different and can appear discordant |
| Reidy-Lagunes, 201725 | · Electronic medical records were searched to identify patients with metastatic ACC treated and prescribed single agent mitotane at Memorial Sloan Kettering Cancer Center from March 15, 1989-September 18, 2015. | · Thirty-six patients identified. | · What made the complete responders different? The authors noted the indolent disease and good performance status of responders and a mitotane level > 14 µg/mL in one patient and remarked that "Although one possibility is that the higher thera- peutic levels led to a higher response, a second and equally plausible hypothesis is that those patients (who achieved) higher levels were healthier, result- ing in an undetected selection bias in patients who were going to have a better prognosis because of the biologically favorable tumors. This is an important consideration, because in general, clinicians are will- ing to aggressively use mitotane in patients who are higher risk and/ or have more aggressive disease; in our series, however, none of the higher tumor bur- den and/or poor performance patients responded to single agent mitotane, bringing such an approach into question" |
· Response Assessment:
- Progression of disease as best response: 30/36
- Clinical progression: 1/36 (3%)
(83%)
- Complete response: 3/36 (8%).
- Partial response: 1/36 (3%) - Stable Disease: 1/36 (3%)
· All responders had nonfunctional tumors.
· All responders had nonfunctional tumors and an excellent performance status prior to initiating mitotane (ECOG 0-1).
. Two CR patients had clinical and radiographic
asymptomatic and indolent disease prior to initiating mitotane therapy. The third CR had biopsy-proven liver-only disease growing quite rapidly prior to mitotane treatment.
· Reference radiologists reviewed all imaging
and determined efficacy according to Response Evaluation Criteria in Solid Tumors [RECIST] 1.1.
Subjects
Table 1. Continued Report
7 patients with plasma mitotane levels <14 p/mL (P =. 02).28 Additionally, Reidy-Lagunes et al looking at serial radio- graphs of 36 patients who received single-agent mitotane at Memorial Sloan Kettering Cancer Center, reported 4 (11%) responses, of which 3 (8%) were complete responses. They discussed possible explanations for the responses, noting that while higher therapeutic levels could have led to responses, they could not exclude a bias that led to the selection of single agent mitotane for patients destined to have a better progno- sis because of their biologically favorable tumors.30
Given the limited activity of single-agent mitotane, the ther- apy of ACC in the advanced/metastatic settings has largely emulated therapies for other solid tumors in looking for drug combinations. In this regard, several studies have reported using mitotane in the metastatic setting in combination with chemotherapy, tyrosine kinase inhibitors, and immunother- apy. However, none have included a control arm without mitotane, reflecting the hesitancy of investigators designing studies to exclude a drug most feel has value.
Although combining other therapies with mitotane may appear advantageous, some have cautioned that induction of CYP3A4 by mitotane may impact the efficacy of therapeu- tic agents metabolized by this hepatic microsomal enzyme. Examples include initial reports that suggested mitotane induction of CYP3A4 led to a requirement for increased war- farin doses31 and the well-known phenomena of increased steroid requirements in patients receiving mitotane.32 A sub- sequent report described 4 patients with ACC concomitantly treated with the tyrosine kinase inhibitor, sunitinib, as well as midazolam and mitotane and reported decreased exposure to sunitinib and midazolam across a broad range of mitotane plasma levels.33 The pharmacokinetic data from this study was consistent with the induction of CYP3A4 by mitotane, an observation subsequently confirmed by others. 34,35
While induction of CYP3A4 may impact efficacy, it is less likely to lead to added toxicity, an expectation supported by clinical trials. Notable amongst trials examining combina- tion regimens, the First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment (FIRM-ACT) assigned patients with advanced ACC not amenable to surgical resection to either mitotane with the combination of etoposide, doxorubicin, and cispla- tin (EDP) or single agent streptozocin (Sz).36 Cross over to the alternate regimen after disease progression was allowed/ encouraged. The objective response rate was significantly higher (23.2% vs. 9.2%, P <. 001), and median progression- free survival was significantly longer (5.0 vs. 2.1 months, HR 0.55, 95%CI, 0.43-0.69, P < . 001) in the EDP group, but with comparable efficacy of both regimens as salvage therapies in second-line-PFS values of 5.6 and 2.2 months for EDP-M and Sz-M, respectively-median overall survivals of 14.8 and 12.0 months in those assigned initially to the EDP-M or Sz-M arms, respectively were found to be statistically indistinguish- able (HR 0.79, 95%CI, 0.61-1.02, P = . 07).
