Approach to the Patient
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Learning Objectives
Upon completion of this educational activity, participants should be able to
· Review the approaches to investigate and treat patients with an adrenal mass that is considered at high risk of being an adrenal carcinoma.
· Implement anti-neoplastic therapy as appropriate based on knowledge of treatment indications, mode of admin- istration, side effects, and requirements for monitoring and hormone replacement.
· Provide appropriate follow-up of patients after the sur- gical resection of adrenal carcinoma and choice of further therapies if relapse occurs.
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This continuing medical education activity should be of sub- stantial interest to endocrinologists.
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The following individual reported relevant financial relationships:
Andre Lacroix, M.D., has served as a consultant and advi- sory council member for HRA Pharma, Paris.
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Leonard Wartofsky, M.D., reported no relevant financial relationships.
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Activity release date: November 2010 Activity expiration date: November 2011
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A.
Copyright @ 2010 by The Endocrine Society
doi: 10.1210/jc.2010-0990 Received April 30, 2010. Accepted July 14, 2010.
Approach to the Patient with Adrenocortical Carcinoma
André Lacroix
Division of Endocrinology, Department of Medicine, Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Université de Montréal, Montréal, Québec, Canada H2W1T8
Adrenocortical cancer (ACC) is a rare and often aggressive malignancy that re- quires multidisciplinary expertise for optimal management. It can present with symptoms of rapidly appearing excess steroid secretion or an abdominal mass, or it can be discovered incidentally. Thorough imaging and endocrine evaluations can identify the majority of ACCs amongst adrenal tumors; however, some smaller ACCs are better identified using fluorodeoxyglucose-positron emission tomog- raphy/computed tomography scan. Complete resection by an expert surgeon is the only potentially curative treatment for ACC, and tumor spillage should be avoided. Histopathology is important for diagnosis, but immunohistochemistry markers and gene profiling of the resected tumor may become superior to current staging systems to stratify prognosis. Despite complete resection in stage I-III tumors, approximately 40% of patients develop metastasis within 2 yr. Some retrospective studies indicate that adjuvant mitotane therapy prolongs disease- free survival, leading several centers to recommend its administration; prospec- tive studies are under way to provide future evidence-based recommendations. For locally invading ACC, extensive en bloc resection is attempted, followed by adjuvant mitotane and, in selected cases, adjuvant radiotherapy. When ACC is not surgically resectable, mitotane therapy is adjusted to reach serum levels of 14-20 ug/ml. Careful replacement of glucocorticoid and mineralocorticoid deficiency after surgery or mitotane therapy is important; steroid excess from remaining tumor burden should also be controlled to avoid its morbidities. For metastatic disease, combination chemotherapy should be administered, if possible, in the context of multicenter collaborative research protocols. New insights in the molec- ular pathogenesis of ACC should allow the development of improved targeted therapies. (J Clin Endocrinol Metab 95: 4812-4822, 2010)
A 22-yr-old woman was referred after laparoscopic re- section of an 8.6 X 8 cm left adrenal carcinoma. She presented virilization and amenorrhea during the last 6 months. Computed tomography (CT) scan revealed a left adrenal mass without local invasion. Blood pressure, plasma glucose, and potassium were normal, but in- creased serum androgen levels were present (Table 1). Sur- gical resection was believed complete, and pathology in-
Abbreviations: ACC, Adrenocortical cancer (or carcinoma); CS, Cushing’s syndrome; CT, computed tomography; EDP, etoposide, doxorubicin, and cisplatin; FDG, fluorodeoxyglu- cose; FNA, fine-needle aspiration; HU, Hounsfield units; MRI, magnetic resonance imaging; PET, positron emission tomography; R0, complete resection; R1, incomplete resection status; Rx, uncertain resection status; RT, radiotherapy.
| Date (month/yr) | 08-07 | 09-07 | 11-07 | 04-08 | 05-08 | 07-08 | Normal levels |
|---|---|---|---|---|---|---|---|
| Therapy | Left adrenal- ectomy | Extensive abdominal | |||||
| Imaging studies | Large left adrenal tumor | Normal | Adrenal bed and abdominal recurrence | surgery | Small mesenteric and liver nodules | ||
| Hydrocortisone (mg/d) | 20 mg | 20 mg, increase to 30 mg | 30 mg | ||||
| Mitotane dose | Start | 2 g × 5 months, | 6 g | 6 g, increase | |||
| (g/d) | 1 g | increase to 6 g | to 8 g | ||||
| Plasma mitotane (µg/ml) | 3.3 | 7.1 | 14-20 | ||||
| Total testosterone (nmol/liter) | 27.8 | 1.9 | 3.3 | 1.3 | <2.9 | ||
| Androstenedione (nmol/liter) | 17.1 | 3.9 | 10.3 | 5.1 | 1.6-9.2 | ||
| DHEAS | 18.3 | 3.6 | 4.2 | 1.0 | 0.8-11.3 | ||
| (pmol/liter) | |||||||
| Urinary free | 247 | 229 | 156 | 223 | 55-330 | ||
| cortisol (nmol/d) | |||||||
| ACTH (pmol/liter) | 9.7 | 19.4 | 16.3 | 2.0-11.0 | |||
| Renin activity | 0.7 | 6.6 | 0.5 | 0.9-2.5 | |||
| sitting (ng/ml · h) |
DHEAS, Dehydroepiandrosterone sulfate.
