EARLY RELEASE: The Journal of Clinical Endocrinology & Metabolism
The Endocrine Society
Update in adrenocortical carcinoma
Martin Fassnacht, Matthias Kroiss, Bruno Allolio
Dept. of Internal Medicine IV, Clinical Endocrinology, Hospital of the University of Munich, Munich, Germany (M.F.); Dept. of Internal Medicine I, Endocrine and Diabetes Unit, University Hospital, University of Würzburg, Würzburg, Germany (M.F., M.K., B.A.)
Adrenocortical carcinoma (ACC) is an orphan malignancy that has attracted increasing attention during the last decade. Here we provide an update on advances in the field since our last review published in this journal in 2006.
The Wnt/B-catenin pathway and insulin-like growth factor-2 (IGF-2) signaling have been con- firmed as frequently altered signaling pathways in ACC but recent data suggest that they are probably not sufficient for malignant transformation. Thus, major players in the pathogenesis are still unknown.
For diagnostic workup, comprehensive hormonal assessment and detailed imaging are required, because in most ACCs evidence for autonomous steroid secretion can be found and computed tomography or magnetic resonance imaging (if necessary combined with functional imaging) can differentiate benign from malignant adrenocortical tumors. Surgery is potentially curative in localized tumors. Thus, we recommend to perform complete resection including lymphadenec- tomy by an expert surgeon. The pathology report should demonstrate the adrenocortical origin of the lesion (e.g. by SF1 staining) and provide Weiss score, resection status and quantitation of the proliferation marker Ki67 to guide further treatment. Even after complete surgery recurrence is frequent and adjuvant mitotane treatment improves outcome, but uncertainty exists whether all patients benefit from this therapy.
In advanced ACC, mitotane is still standard of care. Based on the FIRM-ACT trial, mitotane plus etoposide, doxorubicin, and cisplatin is now the established first-line cytotoxic therapy. How- ever, most patients will experience progress and require salvage therapies. Thus, new treatment concepts are urgently needed. The ongoing international efforts including comprehensive “omic approaches” and next generation sequencing will improve our understanding of the pathogen- esis and hopefully lead to better therapies.
T he interest in adrenocortical carcinoma (ACC) has tre- mendously increased in the last decade. In only 12 years, more literature has been published than in the 50 years before. Here we provide an update of the major advances in the field since our review published in the JCE&M in 2006 (1). We performed a PubMed search of all articles published between January 2006 and June 2013 using the terms “adrenocortical carcinoma”, “ad- renal cancer”, and “mitotane” (n = 985), screened the
database at www.clinicaltrials.gov and abstracts of the annual meetings of the Endocrine Society and the Amer- ican Society of Clinical Oncology. We identified some 220 publications as most relevant, but due to space limitations not all papers could be included. The recommendations of this review represent our personal view, as the level of evidence in many areas of ACC remains low. However, we specifically acknowledge areas of particular uncertainty.
Received July 31, 2013. Accepted September 24, 2013.
Abbreviations: ACC, adrenocortical carcinoma; CT computed tomography; EDP-M, eto- poside, doxorubicin, cisplatin, and mitotane; ENSAT, European Network for the Study of Adrenal Tumors; FDG-PET, 18F-fluorodeoxyglucose positron emission tomography; FIRM- ACT, First International Randomized trial in locally advanced and Metastatic Adrenocortical Carcinoma Treatment; HU, Hounsfield units; IGF, insulin-like growth factor; LND, lymph node dissection; MRI, magnetic resonance imaging; SF1, steroidogenic factor 1; VEGF, vascular endothelial growth factor
Epidemiology
Adrenocortical carcinoma (ACC) is a rare and highly aggressive malignancy with an annual incidence of 0.7- 2.0 cases per million population (2, 3). ACC can occur at any age with a peak incidence between 40 and 50 years and women are more often affected (55%-60%). The inci- dence in children is particularly high in Southern Brazil due to the high prevalence (0.27%) of a TP53 germline mutation (R337H) (4).
Molecular Pathogenesis
The understanding of the molecular events underlying the pathogenesis of ACC has improved in recent years, but is still not yet satisfactory. Table 1 provides a selection of the most important molecular changes in ACC.
The two most frequent alterations observed in ACC so far are overexpression of IGF-2 (5-7) and constitutive ac- tivation of the Wnt/ß-Catenin pathway (8, 9). IGF-2 over- expression in sporadic ACC results mainly from duplica- tion of the paternal allele (paternal unidisomy) and is associated with altered epigenetic imprinting at 11p15
(10). In vitro inhibition of IGF-2 signaling by blocking IGF-1 receptor agents reduced ACC cell proliferation (11). Activation of the Wnt/ß-catenin pathway occurs in both adrenal adenomas and ACC (12-14)) and is frequently caused by activating mutations of the gene encoding ß- catenin (15). In patients with ACC, ß-catenin activation - as confirmed by the presence of ß-catenin nuclear staining - is associated with decreased overall survival (15, 16) indicating that this staining carries important clinical in- formation. IGF-2 overexpression in transgenic animal models did not result in adrenal tumor development, al- though the IGF signaling pathway was activated (17) (16). Activation of the Wnt/ß-catenin pathway in the adrenal cortex led to adrenal tumors, but only few had malignant characteristics (8). Similarly, the combination of IGF-2 overexpression and Wnt activation induced only a slightly more malignant phenotype (16).