Two smaller single-arm studies have tested the safety of adding mitotane to chemotherapy regimens. The first, a prospective multicenter study describing outcomes in 28 patients with advanced ACC treated with EDP plus mito- tane until disease progression or onset of toxicity, reported a higher-than-expected response rate of 53.5%, including 7.1% with a complete response.37 While the second, another single-center study of daily oral mitotane with a 96-hour infusion of doxorubicin, etoposide and vincristine reported
Results
a 22% overall response rate. Neutropenia was recorded in 66% of cycles, results similar to those in patients with a diag- nosis of lymphoma using the same chemotherapy regimen without mitotane, suggesting no meaningful impact on drug concentrations with grade 1/2 nausea, diarrhea, fatigue, and neuropsychiatric changes ascribed to mitotane in 86%.38
Finally, 2 single-institution phases 2 studies with the PD-1 inhibitor pembrolizumab have reported intention-to- treat response rates of 12.5% (2/16) and 23% (9/39), with a median duration of response not reached in one study.39,40 Additionally, the phase Ib JAVELIN study treated 50 patients with ACC with the PD-L1 inhibitor, avelumab, and reported an objective response rate of 6%.41 While mitotane was not allowed in one of the pembrolizumab studies, 50% of JAVELIN participants continued mitotane, and despite this difference, similar toxicity was observed, arguing for no or minimal impact from continuing mitotane in those receiving a checkpoint inhibitor, a not surprising observation for anti- bodies indifferent to induction of cytochrome P-450.
Supplementary Table S2 summarizes the limited efficacy experience in the pediatric population.
Mitotane levels and treatment efficacy
The final efficacy consideration relates to mitotane levels, an assessment that suffers the burdens of retrospective analyses more than any (Table 2). 42 Retrospectively comparing the out- comes of those who achieve or do not achieve a given mito- tane level-usually ≥14 µg/mL or not-has built-in impactful biases. Mitotane is difficult to take, and higher levels are usu- ally achieved by the more fit, who predictably are also likely to have better outcomes. Additionally, because the median time to achieve levels ≥14 µg/mL is around 4-6 months, cohorts with higher mitotane levels will likely be enriched for those who can survive long enough to allow them time while still fit and in good health to reach such levels. Finally, lower mitotane levels may be comparably effective; however, different cutoffs have not been analyzed. Further random- ized controlled studies are needed to identify therapeutic levels of mitotane with meaningful clinical outcome and less toxicity. Studies that demonstrate these challenges include a single-center study by Wänberg that looked at the impact of achieving levels above/below 14 µg/mL on the long-term sur- vival of 43 patients who had undergone surgical resection. While the study concluded mitotane offered value it exem- plifies the aforementioned potential biases, with difficulties considering the retrospectively selected groups comparable.43 (Supplementary Figure S3)