dicated adrenal carcinoma (modified Weiss score of 6). Thoracic and abdominal CT and fluorodeoxyglucose (FDG)-positron emission tomography (PET) scans and steroid levels performed 6 wk after surgery were normal (Table 1). After discussions with the multidisciplinary team and psychological support, adjuvant mitotane was initiated and increased rapidly to 2 g/d with good toler- ance; hydrocortisone, 20 mg split in three daily doses, and oral contraceptive were added. Six months after surgery, FDG-PET and abdominal CT scans showed masses of 2.1 cm in left adrenal bed and 2.3 cm between superior mes- enteric artery and pancreas; left ovary was enlarged to 6.4 cm, but without FDG uptake. Mitotane dose was in- creased. Three surgical oncology teams resected the two larger nodules and metastasis in left kidney, pancreas tail, epiploon, peritoneal wall, left ovary, and paraaortic and pelvic lymph nodes. Two months later, PET-CT showed foci of mesenteric nodules of 12 mm and a 1.2-cm hepatic lesion without FDG uptake. Mitotane was increased to 8 g daily. Progression of mesenteric lesions, three small he- patic lesions. and peritoneal implants were found on FDG-CT scan 3 months later (Table 2). Mitotane was increased to 10 g/d, and the adrenal tumor board did not recommend further surgery; the patient was randomized
in the First International Randomized trial in locally ad- vanced and Metastatic Adrenocortical Carcinoma Treat- ment (FIRM-ACT) protocol (NCT00094497; www. firm-act.org) to the etoposide, doxorubicin, and cisplatin (EDP) arm with a mitotane dose of 12 g/d. After three cycles, the hepatic lesions had regressed completely, and the mesenteric lesions decreased by 50%. A total of nine cycles were administered with 90% regression of mesen- teric lesions. Mitotane was reduced progressively, discon- tinued transiently because of toxicity, and resumed at 1 g/d (Table 2). Hydrocortisone was increased progressively to 90 mg/d based on symptoms and ACTH levels. No min- eralocorticoid replacement was necessary despite tran- sient increase in circulating renin. Three months after completion of EDP chemotherapy, serum mitotane was subtherapeutic and was increased to 2 g/d. Further pro- gression of target lesions and elevation of androgen levels justified starting the second arm of the FIRM-ACT pro- tocol with streptozotocin and mitotane.
Background
The investigation and treatment of adrenocortical carci- nomas (ACCs) remains with many uncertainties. Most
| Date (month/yr) | 09-08 | 11-08 | 06-09 | 08-09 | 12-09 | 03-10 | Normal levels |
|---|---|---|---|---|---|---|---|
| Therapy | Start EDP chemo- therapy | After 6 cycles EDP | End EDP after 9 cycles | Start streptozotocin arm | |||
| Imaging studies | Progressive liver and mesenteric nodules | >90% regression of nodules | >90% regression of nodules | Stable | Recurrent mesenteric pelvic and hepatic nodules | ||
| Hydrocortisone (mg/d) | 30 mg | 30 mg | 60 mg | 90 mg | 60 mg | 40 mg | |
| Mitotane dose (g/d) | 8 g, | 12 g | 12 g, reduce to 8 g | 6 g, stop mitotane × 2 wk | 1 g | 2 g | |
| increase to 10 g | |||||||
| Plasma mitotane (µg/ml) | 9.1 | 9.4 | 24.9 | 35.0 | 21.0 | 6.9 | 14-20 |
| Total testosterone (nmol/liter) | 1.3 | 1.6 | <1.0 | 1.7 | 20.4 | <2.9 | |
| Androstenedione (nmol/liter) | 3.8 | 7.1 | 0.9 | 3.6 | 1.6-9.2 | ||
| DHEAS | 2.2 | 1.8 | 0.1 | 1.9 | 2.3 | 0.8-11.3 | |
| (pmol/liter) | |||||||
| Urinary free | 231 | 656 | 55-330 | ||||
| cortisol (nmol/d) | |||||||
| ACTH (pmol/liter) | 15.5 | 32.2 | 131.3 | 10.7 | 0.5 | 2.0-11.0 | |
| Renin activity | 1.8 | 5.0 | 25.8 | 1.9 | 0.4 | 0.9-2.5 | |
| sitting (ng/ml · h) | |||||||
DHEAS, Dehydroepiandrosterone sulfate.
