Management of Endocrine Manifestations and the Use of Mitotane As a Chemotherapeutic Agent for Adrenocortical Carcinoma
Irina Veytsman, Lynnette Nieman, and Tito Fojo
From the Medical Oncology Branch, Center for Cancer Research, National Cancer Institute; and Program in Repro- ductive and Adult Endocrinology, Bethesda, MD.
Submitted March 20, 2008; accepted February 23, 2009; published online ahead of print at www.jco.org on August 10, 2009.
Authors’ disclosures of potential con- flicts of interest and author contribu- tions are found at the end of this article.
Corresponding author: Tito Fojo, MD, PhD, National Cancer Institute, Bldg 10, Rm 12N226, 9000 Rockville Pike, Bethesda, MD; e-mail: tfojo@helix .nih.gov.
The Appendix is included in the full-text version of this article, available online at www.jco.org. It is not included in the PDF version (via Adobe® Reader®).
@ 2009 by American Society of Clinical Oncology
0732-183X/09/2727-4619/$20.00
DOI: 10.1200/JCO.2008.17.2775
ABSTRACT
Adrenal cortical carcinoma (ACC) is a rare malignancy in which patients have poor overall 5-year survival. Patients with ACC can present with symptoms of hormone excess, including Cushing’s syndrome, virilization, feminization, or-less frequently-hypertension with hypokalemia. In many patients with ACC, advanced disease at presentation precludes surgery or is followed by local relapse or distant metastatic disease that cannot be managed surgically. In these instances, chemotherapy is often tried, but its limited efficacy all too often leaves the problem of persistent hormonal excess. Physicians who treat patients with ACC and severe hypercortisolism should recognize that uncontrolled hormone production is a malignant disease, which has severe consequences that require aggressive management. Because chemotherapy benefits only a small percentage of patients, steroidogenesis inhibitors, including mitotane, ketoconazole, metyrapone, and etomidate, should be used singly or in combination even as chemotherapy is administered. Diligent management with frequent adjustments is required, especially in patients with chemotherapy-refractory tumors that continue to grow. In the absence of randomized, controlled trials, adjuvant use of mitotane remains controversial, although the authors of a recent case-control study argue for its use. Despite difficulty administering effective doses, most clinicians agree that mitotane should be used if the tumor cannot be removed surgically or should be used as adjuvant therapy if there is a high likelihood of recurrence. The option of long-term monotherapy is restricted to patients who tolerate mitotane and either experience a clinical response or are at high risk for recurrence. Recommendations are provided to help manage patients with this difficult disease and to improve the quality of their lives.
J Clin Oncol 27:4619-4629. @ 2009 by American Society of Clinical Oncology
INTRODUCTION
Adrenal cortical carcinoma (ACC) is a rare malig- nancy, with an incidence of one to two occurrences per 1.7 million of the population.1,2 ACC has a bi- modal distribution, in which there is a higher inci- dence in children younger than 5 years and in adults in their fourth and fifth decades of life. ACC is slightly more common in women.2,3 Because ACC is often at an advanced stage at diagnosis, the overall 5-year survival remains between 20% and 45%.4
CLINICAL PRESENTATION AND GENETICS
ACCs can be asymptomatic or can present with symptoms of hormone excess or complaints refer- able to an abdominal mass. Although early studies reported that approximately 50% of ACCs were functional, recent series report hormone secretion in up to 79%-an increase explained entirely or in
part by improved assays.2,3 Classifying ACCs by hor- mone profile has limited value.5,6
Hormone excess presents clinically as Cush- ing’s syndrome, virilization, feminization, or-less frequently-hypertension with hypokalemia (Table 1).2,7-15 Functional tumors most com- monly produce cortisol, which leads to Cushing’s syndrome. Compared with other causes of Cush- ing’s syndrome, ACCs cause more virilization, especially in children, because of cosecretion of 17-ketosteroids and dehydroepiandrosterone.9,10 Although hypertension and hypokalemia may be caused by excess mineralocorticoids, they are more likely caused by markedly elevated cortisol secretion in a patient with ACC. Excess cortisol overwhelms its normal inactivation to cortisone in the proximal tubule by 11ß-hydroxysteroid dehydrogenase type 2, which allows cortisol to interact with the miner- alocorticoid receptor.16 In contrast, patients with hormonally inactive ACC usually present with ab- dominal discomfort or back pain. Only occasionally
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| Table 1. Clinical and Biochemical Manifestations of Hormone Excess in Adrenal Cortical Carcinoma | ||
|---|---|---|
| Cortisol* (30%-40%)1-3,5,7,10,11 | Estrogen or Androgen (20%-30%)1-3,5,8-11 | Mineralocorticoid (rare)1-3,5,10-15 |
| Clinical manifestations | ||
| Acne | Estrogens/androgens: Acne, decreased libido, precocious puberty | Hypertension |
| Decreased growth in children | Estrogens: Feminization in ment+-gynecomastia, testicular atrophy, and low sperm count | Hypokalemia |
| Hypertension | Androgens: Virilization in women§-hirsutism, deep voice, male pattern baldness, and oligomenorrhea§ | Weakness |
| Hypokalemia Weight gain | ||
| Hormonal manifestations | ||
| Elevated 24-hour urinary free cortisol and serum cortisol | Increased serum or plasma estradiol and estrone | Increased 11-deoxycorticosterone and/or corticosterone |
| Failure to suppress serum cortisol after dexamethasone 1 mg | Increased serum testosterone and adrenal andogens | Increased plasma aldosterone |
| Elevated late-night salivary cortisol | Increased 24-hour urine 17-ketosteroids (DHEA, DHEAS, D5-androstenediol, D4 androstenedione) | Suppressed plasma renin activity |