Other studies raise questions as to the value of the ≥14 mg/L cutoff suggesting an effect with lower levels.44 In the FIRM-ACT trial, for example, overall survival was not statistically different between the 54 patients with a blood mitotane level ≥ 14 mg/L at baseline, compared with 212 with levels < 14 mg/L (HR for death 0.76; 95%CI, 0.54- 1.08; P = . 13).37 While in the report by Baudin et al, plasma mitotane levels ≥14 µg/mL were achieved in 14/24 (58%) patients, but there were few favorable radiographic and hormonal tumor responses observed among those with lev- els ≥14 µg/mL.28 Additionally, Puglisi et al analyzed patients with advanced ACC treated with mitotane for ≥3 months and ≥3 measurements of plasma mitotane.43 While shorter time in mitotane’s plasma target range (TTR) was associ- ated with more rapid progression, the authors addressed the
confounders in such a retrospective analysis that preclude firm conclusions. Finally, a prospective study of the French ENDOCAN-COMETE network found a prognostic value for early total plasma mitotane levels during the first 3 months after treatment but no prognostic value for free plasma mito- tane levels or mitotane bound to lipoprotein fractions during the consecutive 6 months. 45
Mitotane as an anti-hormonal agent
Mitotane, initially reported effective in patients with Cushing syndrome in the 1960s,46,47 can take weeks to months to achieve control of hypercortisolism, with additional therapy frequently required. Ketoconazole, metyrapone, mifepristone, and osilodrostat have a much quicker onset of action and can be quickly titrated.44,48,49 Because mitotane is a strong CYP3A4 inducer, some see ketoconazole and mifepristone, strong CYP3A4 inhibitors, as less favorable. Metyrapone and osilo- drostat on the other hand, can be safely administered but can increase 11-deoxycorticosterone levels incurring mineralo- corticoid effects on the kidney, with hypokalemia and hyper- tension. Therefore, mineralocorticoid receptor antagonists or ENaC inhibitors (eg, amiloride) are preferred in treating patients with mineralocorticoid excess. The same is true for mifepristone, yet with a different mechanism.50 Furthermore, rising cortisol leads to mineralocorticoid effects in the kidney, requiring therapy with mineralocorticoid antagonists.
Mitotane-induced endocrinopathies
Mitotane therapy can induce several endocrinopathies, including adrenal insufficiency, hypothyroidism, and hypogo- nadism (Table 3).35,51-55 Increased hepatic production of the respective binding globulins and increased steroid metabo- lism through induction of cytochrome P450A4 (CYP3A4) are the main mechanisms.
Adrenal Insufficiency, the most common endocrinopathy, occurs in all patients after a few months of treatment. Due to the induction of cytochrome CYP3A4 (an enzyme critical in the metabolism of glucocorticoids), patients on mitotane often require supra-physiologic doses of glucocorticoids to maintain euadrenalism-40-70 mg (or more) of hydrocorti- sone in 2-3 divided doses daily or 10-15 mg of prednisone in 1-2 divided doses daily. Monitoring of sufficient replacement therapy remains challenging. Dose adjustments should occur after careful review for symptoms and signs of adrenal insuf- ficiency. While cortisol levels in blood or urine measurements are unreliable, for many practitioners, elevated ACTH levels lead to a dose increase of hydrocortisone. Mineralocorticoid replacement is often not required; however, with prolonged mitotane therapy, aldosterone deficiency can occur and can be detected by monitoring for increased renin activity, hyper- kalemia, and/or hypotension.
