Adrenocortical Carcinoma Treatment (PDQ®): Treatment - Health Professional Information [NCI]

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Adrenocortical Carcinoma Treatment

Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adrenocortical carcinoma. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.

Information about the following is included in this summary:

  • Prognostic factors.
  • Cellular classification.
  • Staging.
  • Treatment options by cancer stage.

This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version, written in less technical language, and in Spanish.

General Information

Adrenocortical carcinoma is a rare tumor that affects only 1 to 2 persons per one million population. It usually occurs in adults, and the median age at diagnosis is 44 years. Although adrenal carcinoma is potentially curable at early stages, only 30% of these malignancies are confined to the adrenal gland at the time of diagnosis.[1] Radical surgical excision is the treatment of choice for patients with localized malignancies and remains the only method by which long-term disease-free survival may be achieved. Overall 5-year survival for tumors resected for cure is approximately 40%.

Retrospective studies have identified two important prognostic factors: completeness of resection and stage of disease. Patients without evidence of invasion into local tissues or spread to lymph nodes have an improved prognosis.[2] The role of DNA ploidy as a prognostic indicator is controversial, with some [3] studies, such as ECOG-1879, for example, showing correlation between aneuploidy and prognosis, and other studies [2,4] showing no correlation.

Approximately 60% of patients present with symptoms related to excessive hormone secretion, but hormone testing reveals that 60% to 80% of tumors are functioning.[5,6] Nonfunctioning carcinomas may be heralded by symptoms of local invasion by tumor or by metastases. Initial evaluation should include, in addition to appropriate endocrine studies, computed tomography and/or magnetic resonance imaging of the abdomen. Selective angiography and adrenal venography may be helpful in identifying smaller lesions and for distinguishing tumors of the adrenal gland from tumors of the upper pole of the kidney. Although the use of positron emission tomography may be effective in identifying unsuspected sites of metastases, its role as a staging tool is unclear.[7] The detection of metastatic lesions may allow effective palliation of both functioning and nonfunctioning lesions.

The most common sites of metastases are the peritoneum, lung, liver, and bone. Palliation of metastatic functioning tumors may be achieved by resection of both the primary tumor and metastatic lesions. Unresectable or widely disseminated tumors may be palliated by antihormonal therapy with mitotane, systemic chemotherapy, or (for localized lesions) radiation therapy. However, survival for patients with stage IV tumors is usually less than 9 months unless a complete remission is achieved.[6,8,9,10] There is no convincing evidence to date that systemic therapy will improve the survival duration of patients with adrenal cancer.

References:

1. Norton JA: Adrenal tumors. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 1528-39.
2. Lee JE, Berger DH, el-Naggar AK, et al.: Surgical management, DNA content, and patient survival in adrenal cortical carcinoma. Surgery 118 (6): 1090-8, 1995.
3. Camuto P, Schinella R, Gilchrist K, et al.: Adrenal cortical carcinoma: flow cytometric study of 22 cases, an ECOG study. Urology 37 (4): 380-4, 1991.
4. Haak HR, Cornelisse CJ, Hermans J, et al.: Nuclear DNA content and morphological characteristics in the prognosis of adrenocortical carcinoma. Br J Cancer 68 (1): 151-5, 1993.
5. Icard P, Chapuis Y, Andreassian B, et al.: Adrenocortical carcinoma in surgically treated patients: a retrospective study on 156 cases by the French Association of Endocrine Surgery. Surgery 112 (6): 972-9; discussion 979-80, 1992.
6. Luton JP, Cerdas S, Billaud L, et al.: Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. N Engl J Med 322 (17): 1195-201, 1990.
7. Becherer A, Vierhapper H, Pötzi C, et al.: FDG-PET in adrenocortical carcinoma. Cancer Biother Radiopharm 16 (4): 289-95, 2001.
8. Brennan MF: Adrenocortical carcinoma. CA Cancer J Clin 37 (6): 348-65, 1987 Nov-Dec.
9. Cohn K, Gottesman L, Brennan M: Adrenocortical carcinoma. Surgery 100 (6): 1170-7, 1986.
10. Wooten MD, King DK: Adrenal cortical carcinoma. Epidemiology and treatment with mitotane and a review of the literature. Cancer 72 (11): 3145-55, 1993.