| Suppressed plasma ACTH Increased adrenal androgens (DHEA, DHEAS, | Plasma aldosterone-to-renin activity ratio > 20 | |
| D5-androstenediol, D4-androstenedione) | ||
| Increased serum steroid precursors (pregnenolone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, 11-deoxycortisol) | ||
| Abbreviations: ACTH, adrenocorticotropic hormone; DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate. *Also known as Cushing's syndrome. tFeminization occurs with estrogens and/or androstenedione, which is converted to estrogen peripherally. #Effect associated with estrogen excess only. § Effect associated with androgen excess only. |Profile of functional ACC. | ||
do patients present with fever, weight loss, and anorexia. Indeed, the well-being of patients whose tumors do not secrete steroids can be little affected.17
Although the cause of most ACC is unknown and most patients lack identifiable risk factors, heredity plays a role in some patients. Risk factors for ACC include the Li-Fraumeni syndrome, multiple endo- crine neoplasia type 1 (MEN1), familial adenomatous polyposis coli (Gardner syndrome), and the Beckwith-Wiedemann syndrome. With the exception of the latter syndrome, genetic predisposition is thought to arise from mutations in tumor suppressor genes that increase the risk of several cancers, including ACC (Appendix Table A1, online only). Somatic mutations/alterations in genes responsible for these genetic syndromes also occur in sporadic ACC.
EVALUATION AND WORK-UP
The initial evaluation should determine whether the tumor is func- tional and should define the extent of disease. The risk of seeding tumor, although not quantified, and the difficulty in the differentia- tion of benign from malignant tumor argue against a diagnostic bi- opsy in a patient with an isolated adrenal mass without evidence of metastases; surgical resection is indicated as a diagnostic and thera- peutic procedure. However, if widespread metastases argue against surgical resection or if disease elsewhere suggests a primary other than adrenal, a diagnostic procedure is indicated.
Because many patients do not present with symptoms of hor- monal excess, it is important to assess hormonal status and the need for steroid replacement to avoid adrenal insufficiency after remov- ing a functioning tumor that suppressed adrenocorticotropic hor-
mone (ACTH) with involution of the contra-lateral adrenal (Table 1). Some studies report hormone secretion, especially cortisol, as an independent, poor prognostic factor, which is an intuitive observa- tion, given cortisol’s ability to suppress immune function.11,18,19 In addition, a recent series identified three factors significantly associ- ated with a shorter survival: older age at diagnosis, stages III (ie, local lymph nodes) to IV (ie, local organ invasion or distant metas- tases) disease, and cortisol hypersecretion. Abiven et al20 speculated that the association of cortisol hypersecretion could be attributed to either the comorbidity of Cushing’s syndrome, the immunosuppres- sive effects of excess cortisol, or the “pathophysiology of cortisol- secreting ACC” that leads to the growth of a more aggressive tumor. Importantly, neither mineralocorticoid or androgen secretion nor ortho, para, dichlorodiphenyl dichloroethane; mitotane (Lysodren; Bristol-Myers Squibb, Princeton, NJ) treatment was associated with a risk of metastases.2º However, another recent study could not discern a significant difference on survival between functional and nonfunc- tional tumors.21
Although both computed tomography (CT) and magnetic reso- nance imaging (MRI) can be used in the management of patients with ACC, a thin-collimation CT of the chest and abdomen is recom- mended as the initial imaging technique. Both CT and MRI can help discriminate benign adenomas from malignant lesions. On CT scans, ACCs usually have higher density values (ie, lower lipid content) and are typically inhomogeneous; on MRI, they are usually isointense with liver on T1 images, with intermediate to high intensity on T2 images (Appendix Fig A1, online only).22-24 MRI, however, is superior in assessing the extent of vascular invasion, especially into the inferior vena cava with right adrenal tumors and should be obtained before a
Management of Adrenocortical Cancer
surgical resection if there is concern regarding vascular involvement.25 The role of [18F]fluorodeoxyglucose (FDG) -positron emission to- mography (PET) is not well established and cannot be recommended in routine evaluation or follow-up.26-28 Although it might help dis- criminate a benign adenoma from a malignant tumor, it cannot dif- ferentiate ACC from other tumors with high metabolic activities.29
Because of the difficulty distinguishing small ACCs (ie, approxi- mately 4 to 6 cm) without local spread or distant metastases from a benign adenoma, several multiparametric approaches have been pro- posed for establishing malignancy. Among these, the Weiss criteria, first proposed in 1984, is most widely utilized.30-32 It is based on nine histopathologic properties of adrenocortical tumors known to be ma- lignant either because they metastasized or recurred locally. According to Weiss,30 a combination of these “nine criteria was most useful in distinguishing malignant from benign tumors”: (1) nuclear grades 3 to 4; (2) mitotic rate greater than 5/50 high-power fields; (3) atypical mitoses; (4) tumors with 25% or less clear cells; (5) diffuse architec- ture; (6) microscopic necrosis; and (7-9) venous, sinusoidal, and cap- sular invasion. Although Weiss originally noted metastases and/or recurrence in zero of 24 and 18 of 19 tumors with zero to two or four or more criteria, respectively, the threshold for malignancy was sub- sequently lowered to three or more of the nine histopathologic criteria. Although these properties often cluster and the issue of whether the presence of a greater number of criteria is associated with a worse prognosis is not clear, tumors with higher Weiss scores clinically often behave more aggressively.