Patients treated with mitotane should receive training on managing glucocorticoids in times of stress or illness, wear a medic-alert bracelet indicating a diagnosis of adrenal insuf- ficiency and be trained to use intramuscular injections of hydrocortisone for emergencies. Finally, even after prolonged mitotane administration, adrenal steroidogenesis usually recovers, allowing for gradual tapering of glucocorticoid replacement.56
Hypothyroidism can present clinically as primary or, more commonly, secondary hypothyroidism with increased or
| Report | Subjects | Results | Comment | |
|---|---|---|---|---|
| Wänberg, 201041 | · Single-center report evaluating the long-term survival of 43 patients after surgical resection | · 24 patients kept at mitotane levels exceeding 14 µg/ mL. · 19 were not kept at mitotane levels exceeding 14 µg/ mL. The 19 included :- 13 who could not toler- ate the "higher levels" including 5 who "abandoned mitotane therapy" - 6 who "denied mitotane therapy due to high age or severe co-morbidity." | · | Prime example of the problems with retrospective analyses. Although the authors concluded "Patients with high-stage tumors had a clear survival advantage with mitotane levels above a threshold of 14 mg/L in serum," the 19. patients NOT kept at mitotane levels ≥14 µg/mL, cannot be considered comparable to the 24 in whom levels were ≥14 µg/mL |
| · Examined the effect of achieving levels above and below 14 µg/mL. | Estimated 5-year OS stage II tumors | . · | More pronounced impact of mitotane levels ≥14 µg/mL on survival in patients with stages III-IV disease possible given greater morbidity and shorter survival of those with stages III-IV disease more likely to confound results | |
| . 80% for 6 patients with mitotane levels ≥14 µg/mL · 87.5% for 8 patients with mitotane levels < 14 µg/ mL and stage II tumors Estimated 5-year OS stage III/IV tumors . 64% for 18 patients with mitotane levels ≥14 µg/mL · 28.6% for 11 patients with mitotane levels < 14 µg/ mL | With 11/19 (58%) of those NOT kept at mitotane levels ≥14 µg/mL having denied or abandoned mitotane the comparison is as much one of mitotane vs. no mitotane | |||
| Puglisi, 202043 | · Retrospectively analyzed patients with advanced ACC treated with mitotane for ≥ 3 months, with ≥ 3 measurements of plasma mito- tane reported in the Lysosafe Online® database (HRA Pharma, France), followed at 12 tertiary centers in Italy from 2005 to 2017 · Identified 80 patients, initially treated with mitotane alone (56.2%) or plus chemotherapy (43.8%). · Assessed the time in target range (TTR), defined as the number of months in which mitotane concen- trations were ≥ 14 mg/L. | . After the first line of treatment, 25% of valid cases experienced clinical benefit (14.5% objective response, 10.5% stabilization of disease) and 75% progression, without differences between the groups of treatment · Patients with progression had a lower time in the target range (TTR) of plasma mitotane and an unfa- vorable outcome. · Death occurred in 76.2% of cases and multivariate analysis showed that clinical benefit after first treat- ment and longer TTR were favorable predictors of overall survival (OS). · In the overall group, achievement of target mitotane levels required a median time of 6 (3-9) months from the start of therapy while 14 patients (17.5%) never achieved levels ≥ 14 µg/mL. · Patients with ACC progression had a lower TTR (8.6, 0.8-14.1 months, vs. 15.8, 2.7-32.7 months; p = . 033) and an unfavorable outcome (7/57 patients (12.3%) vs. 12/19 (63.2%) patients alive at last follow-up, P = . 022). | · · · · · · | Authors concluded: "Findings support importance of mitotane monitor- ing and strengthen the concept of a therapeutic window for mitotane." Authors aware of concerns that confound retrospective analyses: Preference for combination therapy given to de novo stage IV ACC and younger patients [Concern: Who might be expected to fare better] Patients treated only with mitotane achieved a higher peak of mito- tane concentrations (26.4, 21.7-29.2 µg/mL, vs. 19.2, 14.7-24.6 µg/ mL, P = . 028) and had a more favorable outcome (6/12 (50%) vs. 13/55 (23.6%) patients alive at last follow-up, P = . 