Steroidogenic factor 1 (SF1) plays an important role in adrenal development and is frequently overexpressed in adrenocortical tumors (18, 19). Furthermore, SF1 in-
| Affected genes | Alteration in ACC | Clinical impact |
|---|---|---|
| TP 53 | Germline mutation in children (60 - 80%) and adults (around 4%) (23, 24) Somatic mutations (25 - 35%) and LOH in adult sporadic ACC | Li-Fraumeni syndrome with increased prevalence of other malignancies Poor prognosis |
| CTNNB1 | Activating mutations or other activation of the Wnt/B-catenin pathway (8, 9, 15) | Occurs also in adenomas, aggressive phenotype in ACC (9, 16) |
| 11p15 locus (IGF-2, H19, CDKN1c) SF1 | Germline mutations in Beckwith-Wiedemann syndrome, paternal unidisomy in sporadic ACC leading to high expression of IGF-2 (10) Overexpression in both childhood and adult sporadic ACC (18, 19) | No clear relationship to prognosis due to almost uniform overexpression of IGF-2 (90% of cases) High expression is associated with impaired prognosis (18, 21) |
| CpG islands | Hypermethylation with low expression of tumor suppressor genes (33, 34) | Extensive hypermethylation negatively affects prognosis |
| Mismatch repair genes | Germline mutations in 3.2% of ACC cases (25) | Lynch syndrome |
| BUB1 and PINK1 | High expression of BUB1 together with low expression of PINK1 (26) | Separation of poor prognosis ACC from less aggressive tumors |
| Micro RNAs | Altered expression profiles (e.g. high mRNA 483 5 p) possibly related to TARBP2 overexpression (29-31) | Predictors of prognosis, miRNA 483 5 p in serum may serve as biomarker for aggressive ACC (32) |
| Jag 1 | Upregulation of both mRNA expression and protein levels (28) | Correlates with tumor grade and tumor stage |
creases proliferation in human adrenocortical tumor cells (20) and high expression of SF1 in ACC is associated with poor survival (18, 21). Thus, SF1 may become an impor- tant therapeutic target as SF1 inverse agonists have been shown to inhibit adrenocortical cell proliferation in vitro (22).
Germline mutations in the TP53 tumor suppressor gene have been observed in 50%-80% of children with ACC indicating the presence of a Li-Fraumeni syndrome with susceptibility to a variety of further malignancies. A small but significant percentage (~4%) of adult ACC patients (23, 24) carries a germline mutation in the TP53 gene raising the question whether adults should be screened for TP53 mutations, as this may impact on the future care of the affected patients and their relatives. Furthermore, so- matic mutations of TP53 in tumor tissue or loss of heterozygosity at the TP53 locus is found in more than 50% of adult patients with ACC and TP53 mutated tu- mors are associated with an aggressive phenotype (13). In a recent study, 3.2% of ACCs were associated with germ- line mutations of mismatch repair genes as part of the Lynch syndrome (25).
Gene expression profiling has further contributed to the understanding of the molecular pathogenesis of ACC. Unsupervised cluster analyses of transcriptome data per- mitted the identification of subgroups with different prog- nosis (26, 27). Furthermore, the expression of the two genes DLG7 and PINK1 allowed to discriminate benign from malignant adrenocortical tumors and the combined analysis of BUB1 and PINK1 identified subgroups of ACC with greatly differing prognosis.
Further pathways potentially involved in the pathogen- esis of ACC include changes in Notch signaling (28) and alterations in adrenocortical microRNA profiles (29-31). Of note, high serum miR 483 5p was found to be a useful biomarker for poor prognosis ACC (32). In addition, hy- permethylation of CpG islands has been observed in ACC compared to adrenal adenomas and was shown to lead to suppression of tumor suppressor genes and negatively af- fect the prognosis of ACC (33, 34).
Diagnostic workup
In recent years several reviews have covered the diag- nostic work up of adrenal lesions (35-39). We therefore only summarize principles and highlight some recent advances.
Endocrine work-up
In 2005, the European Network for the Study of Ad- renal Tumors (ENSAT) has suggested a preoperative lab- oratory work-up for suspected ACC (www.ensat.org/AC- C.htm). It comprises assessment of basal cortisol,
corticotrophin (ACTH), dehydroepiandrostenedione-sul- fate, 17-OH-progesterone, androstenedione, testoster- one, and estradiol as well as a dexamethasone suppression test and urinary free cortisol excretion. The aldosterone/ renin ratio is measured in patients with hypertension or hypokalemia. Although the cost-effectiveness of this ap- proach is unproven, we still consider this extensive panel as useful for several reasons: it may prove the adrenocor- tical origin of the lesion, suggest malignancy, and docu- ment autonomous glucocorticoid excess which, if missed, regularly entails postoperative adrenal failure. Autono- mous hormone secretion can be expected in > 80% of patients with ACC. However, routine use of the recently introduced urine steroid metabolomic analysis (40) might further increase this number and may serve as a fingerprint of the tumor facilitating early detection of recurrence. In turn, there is a high likelihood that a large adrenal mass is not an ACC if autonomous steroid secretion is absent.