Cellular Classification

Adrenocortical carcinoma can be classified as follows:

  • Differentiated: Functioning tumors are usually differentiated.
  • Anaplastic: Production of hormones by anaplastic tumors is rare.
  • Hormonal: Approximately 60% of adrenocortical carcinomas produce hormones. The associated clinical syndromes include the following:[1,2,3]
    • Hypercortisolism (Cushing syndrome).
    • Adrenogenital syndrome.
    • Virilization.
    • Feminization.
    • Precocious puberty.
    • Hyperaldosteronism.
    • Primary hyperaldosteronism (Conn syndrome).

References:

1. Javadpour N, Woltering EA, Brennan MF: Adrenal neoplasms. Curr Probl Surg 17 (1): 1-52, 1980.
2. Nader S, Hickey RC, Sellin RV, et al.: Adrenal cortical carcinoma. A study of 77 cases. Cancer 52 (4): 707-11, 1983.
3. Norton JA: Adrenal tumors. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 1528-39.

Stage Information

The stage of adrenocortical carcinoma is determined by the size of the primary tumor, the degree of local invasion, and whether it has spread to regional lymph nodes or distant sites.[1,2,3,4] Proper staging should include computed tomography (CT) of the abdomen. Magnetic resonance imaging (MRI) may add specificity to CT evaluation of an adrenal mass.[5] In-phase and out-of-phase T1-weighted imaging may be the most effective noninvasive method to differentiate benign from malignant adrenal masses. MRI can also often clearly demonstrate any evidence of extracapsular tumor invasion, extension into the vena cava, or metastases. Patency of surrounding vessels can often be demonstrated with gadolinium-enhanced sequences or flip-angle techniques.[6] Vena caval contrast studies and angiography may provide additional staging information and allow for a more complete preoperative assessment. A review of published data from 608 patients revealed the following stage distribution at diagnosis: 3% stage I, 29% stage II, 20% stage III, and 49% stage IV.[7]

Stages are defined by TNM classification.[8]

TNM Definitions

Tumor (T)

  • T1: Tumor 5 cm or less in size; invasion absent
  • T2: Tumor greater than 5 cm in size; invasion absent
  • T3: Tumor outside adrenal in fat
  • T4: Tumor invading adjacent organs

Lymph nodes (N)

  • N0: No positive lymph nodes
  • N1: Positive lymph nodes

Metastases (M)

  • M0: No distant metastases
  • M1: Distant metastases

Stage I

  • T1, N0, M0

Stage II

  • T2, N0, M0

Stage III

  • T1, N1, M0
  • T2, N1, M0
  • T3, N0, M0

Stage IV

  • T3, N1, M0
  • T4, N1, M0
  • Any T, any N, M1

References:

1. Cerfolio RJ, Vaughan ED Jr, Brennan TG Jr, et al.: Accuracy of computed tomography in predicting adrenal tumor size. Surg Gynecol Obstet 176 (4): 307-9, 1993.
2. Brennan MF: Adrenocortical carcinoma. CA Cancer J Clin 37 (6): 348-65, 1987 Nov-Dec.
3. Cohn K, Gottesman L, Brennan M: Adrenocortical carcinoma. Surgery 100 (6): 1170-7, 1986.
4. Nader S, Hickey RC, Sellin RV, et al.: Adrenal cortical carcinoma. A study of 77 cases. Cancer 52 (4): 707-11, 1983.
5. Doppman JL, Reinig JW, Dwyer AJ, et al.: Differentiation of adrenal masses by magnetic resonance imaging. Surgery 102 (6): 1018-26, 1987.
6. Brown ED, Semelka RC: Magnetic resonance imaging of the adrenal gland and kidney. Top Magn Reson Imaging 7 (2): 90-101, 1995 Spring.
7. Wooten MD, King DK: Adrenal cortical carcinoma. Epidemiology and treatment with mitotane and a review of the literature. Cancer 72 (11): 3145-55, 1993.
8. Norton JA: Adrenal tumors. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 1528-39.