022). [Concern noted by Authors: A small subset of our patients were treated with mitotane without any other additional systemic treatment. Interestingly, these patients had a more favorable outcome, and this likely represents a selection bias because more aggressive tumors usually undergo multiple lines of treatment. The inclusion of this patient cohort with less aggres- sive ACC is one of the factors that may explain the long OS observed in the present study. Not surprisingly, higher mitotane concentrations were attained in such patients since the combination with cytotoxic agents increases toxicity and makes it difficult to give high doses of mitotane]. RFS was almost double in the cohort of patients treated with mitotane alone, despite levels of significance not being reached for the low num- bers, thus confirming the validity of the concept that tumors with lower proliferation capability (heralded by prolonged RFS) are best suited for mitotane monotherapy. [Concern: Alternately they are just destined to do better] [Concern: Lower TTR and unfavorable outcome in ACC progression could simply reflect inherent biology and more rapid progression with resultant less TTR] |
| Report | Subjects | Results | Comment | |
|---|---|---|---|---|
| FIRM-ACT trial34 | · | Prospective randomized clinical trial comparing EDP (etoposide + doxo- rubicin + cisplatin) + mitotane vs. streptozocin + mitotane | · Overall survival not statistically different between 54 patients with blood mitotane levels ≥14 µg/mL at enrollment, compared with 212 who had levels < 14 µg/mL (HR for death 0.76; 95% CI, 0.54-1.08; P = 0.13) | · Activity of the chemotherapeutic agents could obscure any impact of mitotane |
| Baudin, 200123 | · Mitotane given to 24 patients referred to Institut Gustave Roussy · 11 in the adjuvant setting; 13 with metastatic disease | · Plasma mitotane levels ≥14 µg/mL were achieved in 14/24 (58%) · 4/13 with metastatic disease all with level ≥14 µg/mL had a response including one radiographic complete response and 3 hormonal responses · Highest mitotane trough levels achieved at median interval of 3.7 months | · Emphasizes the importance of discriminating radiographic tumor reduc- tions from reduction in hormone levels. Both are valuable but different and can appear discordant | |
| Reidy Lagunes, 201725 | · · | Electronic medical records were searched to identify patients with metastatic ACC treated and prescribed single agent mitotane at Memorial Sloan Kettering Cancer Center from March 15, 1989- September 18, 2015. Reference radiologists reviewed all imaging and determined efficacy according to Response Evaluation Criteria in Solid Tumors [RECIST] 1.1. | · Thirty-six patients identified. · Response assessment: -Progression of disease as best response: 30/36 (83%) -Clinical progression: 1/36 (3%) -Complete Response: 3/36 (8%), -Partial response: 1/36 (3%) -Stable Disease: 1/36 (3%) · All responders had nonfunctional tumors. · All responders had nonfunctional tumors and an excellent performance status prior to initiating mito- tane (ECOG 0-1). . Two CR patients had clinical and radiographic asymptomatic and indolent disease prior to initiating mitotane therapy. The third CR had biopsy-proven liver-only disease growing quite rapidly prior to mitotane treatment. | · What made the complete responders different? The authors noted the indolent disease and good performance status of responders and a mito- tane level >14 µg/mL in one patient and remarked that "Although one possibility is that the higher therapeutic levels led to a higher response, a second and equally plausible hypothesis is that those patients selected to achieve higher levels were healthier, resulting in an undetected selec- tion bias in patients who were going to have a better prognosis because of the biologically favorable tumors. This is an important consideration, because in general, clinicians are willing to aggressively use mitotane in patients who are higher risk and/ or have more aggressive disease; in our series, however, none of the higher tumor burden and/or poor performance patients responded to single agent mitotane, bringing such an approach into question" |
| Endocrinop- athy | Etiology | Timing | Clinical presentation | Treatment | Complicating factors | Comment |
|---|---|---|---|---|---|---|
| Adrenal insufficiency | · Inhibition of multiple adrenal cortical enzymes with reduced cortisol | · Clinically relevant glu- cocorticoid deficiency may not occur for | · Elevated ACTH levels [although normal ACTH levels | · Concurrent geucocor- ticoid administration (invariably required), at | · Higher, or more frequent dosing of glucocorticoids required to maintain euadrenalism due to: | · Increased hepatic production of cortisol-binding |
