Adrenal Carcinoma Treatment & Management
- Author: Bagi RP Jana, MD; Chief Editor: Jules E Harris, MD, FACP, FRCPC more...
Because adrenocortical carcinomas (ACs) are so rare, clinical series are small and there has been only limited prospective evaluation of treatment strategies. Therefore, significant controversy over therapy exists, and very few, if any, universally accepted treatment standards have been determined. Current practices are strongly influenced by expert consensus opinion from a few medical centers that specialize in ACs.
When feasible, total resection remains the management modality of choice for the definitive treatment of AC. It also remains the only potentially curative therapeutic modality.
Medical care in patients with AC, which can be supportive or adjuvant to surgical resection, encompasses the following:
Treatment of endocrine excess syndromes
Use of mitotane or several multiagent chemotherapy regimens
Treatment and prevention of potential complications
Strategies for palliative and terminal care issues, including symptom relief and management
Management of nonfunctional tumors
Virtually all authorities agree that because of the significant potential cancer risk, all nonfunctional adrenal tumors of 6 cm or greater should be removed. Authorities also generally agree that nonfunctional adrenal tumors of 3 cm or less have a very low probability of being adrenal cancer; therefore, they can be observed safely.
The management strategy for adrenal masses larger than 3 cm and less than 6 cm is disputed. Some authorities suggest lowering the threshold for surgical removal of nonfunctional masses from 6 cm to 4-5 cm. Others individualize the follow-up of these patients depending on their clinical status, CT scan characteristics, and age. Particularly important is the fact that these criteria do not apply to children, who generally have smaller ACs.
A review of the available data suggests that the incidence rate of malignancy is small (< 0.03%) in all adrenal incidentalomas that are 1.5-6 cm. However, this rate increases considerably with tumors larger than 6 cm (up to 15%). The smallest identified AC associated with metastasis reported in the literature was 3 cm in diameter.
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.
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 the active metabolite 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 the dose is 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/day.
Mitotane’s major beneficial effect is on symptoms; treatment benefits are generally short-lived, and long-term survivors on this therapy are rare.
The potential benefit of postoperative adjuvant therapy with mitotane is still controversial. A retrospective study by Terzolo et al examining adjuvant mitotane therapy in patients who underwent radical surgery for AC, found evidence that mitotane can significantly increase recurrence-free survival. The study included 47 Italian patients who received mitotane postoperatively and control groups of 55 Italian patients and 75 German patients.
In the Italian patients, baseline features were similar in the treatment and control groups; the German patients were significantly older and had more stage I or II disease than did patients in the mitotane group. Median recurrence-free survival was 42 months in the mitotane group, as compared with 10 months in the Italian control group and 25 months in the German control group. Multivariate analysis indicated that mitotane treatment had a significant advantage for recurrence-free survival.
However, a retrospective study by Grubbs et al contradicted these results. In this study, which involved 28 patients with AC who underwent primary resection, the investigators found that, although the overwhelming majority of these patients did not receive adjuvant treatment with mitotane, the patients’ recurrence rate was 50%—indistinguishable from the 49% recurrence rate reported by Terzolo et al for patients who received adjuvant mitotane.
Some reports exist of the potential utility of 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 a greater number of long-term survivors.
Mitotane plus etoposide
The First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment (FIRM-ACT) study group reported that first-line therapy patients who received mitotane and etoposide had higher response rates and longer median progression-free survival than patients treated with streptozocin plus mitotane (5 mo vs 2.1 mo, respectively). Toxicity rates for both of the combinations were similar. Overall survival in the entire group was not significantly better; however, the study revealed that for those patients who did not receive alternative second-line therapy, overall survival was better with mitotane plus etoposide.
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 the disease.
Gossypol also has been tried for metastatic adrenal cancer, but experience and success have been limited. Derived from cottonseed oil, it was originally developed as a spermatotoxin. It has been used widely in China as a male contraceptive with few adverse effects. While the exact mechanism for its action is unclear, gossypol is known to cause selective mitochondrial destruction by the uncoupling of oxidative phosphorylation.
In cases where mitotane fails, chemotherapeutic regimens containing cisplatin alone or in combination often are used. (Cyclophosphamide, doxorubicin [Adriamycin], and cisplatin [CAP]; 5-fluorouracil, Adriamycin, and cisplatin [FAP]; and cisplatin with etoposide-16 have been tried.) Cisplatin also is often used in combination with ongoing mitotane administration.