endocrinologists, surgeons, and oncologists, except those working in specialized referral centers, do not have exten- sive experience or access to the multidisciplinary teams required to treat such patients. Because of the rarity and heterogeneous evolution of ACC, the published small se- ries on its investigation or therapies by single centers have seldom met the criteria for evidence-based medicine. Re- cent efforts to perform multicenter studies (1) and progress in molecular pathophysiology (2, 3) offer hope for better treatment of ACC. We will present our current approach to the investigation and therapy of ACC, while indicating the numerous remaining areas of uncertainties and controversies.
Epidemiology
ACC is rare, with an incidence of one or two per million per year (1,2,4). Women are more often affected than men (1.5:1). ACC can develop at any age, with peaks before age 5 yr and between the fourth and fifth decades of life. Tu- mor aggressiveness is higher in adults than in children (4, 5). ACC incidence is 10-fold higher in Southern Brazil children, where a specific TP53 germline mutation (R337H) occurs (2,5). Although most ACCs are sporadic, some occur as part of hereditary cancer predisposition syndromes including Li-Fraumeni syndrome (TP53 mu- tations) and Beckwith-Wiedemann syndrome (IGF-II overexpression) (2).
Clinical presentation
Adults with hormone-secreting ACC (~60%) present with Cushing’s syndrome (CS) (45%), combined with an- drogens (25%), or with virilization alone (10%) (2, 6). CS usually develops rapidly over a few months. Excess an- drogens can decrease the catabolic effects of CS. Estro- gen or mineralocorticoid excess occurs in less than 10% of cases (2, 6). Children present more virilization (84%), whereas isolated CS is infrequent (6%) (2, 5-7). Patients with nonsecreting tumors may present abdom- inal pain or only incidental adrenal mass. Fever and leukocytosis may occur from tumor necrosis or secre- tion of chemokines (8).
Diagnostic Evaluation: Identify the Adrenocortical Carcinoma
Imaging studies
CT scan can usually distinguish ACCs from adenomas. Mean ACC size was 11.6 + 4.7 cm in 489 cases of the German Registry (4). The challenge is to identify ACC of less than 5 cm. CT attenuation of benign adenoma is usu- ally less than 10 Hounsfield units (HU) on unenhanced scan. ACCs have higher HU values and features of het- erogeneity, irregular borders, calcifications, local inva- sion, or lymphadenopathy. Delayed contrast CT with
attenuation greater than 35 HU after 15 min of washout (<50%) is more suspicious of malignancy (9). Magnetic resonance imaging (MRI) can characterize adrenal lipid content, but considering its higher cost, we prefer CT imaging. MRI may better identify local and vena cava invasion (4).
The use of FDG-PET scanning is emerging as useful to identify ACC from benign adenomas with elevated HU or delayed contrast washout values (10). Integrated PET-CT improves the performance to differentiate ad- renal adenomas from malignant lesions (11). Using PET (standard uptake value cutoff of 3.1), the sensitivity, specificity, positive predictive, and negative predictive values for malignancies vs. adenomas were 99, 92, 89, and 99%, respectively; for PET-CT, they were 100, 98, 97, and 100%, respectively (11). FDG-PET cannot dis- tinguish between ACC, adrenal metastasis, and pheo- chromocytoma. Alternative PET tracers that are under study (11C-metomidate, which binds to 11 ß-hydrox- ylase, and aldosterone synthetase) might further im- prove specificity (4).
Common sites of metastasis for ACC are: liver, lungs, lymph nodes, and bone (4). CT imaging of the chest and abdomen should be performed if ACC is suspected. PET is more sensitive than CT for distant metastases but can miss small pulmonary lesions (11). Bone scan or brain MRI should be performed when patients present symptoms of such metastasis.
Hormonal evaluation
Even in asymptomatic patients, the European Network for the study of Adrenal Tumors (ENSAT; www.ensa- t.org) recommends performing tests shown in Table 3. Using sensitive analysis of 24-h urine reveals abnormal steroidogenesis in almost 100% of ACC cases, which may become useful in follow-up (12). When cortisol excess is severe, appropriate control is necessary before surgery to decrease morbidities such as infection, thomboembolism, or poor wound healing.
Fine-needle aspiration (FNA) biopsy
Cytology from FNA cannot distinguish a benign adre- nal mass from ACC. FNA can be performed for suspicion of adrenal metastasis from another primary cancer (4). Pheochromocytoma should always be excluded before FNA of an adrenal mass.
