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6 Recent advances in adrenocortical carcinoma URRENT PINION in adults

Isabelle Bourdeau, Jessica MacKenzie-Feder, and Andre Lacroix

Purpose of review

Adrenocortical cancer (ACC) is a rare and often aggressive malignancy. The overall 5-year survival rate of ACC is less than 30% in part owing to advanced stage of the disease at diagnosis and limited efficiency of therapies when initial surgery is not curative. So far, studies with large cohorts of patients affected by ACC were lacking because of the rarity of the disease; however, recent international and multicenter collaborative studies provide new insights in the management of ACC.

Recent findings

This review summarizes recent findings in the genetic, hormonal evaluation, imaging, and therapies of ACC in adults. There is new promise for the use of 2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography and metomidate in initial diagnosis and follow-up. Limited studies support benefit of specific surgical approaches such as loco-regional lymph node dissection and metastasectomy in specific subgroups. New developments in the use of mitotane therapy and its drug interactions, on adjuvant radiotherapy and prospective data on combined chemotherapy, have appeared recently.

Summary

These recent findings will provide more evidence-based recommendations in the future to better assist clinicians in the management of patients with ACC. However, there is still an important need to understand the molecular mechanisms underlying this disease to design better therapeutic approaches.

Keywords

adrenocortical cancer, chemotherapy, Cushing’s syndrome, genetics, mitotane

INTRODUCTION

Adrenocortical carcinoma (ACC) is a rare and often aggressive malignancy with an incidence of 1-2 per million per year [1,2”,3”]. Most series on ACC are restricted to a small number of patients and evidence-based medicine is lacking. Recently, efforts to perform international multicenter trials led to the study of larger cohorts of patients with ACC. In this review, we summarize the recent findings in various clinical aspects of ACC that have appeared since more comprehensive reviews on the topic [1,2”,3”].

GENETICS OF ADRENOCORTICAL CARCINOMA

Although ACC is most frequently sporadic, it may be associated with familial cancer susceptibility syndromes including Li-Fraumeni syndrome (LFS), Beckwith-Wiedemann syndrome, multiple endo- crine neoplasia type 1, and familial adenomatous polyposis [4,5]. A detailed medical and family history of patients with ACC should be performed

by clinicians to reveal possible hereditary condition; when genetic analysis is indicated, patients should be referred to a specialized genetic clinic to address prioritization of genetic testing and counseling for emotional, social, and economic issues [4].

LFS is an autosomal-dominant cancer predis- position syndrome including ACC and is caused by mutations in the TP53 gene. In 2008, Chompret criteria proposed that all patients with ACC should be evaluated for the presence of TP53 germ- line mutations [6,7], but the likelihood of TP53

Division of Endocrinology, Department of Medicine and Research Center, Centre hospitalier de l’Université de Montréal (CHUM), Montréal, Qué- bec, Canada

Correspondence to Isabelle Bourdeau, MD, Division of Endocrinology, Department of Medicine, Research Center, CHUM-Hôtel-Dieu, 3850 Saint-Urbain Street, Montréal, QC H2W 1T7, Canada. Tel: +1 514 890 8000/14086; fax: +1 514 412 7204; e-mail: isabelle.bourdeau@ umontreal.ca

Curr Opin Endocrinol Diabetes Obes 2013, 20:192-197

DOI:10.1097/MED.0b013e3283602274

KEY POINTS

· Patients with ACC should be operated on in a referral center with multidisciplinary expertise.

· FDG-PET is a second line tool useful in indeterminate cases or in staging of known ACC.

. Mitotane is a potent inducer of CYP3A4 and decreases the efficacy of other drugs including hydrocortisone replacement that needs to be increased in mitotane- treated patients.

· The First International Randomized trial in locally advanced and Metastatic Adrenocortical Carcinoma Treatment multicenter collaborative study showed that tumor response and median progression-free survival were better in patients with locally advanced and metastatic ACC treated with EDP/mitotane compared with streptozotocin/mitotane.

· Preliminary studies suggest that adjuvant radiotherapy decreases local recurrence of ACC in a subgroup of patients at risk for recurrence.

mutation in patients with adult-onset ACC was unknown whereas in childhood ACC, it is present in 80% of cases [4]. Herrmann et al. [8”], studied 103 White adults with ACC and found a prevalence of 3.9% of TP53 germline mutation; in patients less than 40 years old, the prevalence increased to 13% supporting the recommendation that screening for TP53 germline mutations may be justified in younger adults (<40 years old) with ACC. A prevalence of 5.8% of TP53 mutations was recently found in another cohort of adult patients with ACC, all diagnosed after age 45 years, suggesting that genetic counseling and germline testing for TP53 should be offered to all patients with ACC [9].