| and mineralocorticoid | weeks to months | nearly impossible to achieve] | times, with mineralocor- ticoid replacement | -Increases hepatic production of | globulin makes mea- | |
| production | · Aldosterone deficiency | cortisol-binding globulin with | surements of total | |||
| · Destruction of the adre- | occurs with more | · Aldosterone defi- | -Physiologic glucocorticoid replacement: hydrocor- tisone 20-30 mg daily or prednisone 5-7.5 mg daily | reduced free cortisol concentra- | cortisol not reflective | |
| nal cortex | prolonged therapy. | ciency: elevated renin levels, hyperka- lemia, hyponatremia, and/or hypotension | tions -Induction of cytochrome P450A4 (CYP3A4) by mitotane with increased metabolism of exoge- | of free cortisol concentrations and monitoring relies on careful clinical eval- | ||
| -Mineralocorticoid replace- ment: fludrocortisone 0.05-0.2 mg daily | nous glucocorticoids | uation for symptoms and signs of adrenal insufficiency | ||||
| Hypothyroid- | · Pathophysiology possi- | · Clinically relevant | · Clinical signs of | · Goal in initiating | · Higher dosing of thyroid hor- | · As with glucocor- |
| ism | bly implicates an effect | thyroid hormone defi- | hypothyroidism- fatigue, feeling cold | levothyroxine therapy is normalization of free thy- | mone replacement required to | ticoid replacement |
| of mitotane on thyroid | ciency may -not occur | maintain euthyroid state due to: | increased hepatic | |||
| follicular cells, pituitary | for months | · Occurs in 45%- | roxine since thyrotropin | -Increased hepatic synthesis of thy- | production of | |
| thyrotropin production, | 100% of patients | levels may not be reliable · Thyroid function tests every 3-6 months | roid hormone-binding globulin, | thyroid hormone- binding globulin | ||
| or both | usually within 6 | can result in reduction of free | ||||
| -Primary hypothyroidism, | months of therapy | thyroxine despite increased total | makes monitoring | |||
| with lower thyroid | initiation | thyroxine carrying capacity | adequacy of replace- | |||
| hormone and elevated | · Monitor thyroid function, ideally every 2-3 months | -Increased CYP3A4 activity with | ment challenging | |||
| thyrotropin levels | hypermetabolism of thyroxine | |||||
| -Secondary hypothyroid- ism with both low/ inappropriately low thyrotropin and thyroid hormone levels.51 -Mitotane can inhibit TSH secretion | and exogenous levothyroxine | |||||
| Hypogonad- | Etiology can vary: | · Clinically relevant | · Clinically can | · Testosterone replacement | · Often, even very supra- | · Gynecomastia can |
| ism | · Primary hypogonadism | testosterone deficiency | present as fatigue, | although value uncertain | physiologic doses of intramuscu- | result from |
| with elevated gonado- | may not occur for | decreased libido, gynecomastia and/ | · Efficacy of supraphysio- logic doses of testoster- | lar testosterone fail to increase | -Low testosterone with a relative increase in | |
| tropins | months | free or bioavailable testosterone | ||||
| · Secondary hypo- | · Measure testosterone, | or decreased muscle | one unclear | concentrations. | the estrogen-to- | |
| gonadism (low or | sex hormone-binding | strength | · Contributing factors: | androgen ratio | ||
| inappropriately normal | globulin, and lutein- | . | -Increased in sex hormone-binding | -As a consequence of | ||
| gonadotropins) has been | izing hormone, every | globulin | exogenous testoster- | |||
| observed. | 6 months or when | -Increased CYP3A4 activity | one therapy with an | |||
| indicated by symptoms | -Possible reduction in 5-alpha | increase in aromati- | ||||
| · Can occur in up to 35%, within 6 months of therapy initiation | reductase activity, disabling pro- duction of dihydrotestosterone | zation to estrogen |
| Mitotane-Induced Adverse Outcomes Other than Endocrinopathies | |||||
|---|---|---|---|---|---|
| Dyslipidemia | · Mitotane stimulates the rate-limiting enzyme in cholesterol synthesis resulting in increased blood levels of LDL cholesterol | · Usually after several months of administra- tion | · Can occur in up to 50-60% of patients · Monitor with lipid profile every 3-6 months | · If mild-no therapy is needed · Consider pravastatin or rosuvastatin | |