Pathological diagnosis of ACC
The diagnosis of ACC is difficult and requires an expert adrenal pathologist. The Weiss histopathological score
evaluates malignant risk based on tumor structure (clear cells in cytoplasm, diffuse architecture, necrosis), cytology (atypical high nuclear grade, number of mitosis, abnormal mitosis), and invasion (venous, sinusoidal, capsular) (13); the presence of three or more positive criteria correlates with malignant behavior. Five criteria are used by Aubert et al. (14) in the modified Weiss system: at least six mito- ses/50 high power fields, no greater than 25% clear tumor cells in cytoplasm, abnormal mitoses, necrosis, and cap- sular invasion. Each criterion is scored as zero when ab- sent or, when present, 2 for the first two criteria and 1 for last three; the threshold for malignancy is a total score at least 3.
Other immunohistochemical criteria used include Ki-67 proliferation index, but cutoff values between be- nign and malignant lesions vary from 1.5-10% (4). Over- expression of p53, IGF-II, and cyclin E are found in ACC but are not sufficiently discriminatory. Several markers such as @-inhibin, melan A, and steroidogenic factor 1 can confirm the primary adrenal origin (2-4).
Staging of ACC
In adults, the surgical staging system is based on tu- mor size, nodal involvement, and the presence of me- tastases (15, 16). These TNM criteria were proposed for adoption by the Union Internationale Contre le Cancer (UICC)/World Health Organization (WHO) in 2004. Its prognostic influence was reevaluated in 416 adult German cases (17) in which the 5-yr disease-specific survival rates were not different between stages II and III (Table 4). There was better patient survival with UICC/ WHO stage IV ACC without distant disease compared with those with distant metastases (hazard ratio for death, 0.44). A modified staging was proposed by ENSAT in 2008 (Table 4), which discriminated better stages II and III. The superiority of the ENSAT staging was confirmed in a North American study of 573 cases (18).
In children, a different system identifies only three 5-yr event-free survival distinct groups: completely resected small tumors (≤200 g) with excellent prognosis, 91%; completely resected large tumors (≥200 g), intermediate prognosis 52%; and residual or distant metastatic disease, poor prognosis (5, 7).
Molecular markers for diagnosis and prognosis of ACC
Recent microarray studies suggest that certain tumor gene profiles could better discriminate benign adenomas from ACC than morphology (2, 3, 19, 20); they may also predict
TABLE 3. Recommended hormonal evaluation in patients with suspected or proven ACC
Cortisol excess (minimum 3 of 4 tests)
Dexamethasone suppression test (1 mg, 2300 h)
Urinary free cortisol (24-h urine)
Basal cortisol (serum) Basal ACTH (plasma)
Sexual steroids and steroid precursors
DHEAS (serum)
Androstenedione (serum)
Testosterone (serum)
17-OH-progesterone (serum)
17ß-Estradiol (serum, in men and postmenopausal women) Mineralocorticoid excess Potassium (serum)
Aldosterone/renin ratio (only in patients with arterial hypertension and/or hypokalemia)
Exclusion of pheochromocytoma (minimum 1 of 3 tests) Catecholamine excretion (24-h urine) Metanephrine excretion (24-h urine) Meta- and normetanephrines (plasma)
Data were modified from recommendations of the European Network for the Study of Adrenal Tumors (www.ensat.org/acc.htm) in 2005. DHEAS, Dehydroepiandrosterone sulfate.
survival prognosis (19, 20). Overexpression of IGF-II is the predominant marker of malignancy (2, 3, 19, 20). The pair of cell cycle regulator genes DGL7 (increased in aggressive ACC) and PINK1 (decreased in most aggressive ACC) dis- criminated tumors with worst prognosis (19). These markers may become particularly useful to predict risk of stage 1 and 2 ACC. Genetic profiles were evaluated only in small series and are not available for clinical use yet; they open very ex- citing future perspectives.