HORMONAL EVALUATION

Approximately 60-70% of ACCs in adults pre- sent clinical syndrome of hormone excess [3”]. ACC secrete excessive amounts of adrenal steroid precursors, probably due to decreased expression of several steroidogenic enzymes in undifferentiated tumor. A recent study [10""] using steroid meta- bolomic approach identified increased urinary metabolites of several steroids and precursors of androgens or glucocorticoids in 45 patients with ACC compared with 102 patients with adrenal adenoma and 88 healthy controls. Low urinary aldosterone concentrations, but high con- centrations of aldosterone precursors were found in most ACC but not in adrenal adenoma. A subset

of nine steroids performed best in differentiating adrenocortical adenoma from ACC [10""]. This new approach may provide tumor markers useful during follow-up to estimate the presence of residual tumor or tumor recurrence.

IMAGING

Unenhanced CT (computed tomography) scan is widely used for differentiating benign from malig- nant adrenal lesions when Hounsfield unit criteria (<10 HU) are met and the appearance is consistent with a benign lesion. CT with contrast washout studies and MRI are helpful when the appearance is not classic [11]. A recent retrospective evaluation of 41 patients with ACC found that typical features on CT scan include large size, central low attenu- ation, and a tendency to invade the inferior vena cava. Irregular margins were less frequent than a well defined margin with enhancing rim [12].

2-[FLUORINE-18]FLUORO-2-DEOXY-D- GLUCOSE-POSITRON EMISSION TOMOGRAPHY

In a meta-analysis examining 1391 adrenal lesions, 2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) showed a sensi- tivity of 97% and specificity of 91% for discriminat- ing benign from malignant disease [13]. Another recent study performed on ‘indeterminate’ inci- dentalomas showed that preoperative FDG-PET had a sensitivity of 95% and specificity of 97% using a cut-off standardized uptake value (SUV) ratio of SUV maxtumor to SUVmaxliver of 1.7 [14]. For now, FDG-PET remains a second line tool useful in inde- terminate cases or in staging of known ACC [11]. Studies comparing integrated PET/CT to diagnostic CT performed in staging and follow-up of ACC found that integrated PET/CT detects more lesions than does PET or CT alone. PET was more sensitive than CT in detecting local recurrence, whereas CT was more sensitive in detecting small lung or peritoneal metastases; these imaging modalities are thus complementary [15,16].

METOMIDATE-BASED IMAGING

Metomidate binds to CYP11B enzymes expressed in the adrenal cortex and labeled metomidate is thus taken up by adrenocortical tissue. 11C-metomidate PET and 123I-iodometomidate single-photon emis- sion computed tomography (SPECT) can differen- tiate ACC from metastatic carcinoma and may detect metastatic ACC [17]. A study comparing 11C-metomidate PET results to histopathology in

differentiating adrenocortical lesions from non- adrenocortical lesions found a sensitivity of 89% and a specificity of 96% [18]. 123I-iodometomidate SPECT performed similarly to 11C-metomidate PET with the added benefit that there is promise for treatment with 131I-iodometomidate [17,19]. These compounds are still investigational and not commercially available.

UPDATE ON SURGICAL CARE FOR ADRENOCORTICAL CARCINOMA

Complete surgical resection of the primary tumor is the best prognostic factor for long-term survival in patients with local ACC. Patients with ACC should be operated on in a referral center with multi- disciplinary expertise. Having the initial resection in a center associated to the Dutch Adrenal Network (instead of in a peripheral center) led to statistically significant improvements in survival [20]. There is an ongoing debate about whether or not laparo- scopic adrenalectomy is appropriate for known or suspected ACC. The 2003 International Adrenal Cancer Symposium stated that there was no role for laparoscopic adrenalectomy in known or likely ACC [21]. Retrospective studies showed a higher risk of peritoneal carcinomatosis in patients who had laparoscopic adrenalectomy [22,23]. However, two studies, performed in referral centers, found no difference in overall survival in patients having laparoscopic adrenalectomy versus open adrenalec- tomy for lesions smaller than 10 cm [24,25]. This remains a controversial issue. In many centers including ours, it is common practice to perform open surgery for known or suspected ACC.

For patients with nonmetastatic disease, loco- regional lymph node dissection (LND) during primary surgery should be considered. A retrospec- tive review compared 47 patients treated with LND to 236 patients who did not have LND [26”]. Recurrences occurred in 68.1% of LND patients and 60.6% of non-LND patients. As expected, patients with proven lymph node metastases did worse, however, those with lymph node metastases who had LND (n=12) had a longer disease-free survival than those who had not had LND (n=13). The median survival was more than 86 versus 26.2 months (P=0.06). LND was also important for accurate staging (a quarter of LNDs revealed metastatic lymph node disease) and prog- nostication [27].

