A .- C. Koschker M. Fassnacht S. Hahner D. Weismann
B. Allolio
Adrenocortical Carcinoma - Improving Patient Care by Establishing New Structures1
Abstract
Background: Adrenocortical carcinoma (ACC) is a rare and highly malignant tumour with a poor prognosis. Patients present with signs of steroid hormone excess (e.g., Cushing’s syndrome) or symptoms due to an abdominal mass. Diagnosis: In case of an adrenal mass, hormonal workup before surgery is required for differential diagnosis, perioperative management, and for fol- low-up. The imaging of choice is CT or MRI with MRI being of ad- ditional use when invasion of big vessels is suspected. Apart from that, the use of 18-FDG-PET is becoming increasingly estab- lished. Treatment: Surgical resection is the therapeutic option of choice in stages 1-3. In stage 4, the adrenolytic compound mi- totane is part of the first-line treatment, but often needs to be combined with cytotoxic chemotherapy. Most patients will eventually have a recurrence, so adjuvant treatment (mitotane/ tumour bed radiation) has to be considered in high risk patients, even if randomized controlled trials on adjuvant treatment are
still lacking. Structural Progress: Several national and European structures have recently been established in order to increase our knowledge of ACC, improve therapeutic options and diagnos- tic procedures, and promote research. GANIMED, as a Germany- wide network of experts on adrenal diseases, has been founded allowing for improved gathering of data and joint studies. ENSAT (European Network for the Study of Adrenal Tumours) has been brought to life, aiming at European standards for therapy, diag- nosis and tumour banking. Since 2003, patients can be enrolled in the German ACC Registry. France and Italy have also developed a central registry to collect nationwide data from patients with ACC. For the first time, patients with metastatic/unresectable ACC can participate in a prospective controlled randomized trial comparing two different cytotoxic chemotherapy regimes (FIRM-ACT).
Key words
Adrenocortical carcinoma . ACC . Registry . ENSAT · FIRM-ACT
Introduction
The annual incidence of ACC is approximately 1-3 per million population (Dackiw et al., 2001; National-Cancer-Institute, 1975, Cancer Registry Saarland/Germany) and about 0.2% of can- cer deaths are caused by ACC (Wajchenberg et al., 2000). The age distribution is bimodal with a first peak in childhood and a high-
er second peak in the 4th to 5th decade, but the tumour can oc- cur at any age (Luton et al., 1990; Wajchenberg et al., 2000; Woo- ten and King, 1993). Women are more frequently affected than men (ratio 1.5 : 1, Fig. 1).
Affiliation
Endocrinology and Diabetes Unit, Department of Medicine I, University Hospital Würzburg, Germany
1 This work was supported by the Deutsche Krebshilfe (grant # 106080) to B.A. and the European Union (grant # MOIF-7394) to M. F.
Correspondence
Bruno Allolio, MD . Endocrinology and Diabetes Unit, Department of Medicine I, University Hospital Würzburg · Josef-Schneider-Str. 2 . 97080 Würzburg · Germany · T + 49 931 20 13 61 09 . F + 49931 20 13 62 83 · E-mail: Allolio_b@medizin.uni-wuerzburg.de
Received: August 5, 2005 . First decision: November 4, 2005 . Accepted: December 21, 2005
Bibliography
Exp Clin Endocrinol Diabetes 2006; 114: 45 -51 @ J. A. Barth Verlag in Georg Thieme Verlag KG . Stuttgart · New York .
DOI 10.1055/s-2006-923808 .
ISSN 0947-7349
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age at diagnosis (years)
Pathogenesis
Despite recent advances, the molecular pathogenesis of ACC is still poorly understood. Some insights come from genetic tu- mour syndromes associated with ACC:
The frequency of ACC in patients with Li-Fraumeni-Syndrome is about 1% (Sameshima et al., 1992). Patients have germline muta- tions of the p53 tumour suppressor gene located at the 17p13 lo- cus (Malkin et al., 1990; Wagner et al., 1994), and develop multi- ple malignancies. In these cases, p53 is completely inactivated in the tumour due to a second mutation leading to complete loss of wild-type p53 activity.
Recently, a p53 point mutation (R337H) causing specifically ACC was shown to be present in about 60% of Brazilian children suf- fering from ACC (Ribeiro et al., 2001). The function of the mu- tated protein is altered by subtle changes in pH and temperature (Lee et al., 2003).