Primary Treatment of ACC
Initial surgery
The primary potentially curative treatment for ACC is surgery (1, 4). The surgeon should have specific expertise and avoid tumor spillage and incomplete resection. In pa- tients with CS, suppression of the ACTH-adrenal axis will require replacement with glucocorticoids after complete ACC resection. Using open surgery, complete resection (RO) is possible in most patients with stage I-III disease, but recurrence is high (1, 4). In 202 patients with ACC, 40% had developed metastasis within 2 yr (27, 46, and 63% of patients with stage I, II, and III disease, respec- tively) (21). Open surgery is recommended for large tu- mors with imaging criteria of malignancy and when inva- sion is present; en bloc resection of kidney, spleen, and portions of pancreas, liver, colon, or stomach may be needed (1, 4). When ACC cannot be removed entirely, maximal debulking may improve survival, but this is
controversial (1, 4). In functional tumors, debulking may help to control hormone hypersecretion and improve fur- ther therapy (1, 4). Untreated patients with unresectable disease survive only 3 to 9 months (1, 4, 21). For adrenal incidentalomas in which surgery is proposed because of size criteria (>4 or 6 cm) but without clear evidence of ACC, there is a controversy as to whether open or lapa- roscopic adrenalectomy should be used. Several reports have suggested worst outcome with laparoscopic surgery compared with open surgery for ACC (1, 4); however, recent studies showed that for lesions smaller than 10 cm, laparoscopic adrenalectomy performed by expert sur- geons achieved results comparable to open surgery (22). The most important factor is that surgery should be per- formed by an expert surgeon who can best decide after tumor board discussion which approach is appropriate for each case (1, 4).
Adjuvant Therapies
Adjuvant mitotane therapy
Mitotane is an adrenocorticolytic drug that has effi- cacy in patients with ACC (1, 4, 6). The benefit of post- operative adjuvant mitotane for ACC is controversial, due to lack of prospective clinical trial data. Some ret- rospective studies indicate that mitotane may delay or prevent recurrence, but others do not (1, 4). The best evidence was from a retrospective analysis of 177 pa- tients with stage I-III ACC followed after complete re- section in eight Italian and 47 German centers (23). In Italy, 47 patients received adjuvant mitotane, whereas 55 did not. None of 75 German patients received mi- totane (German control group). The mitotane dose was of 1-3 g/d in 27 patients, and 3-5 g/d in 20 patients with median duration of treatment of 29 months; serum mi- totane levels were not routinely measured. The adjuvant mitotane group had a longer recurrence-free survival (median of 42 vs. 10 and 25 months in the Italian and German control groups). There were fewer deaths from ACC in the mitotane group than in control groups (25 vs. 55 and 41%). Median overall survival duration was 110 months in the mitotane group compared with 52 months in the Italian and 67 months in the German control groups (23).
Several centers, including ours, recommend adminis- tering adjuvant mitotane to all patients with ACC rapidly after surgery. Other groups recommend adjuvant mito- tane only in patients with tumors larger than 8 cm, with microscopic vascular invasion and Ki-67 greater than 10% (4). A prospective study of adjuvant mitotane in
| Stage | UICC/WHO 2004 | ENSAT 2008 | ||
|---|---|---|---|---|
| TNM | 5-yr disease-free survival (%) | TNM | 5-yr disease-free survival (%) | |
| I | T1, N0, M0 | 82 | T1, N0, M0 | 82 |
| II | T2, N0, M0 | 58 | T2, N0, M0 | 61 |
| III | T1-2, N1, M0 | 55 | T1-2, N1, M0 | 50 |
| T3, N0, M0 | T3-4, N0-1, M0 | |||
| IV | T1-4, N0-1, M1 | 18 | T1-4, N0-1, M1 | 13 |
| T3, N1, M0 | ||||
| T4, N0-1, M0 | ||||
T1 tumor, <5 cm; T2 tumor, >5 cm; T3 tumor, infiltration in surrounding tissue; T4 tumor, invasion in adjacent organs (ENSAT, also venous tumor thrombus in vena cava/renal vein); N0, no positive lymph nodes; N1, positive lymph node(s); M0, no distant metastases; M1, presence of distant metastasis.
a Based on data generated in Ref. 17.
patients with low to intermediate risk is now conducted (ADIUVO clinical trial identifier, NCT00777244). Low to intermediate relapse risk is stage I-III ACC with complete resection, no microscopic/radiological resid- ual disease, and Ki-67 less than 10%. Patients are randomized to adjuvant mitotane or none in an open- label study over 6-yr follow-up; results are expected by 2014.
We start adjuvant mitotane at 0.5 g twice daily with meals and increase to 2 g/d within 2 wk. Because of long serum half-life and accumulation in adipose tissue, sev- eral weeks are necessary (Tables 1 and 2) to raise serum mitotane concentrations to the target level of 14-20 ug/ml. For higher risk patients, mitotane is increased rapidly to 6 g/d with monitoring of mitotane level every 2-3 wk (4). There is no consensus on the duration of adjuvant mitotane therapy for patients with stage I or II disease, but a minimum of 2 yr and probably of up to 5 yr is reasonable (1, 4). Women of reproductive age need reliable contraception during mitotane therapy. The gonadal toxicity of mitotane and efficacy of go- nadal-sparing regimens such as oral contraceptives are unknown.