Imaging
Together with a careful endocrine workup modern cross sectional imaging is able to correctly diagnose an adrenal mass as ACC prior to surgery in most cases. Size is an obvious criterion to differentiate an adrenal mass since the median size of ACCs is > 11cm, whereas most adenomas are < 5cm. Tumors between 3 and 10cm may be diagnostically challenging. Currently, no single imag- ing method can characterize with certainty a localized ad- renal mass as ACC, but many studies in the last 15 years have established a threshold of ≤ 10 Hounsfield units (HU) in unenhanced CT for the diagnosis of a benign ad- renal lesions (for review see (41, 42)). Since all series in- cluded only few ACCs, we have now confirmed in 51 ACC cases that none had a density of less than 13 HU (43). However, CT with delayed contrast media washout using a cutoff of 50% washout and an absolute value of > 35 HU after 10-15 minutes has superior diagnostic accuracy (44-47). State-of-the-art MRI including chemical shift and wash-out analysis is probably equally accurate, but the number of published studies is smaller (41, 42). In our experience, it is easier to obtain a standardized CT scan than an optimal MRI. Furthermore preoperative CT can be easily combined with chest imaging for presence of metastatic disease. Thus, we usually recommend CT, if pregnancy can be excluded.
Ultrasound techniques (including contrast enhanced methods) have not been thoroughly investigated but may be particularly valuable for the detection of liver metas- tases and during follow-up in selected patients (48).
In the difficult case, additional functional imaging is often helpful. With virtually no exception ACCs have a high 18F-FDG uptake; however, this is also the case for
most adrenal metastases, pheochromocytomas and even some adenomas (49, 50). The adrenocortical origin of a lesion may be proven using metomidate tracers, which specifically bind to adrenocortical CYP11B enzymes, which catalyze the final steps of steroid synthesis (51). Thus, the specificity of this still experimental method is high, but recent data suggest that the sensitivity in ACC is lower than in adenomas (52).
All patients with suspected ACC require a chest CT scan for pulmonary metastases prior surgery, which un- fortunately is often neglected. Specific imaging of brain and bones is only needed in case of clinical suspicion. There is some evidence that FDG-PET/CT might improve staging of the patients at initial diagnosis or during fol- low-up (50, 53, 54).
Biopsy of an adrenal mass is usually not helpful
In our experience, there is almost no role for a fine- needle biopsy in the diagnostic work-up of an adrenal tumor, as the diagnostic accuracy is often low (55) and violation of the tumor capsule may promote needle track metastases. The only two scenarios with a potential ben- efit comprise (i) the few patients with metastatic disease not scheduled for surgery, in which other methods (eg, endocrine work-up, metomidate imaging) have failed to establish the diagnosis and (ii) patients with a suspicious endocrine-inactive adrenal mass and a history of extra- adrenal malignancy, in whom the result would affect treatment.
Follow-up investigations
Recurrence is a frequent event even after complete re- section and the time to recurrence influences treatment decisions (see below). Therefore, we recommend imaging every three months (CT of the chest and CT/MRI of ab- domen) together with monitoring of steroid hormones ini- tially found to be secreted by the tumor. After the first 2 years of follow-up, we gradually increase imaging inter- vals. However, we recommend follow-up in patients with- out evidence of disease for a minimum of 10 years after surgery. In patients with advanced disease, imaging inter- vals are guided by the treatment protocol.
Areas of uncertainty: Diagnostic work-up
Will the urinary GC-MS steroid profile prove to be of superior diagnostic accuracy at initial diagnosis and dur- ing follow-up?
The best methods, time intervals of tumor evaluation and the optimum duration of follow-up have never been studied.
Patho-histological diagnosis
The patho-histological diagnosis of adrenal tumors re- mains challenging; eg, the rate of incorrect initial histo- pathological diagnosis in Germany was 13% (56). Two major problems need to be addressed: First, the adreno- cortical origin of the mass must be established. Here ex- pression of SF1 has emerged as the most valid marker (18, 21, 57). Second, the discrimination of benign from ma- lignant adrenocortical tumors requires the evaluation of multiple parameters. The Weiss score (58) is still the best validated score and should be used for this purpose. Un- fortunately, interobserver variability is rather high. A sim- plified score together with a structured training program may improve the reproducibility of the pathological diag- nosis in the future (59-62). In addition, two large ENSAT studies demonstrated that the quantification of the pro- liferation marker Ki67 is highly important since Ki67 is the most powerful prognostic marker in both localized and advanced ACC (63, 64) to guide treatment decisions.
Staging and Prognosis
Consensus has been obtained during the last 4 years that the tumor staging classification suggested by ENSAT, which is a modification of the Lee classification from 1995, reliably predicts outcome of patients (65, 66). In this staging system, stage 1 and stage 2 are defined as strictly localized tumors with a size of ≤ 5 cm or > 5 cm, respec- tively. stage 3 tumors are characterized by infiltration in surrounding tissue, positive regional lymph nodes or a tumor thrombus in vena cava/renal vein. stage 4 is re- stricted to patients with distant metastasis. Although this staging system can differentiate patient cohorts with dif- ferent prognosis and a 5-year stage-dependent survival of 81, 61, 50, and 13% (65), there is a need for further im- provements; eg, by adding a grading system (63, 67). Mo- lecular markers like matrix metalloproteinase type 2 (68), glucose transporter GLUT1 (69), SF1 (18), BUB1B and PINK1 (26) might help in the future, but none of them is yet validated.