Mutations in the p53 tumour suppressor are also frequent in pa- tients with sporadic ACC, and accumulation of mutated p53 was reported to correlate with a more aggressive clinical behaviour (Sredni et al., 2003).
Beckwith-Wiedemann-Syndrome is characterised by malignan- cies like hepatoblastoma or Wilm’s tumour and is also associated with ACC. The corresponding mutation has been mapped to the 11p15.5 locus where the genes for IGF-II, H19 and p57/Kip2 are located. These genes show functional imprinting. Normally, the paternal IGF-II and the maternal H19 and p57/Kip2 genes are transcribed. Uniparental paternal isodisomy for this locus lead- ing to an overexpression of IGF-II was demonstrated in Beck- with-Wiedemann-Syndrome.
IGF-II expression is also increased in sporadic ACC in the vast ma- jority of cases (Giordano et al., 2003), suggesting that IGF-II plays a crucial role in ACC progression.
Symptoms
Clinical manifestation depends on hormone production by the tumour and local effects of rapid tumour growth. Approximately 60% of patients present with symptoms caused by hormone ex-
cortisol (16%)
no work up done (37%)
cortisol + androgens (16%)
Other combinations of hormonal secretion (3%)
androgens (7%)
cortisol + androgens + estrogens (3%)
inactive (13%)
cortisol + androgens + aldosterone (1%)
cortisol + aldosterone (2%)
aldosterone (2%)
35
30
25
number
20
15
10
5
0
<4
6 .. 8
10 .. 12
14 .. 16
18 .. 20
tumour size (cm)
cess, most frequently Cushing’s syndrome (Fig. 2). Androgen ex- cess is also common, leading to hirsutism and virilization in women but may go unnoticed in men. Adrenal tumours secreting estrogens that may cause gynaecomastia in men are rare but highly indicative for a malignant tumour. In case of tumours without obvious endocrine activity, local symptoms due to tu- mour mass (e.g., abdominal pain or fullness) lead to the diagno- sis. Even then, detailed hormone measurements often reveal subclinical autonomous hormone production, e.g., increase in hormone precursors like 17-hydroxy-progesterone (17-OHP). Additionally, a growing number of adrenal masses are detected serendipitously by abdominal imaging performed for other rea- sons (so called adrenal incidentalomas). However, the vast ma- jority of these incidentalomas are small benign lesions and only very few are ACCs. Most ACCs are more than 8 cm in diameter at primary diagnosis (Fig. 3). At this time, about 30% of the tumours have already metastasized. The majority of the remaining 70% will eventually also develop metastases, even after seemingly complete resection. Apart from local lymph nodes, disease most frequently spreads to the lungs, liver, and - in a smaller percent- age - bone (Fig. 4).
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Diagnostic Procedures/Staging
The first diagnostic step in order to evaluate the dignity of an adrenal tumour is imaging (e.g., Computed Tomography (CT) in Fig. 5). Tumour size remains the single most important marker for malignancy. Adrenal masses of more than 6 cm in diameter are considered malignant until proven otherwise. In recent years, additional criteria for malignancy were defined for CT and Mag- netic Resonance Imaging (MRI) which require special techniques (e.g., wash-out of contrast medium in CT or chemical-shift MRI) (for review see Fassnacht et al., 2004). Endosonography has not come to play a major role in diagnostic procedures for ACC. This is probably due to the fact that most ACC can easily be detected due to their size with other imaging modalities. Endosonography may be of potential use when a small local recurrence is sus- pected, causing difficulties differentiating scar tissue from tu- mour masses (Kann et al., 2004). A careful preoperative hormon- al workup is mandatory in all cases, even if the decision for adre- nalectomy has already been made based on tumour size or other signs of malignancy. Hormonal analyses are a prerequisite for both optimum perioperative management (e.g., glucocorticoid replacement therapy) and establishing suitable tumour markers for follow-up. Phaeochromocytoma has to be excluded bio- chemically prior to any invasive procedure. This is particularly
70%
60%
50%
percentage of patients
40%
30%
20%
10%
0%
lung
liver
skeleton
other locations
location of distant metastases
important as some phaeochromocytomas mimic ACC in imaging and phaeochromocytomas require a specific perioperative man- agement. Table 1 describes a basic diagnostic workup (based on the recommendations of the ENSAT initiative, see below) that should always be performed. Not only because of the risk of nee- dle-tract metastases, the indication for a biopsy of an adrenal tu- mour is limited to rare exceptions (Saeger et al., 2003).