TREATMENT
General Considerations
Management of patients with ACC requires a multidisciplinary approach, both at presentation and at disease relapse. At presentation, the principal considerations are surgical, which is the only curative option for ACC and which should be pursued aggressively with a qualified oncologic surgeon. For an adrenal mass that is deemed likely malignant radiologically, laparoscopic resection is contraindicated be- cause of the seeding of tumor than unfortunately occurs. Unfortu- nately, despite aggressive surgery, 70% to 85% of patients experience relapse locally or develop metastases, which explains a 5-year survival after complete resection of only 16% to 35% and survival for less than 1 year in patients with incomplete resection.33-35 The latter survival rate argues strongly against a surgical procedure that removes only a part of the tumor, because this can lead to intraoperative seeding and a poor outcome.
Recurrence in the surgical field is common after an optimal resection, and serious consideration should be given to a re-operation, especially if sufficient time-arbitrarily defined as 6 months to a year-have elapsed since the initial operation. Although we believe that repeat surgery may improve survival, the extent of benefit is difficult to discern, because most nonrandomized comparisons en- cumber no-surgery cohorts with patients who likely had more aggres- sive disease not amenable to re-operation.36 Even less clear is the role, if any, of administering radiation to the surgical field. Initial studies37 reported a lack of benefit with adjuvant radiation, but later studies, which possibly used better techniques, claim high response rates with little toxicity.38,39 Because of questionable benefit and likelihood that a subsequent re-operation will be technically more difficult, postopera-
tive radiation should only be administered rarely after initial surgery and should be reserved for a select group after a second or subsequent re-operation. Finally, for patients in whom surgery is not possible, chemotherapy is often tried, albeit with only modest success. With the exception of a single regimen that had reported response rates of 54% to 65%,40,41 the majority of trials report response rates of 13% to 39%, nearly all of which were short-lived, partial responses.40-47 As regards mitotane early in the disease, the lack of convincing data and the difficulty in administration of most doses argue for its use only if the tumor cannot be removed surgically or as adjuvant therapy only if there is a high likelihood of recurrence. (See Mitotane section).
Both at the outset and especially when tumors grow despite chemotherapy, it is critical to recognize that uncontrolled hormone production by an ACC is a malignant disease with severe conse- quences. Excess hormone production can impact quality of life and may cause death.5,48,49 Antihypertensive therapy and deep venous thrombosis prophylaxis should be instituted if clinically indicated. In this Treatment section, we discuss the most commonly used inhibitors of steroidogenesis, provide guidelines for therapy, and consider drug interactions important in patients with cancer. We conclude with general recommendations that integrate various agents.
Mitotane
Background and mechanism of action. Mitotane, or o,p’DDD, is an isomer of the insecticide para (p’) p’DDD and is a chemical con- gener of the insecticide dichlorodiphenyltrichloroethane. This adre- nolytic drug was used first for the treatment of ACC and then was used for other causes of Cushing’s syndrome.5º The development of mitotane dates to the 1960s, when investigators first noted de- struction of the zona reticularis and the zona fasciculata in dogs that received mitotane and experienced marked decreases in 17- hydroxycorticosteroids and the glucocorticoid response to ACTH. Subsequent studies demonstrated mitotane inhibition of adrenocor- tical steroid synthesis by inhibition of cholesterol side-chain cleavage (ie, human cytochrome P450 [CYP], cholesterol desmolase, or 20, 22 desmolase) and 11ß-hydroxylase (ie, P450 11ß or CYP11b1). This inhibition affects extra-adrenal cortisol disposition by inducing its hepatic clearance, reducing hormone production, and ameliorating the symptoms of hormone excess (Fig 1).51