Treatment
With the exception of one trial (70) treatment of ACC is based on nonrandomized trials or retrospective analy- ses. Therefore, the level of evidence for most recommen- dation is class II-IV. Whenever possible, patients should be treated within clinical trials (www.clinicaltrials.gov).
In all tumor stages, the adrenotoxic drug mitotane is of paramount importance and therefore discussed separately.
ACC amenable to radical resection (Figure 2A)
Surgery is the single most important intervention in the treatment of nonmetastastic ACC. During the last five
years there has been a lively debate on the best surgical approach to localized ACC. While preoperative evidence of locally advanced disease undoubtedly requires open ad- renalectomy, some groups have postulated that tumors with a diameter of < 10 cm may be safely treated by lapa- roscopic adrenalectomy (LA), whereas others are con- vinced that this carries a increased risk for recurrence. As all studies are retrospective and methodologically disput- able (71-75) no final conclusion can be drawn (76, 77). Open adrenalectomy should still be regarded as standard treatment for ACC and laparoscopic surgery should be performed within a clinical trial or at least as part of an observational study.
More importantly, (i) the extent of local resection and (ii) the experience of the surgeon may be key variables for the long-term outcome of surgery. Although no standard has been established concerning the extent of the first op- eration (78), the results of a recent retrospective analysis of 283 patients with stage I-III ACC suggest that locore- gional lymph node dissection (LND) might improve both diagnostic accuracy and therapeutic outcome (79). In mul- tivariate analyses we found a significantly reduced risk for tumor recurrence (HR 0.65) and disease-related death (HR: 0.54) in LND patients when compared with no-LND patients. On the other hand, there seems to be little benefit of systematic ipsilateral nephrectomy in the absence of gross local invasion (80). However, to achieve an R0 re- section locally involved organs or large veins should be resected en bloc, including tumor thrombus embolectomy (81, 82).
Irrespective of the surgical approach, we strongly rec- ommend that surgery for ACC should be performed by a surgeon with long-standing experience in adrenal surgery. Although we acknowledge that there is no consensus about what qualifies an expert ACC surgeon, we propose - based on recent data (83, 84) and personal experience - that surgery for suspected ACC should be limited to sur- geons with > 20 adrenalectomies per year.
Adjuvant therapy
Although the natural rate of recurrence is uncertain (85, 86), there is no doubt that an effective adjuvant treat- ment would be of great benefit. The treatment modalities currently considered include mitotane, irradiation of the tumor bed, cytotoxic agents or combinations of them. All available data are retrospective, but the most convincing results derive from a large retrospective analysis by Ter- zolo et al (87). In comparison to two independent control groups, patients with adjuvant mitotane had a signifi- cantly improved recurrence-free and overall survival (42 months vs. 10 and 25 months, and 110 months vs. 52 and 67 months, respectively). Nonetheless, it remains a matter
of discussion, whether adjuvant mitotane is of long-term benefit for all patients (88, 89). This is particularly true for patients with presumably low or intermediate risk of re- currence, eg, defined by R0 resection, absence of metas- tases and a Ki67 ≤10%(90). For this group of patients we recommend inclusion in the international randomized ADIUVO trial (www.adiuvo-trial.org) comparing mito- tane with a strategy of watchful waiting.
External beam radiation therapy of the tumor bed might be a means to lower the high incidence of local recurrence. Currently there are 3 retrospective studies with 14, 10, and 16 patients plus corresponding controls, of which the first two showed a benefit in preventing local recurrence (91-93). None of them demonstrated an ad- vantage for overall survival. Therefore, we currently rec- ommend adjuvant radiotherapy only in case of particu- larly high risk for local recurrence, eg, R1 resection.
Data on adjuvant cytotoxic chemotherapy are scarce. The only study dates back to 2000 and investigated 17 patients treated with streptozotocin plus mitotane (94). In this nonrandomized study it remained uncertain whether the positive effects were related to mitotane, streptozoto- cin or the combination of both drugs. Other cytotoxic drugs have not been investigated in adult ACC in this setting, although we believe that a platinum-based adju- vant therapy might be of benefit for patients at very high risk of recurrence.
Based on the available data we currently stratify pa- tients according to their perceived risk of recurrence. Re- cent data from the ENSAT ACC study group indicate that resection status and Ki67 index are the most relevant prog- nostic parameters. As shown in Figure 1A, we define three risk groups and recommend treatment as indicated. In se- lected patients with very high risk we consider additional treatment options. For instance, we would offer a patient with Ki67 > 30% and a large tumor thrombus in the vena cava a combination therapy of mitotane and three cycles of cisplatin (eg, 80 mg/m2).
Areas of uncertainty: localized disease
Is clinical outcome in expert centers with > 20 adre- nalectomies per year superior compared to smaller centers?
Is outcome after laparoscopic surgery comparable to open surgery in stage I-II ACC?
Is lymph node dissection required in all patients with suspected ACC?
Is a combined adjuvant treatment (eg, mitotane + cis- platin) of benefit in a subset of high-risk patients?