Ronchi et al found that, as with other types of cancer, expression of excision repair cross-complementing group 1 (ERCC1) by ACs predicts resistance to platinum-based chemotherapy. Median overall survival after platinum treatment was 8 months in patients with high ERCC1 expression, versus 24 months in those with low ERCC1 expression.
In the future, the treatment of adrenal carcinoma may utilize novel chemotherapeutic agents, vascular growth inhibitors, and small-molecule therapy based on a better understanding of the molecular pathways involved in tumorigenesis.
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, eplerenone, amiloride, triamterene, and various antihypertensives, especially long-acting dihydropyridine calcium channel blockers.
For hyperandrogenism or hyperestrogenism, several options are available if adverse effects from androgen or estrogen significantly affect patient well-being. Antiestrogens may include the following:
Potential antiandrogens include the following:
Ketoconazole, spironolactone, and cimetidine also have a significant antiandrogen effect. The various aromatase inhibitors (eg, testolactone, anastrozole, letrozole, fadrozole) have some antiandrogen effect as well; 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 endocrine syndrome from adrenal cancer is similar to that in pheochromocytoma, with use of long-acting alpha blockers (usually phenoxybenzamine), followed by long-acting beta blockers (eg, propranolol) and, finally, metyrosine. There is no evidence suggesting that a combination of radiotherapy with mitotane (or any other chemotherapeutic regimen for that matter) confers any survival benefit.
Patients treated with mitotane may present with features of both glucocorticoid and aldosterone insufficiency requiring replacement therapy.
Some experts recommend that the use of radiation therapy be restricted to palliation of local disease, such as symptomatic metastases to the bone and local luminal obstructive disease.
A meta-analysis by Polat et al suggested that radiotherapy to the tumor bed may be considered in patients at high risk for local recurrence. These researchers recommended administering a total dose of more than 40 gray (Gy), with single fractions of 1.8-2 Gy (including a boost volume to reach from 50-60 Gy in individual patients).
Removal of all nonmetastatic adrenal masses larger than 6 cm is advisable (although several authorities have said 4 or 5 cm), regardless of the patient's hormonal profile. Include a full evaluation to determine the extent of disease and staging, which has implications for the ultimate prognosis.
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.
Preoperative diagnostic accuracy should increase in the future with improved MRI technology, percutaneous core needle biopsy technology, and advances in molecular, genetic, and immunotyping interpretation.
When feasible, total resection remains the treatment of choice for the definitive management of AC. It also is still the only potentially curative therapeutic modality.
Open versus laparoscopic surgery
While open laparotomy for adrenalectomy represents the standard of care, several reports suggest a role for laparoscopic resection if the adrenal tumor is small and there is no evidence of metastatic disease preoperatively.[22, 23, 24]
A study by Agha et al suggested that laparoscopic adrenalectomy can be effectively performed even on larger tumors (>6 cm). Data from 279 patients who underwent the minimally invasive procedure (227 with tumors of 6 cm or smaller and 52 with tumors >6 cm) showed that although the mean duration of surgery, estimated blood loss, intraoperative bleeding rate, conversion rate, and postoperative complication rate were greater in the patients with larger tumors, the two tumor groups each had only one major complication.
Recurrent and metastatic tumor management
Recurrent local and metastatic tumors are common in AC, even among patients who undergo a successful complete resection. In such settings, the only effective treatment is attempted reoperation.[26, 27] Case reports indicate that repeated thoracotomy can allow for more than 10 years of high-quality survival despite recurring crops of metastatic disease. Moreover, a large, retrospective series showed that pulmonary metastasectomy may be beneficial in carefully selected patients. In the study, by Kemp et al, median overall survival was 40 months and five-year actuarial survival was 41%, following resection of pulmonary metastasis.
In a study at Memorial Sloan-Kettering Cancer center, investigators found that in patients with AC, aggressive primary surgical removal and aggressive surgical treatment of local or distant relapse led to long-term survival rates far superior to those reported in previous studies, regardless of the patients' ages. One important feature of this study was that patients who underwent a complete second resection had a median survival of 74 months (5-y survival rate, 57%).
If lesions seem particularly sensitive to chemotherapy, with dramatic diminishment of tumoral masses in the chest or elsewhere, autologous stem-cell transplantation may be a consideration. However, only anecdotal data suggest that transplantation is helpful in managing AC. One study reported the use of a combination of adrenalectomy, chemotherapy, surgical debulking of lung metastases, and autologous transplantation; two years of continuous complete remission were reported.