Although not conclusively proven, metabolic transformation and oxidative damage through production of free radicals are gener- ally accepted as the mechanisms that mediate mitotane cytotoxicity, with some transformation occurring in the tumor. Metabolism occurs via a reactive acyl chloride thought to bind adrenal cortical bionucleo- philes as well as to serve as the intermediate in the formation of o,p’-DDA (1,1-[o,p’-dichlorodiphenyl] acetic acid). The metabolic reaction is dependent on oxygen and nicotinamide adenine dinucle- otide phosphate, and is inhibited by ketoconazole but not by amin- oglutethimide, metyrapone, or other steroids. This has led to the suggestion that mitotane is metabolized by a novel, nonsteroidogenic CYP that is active in xenobiotic metabolism in the adrenal cortex.52 An ex vivo tritium release assay (in which tritiated mitotane is the sub- strate) has shown a possible correlation between the ability of tumors to metabolize mitotane and the response to mitotane; however, this has not found widespread use.53
Treatment recommendations. Mitotane is formulated as 500- mg, scored tablets for oral administration (Table 2). After oral admin- istration, 60% is excreted in stool, usually unchanged, and 40%
Cholesterol
Side chain cleavage
I
(20, 22 Desmolase)
M
K
E
Pregnenolone
17a-hydroxylase
17OH-Pregnenolone
17-Lyase
Dehydroepiandrosterone
3ß-HSD
3ß-Hydroxysteroid dehydrogenase
3ß-HSD
Progesterone
17OH-Pregnenolone
Androstenedione
21-Hydroxylase
21-Hydroxylase
Peripheral tissue
Deoxycorticosterone
11-Deoxycortisol
Testosterone
11ß-Hydroxylase
11ß-Hydroxylase
M
M
K
K
- Mitotane (M)
Me
Me
E
E
- Ketoconazole (K)
- Metyrapone (Me)
Aldosterone
Cortisol
- Etomidate (E)
concentrates in liver, brain, adipose, and adrenal tissues. At initiation of therapy, adipose tissue accumulation delays achievement of thera- peutic serum levels for 12 to 14 weeks. Conversely, after discontinua- tion of mitotane, its slow release from adipose tissue results in measurable serum levels for months.54-57 Although a rare patient tolerates high doses from the outset, a rapid increase is not possible in the majority of patients. A preferable administration schedule is to start with 1 to 2 g/d and to increase the daily dose by 1 to at most 2 g every 1 to 2 weeks to the maximum-tolerated dose (never > 6 to 10 g/d). Four to six grams is usually sufficient.58 Mitotane levels should be monitored by using a gas chromatography-flame ionization detection assay initially at 4 to 8 weeks intervals until a level of 10 to 14 mg/L is reached and subsequently at 3-month intervals59 (Data Supplement: Notes, online only).
As body stores saturate, lower doses are needed. In patients who receive long-term therapy, mitotane doses should be adjusted every 4
to 8 weeks on the basis of serum levels until a stable level on a stable dose is achieved with tolerable adverse effects.
Toxicities and drug interactions. Although mitotane can effec- tively manage hormone excess, its toxicity profile limits tolerability. GI toxicity, including anorexia, nausea, vomiting, and diarrhea, is re- ported by 78% of patients who receive daily doses of 2 g or more.37 At higher doses, neuromuscular manifestations, including ataxia, speech disturbance, confusion, somnolence, muscle tremors, and vertigo, may appear. Rare adverse effects include hyperbilirubinemia, hyper- cholesterolemia, and a skin rash.60,61 The latter should be treated symptomatically, because it subsides in most patients. Mitotane in- creases hepatic production of sex hormone binding globulin and cortisol binding globulin, which factitiously increases total serum lev- els of gonadal steroids and cortisol. As a result, urinary free cortisol must be used to monitor efficacy. Mitotane can also decrease thyroid hormone, so that thyroid-stimulating hormone and free thyroxine
| Table 2. Drugs Used to Manage Hormonal Symptoms in Adrenal Cortical Carcinoma | ||||
|---|---|---|---|---|
| Drug | Initial Dose | Titration | Maximum Dose | Adverse Effects |
| Mitotane | 1-2 g/d as single or divided dose | 1-2 g/d every 1-2 weeks | 6-10 g/d with target serum level of 10-14 mg/L | Nausea, vomiting, anorexia, diarrhea, ataxia, speech disturbance, confusion, skin rash, and hyperbilirubinemia |
| Ketoconazole | 200 mg three or four times per day | 400 mg/d every 1-2 days | 3,600-6,400 mg/d | Nausea, vomiting, abdominal pain, fever, weakness, hypertension, hypothyroidism, gynecomastia, and hypertriglyceridemia |
| Metyrapone | 0.5-1 g/d in two to four divided doses | 0.5-1 g/d every few days | 4-6 g/d | Hypertension, alopecia, hirsutism, acne, nausea, abdominal discomfort, headache, weakness, and leukopenia |
| Etomidate* | 0.1-0.3 mg/h infusion or 0.2-0.6 mg/kg intravenous bolus | 0.1-0.3 over a few hours | 3 mg/ht | Hypotension, myoclonus, and sedation |
| *Propylene glycol vehicle. tDaily dose of propylene glycol should not exceed 25 mg/kg. | ||||
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should be monitored every few months, and replacement should be instituted if needed.