Recurrent ACC (Figure 1B)
Although ACC recurrence is frequent, only few data exist on the optimal management of recurrent ACC. Three
recent papers describe the experience with chemoemboli-
zation, radiofrequency ablation and surgical resection for
a
ACC amenable to radical resection1
b
Recurrent ACC
complete resection (RO)
Rx / R1 resection2
DFI > 12 months
DFI 6-12 months 1
DFI < 6 months
Ki67 ≤10%3
Ki67>10%3
Individualized decision
low/intermediate risk
high risk
adjuvant mitotane + irradiation of the tumor bed
completely resectable1
not completely resectable1
ADIUVO trial4
adjuvant mitotane5
Surgery2
Consider reduction of tumor burden3 + medical treatment4
or
Treat like advanced ACC (Fig 1C)
follow-up every 3 months6: imaging and tumor markers
Mitotane at the time of recurrence?
tumor free
recurrence
no
yes
Re-consider surgery if stable disease is achieved
See Figure 1 B+C
mitotane
mitotane+cytotoxic drugs5
C
Advanced ACC1
Debulking surgery1
No prior systemic therapy
After failure of (adjuvant) mitotane
High dose mitotane monotherapy2
rapidly progressing3
Mitotane level at 3 weeks
< 5 mg/l4
> 8 mg/l
Continue monotherapy
Mitotane plus EDP
follow-up every 2 months
tumor regression / stable disease
progressive disease5
continue therapy consider surgery
add / switch chemotherapy6
liver metastases (80, 95, 96). Although all but one of these 76 patients experienced secondary recurrence, individual patients took advantage from these procedures. In 2011, two groups reported their results on pulmonary resection for metastastic ACC in 24 and 26 patients (97, 98) and came to similar conclusions: pulmonary surgery might be useful in selected patients (eg, young patients with slowly progressing disease), because long-term disease control can be achieved in a subset of patients.
Based on the results of two recent studies in 45 and 154 patients with first recurrence (99, 100), we suggest the following approach (Figure 1B): surgery for recurrent ACC should be performed patients with a disease-free in- terval of more than 12 months, in whom a complete re- section is feasible. However, we advocate against surgery if the time between surgery and recurrence is less than 6 months. These patients are likely to benefit more from aggressive medical treatment. In all other patients, an in- dividualized decision is required and they may be candi- dates for a combined approach of medical therapy and ablative procedures.
Advanced disease (Figure 1C)
All patients not qualifying for a localized treatment who are in acceptable clinical condition require systemic therapy. Although there is significant heterogeneity even in advanced ACC (101, 102), the disease has a strong tendency towards rapid progression and a stabilization for more than 3 months is a rare exception. The median sur- vival in these patients in most series is about 12 months.
The only approved drug in advanced ACC is mitotane. Despite the lack of prospective, controlled trials mitotane was approved in the US already in 1970 and in Europe in 2004. Most data derive from retrospective series and the objective response rate is at best 24% (103). Many years ago, the concept of targeting a certain mitotane plasma level was introduced (104, 105), and recently another ret- rospective study provided evidence that reaching a mito- tane plasma level > 14 mg/l is associated with improved overall survival (106).
Only the combination chemotherapy of etoposide, doxorubicin, cisplatin and mitotane (EDP-M) has been validated in a randomized controlled trial (RCT). This FIRM-ACT trial included a total of 304 patients and com- pared EDP-M with Streptozotocin and Mitotane (Sz-M), both as first- and as second-line cytotoxic treatment. Al- though overall survival was not significantly different (14.8 months (EDP-M) vs 12.0 months (Sz-M); HR 0.79; P = . 07), objective response rate and progression-free sur- vival clearly favored EDP-M (23.2% vs. 9.2%, P <. 001 and 5.0 months vs. 2.1 month; HR 0.55; P < . 001). Fur- thermore, EDP-M was similar effective in second-line
therapy in patients failing Sz-M as first-line treatment. Therefore, it is tempting to speculate that the cross-over design of the study attenuated the survival benefit of EDP-M. Due to these data and the fact that the rate of serious adverse events and quality of life (QOL) during the treatment were comparable between the groups, most ex- perts now advocate EDP-M as first-line therapy for pa- tients requiring cytotoxic treatment (39, 107, 108).
However, the observation that EDP-M is similarly suc- cessful in first- and second-line therapy leads us to two main additional conclusions: (i) Based on a study by Assie et al (101) we select patients with presumably less aggres- sive disease (eg, slowly progressing tumor growth, only 2 involved organs, long disease-free interval after initial sur- gery) and treat them with mitotane monotherapy (Figure 1C). Based on a study by Mauclere-Denost et al (109), we increase the mitotane dosage within few days to 6 g per day. We continue mitotane as monotherapy in patients with a mitotane concentration > 8 mg/l after 3-4 weeks of treatment and in patients with a blood level < 5 mg/l we usually add EDP, because the likelihood to reach a blood level > 14 mg/l in a reasonable time frame is extremely low (110). In all other patients we decide individually based on tolerability of mitotane and the clinical condition of the patient. (ii) We believe that the FIRM-ACT results justify to test new drugs as first-line treatment in selected patients with a presumed life expectancy of > 6 months allowing them to receive EDP-M in case of progression at first tu- mor evaluation. This concerns particularly targeted ther- apies, because mitotane might diminish their antitumor efficacy by enhanced drug metabolism (111) (see also below).