Percutaneous radiofrequency ablation may have a place in the control of local symptoms related to local compression by an invasive tumor.
Ambulatory follow-up should occur every month for the first two years after treatment because repeat resection of locally recurring disease and resection of metastatic lung disease can substantially affect long-term survival.
Scanning of the local area in the abdomen or pelvis and of sites of metastatic disease should continue every three months for the first two years, every four months for the next two years, and every six months during the fifth year.
Patients should be monitored for the reappearance of adrenocortical hormone hyperactivity, along with scanning, unless their history suggests that Cushing syndrome or autonomous adrenocortical hormonal production is present. If this is the case, the physician should immediately search for recurrence.
No definitive guidelines exist for all nonfunctional adrenal masses being followed serially. A suggested follow-up regimen is to perform repeat adrenal CT or MRI scans 3-6 months after the initial evaluation, then yearly (some suggest every 6 mo for the first few years) in order to detect any change in tumor size. Accompany these with periodic checks of hormonal profiles (after 1 y, then every 1-2 y thereafter).
Michalkiewicz E, Sandrini R, Figueiredo B, Miranda EC, Caran E, Oliveira-Filho AG, et al. Clinical and outcome characteristics of children with adrenocortical tumors: a report from the International Pediatric Adrenocortical Tumor Registry. J Clin Oncol. 2004 Mar 1. 22(5):838-45. [Medline].
Dehner LP, Hill DA. Adrenal cortical neoplasms in children: why so many carcinomas and yet so many survivors?. Pediatr Dev Pathol. 2009 Jul-Aug. 12(4):284-91. [Medline].
Tritos NA, Cushing GW, Heatley G, Libertino JA. Clinical features and prognostic factors associated with adrenocortical carcinoma: Lahey Clinic Medical Center experience. Am Surg. 2000 Jan. 66(1):73-9. [Medline].
Chen QL, Su Z, Li YH, Ma HM, Chen HS, Du ML. Clinical characteristics of adrenocortical tumors in children. J Pediatr Endocrinol Metab. 2011. 24(7-8):535-41. [Medline].
Shah NS, Lila A. Childhood Cushing disease: a challenge in diagnosis and management. Horm Res Paediatr. 2011. 76 Suppl 1:65-70. [Medline].
Angeli A, Osella G, AlÃ¬ A, Terzolo M. Adrenal incidentaloma: an overview of clinical and epidemiological data from the National Italian Study Group. Horm Res. 1997. 47(4-6):279-83. [Medline].
Hamrahian AH, Ioachimescu AG, Remer EM, Motta-Ramirez G, Bogabathina H, Levin HS, et al. Clinical utility of noncontrast computed tomography attenuation value (hounsfield units) to differentiate adrenal adenomas/hyperplasias from nonadenomas: Cleveland Clinic experience. J Clin Endocrinol Metab. 2005 Feb. 90(2):871-7. [Medline].
Williams AR, Hammer GD, Else T. Transcutaneous biopsy of adrenocortical carcinoma is rarely helpful in diagnosis, potentially harmful, but does not affect patient outcome. Eur J Endocrinol. 2014 Jun. 170(6):829-35. [Medline].
Villelli NW, Jayanti MK, Zynger DL. Use and Usefulness of Adrenal Core Biopsies Without FNA or On-site Evaluation of Adequacy: A Study of 204 Cases for a 12-Year Period. Am J Clin Pathol. 2012 Jan. 137(1):124-31. [Medline].
Lau SK, Weiss LM. The Weiss system for evaluating adrenocortical neoplasms: 25 years later. Hum Pathol. 2009 Jun. 40(6):757-68. [Medline].
Soon PS, Gill AJ, Benn DE, Clarkson A, Robinson BG, McDonald KL, et al. Microarray gene expression and immunohistochemistry analyses of adrenocortical tumors identify IGF2 and Ki-67 as useful in differentiating carcinomas from adenomas. Endocr Relat Cancer. 2009 Jun. 16(2):573-83. [Medline].
Duregon E, Molinaro L, Volante M, Ventura L, Righi L, Bolla S, et al. Comparative diagnostic and prognostic performances of the hematoxylin-eosin and phospho-histone H3 mitotic count and Ki-67 index in adrenocortical carcinoma. Mod Pathol. 2014 Jan 17. [Medline].