Mitotane increases the clearance of exogenously administered steroids so that replacement hydrocortisone doses need to be in- creased by about one third, from 15 mg in the morning and 7.5 mg in the afternoon to approximately 30 mg daily (ie, 20 mg in morning and 10 mg in afternoon).62 Higher doses are rarely required, and a decision to administer additional steroids is usually made clinically. Mitotane effects on other drugs are not well documented. For example, full doses of adriamycin, etoposide, and vincristine-chemotherapy agents metabolized principally by CYP3A4-have been administered with mitotane without evidence of more tolerability or additional toxicities.42 Data that support inhibition of other CYP involvement are limited.63
One case report suggests that spironolactone may reduce mito- tane efficacy, although the magnitude of the effect is uncertain. Given the lack of convincing evidence, we feel that spironolactone in combi- nation with mitotane is warranted in the management of a patient with hypertension from excess mineralocorticoids.64
Ketoconazole
Background and mechanism of action. Ketoconazole is a broad- spectrum antifungal drug with a low toxicity profile that has been in use since the 1970s.65 The observation that ketoconazole caused gy- necomastia was evidence that it could inhibit the synthesis of steroids in mammals.66,67
Ketoconazole inhibits C17-20 desmolase, the enzyme responsi- ble for androstenedione biosynthesis, and this can lead to stronger inhibition of testosterone biosynthesis compared with its inhibi- tion of cholesterol side-chain cleavage, 11ß-hydroxylation, and 18- hydroxylation.68-70 In vitro, ketoconazole binds the glucocorticoid receptor directly to prevent ligand binding and stimulation.71 Keto- conazole inhibition of CYP3A4 occurs at antifungal doses and at the higher cancer treatment doses.72
Treatment recommendations. Although an initial ketoconazole dose of 200 mg twice daily is usually recommended for antifungal therapy, patients with ACC and Cushing’s syndrome treatment can start with 200 mg three or four times per day (Table 2). The dose can be increased by 400 mg/d every few days while liver function is moni- tored, and it can reach a maximum of 1,200 to 1,600 mg administered three or four times daily (ie, total daily dose of 3,600 to 6,400 mg). Because ketoconazole requires stomach acidity for absorption, proton pump inhibitors should be avoided.
Toxicities and drug interactions. Occurrences of hepatitis and transient elevations in liver function tests (LFTs; ie, ALT, AST, alkaline phosphatase, bilirubin) have been reported, although death as a result of hepatic dysfunction is rarely reported (one of 10,000 patients).73 Hepatotoxicity has been observed in patients who received as little as 200 to 800 mg daily. Symptoms begin within 1 to 3 weeks to as late as 12 to 15 months after starting therapy, and this requires continued LFT monitoring. Accompanying symptoms include nausea, back- ache, fever, and weakness. Withdrawal or reduction of ketoconazole can normalize LFTs within days to weeks.74
Other dose-related toxicities that have occurred in more than 40% of patients at ketoconazole doses greater than 800 mg/d include nausea, vomiting, and abdominal pain.75 Less common adverse effects include hypertension,76 alopecia,77 contact dermatitis, an erythema
multiforme-like syndrome,78 adrenal insufficiency,79 gynecomastia,80 hypertriglyceridemia,81 and hypothyroidism.82
As a CYP inhibitor, ketoconazole can affect the metabolism of doxorubicin and other anthracyclines, etoposide, the taxanes, and the vinca alkaloids, and it can increase drug toxicity. When using these drugs it is best to avoid coadministration of ketoconazole. However, if ketoconazole is an integral component of the management of hor- monal excess, it should be discontinued 24 to 48 hours before giving the chemotherapy drugs listed in Table 3 and may be resumed 24 to 48 hours after the administration of these drugs. Other drugs used in patients with cancer are also affected.83-85
Metyrapone
Background and mechanism of action. Metyrapone (also known as metapyrone or metopirone), which was first used in 1959 to assess the pituitary-adrenal axis,86,87 inhibits adrenal steroidogenesis and is used alone or in combination for Cushing’s syndrome as a result of Cushing’s disease, ectopic ACTH, or ACC.88-90 Metyrapone reduces cortisol and aldosterone production by inhibiting 11ß-hydroxylation in the adrenal cortex.91 Because metyrapone inhibits a distal step in the pathway, there is an increase in precursors, including the weak min- eralocorticoid 11-deoxycortisol, which obviates the need for long- term mineralocorticoid replacement.92,93
The largest series to use metyrapone as a single agent evaluated 91 patients with Cushing’s syndrome, including six patients with ACC.94 In 10 patients with adrenocortical adenomas and in six with ACC, a median metyrapone dose of 1,750 mg/d (range, 750 to 6,000 mg/d) reduced mean cortisol levels to less than 400 nmol/L in 13 patients (81%). Other than causing transient hypoadrenalism and hirsutism, metyrapone was well tolerated.