Imaging follow-up after surgical resection
After initial surgical resection of ACC, patients with or without adjuvant mitotane should undergo close im- aging follow-up. There is no consensus for a precise imag- ing protocol schedule; we perform CT of the chest and upper abdomen and FDG-PET scan every 3 months for 1 yr and alternate CTs and FDG-PET scans every 3 months the second year, every 6 months for 5 yr, and annually thereafter. Other centers use FDG-PET at lesser frequency at 3 and 12 months or in the presence of suspicious CT imaging.
Steroid hormone markers are also performed every 3-6 months.
Adjuvant radiation therapy
The efficacy of adjuvant radiotherapy (RT) after sur- gery is controversial. There are no randomized trials, and data from retrospective series are conflicting. The largest retrospective report was of 14 patients (stages I-III) without residual disease who received postoper- ative RT and were compared with 14 matched patients who did not receive RT (24). Local recurrence devel- oped in two of 14 irradiated patients compared with 11 of 14 who did not; distant metastasis and overall survivals were not significantly better in irradiated pa- tients. Many recurrences developed in the inter-aorto- caval region, leading to a recommendation of covering this area and the ipsilateral lymphatic drainage bed (25).
The German ACC group recommends adjuvant RT no later than 3 months after surgery in patients with micro- scopically incomplete (R1) or uncertain (Rx) resection sta- tus, in those with stage III disease even if surgical resection was believed complete (4, 24, 25); it is also considered in patients with R0 resection but in whom tumor was larger than 8 cm with tumor invasion of blood vessels and a Ki-67 index of proliferation greater than 10%. Larger pro- spective randomized studies are needed to define better the role of adjuvant RT after resection of ACC.
Recurrent or Advanced ACC
Therapy with mitotane
For patients with advanced ACC, mitotane is admin- istered rapidly to 6 g/d or to tolerance and titrated to
reach target serum levels of 14-20 µg/ml. Decrease in excess steroids is achieved in up to 75% of patients, and tumor regression in up to one third of cases (1, 4, 6, 21, 26). Treatment benefits are generally short-lived, and survival is not consistently prolonged in patients with unresectable disease; rare long-term survivors were reported.
Serum mitotane levels correlate with antitumor effi- cacy. In 24 patients, only 58% achieved serum mitotane concentration above 14 µg/ml (26). Toxicity correlated to serum levels above 20 µg/ml.
We strongly suggest monitoring serum mitotane levels. After requiring several weeks of mitotane to reach target levels, a decrease in dose is often necessary to maintain target mitotane levels (the case and Tables 1 and 2). We observed increased requirements of mitotane dose in pa- tients receiving chemotherapy, possibly secondary to mal- absorption; when chemotherapy is discontinued, mito- tane doses need to be reduced.
Adrenal replacement therapy under mitotane
Mitotane is adrenolytic and reduces normal adreno- cortical function. Replacement therapy should be started with mitotane treatment or when it reaches 2 g/d. We use hydrocortisone (10 to 15 mg in the morning and 5 mg at lunch and dinner); as mitotane increases cortisol binding globulin levels (serum cortisol values are artifactually elevated) and cortisol metabolism, pa- tients eventually require a 2- to 3-fold increase in hy- drocortisone doses for adequate replacement (1, 4). The zona glomerulosa is more resistant to the adrenolytic mitotane effect, and aldosterone deficiency may not oc- cur before several months. Mitotane also increases dexamethasone and fludrocortisone metabolism (1, 4). Monitoring blood levels of ACTH, renin, sodium, po- tassium, as well as urinary free or salivary cortisol levels is necessary to adjust steroid replacement doses (the case and Tables 1 and 2). Patients should wear a medical bracelet and be instructed to increase hydrocortisone dose during stress.
In patients with residual ACC and increased cortisol production, replacement is not initiated until hypercor- tisolism is controlled with mitotane and steroid enzyme inhibitors.
Mitotane side effects
Mitotane has many side effects, particularly when se- rum levels are above 20 µg/ml, but they can be present even with lower blood levels (26, 27). The most common are nausea, vomiting, and anorexia, but rash, diarrhea,
lethargy, sedation, dizziness, ataxia, gynecomastia, ar- thralgias, leucopenia, and reversible growth arrest in children also occur (1, 4, 6, 26, 27). Other side effects include hypercholesterolemia (requiring statin ther- apy), hypouricemia, and hepatotoxicity. Some side ef- fects may result from cortisol deficiency; higher hydro- cortisone dose may correct symptoms. Antinausea drugs are useful, but temporary discontinuation of mi- totane may be necessary, followed by reinstitution at a lower dose.
Mitotane increases serum concentrations of SHBG and TBG. Serum concentrations of TSH, free testoster- one, and free T4 may be decreased, suggesting inhibitory effects of mitotane on thyreotrope (4, 27, 28). Because patients often present with fatigue, thyroid function tests should be monitored periodically and T4 replacement may become necessary. Serum testosterone levels should be interpreted taking into account the changes of SHBG, but replacement with testosterone in males may become neces- sary also (27).
