eMedicine Specialties > Oncology > Carcinomas of Endocrine Organs

Adrenal Carcinoma: Treatment & Medication

Author: Gabriel I Uwaifo, MBBS, Clinical and Research Attending, Assistant Professor of Medicine and Endocrinology, MedStar Clinical Research Center, The MedStar Research Institute and the Washington Hospital Center
Coauthor(s): Antonio Tito Fojo, MD, Senior Clinical Investigator, Medicine Branch, Division of Cancer Treatment, National Cancer Institute, National Institutes of Health
Contributor Information and Disclosures

Updated: May 22, 2006

Treatment

Medical Care

• Mitotane
  • This drug remains the major chemotherapeutic option for the management of AC because it is a relatively specific adrenocortical cytotoxin. It is used as primary therapy, as adjuvant therapy, and as therapy in recurrent or relapsing disease.
  • Its capacity to prolong clinical survival is uncertain. At best, only 20-25% of patients respond to mitotane. Therapy may be required for at least 3 months before deciding that mitotane has no efficacy in the management of an individual case.
  • Mitotane apparently causes adrenal inhibition without cellular destruction. The exact mechanism of action is unknown. It inhibits cholesterol side-chain cleavage and 11-beta-oxyhydrase reactions. It also appears to reduce the peripheral metabolism of steroids. Alteration of extra-adrenal metabolism of cortisol reduces measurable 17-hydroxy corticosteroid while stimulating the formation of 6-beta-hydroxy cortisol. Plasma levels of corticosteroids do not fall.
  • This drug may be considered in the treatment of inoperable adrenal cortical carcinoma (functional, nonfunctional). It controls endocrine hypersecretion in 70-75% of patients. While objective tumor responses often are cited in as many as 20-25% of patients, a study has yet to be conducted with modern imaging techniques and response criteria accepted by clinical oncologists. Tumor response has been reported to correlate with serum levels and often requires several months of continuous therapy. Assaying mitotane levels during therapy is valuable because therapeutic efficacy depends on achieving serum levels of at least 15 mcg/mL.
  • Approximately 40% of the drug is absorbed, and approximately 10% of the dose is recovered in the urine as a water-soluble metabolite. Active metabolite excreted in the bile varies from 1-17%. The balance apparently is stored in tissues. Autopsy data indicate that fat tissue is the primary storage site, but it is found in most tissues.
  • After therapy, plasma terminal half-life varies from 18-159 days.
  • Experience suggests that the best approach is continuous treatment with the maximum possible dosage.
  • If tolerated and an improved clinical response appears possible, increase the dose until adverse reactions interfere. The aim is to achieve doses as high as 10-20 g daily.
  • The major beneficial effect is on symptoms rather than a specific antitumor or mortality benefit. Generally, treatment benefits are short-lived, and long-term survivors on this therapy are rare.
  • The potential benefit of postoperative adjuvant therapy with mitotane is still controversial. Although some reports suggest that its use may delay or even prevent tumor recurrence postsurgical extirpation, no randomized trials compare this strategy to just surgery alone in subjects of similar stage AC. Those who advocate this strategy begin it immediately after surgery and then continue it indefinitely. However, several other reports have not shown any benefit of mitotane adjuvant therapy in terms of disease-free survival or overall mortality rates, and the naysayers of its use in this setting point to the serious side effects associated with the medication as tilting the balance against quality of life in treated patients with no hard evidence for meaningful benefit.
  • Some reports exist of the potential utility of using streptozotocin in combination with mitotane (at a dose of 1 g qd for first 5 d followed by 2 g q3-4wk thereafter). This regimen has been reported to be associated with a significantly better disease-free interval and with more long-term survivors.
• Suramin: Although a few reports suggest the potential utility of suramin as an additional chemotherapeutic agent in the treatment of AC, this drug is not recommended for AC.
• Gossypol
  • Gossypol also has been tried for metastatic adrenal cancer, with limited experience and success.
  • It was originally developed as a spermatotoxin and was derived from cottonseed oil. It has been used widely in China as a male contraceptive with few adverse effects. While the exact mechanism for its action is unclear, it is known to cause selective mitochondrial destruction by the uncoupling of oxidative phosphorylation.
• Cisplatin-based chemotherapy
  • In cases where mitotane fails, chemotherapeutic regimens containing cisplatin alone or in combination often are used. It also is used often in combination with ongoing mitotane administration.
  • Cyclophosphamide, Adriamycin, and cisplatin (CAP), 5-fluoro uracil, Adriamycin, and cisplatin (FAP), and cisplatin with VP-16 have been tried.
  • Due, in part, to the rarity of this disease, no convincing evidence exists suggesting that any of these regimens confer survival advantage; nor are there clinical trials which assess the efficacy of one combination over another. In vitro evidence exists that indicates mitotane can block drug efflux mediated by p-glycoprotein, although clinical data are not available presently.
• Management of endocrine syndromes
  • In functional tumors, management of the endocrine syndromes is often important because the associated systemic effects may significantly impact patient well-being.
  • Therapeutic options for Cushing syndrome include mitotane, ketoconazole, metyrapone, aminoglutethimide, RU 486 (mifepristone), and intravenous etomidate, alone or in various combinations.
  • For hyperaldosteronism, the major therapeutic options are spironolactone, elpreninone (presently in phase 3 trials), amiloride, triamterene, and various antihypertensives, especially long-acting dihydropyridine calcium channel blockers.
  • For hyperandrogenism or hyperestrogenism, several options are available if adverse effects from these hormones significantly impact patient well-being. Antiestrogens may include clomiphene citrate, tamoxifen, toremifene, and danazol. Potential antiandrogens include flutamide, cyproterone acetate, bicalutamide (Casodex), nilutamide, and megestrol acetate. Ketoconazole, spironolactone, and cimetidine also have a significant antiandrogen effect. The various aromatase inhibitors (eg, testolactone, anastrozole, letrozole, fadrozole) also have some antiandrogen effect; therefore, they may be used. Controlled studies have not yet been performed to assess which of these agents, either alone or in combination, achieves the best metabolic control. The choice of medication often is guided by cost, availability, patient preference, adverse effects, and tolerance.
  • In the rare setting of mixed carcinoma associated with pheochromocytoma components, high-dose radiolabeled metaiodobenzylguanidine (MIBG) has a potential role.
  • The management of blood pressure elevation in this setting is similar to that in pheochromocytoma, using long-acting alpha-blockers (usually with phenoxybenzamine), followed by long-acting beta-blockers (eg, propranolol) and, finally, metyrosine. Evidence does not exist that suggests a combination of radiotherapy with mitotane (or any other chemotherapeutic regimen for that matter) confers any survival benefit. The only place for radiotherapy in the management of this condition is for palliation of painful bone disease and local luminal obstructive disease.
  • Patients treated with mitotane may present with features of both glucocorticoid and aldosterone insufficiency requiring replacement therapy.
• In summary, medical management encompasses (1) the treatment of endocrine excess syndromes; (2) the use of mitotane or several multiagent chemotherapy regimens; (3) the treatment and prevention of potential complications; and (4) strategies for palliative and terminal care issues, including symptom relief and management.
• Radiation therapy
  • Although radiation therapy has been used alone or in combination with surgical resection, no evidence suggests that it is of any benefit in managing primary AC.
  • Its use should be restricted to palliation of local disease such as bony metastases.
  • A few reports suggest that a potential utility for radiation is the palliative management of symptomatic adrenal metastatic deposits.
  • Recurrent or relapsing AC is usually a bad omen. Although symptoms of hormonal excess can often be medically managed in this setting, cure is virtually unknown, and finding metastatic disease gives a particularly poor prognosis. Most of these patients die within 1 year. The prognosis is better in children in whom some cases of long-term survival have been described.