Treatment recommendations. Metyrapone is available as a 250- mg, soft gelatin capsules (Table 2; Data Supplement: Notes, online only). The dose needed to inhibit cortisol production ranges from 500 to 6,000 mg/d, although little is gained with daily doses greater than 2,000 mg. As with mitotane, metyrapone is begun at a low daily dose of 500 to 1,000 mg (in two to four divided doses) and is escalated every few days.95
Toxicities and drug interactions. Adverse effects with metyrap- one include hypertension, which caused by excessive secretion of desoxycorticosterone96,97; alopecia, hirsutism, and acne, which are most likely secondary to elevated adrenal androgens and testoster- one; and abdominal discomfort and nausea.97,98 Rare adverse ef- fects include bone marrow depression and leukopenia, dizziness, headache, weakness, confusion, and sedation. Drug interactions occur frequently, because metyrapone is a CYP inhibitor. A few occurrences of acetaminophen overdose while on metyrapone have been reported.99
Etomidate
Background and mechanism of action. Etomidate, like ketocon- azole, is an imidazole derivative that was first marketed as an ultrashort-acting, nonbarbiturate hypnotic that was used in the intensive care unit for rapid hypnosis induction and long-term sedation.100 However, mortality noted with long-term use uncov- ered adrenal insufficiency, and this discovery led to use of etomi- date in hypercortisolemia.101
| Table 3. Ketoconazole Interaction With Other Drugs | ||||
|---|---|---|---|---|
| Drugs Potentiated by Ketoconazole by Degree of Effect | Drugs Contraindicated With Ketoconazole | |||
| Major | Moderate | Minor | Synergistic | |
| Aprepitan | Amlodipine | Armodafinil | Amprenavir | Alprazolam |
| Fentanyl | Benzodiazepines | Ciclesonide | Darunavir | Astemizole |
| Irinotecan | Budesonide | Etoposide | Doxorubicin | Cisapride |
| Lapatinib | Coumarin-like | Mifepristone | Erythromycin | Ergotamine |
| Levomethadyl | Cyclosporine | Modafinil | Fosamprenavir | |
| Midazolam | Docetaxel | Phenytoin | Lopinavir | |
| Simvastatin | Methylprednisone | Vinorelbine | Ritonavir | |
| Statins | Donepezil | |||
| Sunitinib | Erlotinib | |||
| Temsirolimus | Estrogens | |||
| Felodipine | ||||
| Fluticasone | ||||
| Gefitinib | ||||
| Imatinib | ||||
| Indinavir | ||||
| Isoniazid | ||||
| Mefloquine | ||||
| Methadone | ||||
| Nifedipine | ||||
| Prednisolone | ||||
| Quinidine | ||||
| Salmeterol | ||||
| Tacrolimus | ||||
| Tretinoin | ||||
Etomidate inhibits the same two enzymes that mitotane inhibits, cholesterol side-chain cleavage and 11ß-hydroxylase, and thus im- pairs cortisol and aldosterone synthesis.101,102 Inhibition of 11ß- hydroxylase occurs at low doses, and impairment of side-chain cleavage occurs at higher doses.102
Treatment recommendations. As the only parenteral steroido- genesis inhibitor, etomidate has been used clinically for 2 to 22 weeks in patients in the intensive care unit (Table 2).103,104 Administration begins as a low-dose infusion of 0.1 to 0.3 mg/h105,106 or as single-dose boluses of 0.2 to 0.6 mg/kg intravenously.103 Etomidate can decrease cortisol levels within 11 to 24 hours of initiation of therapy, and dosing should be adjusted to achieve the desired level.106 To avoid toxicity, the daily dose of the propylene glycol vehicle should not exceed 25 mg/ kg.107 Because of limited clinical experience, the requirement for par- enteral administration with daily monitoring, and the occurrence of adverse events, etomidate should be reserved for patients who cannot take oral medications.
Toxicities and drug interactions. At higher doses than those used to inhibit steroidogenesis, etomidate can cause hypotension, myoclo- nus, and sedation; the addition of other sedating agents may induce hypnosis. Etomidate should be given carefully with calcium chan- nel blockers.108
INTEGRATED RECOMMENDATIONS FOR MANAGING HORMONAL SYMPTOMS
Oncologists treating patients with ACC who have severe hypercorti- solism should aggressively manage these symptoms in anticipation of a surgical intervention or concurrently with systemic chemotherapy.
Because chemotherapy is often inadequate, treatment of the hor- monal excess should not be delayed with the expectation that chemo- therapy will reduce the tumor burden and improve symptoms. Instead, an aggressive medical approach to the management of excess hormone secretion by using steroidogenesis inhibitors singly or in combination should be adopted, even as chemotherapy is adminis- tered. Mitotane, the cornerstone of any strategy, should be started as soon as a diagnosis has been made and should be used in all patients at the highest tolerable dose. Even as mitotane is started, the physician must be aware that a therapeutic level and steady-state level will not be reached for several months, so that other agents must be initiated concurrently, especially if the symptoms are severe. In patients with LFTs within three times the normal levels, we recommend initiation of therapy with ketoconazole to rapidly reduce cortisol production, and we recommend mindfulness of the potential for a pharmacokinetic interaction with chemotherapy agents (Table 3). If LFTs are elevated, if an aggressive ketoconazole dose escalation is unsuccessful in con- trolling symptoms, or if toxicity develops, metyrapone alone or in combination with ketoconazole can be added. In patients unable to take oral medications, an intravenous infusion or bolus of etomidate can be used with plans to switch to an oral regimen when possible. We would emphasize that physicians must see or speak with these patients once per week, at a minimum, because dose adjustments are often required weekly. Cortisol levels must be monitored frequently to ad- just dosage and to avoid adrenal insufficiency, which occurs infre- quently in patients with cortisol-producing tumors. Should this occur, hydrocortisone and mineralocorticoid replacement should be insti- tuted as indicated in the Caveats Regarding the Use and Monitoring of Steroidogenesis Inhibitors section.
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We note here that, in a patient with advanced ACC and an anticipated short life span, the physician could consider a palliative approach that emphasizes the benefit of managing Cushing-related symptoms while avoiding the adverse effects of chemotherapy. Mito- tane in this setting could effect a reduction in tumor; however, given its limited activity as a cytotoxic agent in patients with advanced disease, this should not be expected by either the patient or the caregivers.
Caveats Regarding the Use and Monitoring of Steroidogenesis Inhibitors
All adrenal steroidogenesis inhibitors can cause adrenal insuffi- ciency. It can be difficult to distinguish between adrenal insufficiency and drug toxicity, and the physician must often rely on clinical intu- ition to ascertain the adequacy of adrenal function.