Medical treatment of hypercortisolism
Control of CS is important because patients can die prematurely of infections and hypercortisolism- and chemotherapy-induced immunosuppression rather than from tumor burden. In North America, ketoconazole is the steroidogenic enzyme inhibitor used, starting with 200 mg three times daily, which can be increased to 1200 mg daily. Its effect is assessed by measuring 24-h urine cortisol or serum androgen levels. Metyrapone can be added at 250 mg four times daily and increased up to 6 g/d. In critical patients, iv etomidate (which blocks 11-ß-hydroxylase) can be administered at 0.3 mg/kg · h.
Hypokalemia should be replaced with potassium sup- plements, spironolactone, eplerenone, or amiloride; fre- quent serum potassium monitoring is necessary because acute hyperkalemia can occur when hypercortisolism is controlled or renal function is impaired. Hydrocortisone replacement is recommended when steroidogenic enzyme inhibitors control hypercortisolism.
Local therapy for advanced disease
Aggressive surgical resection of locally recurrent or dis- tant disease may prolong survival (1, 4). Five-year survival rates for patients with completely and incompletely re- sected locally recurrent disease were 57 and 0%, respec- tively (29). Resection of isolated liver metastases from ACC led to a 5-yr survival rate of 66% (30). Resection of locally recurrent disease is indicated in patients where su
rgery will remove a majority of tumor or decrease severe hypercortisolism (1, 4).
Radiation therapy may be beneficial for tumors causing pain, such as in bone metastasis (25). Percutaneous radiofre-
quency ablation may provide short-term local control of an un- resectable tumor, particularly for those less than 5 cm in diam- eter including small liver metastases (1, 4, 31). The long-term impact of radiofrequency ablation on survival is unknown.
| Area | Practice point |
|---|---|
| Investigation of adrenal mass Imaging | Unenhanced CT scan attenuation >10 HU; review with radiologist for features suggesting ACC |
| Endocrine evaluation | FDG-PET for suspicious lesions on CT scan For lesions highly suspicious of ACC, look for extent of disease with thorax CT and FDG-PET; bone imaging or brain MRI if patients present symptoms of metastasis at these sites Follow recommendations of Table 3 |
| Initial therapy Comprehensive care | Refer patient to be followed by multidisciplinary team including social worker, psychologist, palliative care, specialized oncology nurse |
| Initial surgery | <10 cm noninvading lesion: laparoscopic or open surgery according to expert surgeon evaluation |
| >10 cm or local invasion: open radical surgery Distant disease: remove primary lesion only if this allows high proportion of tumor burden and improve excess steroid secretion | |
| Pathology | Review slides of tumor or biopsy material with expert pathologist and assess Weiss score (14) Request evaluation of Ki-67 index, and if needed of IGF-II, P-53, and cyclin E immunohistochemistry |
| Staging Adjuvant mitotane | Use ENSAT 2008 staging system for adult ACC (17, 18) Recommend adjuvant mitotane for tumors with revised Weiss criteria ≥3 Use 2 g/d initially for stage I and II tumors during a minimum period of 2 yr Use 6 g/d rapidly for stage III tumors or stage I or Il tumors with Ki-67 >10% (5-yr duration) Monitor serum mitotane levels and adjust dose to reach levels between 14-20 µg/ml Initiate replacement with hydrocortisone Monitor cholesterol, liver function, free T4, testosterone levels Oral contraceptives to female patients during reproductive age Monitor urinary cortisol, ACTH, renin, and marker steroid levels |
| Follow-up imaging | Follow-up imaging with CT scan of thorax and abdomen and if needed FDG-PET scan every 3 months for 1 yr, every 6 months for 5 yr, and annually if there is no evidence of tumor recurrence |
| Adjuvant radiotherapy | Consider in patients with stage III disease, R1 incomplete resection, R0 or Rx resection with initial tumor >8 cm, blood vessel invasion and Ki-67 >10 |
| Therapy of advanced disease Mitotane | Increase rapidly to 6 g/d split during three meals to reach serum levels of 14-20 µg/ml; monitor every 2-3 wk initially to adjust dose |
| Control of steroid excess | Use antinausea drugs as needed (prochlorperazine, metoclopramide, ondansetron) Use mitotane and steroid enzyme inhibitors such as ketoconazole and metyrapone Correct hypokalemia with potassium supplements, spironolactone, eplerenone, or amiloride Frequent monitoring of electrolytes, creatinine, urinary cortisol to avoid acute hyperkalemia when cortisol excess is controlled Treat diabetes and high blood pressure |
| Adrenal replacement | Administer hydrocortisone in three split doses as soon as hypercortisolism is resolved Adjust doses based on symptoms and levels of plasma ACTH and urinary free cortisol Mitotane usually increases requirements 2- to 3-fold higher than usual, particularly during combined chemotherapy Add fludrocortisone replacement when renin levels increase; requirements may also be increased 2- to 3-fold by mitotane |
| Surgery Systemic chemotherapy | Serum cortisol levels are not reliable because mitotane increases CBG levels Surgically remove resectable residual tumor or isolated metastatic lesions In advanced metastatic disease, administer combination of EDP or streptozotocin and mitotane (33, 34) or other combination therapies preferably in the context of multicenter collaborative research protocols |
| Consider salvage therapy with new drugs such as IGF-I receptor antagonists or tyrosine kinase inhibitors within multicenter research protocols |
CBG, Cortisol binding globulin.