Surgical Care

• Preoperative screening
  • Include a full evaluation to determine the extent of disease and staging, which has implications for the ultimate prognosis. The most commonly used staging method is that first described by MacFarlane, then subsequently modified by Sullivan and associates.
  • The most common sites for metastases are the lungs, liver, bone, and lymph nodes. Contiguous spread to the kidney and liver (if the primary is on the right side) and tumor extension into the venous drainage system of the adrenals and the inferior vena cava are common.
• Surgical resection
  • When feasible, total resection remains the management modality of choice for the definitive management of AC. It also remains the only potentially curative therapeutic modality.
  • Recurrent local and metastatic disease is common, even among patients who undergo a successful complete resection. In such settings, the only effective treatment is attempted reoperation.
  • Preoperative diagnostic accuracy should improve in the following years with improved MRI technology, percutaneous core needle biopsy technology, and advances in molecular, genetic, and immunotyping interpretation.
• While open laparotomy for adrenalectomy remains the standard of care, several reports suggest a role for laparoscopic resection in those cases where the adrenal tumor is small and where no evidence of metastatic disease is present preoperatively. Aggressive resection of locally recurrent disease may prolong survival in some patients, while the new technology of percutaneous radiofrequency ablation (RAF) may have a place in providing local symptom control related to local compression by an invasive tumor.
  • Advances in the treatment of ACs currently include an international phase III trial evaluating chemotherapy regimens and establishment of national tumor registries. Further improvements in therapy may utilize novel chemotherapy agents, vascular growth inhibitors, or small molecule therapy based upon a better understanding of the molecular pathways involved in tumorigenesis.

Medication

The goal of pharmacotherapy is to reduce morbidity, prevent complications, and eradicate the carcinoma if possible.

Chemotherapeutic agents

These agents inhibit cell growth and proliferation.

Mitotane (Lysodren)

An option for the management of AC because it is a relatively specific adrenocortical cytotoxin.

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