For patients failing EDP-M, only a limited number of regimens has been investigated. One is Sz-M (investigated as part of the FIRM-ACT study), but only about 15% of patients showed at least a stabilization for > 6 months during this second-line treatment (unpublished data). Therefore, we currently offer our patients in this situation the combination of gemcitabine and capecitabine. As sec- ond-line chemotherapy this combination achieved disease stabilization for at least 6 months in 8 of 28 patients (29%) (112). In patients with painful skeletal metastases pallia- tive radiotherapy is often of benefit (113). When the dis- ease has progressed despite different cytotoxic treatments and a mitotane level > 14 mg/l, it might be reasonable to stop mitotane to reduce the problem of drug interaction for subsequent therapies.
In case a given therapy is able to stabilize a progressive disease for at least 4 months, we reconsider surgery or other loco-regional approaches.
Areas of uncertainty: recurrent and advanced disease
Is surgery of the primary tumor or debulking surgery in general of benefit or harm in patients with metastatic ACC?
Which patients are candidates for mitotane monotherapy?
For which combination therapies is concomitant mito- tane beneficial?
When to stop mitotane treatment in progressing disease?
Targeted therapies and salvage treatment
Current treatment concepts fail in many patients with advanced ACC. This stimulated interest in molecular-tar- geted therapies (Table 2). The first trial targeted the epi- dermal growth factor (EGF) receptor, but both gefitinib (114) and the combination of erlotinib and gemcitabine (115) did not lead to promising results.
Targeting of tumor vasculature has attracted more at- tention in ACC since vascular endothelial growth factor (VEGF) and its receptor VEGF-R2 have been demon- strated to be highly expressed in ACC (116) and antian- giogenic drugs exhibited modest antitumor effects in pre- clinical tumor models (117, 118). However, bevacizumab, a humanized anti-VEGF monoclonal antibody, in combi- nation with capecitabine did not yield any tumor response (n = 10) (119). Similarly, the multityrosine kinase inhib- itor (TKI) sorafenib in combination with paclitaxel failed to demonstrate clinical efficacy in 9 ACC patients (120).
Among the VEGF-targeting TKIs, only sunitinib has demonstrated modest antitumor effects in a phase II clin-
ical trial (111). The primary endpoint of progression-free survival at 12 weeks was met by five patients (14.3%). In this trial, we confirmed that concomitant mitotane treat- ment strongly diminished plasma levels of sunitinib and its active metabolite. Therefore, one of the main lessons from this trial is that sunitinib and other multi-TKI should pref- erentially be administered in patients without mitotane pretreatment or with dose adjustments of the respective TKIs.
Preliminary results have been reported during the 2013 ASCO meeting for the multi-TKI dovitinib (NCT01514526). Disease-stabilization > 6 months has been observed in 23% of 17 ACC patients (121).
Only recently drugs targeting IGF-2, the most upregu- lated gene in ACC, and its receptor IGF-1R became clin- ically available. Activity of IGF-1R antagonists has been demonstrated in vitro and in a xenograft model of ACC (11). Results of phase I trials with the highly specific IGF-1R inhibitor linsitinib (OSI-906) were promising and led to the first industry-sponsored randomized placebo- controlled, double-blind phase III clinical trial in ACC (GALACCTIC, NCT00924989). 138 patients have been enrolled and results are expected to be published by 2014.
In an extended phase I trial with the IGF-1R antibody cixutumumab in combination with temsirolimus, an in- hibitor of mTOR, one of the downstream targets of IGF-1R signaling, 26 patients with advanced ACC have been treated. In 11 of these patients (42%) disease stabi- lization for six months or longer has been observed (122). However, targeting mTOR alone using everolimus re- sulted in no meaningful response in four patients (123).
| Agents | Rationale | n | Outcome | Reference |
|---|---|---|---|---|
| Sunitinib | Multi TKI (VEGFR, PDGFRØ, c-kit, FLT3, RET) | 35 | 5 stable disease | (111) |
| Cixutumumab + temsirolimus | IGF1R antibody + mTOR inhibitor | 26 | 11 stable disease | (122) |
| Gefitinib | Inhibition of EGFR signaling | 19 | no response | (114)* |
| Dovitinib | Multi TKI (FGFR, PDGFR, VEGFR) | 17 | 4 stable disease | (121)* |
| Bevacizumab + capecitabine | Inhibition of VEGF signaling + cytotoxic drug | 10 | no response | (119) |
| Erlotinib + gemcitabine | Inhibition of EGFR signaling + cytotoxic drug | 10 | 1 stable disease | (115) |
| Sorafenib + paclitaxel | Multi TKI (BRAF, VEGFR, c-kit, PDGFRØ) + cytotoxic drug | 9 | no response | (120) |
| Imatinib | Inhibition of c-KIT and PDGF | 4 | no response | (140) |
| Everolimus | mTOR inhibitor | 4 | no response | (123) |
# only studies reporting at least 3 patients have been included.
* published only as abstract
Overall it appears that using only one drug may not suffice to induce objective response. Although enthusiasm towards IGF-1R antagonists in general has markedly de- creased, we - not only due to impressive tumor responses in individual patients - still believe that ACC is a malig- nancy, in which this class of drugs, probably in combina- tion with other drugs, holds therapeutic potential.
Our group has recently developed a radionuclide ther- apy based on [131 I]iodometomidate ([13]]]IMTO) and we have applied this method on a compassionate-use basis in 11 patients with advanced, progressing ACC (124). In one patient a decrease of tumor burden of some 50% lasting for 26 months has been demonstrated and 5 additional patients experienced stable disease, in 3 lasting for at least 10 months.