International Union Against Cancer. TNM Classification of MalignantTumours - 7th edition. Available at http://blogs.globalink.org/uicc/templates/uicc/pdf/tnm/tnm_7th_edition_summary_091016.pdf. Accessed: December 1, 2009.
Fassnacht M, Johanssen S, Quinkler M, Bucsky P, Willenberg HS, Beuschlein F, et al. Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a Revised TNM Classification. Cancer. 2009 Jan 15. 115(2):243-50. [Medline].
Baudin E, Leboulleux S, Al Ghuzlan A, Chougnet C, Young J, Deandreis D, et al. Therapeutic management of advanced adrenocortical carcinoma: what do we know in 2011?. Horm Cancer. 2011 Dec. 2(6):363-71. [Medline].
Terzolo M, Angeli A, Fassnacht M, Daffara F, Tauchmanova L, Conton PA, et al. Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med. 2007 Jun 7. 356(23):2372-80. [Medline].
Grubbs EG, Callender GG, Xing Y, Perrier ND, Evans DB, Phan AT, et al. Recurrence of Adrenal Cortical Carcinoma Following Resection: Surgery Alone Can Achieve Results Equal to Surgery Plus Mitotane. Ann Surg Oncol. 2009 Oct 23. [Medline].
Fassnacht M, Terzolo M, Allolio B, Baudin E, Haak H, Berruti A, et al. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med. 2012 Jun 7. 366(23):2189-97. [Medline].
Ronchi CL, Sbiera S, Kraus L, Wortmann S, Johanssen S, Adam P, et al. Expression of excision repair cross complementing group 1 and prognosis in adrenocortical carcinoma patients treated with platinum-based chemotherapy. Endocr Relat Cancer. 2009 Sep. 16(3):907-18. [Medline].
Polat B, Fassnacht M, Pfreundner L, Guckenberger M, Bratengeier K, Johanssen S, et al. Radiotherapy in adrenocortical carcinoma. Cancer. 2009 Jul 1. 115(13):2816-23. [Medline].
Kazaryan AM, Marangos IP, Rosseland AR, Røsok BI, Villanger O, Pinjo E, et al. Laparoscopic adrenalectomy: Norwegian single-center experience of 242 procedures. J Laparoendosc Adv Surg Tech A. 2009 Apr. 19(2):181-9. [Medline].
Zografos GN, Vasiliadis G, Farfaras AN, Aggeli C, Digalakis M. Laparoscopic surgery for malignant adrenal tumors. JSLS. 2009 Apr-Jun. 13(2):196-202. [Medline].
Kulis T, Knezevic N, Pekez M, Kastelan D, Grkovic M, Kastelan Z. Laparoscopic Adrenalectomy: Lessons Learned from 306 Cases. J Laparoendosc Adv Surg Tech A. 2011 Dec 13. [Medline].
Agha A, Iesalnieks I, Hornung M, Phillip W, Schreyer A, Jung M, et al. Laparoscopic trans- and retroperitoneal adrenal surgery for large tumors. J Minim Access Surg. 2014 Apr. 10(2):57-61. [Medline]. [Full Text].
Datrice NM, Langan RC, Ripley RT, Kemp CD, Steinberg SM, Wood BJ, et al. Operative management for recurrent and metastatic adrenocortical carcinoma. J Surg Oncol. 2011 Dec 20. [Medline].
Hermsen IG, Gelderblom H, Kievit J, Romijn JA, Haak HR. Extremely long survival in six patients despite recurrent and metastatic adrenal carcinoma. Eur J Endocrinol. 2008 Jun. 158(6):911-9. [Medline].
Kemp CD, Ripley RT, Mathur A, et al. Pulmonary resection for metastatic adrenocortical carcinoma: the National Cancer Institute experience. Ann Thorac Surg. 2011 Oct. 92(4):1195-200. [Medline].
Schulick RD, Brennan MF. Long-term survival after complete resection and repeat resection in patients with adrenocortical carcinoma. Ann Surg Oncol. 1999 Dec. 6(8):719-26. [Medline].
Hah JO. Intensive chemotherapy with autologous PBSCT for advanced adrenocortical carcinoma in a child. J Pediatr Hematol Oncol. 2008 Apr. 30(4):332-4. [Medline].