Although control of hormone production may not be possible in most patients with rapid tumor growth, an aggressive management occasionally is successful in achieving partial or-rarely-complete inhibition of hormone production. In patients receiving mitotane, serum cortisol cannot be used to monitor treatment efficacy, because it increases cortisol-binding globulin and artificially raises total corti- sol. These patients should be monitored by using urinary free cortisol (Data Supplement: Notes, online only).98 If it is possible to block cortisol synthesis, patients should receive replacement therapy. Many physicians prefer this option so as to avoid the risk of adrenal insuffi- ciency (and death). Hydrocortisone (20 mg in the morning and 10 mg in the afternoon) and fludrocortisone (100 to 200 µg in the morning)
should be administered, and the patient should be advised to obtain a bracelet or necklace that will alert emergency personnel to the possi- bility of adrenal insufficiency in the case of an acute emergency. Fi- nally, we would note that, when mitotane is used as an antitumor agent in a patient without evidence of hormonal excess, replacement therapy must be instituted at the outset or within the first few months of starting mitotane, because its adrenolytic properties reduce normal adrenal hormone production.
MITOTANE AS AN ANTITUMOR AGENT: ISSUES AND CONTROVERSIES
Because mitotane has both antitumor and antihormonal properties, we discuss here the use of mitotane as an antitumor agent. Unfortu- nately, the rarity of ACC has precluded conduct of studies needed to answer many questions (Data Supplement, online only).
Single-Agent Mitotane
Mitotane (Table 4) was initially used as monotherapy in patients with locally advanced or metastatic ACC; tumor regression was re- ported in 34% to 61% of patients with measurable disease, and a reduction in urine hormone levels of 69% to 85% was reported (Table 4).109-111 Unfortunately, the high response rates in these early studies have not been supported by subsequent trials, and it appears that partial response occurs in, at most, 10% to 30% of patients and likely
| Table 4. Mitotane As Monotherapy | ||||||
|---|---|---|---|---|---|---|
| Study | No. of Patients | Response Type | Patients Who Responded (%) | Comment | ||
| CR | PR | |||||
| Bergenstal et al109* | 18 | — | 7 | 39 | Evaluated by x-ray and steroid response | |
| Hutter et al110* | 59 | with measurable disease | — | 20 | 34 | Evaluated by x-ray and/or physical exam |
| Hutter et al110* | 62 with measurable steroid secretion | — | 43 | 69 | Evaluated by corticosteroid response | |
| Lubitz et al111* | 75 with measurable disease | — | 46 | 61 | Evaluated by x-ray and/or physical exam | |
| Lubitz et al111* | 61 with measurable steroid secretion | — | 52 | 85 | Evaluated by steroid response | |
| Venkatesh et al112+ | 72 | — | 21 | 29 | — | |
| Luton et al11¢ | 37 | — | 8 | 22 | Mitotane did not have a significant effect on survival | |
| Decker et al113§ | 36 | 2 | 6 | 22 | Poorly differentiated tumors excluded; adriamycin treatment | |
| Haak et al1141 | 55 | 8 | 7 | 27 | Responses were observed only in patients with levels > 14 mg/L | |
| Barzon et al1151 | 11 | — | 2 | 18 | — | |
| Williamson et al44&# | 16 | — | 2 | 13 | Only patients without benefit from cisplatin/ etoposide were treated | |
| Baudin et al57§ 1] | 13 | 1 | 3 | 31 | Responses were observed only in patients with levels > 14 mg/L | |
Abbreviations: CR, complete response; PR, partial response.
*Early studies used chest x-ray for evaluation of metastatic lesions. CR was defined as disappearance of all evidence of tumor, and PR was defined as a diminution in size of the tumor. Steroid response was good if a decrease in urinary excretion > 50% was recorded; was moderate if a decrease of 30% to 50% was reported; and was poor if a < 30% decrease was reported.
tTreatment was defined as moderately effective if the tumor decreased in size but survival was less than 2 years, or if stable disease for greater than 2 years was achieved, and it was defined as very effective if a decrease in tumor size was associated with survival for more than 2 years or if metastases were stable for more than 3 years; in this table, responses are given as PR.
PR was defined as a ≥ 10% regression of the area of at least one measurable tumor deposit.
§In latter studies, CR was defined as the disappearance of all tumor.
|PR was defined as a ≥ 50% decrease in the sum of the cross-sectional areas of all lesions with no progression in any lesion.
1WHO criteria, as follows, were used: PR was defined as at least a 50% decrease in the sum of the products of the longest diameter of the greatest perpendicular dimensions of all measurable lesions for at least 1 month without the appearance of new lesions.
PR was defined as ≥ 50% decrease in the sum of the products of the perpendicular dimensions of all measurable lesions on at least two evaluations.
| Table 5. Adjuvant Mitotane | |||||||
|---|---|---|---|---|---|---|---|
| Study | Mitotane | Control | Study Results | ||||
| No. of Patients | Survival (months) | No. of Patients | Survival (months) | ||||
| DFS | OS | DFS | OS | ||||
| Pommier et al34 | 7 | 29 | NR | 43 | 30 | NR | Negative |
| Vassilopoulou-Sellin et al117 | 8 | 10 | 14 | 6 | 23 | 34 | Negative |
| Haak et al114 | 11 | NR | 51 | 15 | NR | 61 | Negative |
| Barzon et al115 | 7 | 8 | 24 | 11 | 13 | 54 | Negative |
| Dickstein et al118 | 6 | ≥ 46 | ≥ 46 | — | — | — | Positive* |
| Baudin et al57 | 11 | 7 | 24 | — | — | — | Negative* |
| Terzolo et al, group 121+ | — | — | — | 55 | 10 | 52 | Positive |
| Terzolo et al, group 221+ | 47 | 42 | 110 | 75 | 25 | 67 | |
Abbreviations: DFS, disease-free survival; OS, overall survival; NR not reported.