All other targeted treatment approaches are still in a preclinical stage. From our perspective the following con- cepts merit further investigations: inhibition of heat shock protein 90 (125), the proteasome inhibitor bortezomib (126), and targeting SF1 (22).
Other salvage therapies are based primarily on small series like oral etoposide and oral cyclophosphamide (127) or case reports (128, 129).
Overall, the poor efficacy of several classes of targeted therapies has markedly dampened expectations of ACC tumor control in metastatic disease
Mitotane: Mechanism of action, pharmacokinetics and management
As described above mitotane is currently the corner- stone of medical treatment for ACC. It is given orally in 500 mg tablets (Lysodren® HRA Pharma Paris, Bristol- Myers Squibb New York). Despite its use for more than fifty years, little is known about the molecular mechanism of mitotane action and some observations, such as binding of mitotane to a protein receptor, have not been conclu- sively confirmed. Recent data suggest that down-regula- tion of mitochondrial respiratory chain is involved (130, 131) but the pathway leading to these changes has not been clarified even using high-throughput techniques such as gene expression microarrays and proteome profiling (30, 132, 133).
Like the mechanism of action, pharmacokinetic data are limited. Nested in the FIRM-ACT trial, a study on the pharmacokinetics of mitotane investigated the relation- ship between mitotane dose and plasma concentration comparing two dosing regimens (110). Surprisingly, a “high-dose starting regimen” only led to a small, nonsig- nificant difference in mitotane levels with a similar rate of adverse events. Only among patients not receiving con- comitant cytotoxic treatment, there was a clear trend to- wards higher mitotane exposure in the high-dose group
(AUC0-12 weeks: 1013 mg x d/L vs 555 mg x d/L, P = .080). However, the variability of individual plasma levels reached by a given dosage is high and it remains unclear which enzymes metabolize mitotane in humans, although there is first evidence that CYP2B6 might be involved (134). Several studies have demonstrated that a mitotane plasma level > 14 mg/l is required for clinical efficacy of the drug (104-106), making regular monitoring of the drug level mandatory. Of note, this concept has very re- cently also introduced in the adjuvant setting (135).
The recent observation of a strong and sustained in- duction of cytochrome P450 3A4 (CYP3A4) by mitotane (136) has now been confirmed using a steroidomics ap- proach (137). The induction of CYP3A4 has major impact on the care of ACC patients, because mitotane is one of the strongest CYP3A4 inducers lowering the blood levels of many drugs frequently coadministered with mitotane (in- cluding but not limited to steroids, antihypertensives, and antibiotics) (138). A list of drugs with a high potential of interaction is nested in Table 3.
Mitotane comes with significant toxicity and patients should be monitored closely by an experienced physician. The incidence and severity of adverse drug effects have been systematically evaluated only in few cohorts (109, 110, 139). However dizziness, vertigo and other central- nervous disturbances are common and virtually all pa- tients suffer some kind of gastrointestinal (GI) symptoms requiring active management with antiemetics and lop- eramide as individually indicated. Although grade 3/4 tox- icity is overall rare, we have seen life-threatening agran- ulocytosis and liver failure in single patients. In contrast, in virtually all patients a strong elevation of the y-glutam- yltransferase is detectable, which in our view is clinically not relevant. Furthermore, all patients develop adrenal insufficiency, which has to be replaced with high dosage of hydrocortisone (due to the induction of CYP3A4 with increased metabolism of cortisol and increased cortisol- binding globulin).
Areas of uncertainty: targeted therapy and mitotane management
Which combinations of molecular-targeted drugs are most useful to combat advanced ACC?
Which drugs could be usefully combined with mitotane despite mitotane-induced CYP3A4 activity?
Are there means to reduce mitotane-induced CYP3A4-activity?