More than 50% of ACC presents with stage III-IV disease, and more than 25% of ACC presents with distant metastases. Two retrospective chart reviews examining resection of pulmonary meta- stases [28,29] suggested a longer survival for patients

who had initial and repeat pulmonary meta- stasectomy particularly in patients with only a solitary metastasis [29]. The National Institutes of Health (NIH) retrospectively evaluated 27 patients who underwent either surgical resection (n=19) or radiofrequency ablation (n=8) for hepatic meta- stases [30]. Median overall survival was 1.9 years and 5-year actuarial survival was 29%. The only positive prognostic factor affecting survival was disease-free interval (DFI) greater than 9 months after primary adrenalectomy. A study from the NIH [31] analyzed patients together who had metastasectomy of any site and found that DFI greater than 12 months resulted in median survival of 6.6 versus 1.7 years. This may be attributable to cancer biology (i.e., slower growing tumor) and not to the intervention itself. The most recent study [32”] using a multi- variate model demonstrated that the only signifi- cant prognostic factors after recurrence were: DFI between primary adrenalectomy and the first recurrence (>12 months), and complete (R0) resec- tion of the locally recurrent tumor or metastatic burden.

MITOTANE THERAPY

Mitotane (Lysodren, o,p’-DDD) is an adrenocortico- lytic drug that has efficacy in patients with ACC. It has been used for adjuvant therapy after initial surgical removal, for primary therapy of un- resectable disease, and for the treatment of metastatic disease alone or in combination with other cytotoxic agents [2”,3”]. Adjuvant mitotane improved outcomes for patients with resected stage I to III ACC in a retrospective analysis of 177 patients in Italian and German centers [33]. Mitotane treatment was associated with a significantly longer recurrence-free survival of 42 versus 10 months and 25 months in the Italian and German control groups and longer median overall survival (110 versus 52 months and 67 months). Benefit of adjuvant mitotane was confirmed in a study of 149 German patients with stage II ACC, in which the subgroup of 35 patients receiving adjuvant mitotane had a better 5-year survival than those not receiving mitotane (87 versus 53%, respectively) [34].

There is an ongoing debate as to which patients are in need of adjuvant therapy. An international Consensus Panel on ACC therapy, concluded that adjuvant mitotane was indicated for patients with a potentially incomplete resection and for all patients with a high proliferative rate (as assessed by Ki67 staining of more than 10% of cells) [35]. Adjuvant mitotane was not believed mandatory for stage I or II disease, histologically proven complete resection (R0), and Ki67 staining of at most 10% of cells.

National Comprehensive Cancer Network guide- lines suggest that mitotane be ‘considered’ for all patients with resected localized ACC regardless of stage or tumor size.

A large international randomized trial in 200 patients with low to intermediate risk-resected disease [stage I to III, microscopically complete (R0) resection, Ki67<10%] is currently ongoing (the ADIUVO trial, NCT00777244).

Treatment protocols of mitotane are based upon achieving therapeutic serum levels (that measures mitotane and not its active metabolite) ranging from 14-20 µg/ml. This has been validated recently in a retrospective series of 91 patients receiving mitotane for unresectable or metastatic ACC [36]. Patients with serum mitotane levels greater than 14 µg/ml were higher responders and had signifi- cant longer survival.

Patients metabolize mitotane to different degrees. Volante et al. [37], showed that patients with low ribonucleotide reductase large subunit 1 (RRM1) in ACC tissue had improved disease-free survival supporting a possible role of RRM1 as a biomarker predicting response to adjuvant mitotane therapy.

Use of mitotane routinely induces atrophy and/ or steroidogenic inhibition of the normal adrenal glands, thereby necessitating replacement therapy for cortisol deficiency; aldosterone deficiency may not occur before several months of therapy [2”,3”]. Mitotane was found to be a potent inducer of CYP3A4 metabolism [38”]. In a recent European study [39""] of 127 patients with ACC before and during mitotane therapy 24-h urinary steroid metabolite excretion was profiled in comparison with healthy controls. The contribution of 6ß- hydroxycortisol to total glucocorticoid metabolites increased from 2 to 56% during mitotane secondary to induction of CYP3A4 and probably explains the need to increase hydrocortisone replacement of at least two-fold to three-fold in mitotane- treated patients. In addition, a strong inhibition of systemic 5a-reductase activity may explain the relative inefficiency of testosterone replacement in mitotane-treated men [39""].

Mitotane administration can result in import- ant drug-drug interactions and could reduce the efficacy of other drugs such as sunitinib, steroid hormone replacement, benzodiazepines, macrolide antibiotics, some opioids and statins, and dihydro- pyridine type calcium channel antagonists [38”]. In addition to its effect on cortisol-binding globulin, mitotane increases serum concentrations of other binding globulins, including sex-hormone bind- ing globulin [2”,3”] and thyroid hormone bind- ing globulin; therefore, serum concentrations of

testosterone and FT4 may be decreased [2”,3”]. Moreover, newer studies indicate a direct inhibitory effect of mitotane on thyroid-stimulating hormone secretion [40].