In many cases, the final pathological diagnosis is difficult to es- tablish. Therefore, it is essential to have the tissue examined by a pathologist with long standing experience in adrenal diseases. In the past few years the initial diagnosis of ACC in several of our patients was revised by our reference pathologist Wolfgang Saeger (Hamburg, Germany). In addition, a recent multicentre trial could demonstrate that the diagnosis was only made by the reference pathologist but not by the local pathologist in 6 out of 22 cases of ACC (Saeger et al., 2003).
For staging, all patients with ACC receive a CT-scan of thorax and abdomen. Bone scintigraphy and FDG-PET can be useful to com- plete staging. The staging system is currently under revision and three different classifications are in use (Table 2).
Table 1 Hormonal workup and imaging in patients with suspected or proven ACC (recommendation of the ENSAT ACC work- ing group, May 2005)
Hormonal workup
Glucocorticoid excess (minimum 3 out of 4 tests)
- Dexamethasone suppression test (1 mg, 23:00 h)
- Excretion of free urinary cortisol (24 h urine)
- Basal cortisol (serum)
- Basal ACTH (plasma)
Sexual steroids and steroid precursors
- DHEA-S (serum)
- 17-OH-progesterone (serum)
- Androstendione (serum)
- Testosterone (serum)
- 17-beta-estradiol (serum, only in men and postmenopausal women)
Mineralocorticoid excess
- Potassium (serum)
- Aldosterone/renin ratio (only in patients with arterial hypertension and/or hypokalemia)
Exclusion of a phaeochromocytoma
- Catecholamine excretion (24 h urine)
- Meta- and Normetanephrines (plasma)
Imaging
- CT or MRI of abdomen and thorax
- Bone scintigraphy (when suspecting skeletal metastases)
- FDG-PET (optional)
| Stage | Criteria | Sullivan | Lee | WHO |
|---|---|---|---|---|
| I | Size | ≤ 5 cm | ≤ 5 cm | ≤ 5 cm |
| Infiltration/Invasion | – | – | – | |
| Local lymph nodes | – | – | – | |
| Distant metastases | – | – | – | |
| II | Size | > 5 cm | > 5 cm | > 5 cm |
| Infiltration/Invasion | – | – | – | |
| Local lymph nodes | – | – | – | |
| Distant metastases | – | – | – | |
| III | Size | NR* | NR | NR |
| Infiltration/Invasion Local lymph nodes | Either invasion ** or positive lymph nodes | Microscopic invasion in adjacent organs and/or Tumour (thrombus) in IVC/renal vein and/or positive lymph nodes | Either locally invasive but without infiltration of adjacent organs or positive regional lymph nodes | |
| Distant metastases | – | – | - | |
| IV | Size | NR | NR | NR |
| Infiltration/Invasion Local lymph nodes Distant metastases | Either invasion ** and positive lymph nodes or distant metastases | NR NR + | Either locally invasive with- out infiltration of adjacent organs and positive lymph nodes or tumour involving adjacent organs or any T, any lymph node status with distant metastases |
*NR not relevant for staging ** Invasion: macroscopic tumour infiltration of neighbouring structures, either fatty tissue or adjacent organs
Treatment (Fig. 6)
Due to the rarity of the disease, the number of published studies is limited, and treatment of patients with ACC has never been ad- equately standardized. The choice of therapy is based rather on personal experience and data from phase II trials. No single pro- spective trial comparing different treatment options has been conducted so far. Thus, for systematic progress in therapy new trials are urgently needed.
Complete surgical resection of the tumour is the treatment of choice in stages 1-3, as it is the only potentially curative thera- peutic option. Adjuvant treatment (mitotane and/or tumour bed radiation) after successful surgery is still disputed. However, some form of adjuvant therapy is plausible as ACC frequently re- curs. In patients with a particularly high risk of recurrence (e.g., tumour size > 12 cm, high mitotic activity) additional adjuvant treatment with streptozotocin can be considered.
Mitotane (o,p’-DDD) is the only specifically adrenotoxic com- pound available. It has been used in patients with ACC for more than 40 years, but it had been approved in only a few countries. Eventually in 2004, mitotane (Lysodren®) was approved for ad- vanced ACC in all European countries thus facilitating its use. Mi- totane treatment is monitored through blood levels. The targeted plasma levels are between 14 and 20 mg/l. Drug levels < 10 mg/l are rarely effective, whereas levels > 20 mg/l are often associated with severe side effects. As mitotane therapy is associated with a number of specific side effects, it should always be monitored by
a physician with experience in mitotane treatment (for more de- tails see Allolio et al., 2004; Hahner and Fassnacht, 2005).