| Gastroin- testinal side effects (nau- sea, vomiting, | · Consider suboptimal glucocorticoid replace- ment as a cause (ie, cortisol deficiency) · Actual ingestion of pills | · Early or late onset; monitor for symptoms | · Occurs at some level in 50% · Severe in 5% | · Metoclopramide, ondan- setron, loperamide · If severe-hold or decrease mitotane · Adjust timing and dose distribution of mitotane . Ingest mitotane with fatty foods (eg, milk- shake) | · Commonly improves over the course of mitotane therapy |
| diarrhea, | |||||
| anorexia) | can cause some gastroin- testinal symptoms | ||||
| Neurological | · Consider suboptimal | · Can occur in up to 30%, Usually mild . More frequent and more severe at higher/toxic levels of mitotane, ie, ataxia usually occur at higher mitotane levels | · Hold or decrease mito- tane dose in order to decrease mitotane levels | · Almost invariably reversible with supportive therapy and reduction of | |
| (lethargy, | glucocorticoid replace- | ||||
| sedation, | ment as a cause (ie, | ||||
| confusion, | adrenal insufficiency) | ||||
| sedation, | and/or excessive mito- | mitotane dose | |||
| ataxia, and | tane levels | ||||
| dizziness) | |||||
| Hepatic | · Monitor with liver function tests every 3 months | · Can occur in up to 15%, usually mild | · Decrease or stop mitotane | ||
| toxicity | |||||
reduced thyrotropin levels.57 Whether these patterns impli- cate an effect of mitotane action on thyroid follicular cells, pituitary thyrotropin production, or both is unclear. Thyroid function must be monitored by measuring thyrotropin, free thyroxine, or total thyroxine plus thyroid-binding globulin. As with adrenal hormone replacement, patients treated with mitotane sometimes require larger doses of levothyroxine to achieve/maintain a euthyroid state.
Hypogonadism and gynecomastia can develop in men treated with mitotane. Both primary (elevated gonadotropins) and secondary (low/inappropriately normal gonadotropins) hypogonadism have been observed. As with glucocorticoid and thyroid replacement, increases in sex hormone-binding globulin and CYP3A4 activity present therapy challenges. Some evidence suggests that a reduction in 5-alpha reductase activity can further disable the production of dihydrotestos- terone.35 Pre-menopausal women treated with mitotane can develop oligomenorrhea or amenorrhea, often as a conse- quence of secondary hypogonadism. Cases of endometrial hyperplasia and ovarian cysts with prolonged treatment argue for considering pelvic ultrasonography when there are con- cerning changes to menstrual regularity.53 The safety of mito- tane during pregnancy has not been studied, so non-hormonal barrier contraception and counseling regarding pregnancy risk should be discussed with all pre-menopausal women.
Mitotane-induced adverse outcome other than endocrinopathies
Mitotane therapy also has non-endocrine adverse events; thus, all patients treated with mitotane require clinical and biochemical monitoring (Table 3). 19,35,46,51-53,58-60 The most common non-endocrine adverse events are fatigue and gastrointestinal side effects occurring in at least half of patients.59,60 Gastrointestinal symptoms related to mitotane including nausea, diarrhea, anorexia and less commonly vomiting and can usually be treated pharmacologically or by changing the timing and the dose of mitotane adminis- tration. However, in a small percentage of patients, gastro- intestinal adverse events can lead to the discontinuation of mitotane.46 Gastrointestinal side effects tend to improve throughout mitotane therapy and can also be mitigated by adjusting dose distribution over the day. Increased transami- nases are reported in 15%-17% of patients, usually <3 times upper normal range and resolve with the reduction in the mitotane dose, while increased gamma-glutamyltransferase is seen in almost 50% of patients.59,60 Rarely, fulminant hepatic failure has been observed. Neurological signs such as ataxia, confusion, memory difficulties, and dizziness are reported in 30% of patients but are impactful in only 9%. Neurological symptoms are usually related to high mitotane levels and can almost invariably be reversed by temporarily holding mito- tane or reducing the dose.59-62