ADJUVANT RADIOTHERAPY

There have been no randomized trials testing the efficacy of adjuvant radiotherapy in patients with resected ACC [2”,3”]. The largest retrospective report addressing the benefit of adjuvant radiotherapy is from the German ACC registry [41]. Outcomes of 14 patients (stage I, II, and III) without macroscopic residual disease who received postoperative radio- therapy were compared with 14 others who did not. Local recurrence developed in two of 14 irradiated patients compared with 11 of 14 who did not receive radiotherapy but neither disease-free nor overall survival were significantly different. Sabolch et al. [42”] reported a 4.7 times increased risk of local recurrence in patients who did not receive adjuvant radiotherapy compared with those who did. The German ACC group recommends adjuvant radio- therapy for all patients with microscopically incom- plete (R1 or R2) or uncertain (Rx) margin status, and for those with stage III disease [according to the European network for the study of adrenal tumors (ENS@T) criteria] even if resection has been com- pleted [2”,3”]. They suggest that adjuvant radio- therapy be considered for patients who have had a complete (R0) resection of a tumor greater than 8 cm in size with tumor invasion of the blood vessels (but not large tumor thrombus in the vena cava) and a Ki67 proliferative index of greater than 10%, and for patients who have intraoperative violation of the tumor capsule, tumor spillage, or dissemina- tion of ‘necrotic’ fluid. They recommend starting radiotherapy no later than 3 months after surgery.

COMBINED CHEMOTHERAPY

Small prospective trials had explored combination regimens that contain mitotane [43,44]. The First International Randomized trial in locally advanced and Metastatic Adrenocortical Carcinoma Treatment trial studied 304 patients with advanced ACC not amenable to radical surgery that were randomly assigned to mitotane with either etoposide, doxoru- bicin and cisplatin (EDP) or streptozotocin [45""]. Rates of objective tumor response (23 versus 9%) and median progression-free survival (5 versus 2.1 months) were both significantly better in the EDP/mitotane group, although these benefits did not translate into a significantly prolonged survival (median 14.8 versus 12 months). At final analysis, 76.3% of patients had died, mainly due to

progressive disease reflecting the poor prognosis of advanced ACC [45”].

EMERGING THERAPIES

Initial reports described sustained responses to sorafenib and sunitinib in patients with ACC [46], however, very recently a phase II study of sunitinib in 38 patients with refractory ACC reported stable disease as the best response in only five patients [47]. In this study, sunitinib serum levels might have been reduced by mitotane induced cytochrome P450-3A4 activity underestimating its real anti- tumor activity. The majority of ACCs express the epidermal growth factor receptor (EGFR), but agents that target the EGFR were of little benefit in a recent trial of 10 patients with advanced ACC [48]. Approxi- mately 80% of ACCs overexpress insulin-like growth factor type 2 (IGF2); preclinical studies and phase I trials using anti-IGF-1R monoclonal antibody have shown promising results [49,50] and ongoing phase II and III trials are close to completion.

GENETIC AND MOLECULAR PROFILE OF ADRENOCORTICAL CANCER GIVES INSIGHTS ON PATIENT SURVIVAL

Recent studies better characterized the molecular profiling of ACC and underline their heterogeneity [51,52]. Combined gene expression of DFG7 and PINK1 was found to be the best predictor of ACC, whereas combined expression of BUB1B and PINK1 allowed the estimation of overall survival [52]. Very recently, these results were confirmed in an adult Brazilian cohort in which DLGAP5-PINK1 and BUB1B-PINK1 were strong predictors of disease-free survival and overall survival, respectively [53].

Somatic ß-catenin gene (CTNNB1) mutations are found in about 20% of ACC [54-57]. Moreover, B-catenin nuclear staining and CTNNB1 mutations were linked with decreased overall and disease-free survival [57].

CONCLUSION

In conclusion, new clinical and molecular findings were identified and will contribute to better man- agement of patients with ACC. Together these data may lead to improved evaluation and earlier diagnosis of patients with ACC and to new and more personnalized therapeutic strategies for the affected patients.

Acknowledgements

None.

Conflicts of interest

This work was supported by Grant FRSQ-15907 from Fonds de la recherche en santé du Québec (PI: I.B.). J.M.F. received fellowship support from CHUM Founda- tion. I.B. and J.M.F. have nothing to disclose. A.L. is editor of adrenal section of UpToDate, investigator and consultant on therapy of pituitary tumors and Cushing’s disease with Novartis; he has no conflict of interest on the topic of this article.

REFERENCES AND RECOMMENDED READING

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Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 248-249).

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