Stage I Adrenocortical Carcinoma

STANDARD TREATMENT OPTIONS:

  • Complete surgical removal of the tumor is the treatment of choice for patients with stage I adrenocortical carcinomas. The long-term survival of patients with nonfunctioning tumors is comparable to that of patients with functioning tumors. The removal of regional lymph nodes that are not clinically enlarged is not indicated.[1,2,3,4,5]

TREATMENT OPTIONS UNDER CLINICAL EVALUATION:

  • Adjuvant radiation or chemotherapy with mitotane has not been proven to be of value in improving survival.[5,6]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage I adrenocortical carcinoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Javadpour N, Woltering EA, Brennan MF: Adrenal neoplasms. Curr Probl Surg 17 (1): 1-52, 1980.
2. Brennan MF: Adrenocortical carcinoma. CA Cancer J Clin 37 (6): 348-65, 1987 Nov-Dec.
3. Cohn K, Gottesman L, Brennan M: Adrenocortical carcinoma. Surgery 100 (6): 1170-7, 1986.
4. Icard P, Chapuis Y, Andreassian B, et al.: Adrenocortical carcinoma in surgically treated patients: a retrospective study on 156 cases by the French Association of Endocrine Surgery. Surgery 112 (6): 972-9; discussion 979-80, 1992.
5. Luton JP, Cerdas S, Billaud L, et al.: Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. N Engl J Med 322 (17): 1195-201, 1990.
6. Vassilopoulou-Sellin R, Guinee VF, Klein MJ, et al.: Impact of adjuvant mitotane on the clinical course of patients with adrenocortical cancer. Cancer 71 (10): 3119-23, 1993.

Stage II Adrenocortical Carcinoma

STANDARD TREATMENT OPTIONS:

  • Complete surgical removal of the tumor is the treatment of choice for patients with stage II adrenocortical carcinomas. The long-term survival of patients with nonfunctioning tumors is comparable to that of patients with functioning tumors. The removal of regional lymph nodes that are not clinically enlarged is not indicated.[1,2,3,4,5]

TREATMENT OPTIONS UNDER CLINICAL EVALUATION:

  • Adjuvant radiation or chemotherapy with mitotane has not been proven to be of value in improving survival.[5,6]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage II adrenocortical carcinoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Javadpour N, Woltering EA, Brennan MF: Adrenal neoplasms. Curr Probl Surg 17 (1): 1-52, 1980.
2. Brennan MF: Adrenocortical carcinoma. CA Cancer J Clin 37 (6): 348-65, 1987 Nov-Dec.
3. Cohn K, Gottesman L, Brennan M: Adrenocortical carcinoma. Surgery 100 (6): 1170-7, 1986.
4. Icard P, Chapuis Y, Andreassian B, et al.: Adrenocortical carcinoma in surgically treated patients: a retrospective study on 156 cases by the French Association of Endocrine Surgery. Surgery 112 (6): 972-9; discussion 979-80, 1992.
5. Luton JP, Cerdas S, Billaud L, et al.: Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. N Engl J Med 322 (17): 1195-201, 1990.
6. Vassilopoulou-Sellin R, Guinee VF, Klein MJ, et al.: Impact of adjuvant mitotane on the clinical course of patients with adrenocortical cancer. Cancer 71 (10): 3119-23, 1993.

Stage III Adrenocortical Carcinoma

STANDARD TREATMENT OPTIONS:

  • Complete surgical removal of the tumor, with or without regional lymph node dissection is the treatment of choice for patients with stage III adrenocortical carcinomas. The treatment of patients who have tumors with local invasion, but without clinically enlarged regional lymph nodes, is complete surgical removal as for stage I and stage II tumors. For those with enlarged regional lymph nodes, a lymph node dissection should be included in the procedure. These patients are at a high risk for disease recurrence and should be considered for enrollment in a clinical trial.