Mitotane stimulates hydroxymethylglutaryl-coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis, leading to low-density lipoprotein increase in up to 60% of patients.59 Whether this increase is associated with an increased cardiovascular risk in patients treated with mito- tane is unclear. Pravastatin or rosuvastatin can be used when treating mitotane-induced dyslipidemia.19 Less common adverse events observed with mitotane include skin rash, noted in 10% of patients and mild leukopenia observed in 5%-10% of patients. 59,60
Conclusion
Fifty years after its USFDA approval, mitotane remains an important part of the treatment armamentarium for ACC. As a very rare disease with heterogeneity in disease behavior, the conduct of randomized prospective trials has been difficult and hence most information consists of retrospective analyses of data and in some cases, a collection of anecdotes. While one can be critical of such data, therein lies valuable information that has helped inform the use of this unique agent in a rare disease. Its activity as an anti-hormonal agent is unquestioned. With confidence we can now say it should not be used as an adjuvant in patients with low-risk of recurrence, and that lim- ited data support its use as recommended by the European Society of Endocrinology. In the advanced/metastatic setting its use in combination regimens is largely accepted as valuable with the available randomized data. A sizeable percentage of advanced/metastatic tumors secrete hormones and will unfor- tunately suffer disease progression, and in such cases, the use of mitotane in combination regimens allows one to build the foun- dation on which to eventually add other drugs. The data indi- cate its safety with several agents with advice given to consider adjusting drugs that are impacted by the induction of CYP3A4. Regarding serum levels, despite guidelines recommending a level of 14 µg/mL as a threshold for anti-tumor activity, efficacy has been seen at lower levels. When using it as anti-hormonal strategy, its use is encouraged even if the 14 µg/mL thresh- old has not been reached, titrating dosage to patient-reported symptoms and tolerance. Finally, a practical understanding of the nuanced management strategies around dosing, monitoring, side effect management, and addressing drug-drug interactions will help clinicians use this agent more effectively to optimize the outcomes and clinical experience of patients with ACC.
Acknowledgments
We acknowledge the assistance and organizational help of John M. York, PharmD, MBA. This article grew out of an HRA Pharma Rare Diseases US Adrenocortical Carcinoma Advisory Board that involved 13 academic physicians, includ- ing medical oncologists and endocrinologists. All participants received a small honorarium for their time. At the conclu- sion of the meeting, the participants believed that an article describing the content herein would be a good idea and all were invited to voluntarily participate. Eventually 11 took part in this effort. Sections were assigned, and all read and contributed to other sections as well. This was an academic effort for the benefit of doctors who encounter patients with adrenocortical cancer, a rare disease. The order of the senior authors Drs. Irina Bancos and Antonio Tito Fojo is arbitrary.
Author contributions
All authors contributed equally to the conception/design, col- lection and/or assembly of data, data analysis and interpreta- tion, manuscript writing, and final approval of manuscript.
Conflicts of interest
Tobias Else serves on the advisory board for HRA Pharma. Julie Hallanger-Johnson was a consultant for HRA Pharma. Katja Kiseljak-Vassiliades reported a consultant/advisory relationship with HRA Pharma. Nitya Raj reported research
funding (to institution) from ITM, Camarus AB, and Corcept Therapeutics; Scientific Advisory Board for Ipsen Pharma, HRA Pharma, Progenics Pharmaceuticals, and AAA; and honoraria from ITM. Jill Gilbert was on the scientific advisory board for HRA Pharma in 2021. Anand Vaidya reported con- sulting/advisory relationships with HRA Pharma, Corcept, and Mineralys. Irina Bancos reported consulting/advi- sory relationships with HRA Pharma, Corcept, Recordati, Sparrow, Neurocrine, Adrenas, Spruce, and Diurnal; and research funding from Recordati. All participants in the HRA Pharma Rare Diseases US Adrenocortical Carcinoma Advisory Board received a small honorarium for their time.
Data availability
No new data were generated or analyzed in support of this research.
Supplementary material
Supplementary material is available at The Oncologist online.
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