Tumour bed radiation may be an alternative, or rather an addi- tional therapeutic option, for adjuvant treatment even though data on radiation therapy remain very limited. According to our experience, the high risk of local recurrence can be reduced. However, to reduce side effects, most advanced technology and an experienced radiotherapist are required.
In case of metastases or a local recurrence, surgery should be considered. Although rarely curative, complete resection of re- current tumour manifestations seems to prolong survival. Whether surgery is useful in the case of multiple metastases mainly depends on the patient’s symptoms (e.g., Cushing’s syn- drome) and physical condition. It is a matter of contention whether tumour debulking improves survival.
Also, in advanced ACC (stage 4), mitotane is part of first-line drug therapy. The efficacy of mitotane monotherapy varies in different reports, a lasting remission is rare, but some cases have been re- ported (Hahner and Fassnacht, 2005). In hormonally active tu- mours, control of symptoms due to hormone excess can be achieved in most cases. We recommend considering additional cytotoxic chemotherapy at an early stage, although clear evi- dence for single chemotherapy regimes is still lacking. Until now, only 9 prospective chemotherapeutic studies that em- ployed standardized criteria of response encompassing more than ten patients with advanced ACC have been published. The
Stage I-III
Stage IV
complete surgical resection
consider surgery (incl. metastases)
successful
not successful
complete resection
not possible or incomplete resection
consider adjuvant therapy ª:
- Mitotane (+/- Streptozocin) and / or - tumour bed radiation
Mitotane only c or combined with Streptozocin or EDP (FIRM-ACT-Study)
follow-up every 2 months
imaging and tumour markers for follow-up every 3 months b
tumour regression / stable disease
progression
tumour free
recurrence
consider surgery + continue therapy
add / switch chemotherapyª
Fig. 6 Therapeutic concept in ACC, Würz- burg 2005. ª adjuvant therapy should be considered in all patients with a high risk of recurrence (tumour size > 12 cm, high mitotic rate) b after > 2 years of complete remission, the intervals may be prolonged; cblood levels required regularly; dafter con- sultation with a reference centre.
average objective response rate was 27% (Allolio et al., 2004). Ac- cording to data from these studies, the combination of etoposide, doxorubicin, cisplatin, and mitotane (Berruti et al., 2005) or the combination of streptozotocin and mitotane (Khan et al., 2000) seem to be the most promising approaches. In case of disease progression after both of these chemotherapy regimes, an indi- vidual decision for third-line chemotherapy should be made after consultation with a centre specialized in ACC treatment.
If symptomatic hormone excess persists despite mitotane treat- ment and cytotoxic chemotherapy, inhibitors of steroidogenesis are available (e.g., ketoconazole, aminoglutethimide).
Prognosis
Initially, patients with untreated ACC had a median survival of only 3 months (MacFarlane, 1958). There is some evidence indi- cating that survival has improved in the past 2 decades due to earlier diagnosis, better surgical management and treatment in specialised centres. Yet, the overall prognosis remains poor. Pa- tients with a stage 1 or 2 tumour have a 5 year survival of about 60%, in stage 3 five year survival is approximately 25% and in stage 4 only few patients are alive after 2-3 years.
National and European Structures to Improve Patient Care in ACC
Due to its low incidence, most of the data on the clinical features and diagnosis derive from retrospective analyses or the personal experience of experts, respectively.
Most published series describe less than 100 patients. The larg- est report included retrospective data of 253 patients from France operated between 1978 and 1997. These low numbers ex-
plain why evidence levels for consensus statements concerning diagnosis, treatment, and prognosis remain unsatisfactory. Ac- cordingly, as no generally accepted guidelines exist, most pa- tients are treated based on the experience of their local physi- cian. However, there are very specific aspects which need to be taken into consideration when treating these patients (hormone measurements and glucocorticoid replacement, mitotane moni- toring). Yet many patients are still treated without consulting specialised centres. This situation often leads to insufficient pre- operative diagnostic workup and deficits in peri-/postoperative management.
Recently, within Germany, Europe and worldwide, steps were taken to establish structures to improve the management of pa- tients with ACC. These new structures mainly encompass nation- al and European initiatives.