TREATMENT OPTIONS UNDER CLINICAL EVALUATION:

1. Clinical trials are appropriate for newly diagnosed patients when possible.
2. Radiation therapy: 4,200 rads to 5,000 rads given for a period of 4 weeks to patients with localized but unresectable tumors.[1]
3. For patients unable to undergo complete resection, mitotane in doses as high as 10 to 12 grams per day can be considered. This antitumor drug produces useful clinical responses that average 10 months in duration in about 30% of patients with measurable metastases. Responses in patients who achieve complete remission can be durable. Approximately 80% of treated patients with functioning tumors will show substantial diminution in hormone production. The drug is not usually used unless either radiologically evaluable metastases are present or the residual tumor is producing measurable levels of hormone.[2,3] Currently, no apparent role exists for mitotane as adjuvant therapy if the patient has undergone complete resection of the tumor.[3,4]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage III adrenocortical carcinoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Percarpio B, Knowlton AH: Radiation therapy of adrenal cortical carcinoma. Acta Radiol Ther Phys Biol 15 (4): 288-92, 1976.
2. Lubitz JA, Freeman L, Okun R: Mitotane use in inoperable adrenal cortical carcinoma. JAMA 223 (10): 1109-12, 1973.
3. Luton JP, Cerdas S, Billaud L, et al.: Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. N Engl J Med 322 (17): 1195-201, 1990.
4. Vassilopoulou-Sellin R, Guinee VF, Klein MJ, et al.: Impact of adjuvant mitotane on the clinical course of patients with adrenocortical cancer. Cancer 71 (10): 3119-23, 1993.

Stage IV Adrenocortical Carcinoma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Temporary palliation of disseminated adrenocortical carcinomas can sometimes be achieved with the chemotherapeutic agent mitotane. Although measurable partial remissions are unusual and are reported in only 19% to 34% of cases, excellent palliation of hormone symptoms is commonly observed.[1] Prolonged treatment with mitotane, however, is often limited by gastrointestinal and neurologic toxicity. Local recurrences and selected sites of metastatic disease can sometimes be palliated surgically.[2]

Clinical trials such as ECOG-1879 and SWOG-8325 are appropriate and should be considered whenever possible, especially phase I and II trials that evaluate newer chemotherapeutic and biologic agents.[3,4,5,6] Palliative chemotherapy with cisplatin-based regimens has produced objective responses in approximately 30% of patients treated.[4,5,7,8] One study reported that doxorubicin produced objective responses in 3 of 16 patients with poorly differentiated, nonhormone-producing tumors but no responses in 15 patients whose disease did not respond to mitotane.[3] Use of both platinum-based chemotherapy and mitotane achieved a 48.6% objective response and median time-to-progression of 18 months in responders.[9][Level of evidence: 3iiDiv] In 10 of 72 patients, subsequent surgical resection was possible.

STANDARD TREATMENT OPTIONS:

1. Chemotherapy with mitotane.[1]
2. Radiation therapy to bone metastases.[10]
3. Surgical removal of localized metastases, particularly those that are functioning.[2]

TREATMENT OPTIONS UNDER CLINICAL EVALUATION:

1. Cisplatin has been reported to produce beneficial effects in some selected patients with metastatic disease.[7,8,11]
2. Clinical trials of other chemotherapy regimens.[3,4,5,6]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage IV adrenocortical carcinoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Lubitz JA, Freeman L, Okun R: Mitotane use in inoperable adrenal cortical carcinoma. JAMA 223 (10): 1109-12, 1973.
2. Pommier RF, Brennan MF: An eleven-year experience with adrenocortical carcinoma. Surgery 112 (6): 963-70; discussion 970-1, 1992.
3. Decker RA, Elson P, Hogan TF, et al.: Eastern Cooperative Oncology Group study 1879: mitotane and adriamycin in patients with advanced adrenocortical carcinoma. Surgery 110 (6): 1006-13, 1991.
4. Bukowski RM, Wolfe M, Levine HS, et al.: Phase II trial of mitotane and cisplatin in patients with adrenal carcinoma: a Southwest Oncology Group study. J Clin Oncol 11 (1): 161-5, 1993.
5. Hesketh PJ, McCaffrey RP, Finkel HE, et al.: Cisplatin-based treatment of adrenocortical carcinoma. Cancer Treat Rep 71 (2): 222-4, 1987.
6. Schlumberger M, Ostronoff M, Bellaiche M, et al.: 5-Fluorouracil, doxorubicin, and cisplatin regimen in adrenal cortical carcinoma. Cancer 61 (8): 1492-4, 1988.
7. Tattersall MH, Lander H, Bain B, et al.: Cis-platinum treatment of metastatic adrenal carcinoma. Med J Aust 1 (9): 419-21, 1980.
8. Chun HG, Yagoda A, Kemeny N, et al.: Cisplatin for adrenal cortical carcinoma. Cancer Treat Rep 67 (5): 513-4, 1983.
9. Berruti A, Terzolo M, Sperone P, et al.: Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase II trial. Endocr Relat Cancer 12 (3): 657-66, 2005.
10. Percarpio B, Knowlton AH: Radiation therapy of adrenal cortical carcinoma. Acta Radiol Ther Phys Biol 15 (4): 288-92, 1976.
11. Haq MM, Legha SS, Samaan NA, et al.: Cytotoxic chemotherapy in adrenal cortical carcinoma. Cancer Treat Rep 64 (8-9): 909-13, 1980 Aug-Sep.

Recurrent Adrenocortical Carcinoma

The question and selection of further treatment for patients with adrenocortical carcinoma depends on many factors, including previous treatment and site of recurrence as well as individual patient considerations. Local recurrence and selected sites of metastatic disease can sometimes be palliated by surgery. Although none of these patients can be considered curable, palliation of hormonal symptoms and occasional 5-year survivals can be achieved.[1,2] Substantial morbidity, however, is associated with resection of these recurrent tumors.[2] Clinical trials, such as ECOG-1879 and SWOG-8325, are appropriate and should be considered whenever possible, especially phase I and II trials that evaluate newer chemotherapeutic and biological agents.[3,4,5,6,7]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent adrenocortical carcinoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Pommier RF, Brennan MF: An eleven-year experience with adrenocortical carcinoma. Surgery 112 (6): 963-70; discussion 970-1, 1992.
2. Jensen JC, Pass HI, Sindelar WF, et al.: Recurrent or metastatic disease in select patients with adrenocortical carcinoma. Aggressive resection vs chemotherapy. Arch Surg 126 (4): 457-61, 1991.
3. Decker RA, Elson P, Hogan TF, et al.: Eastern Cooperative Oncology Group study 1879: mitotane and adriamycin in patients with advanced adrenocortical carcinoma. Surgery 110 (6): 1006-13, 1991.
4. Bukowski RM, Wolfe M, Levine HS, et al.: Phase II trial of mitotane and cisplatin in patients with adrenal carcinoma: a Southwest Oncology Group study. J Clin Oncol 11 (1): 161-5, 1993.
5. Hesketh PJ, McCaffrey RP, Finkel HE, et al.: Cisplatin-based treatment of adrenocortical carcinoma. Cancer Treat Rep 71 (2): 222-4, 1987.
6. Schlumberger M, Ostronoff M, Bellaiche M, et al.: 5-Fluorouracil, doxorubicin, and cisplatin regimen in adrenal cortical carcinoma. Cancer 61 (8): 1492-4, 1988.
7. Berruti A, Terzolo M, Sperone P, et al.: Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase II trial. Endocr Relat Cancer 12 (3): 657-66, 2005.

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Changes to This Summary (05 / 16 / 2008)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

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Date Last Modified: 2008-05-16

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