Future perspectives
Despite advances in the molecular pathogenesis of ACC the initiating and driving mutations remain incompletely understood, but are of key importance for the develop-
| Parameter | Recommendations | |
|---|---|---|
| Initiation of treatment | Optimal distribution of mitotane during the day has not been studied; thus we respect patient preference. | |
| High-dose regime | Preferred regimen for | Start with 1.5 g/d and increase within |
| monotherapy. | 4-6 days to 6 g/d. Adapt dose according plasma levels (maximum dose 12 g/d, but most patients do not tolerate >8 g/d). | |
| Low-dose regime | Preferred regimen in patients with reduced clinical | Start with 1g/ and increase within 1 week to 3 g/d mitotane daily dose. |
| conditions and in combination therapy. | Adapt dose according plasma levels. | |
| Drug monitoring | ||
| Mitotane plasma level | Check every 3-4 weeks during the | |
| first 6 months, then intervals might be prolonged | ||
| Target plasma level | 14 - 20 mg/liter In patients without adverse effects plasma levels > 20 mg/liter can be accepted. | |
| Safety parameters | ||
| GOT, GPT, bilirubin, (GGT) | GGT is invariably elevated | Check initially every 3-4 weeks, after |
| without clinical consequences. | 6 months every 8 weeks. | |
| If GPT/GPT increase >3-fold | ||
| ULN interrupt mitotane treatment | ||
| Blood count | Bone marrow toxicity is rare, | Check for relevant leucopenia, |
| but agranulocytosis might be life-threatening. | thrombocytopenia, and anemia (rare) | |
| initially after 3-4 weeks, then every 3-4 months. | ||
| Cholesterol (HDL, LDL), triglycerides | Lipid alterations occur | In adjuvant setting, check every 3-4 |
| frequently. | months. If LDL/HDL 1 1 | |
| consider treatment with rosuvastatin or pravastatin | ||
| Hormonal changes and hormone replacement | ||
| Glucocorticoids | Due to accelerated metabolism (CYP3A4 induction) and increased cortisol-binding globulin, a high hydrocortisone replacement dosage is required (in the long-run, average dosage 40-60 mg/d). | We start usually with 20 mg/d and taper dosage according clinical signs. |
| Plasma ACTH is probably the best of poor monitoring parameters and should be in the upper normal range or slightly above. | ||
| Mineralocorticoids | Replacement is needed only in a subset of patients | Check renin every 3-6 months and |
| treat with fludrocortisone according to renin concentration and blood pressure | ||
| Androgens | Due to CYP3A4 induction, | Difficult to diagnose without |
| increased SHBG, and inhibition of 5-a reductase, hypogonadism is frequent (but clinically variable) | measuring dihydrotestosterone. | |
| Replacement with dihydrotestosterone may be individually considered. | ||
| (Continued ) | ||
ment of better treatments. Here international efforts are underway to provide a comprehensive molecular analysis
including whole genome sequencing in a large number of ACC cases. Urinary steroid profiling seems to be a prom-
| Parameter | Recommendations | |
|---|---|---|
| Oral contraception | CYP3A4 induction leads to increased clearance and reduced efficacy (and estrogens might play a role in ACC tumorigenesis) | Use mechanical contraception. |
| Thyroid hormones | Alternations of thyroid hormones are frequent, but variable (and not yet fully elucidated) | Check TSH, fT3, fT4 every 3-4 months Replacement with levothyroxine in case of hypothyroidism |
| Selection of other relevant | drug interactions | |
| Examples of drugs metabolized by CYP3A4 | ||
| Hypertension Hypercholesterolemia | Calcium antagonists | Use instead ACE inhibitors, ß-blockers, a-blockers, angiotensin 2-antagonists, diuretics. Use pravastatin or rosuvastatin. |
| Most HMG-coA reductase | ||
| inhibitors (e.g. atorvastatin, cerivastatin, lovastatin, simvastatin) | ||
| Insomnia, agitation | Benzodiazepines (e.g. midazolam, diazepam), Z-drugs (e.g. zopiclone, zolpidem) | For many cases no alternatives are available. Consider increased dosage. |
| Infection | Some macrolide antibiotics (e.g. erythromycin, clarithromycin) | Use alternative antibiotics like azithromycin, moxifloxacin, ciprofloxacin. |
| Analgesia | Some opioids (e.g. fentanyl, methadone, oxycodone, tramadol) | Use instead morphine or hydromorphone. |
ising diagnostic tool, however, its true value has to be demonstrated in large scale prospective, multicenter trials. Concerning surgery the time has come for randomized trials to assess the best operation strategy (eg, with or without lymph node dissection). We expect that the ADIUVO trial will shed further light on the value of ad- juvant mitotane in ACC. A better understanding of the molecular action of mitotane is now urgent to allow pre- diction of the individual response to this difficult drug and as a prerequisite for the development of less toxic com- pounds. Although targeted therapies have been largely dis- appointing in advanced ACC, this may be in part related to insufficient drug levels due to concomitant or previous mitotane administration and to the fact that they were mostly studied as salvage therapy in refractory disease. The occasional impressive response to inhibition of IGF1 signaling indicates its therapeutic potential, but it proba- bly needs to be combined with other drugs for optimum activity. Furthermore, earlier use of targeted therapies might lead to improved results without jeopardizing the efficacy of later cytotoxic therapy. Currently only four
intervention trials are recruiting patients (NCT01832974; NCT01048892, NCT00777244, NCT01898715). Therefore, it is the task of the ACC community convince public stake holders and pharmaceutical companies to a stronger commitment for clinical trials in ACC. However, the highly successful international cooperation in the fight against this dreadful disease which was triggered by the European Network for the Study of Adrenal Tumors (EN- SAT) and the FIRM-ACT consortium has undoubtedly set the stage for major progress in the coming decade.
Acknowledgments
Address all correspondence and requests for reprints to: Corre- sponding author; address for reprint requests: Prof. Dr. Martin Fassnacht, Department of Internal Medicine IV, Hospital of the University of Munich, Ziemssenstraße 1, 80336 München, Email: martin.fassnacht@med.uni-muenchen.de, phone: +49- 89-5160-2940, fax: +49-89-5160-2942.
Funding acknowledgment: This work was supported by Deutsche Forschungsgemeinschaft DFG Grant FA 466/4-1 to
M.F. and KR 4371/1-1 to M.K and the European Union (Sev- enth Framework Programme (FP7/2007-2013) under grant agreement nº 259735) to M.F. and B.A.
Disclosure Summary: The authors received support for a clin- ical trial from Pfizer Pharma, and participated in a pharmaco- kinetic trial on mitotane sponsored by HRA Pharma and in a trial on OSI-906 sponsored by Astellas Pharma.
This work was supported by .
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