Systemic chemotherapy
Many cytotoxic drugs have been studied in advanced ACC patients, but relatively few large trials have been conducted (4, 32). Mitotane increases the cytotoxic activ- ity of several chemotherapeutic drugs on human ACC cells, possibly as p-glycoprotein antagonist (4, 32). The best chemotherapy results involved a group of 72 patients who received a monthly combination of EDP, as well as mitotane up to 4 g/d (33). Complete response was achieved in five patients and partial response in 30 (overall response rate, 49%). The average time to progression in responding patients was 24 months. The second best response rate was provided by the combination of mitotane (1-4 g/d) plus iv streptozocin (1000 mg/d for 5 d, followed by 2000 mg every 3 wk), with a partial or complete response in 36% of patients (34); 2- and 5-yr survival rates were 70 and 33%, respectively. The FIRM-ACT is comparing the ef- ficacy of EDP plus mitotane vs. streptozotocin plus mito- tane as first-line treatment in patients with locally ad- vanced or metastatic disease. The study has already randomized 300 patients (largest ACC study ever), and initial analysis should become available in 2011.
Other new second-/third-line therapies currently con- ducted are targeted at pathways suggested by new molec- ular findings in ACC, including growth factors such as IGF-II or their receptors (IGF-I receptor, epidermal growth factor receptor) and tyrosine kinases (4, 32). Un- fortunately, to date, salvage chemotherapies with erlo- tinib plus gemcitabine or gefitinib, or bevacizumab plus capecitabine, or sunitinib were of little benefit (4, 35, 36); gemcitabine plus metronomic 5-fluorouracil showed moderate response rate in heavily pretreated ACC (37). Case reports of tumor responses have been published for the antiangiogenic compound thalidomide (38) or with zoledronic acid (39). Clearly, large multicenter studies will be necessary to achieve any significant progress in the ther- apy of advanced ACC.
Returning to the Case
Unfortunately, this young woman’s prognosis deteriorated because her metastatic ACC is progressing despite the com- bination of mitotane and the most efficient chemother- apy regimens. It is hoped that she will have further remission with streptozotocin and mitotane. Sal- vge therapy with IGF-I receptor antagonist OSI-906 (NCT00924989 protocol) vs. placebo will then be offered to the patient. Multidisciplinary support including psy- chologist, social worker, adrenal oncology nurse, and medical teams in palliative care are actively involved. It is hoped that better molecular markers of poor prognosis
will become more widely available in the near future to assist in identifying patients who should receive more ag- gressive adjuvant therapy with mitotane or other targeted therapies to avoid such dismal progression as that expe- rienced by this young woman.
Conclusion
Considering the rarity and complexity of ACC, it is recommended that such patients are referred to special- ized multidisciplinary centers experienced in the man- agement of this disease. This will provide patients with optimal options to treat their disease taking into con- sideration all of its aspects as summarized in Table 5. Despite the too frequent aggressive nature of ACC, a growing number of patients now have longer survival and require expert management to decrease side effects of their therapies. In addition, new investigative and therapeutic approaches can be accomplished only through national and international networks of centers of expertise in adrenal pathologies.
Acknowledgments
I express my gratitude to Drs. Diane M. F. Savarese and Lynnette K. Nieman for their contributions as co-authors to pre- vious reviews on the same topic in UpToDate. I also thank my colleagues Drs. Isabelle Bourdeau and Maria Candida Barisson Vil- lares Fragoso for their helpful discussions on this topic and manuscript.
Address all correspondence and requests for reprints to: Dr. André Lacroix, Hôtel-Dieu du Centre hospitalier de l’Université de Montréal, 3840 rue Saint-Urbain, Montréal, Québec, Canada H2W 1T8. E-mail: andre.lacroix@umontreal.ca.
Disclosure Summary: The author of this manuscript has noth- ing to disclose.
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