*Results found with small sample size and lack of control arm.
tGroup 1 control group was from centers in Italy; Group 2 control group was from centers in Germany.
Copyright @ 2026 American Society of Clinical Oncology. All rights reserved.
much less than this. 4,11,57,112-116 The discrepancies may be explained in part by more accurate imaging modalities in later studies and by the possibility that, in early studies, assessment of efficacy was influenced by the effect of mitotane on steroid production and clinical symptoms, which can occur without tumor reduction. These discrepancies aside, mitotane has measurable activity in ACC and should be considered as a single agent or in combination in the therapy of disease that cannot be surgically removed. Although the extent of tumor reduction may not be great, most clinicians with experience using mitotane believe it slows tumor progression and advocate its continued use in patients who have shrinking or stable disease and who are tolerating therapy well. Two small studies demonstrated measurable antitumor activity only with serum mitotane levels greater than 10 to 14 mg/L. 57,114 Consequently an attempt should be made to achieve these levels, even if done gradually over several months. However, if the clinical impres- sion is of benefit, even if serum levels are less than 10 mg/L, therapy should be continued, because these small studies only examined cor- relations with response to therapy, not time to progression or other outcomes; this examination precludes the conclusion that lower doses have no value in delaying growth. Especially in patients with a more indolent disease course, the clinician’s assessment of benefit should guide the decision on whether to continue therapy.
Mitotane in the Adjuvant Setting
Even less clear is whether mitotane should be used after surgical resection, in an adjuvant setting (Table 5).33-35 Initial studies reported improved survival with mitotane.112,119 However, several subsequent studies failed to demonstrate a survival benefit for mitotane11,114,115 or suggested a negative effect.34,114,117 A more recent analysis compared the outcome in 47 patients treated with adjuvant mitotane therapy with that of two control groups. Surprisingly, more tolerable mitotane doses of 2 to 3 g/d demonstrated significant benefit in the adjuvant setting.21,120 However, the results of this retrospective nonrandomized study must be viewed cautiously, especially since the advantage was confined to time to recurrence but not to overall survival, although one cannot exclude the possibility that a longer duration of adminis- tration might have had even greater benefit. The lack of convincing evidence and the difficulty administering therapeutic doses (see Length of Mitotane Administration and online-only Appendix) have often guided the following two recommendations: (1) Adjuvant mi-
totane therapy should be used only in patients with a high likelihood of recurrence (ie, in patients who have large tumors with many of the features that comprise the Weiss score; see Evaluation and Work Up)30-32 and small or questionable surgical margins. (2) Mitotane should be used early in the course of therapy for instances in which the tumor cannot be fully removed surgically.31 Until additional data are available, we would continue to counsel such an approach.
Length of Mitotane Administration
Long-term mitotane monotherapy should be given only to pa- tients who tolerate it well and who experience a clinical response or to those who are at high risk for recurrence. The optimal duration of therapy in such patients is not known. A recommendation of indefi- nite is most conservative and may be possible in a patient who has tolerated therapy well. Continuation of a difficult therapy for a pro- longed period of time is possible, because months of therapy finally saturate body stores, which reduces the maintenance dose and im- proves tolerability. However, suboptimal therapy (judged by serum mitotane levels) limited by adverse effects should not be continued, because there is little chance of benefit in the face of continued toxicity. Although suboptimal therapy cannot be accurately defined-levels of 10 to 14 mg/L are often cited as optimal on the basis of the two small studies cited in the Single-Agent Mitotane section-lower doses are likely of some value, because tumor shrinkage or stable disease can occur with levels in the 5 to 10 mg/L range, a clinical observation also noted in the recent retrospective analysis.21
In conclusion, oncologists who treat patients with ACC will find that not only is reducing the tumor burden difficult, but so too is the deceptively easier goal of achieving eucortisolism; full symptom con- trol cannot be achieved in many patients. The rapidly changing clinical presentation in a patient with progressive disease may require frequent dose adjustments to achieve optimal control of hormone excess. This palliative care is designed to reduce morbidity and to improve the quality of life, both important goals in patients with ACC as in patients with other cancers.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest.
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Management of Adrenocortical Cancer
AUTHOR CONTRIBUTIONS
Conception and design: Irina Veytsman, Lynnette Nieman, Antonio Tito Fojo
Collection and assembly of data: Irina Veytsman, Antonio Tito Fojo
Data analysis and interpretation: Irina Veytsman, Lynnette Nieman, Antonio Tito Fojo
Manuscript writing: Irina Veytsman, Lynnette Nieman, Antonio Tito Fojo Final approval of manuscript: Irina Veytsman, Lynnette Nieman, Antonio Tito Fojo
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