GANIMED and ENSAT
In rare diseases, the cooperation of centres of excellence sharing their expertise has shown to significantly impact patient care. For this reason, the GANIMED (German Adrenal Network: Im- proving Medical research and EDucation) network was founded in 2000 by more than 40 scientists (clinicians and basic research- ers) from all over Germany. GANIMED mainly aims at improving both basic and clinical research and patient care in adrenal dis- eases.
One year later, GANIMED contributed to the foundation of the European Network for the Study of Adrenal Tumours (ENSAT). This European network was proposed by X. Bertagna and P. F. Plouin from Paris and consists of the national adrenal network initiatives in France, Italy, Great Britain, and Germany. First steps towards a joint adrenal tumour data bank have already been tak- en. As part of this work, guidelines for the diagnosis and therapy
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of adrenal tumours were defined to ensure comparability of na- tional data sets.
The German ACC Registry
In June 2003, the German ACC Registry was established in coop- eration with the GANIMED network and the study-group “Malig- nant Endocrine Tumours in Childhood and Adolescence”. The registry consists of a retrospective part including patients with a diagnosis of ACC between 1983 and 2003 and a prospective part including patients diagnosed since June 2003. Similar regis- tries have been established recently in France and Italy.
The German registry has three main goals: First of all, to create a data base to assess current deficits in patient care. Second, to im- prove patient care by providing guidelines for diagnosis and therapy using internet based technology. Third, to facilitate re- cruitment of patients for clinical trials.
A preliminary analysis of the first 160 patients already revealed clear deficits in diagnosis and treatment: In 37% of patients, pre- operative hormone diagnostic was either not performed or not documented (Fig. 2). In a high percentage, even complete records (including surgical and pathological reports) were not sufficient to decide whether or not a R0-resection had been achieved. In many cases, follow-up was neglected as surgery was considered curative. Accordingly, relapses were detected with a delay ham- pering surgery for tumour recurrence.
The FIRM-ACT trial
In September 2003, at the International Consensus Conference on Management of Adrenal Cancer in Ann Arbor (USA) (Schtein- gart et al., 2005), the initiative for a worldwide phase 3 trial in patients with advanced ACC was taken. The Firm-ACT trial will be the first ever conducted randomized controlled trial in ACC. It will provide results leading to the establishment of the ur- gently needed gold standard chemotherapy regimen for patients with locally advanced or metastatic ACC. To this end, the trial compares the two most promising drug combinations investi- gated in phase II trials, considered by the consensus conference as valuable first line treatments for advanced ACC. The first regi- men consists of etoposide, doxorubicin, cisplatin plus mitotane (EDP-M), the second regimen employs streptozotocin plus mito- tane (Sz-M).
Blood mitotane concentrations will be monitored, aiming at drug levels between 14-20 mg/L. Patients not responding to the first line treatment will be switched to the alternative regimen. The primary objective of this trial is to investigate whether EDP-M, given as first line treatment, will prolong survival as compared to Sz-M. Secondary endpoints are quality of life, time to progres- sion, best overall response rate and duration of response. In addi- tion, the trial evaluates the role of reaching therapeutic mitotane serum concentrations for survival and tumour response and as- sesses the value of the two alternative treatment regimens as second line therapy in advanced ACC.
Over a period of 5-6 years, this international trial will include 300 patients with advanced ACC from different European coun- tries, USA, Canada and Australia. Patient recruitment started in a few centres as an embedded pilot trial in summer 2004. Mean-
while, 11 centres have enrolled 29 patients and 28 more centres are starting to recruit. For more information see www.firm- act.org or http://www.clinicaltrials.gov/ct/show/NCT00094497 or contact Fassnacht_m@medizin.uni-wuerzburg.de, Allolio_b@- medizin.uni-wuerzburg.de or Britt.Skogseid@medsci.uu.se.
Importantly, the FIRM-ACT trial will generate a lasting structural basis for successful future trials in ACC and will, therefore, facili- tate continuous therapeutic advances in ACC.
The COllaborative group for Adrenocortical Carinoma Therapy (CO-ACT), which has developed the FIRM-ACT-protocol, has now begun to plan a second trial to compare adjuvant treatment options after successful R0-resection.
Conclusions
Progress in the management of ACC has been hampered by its low incidence and poor prognosis. Only multi-centre and multi- national efforts have the potential to change this picture. With the initiatives presented here, the foundations were laid to mark- edly improve the situation of our patients in coming years. To achieve this goal, the support and cooperation of as many col- leagues as possible is essential. It is a major challenge for all clinicians caring for patients with ACC to support the following goals:
1. a successful FIRM-ACT trial leading to an accepted first line chemotherapy;
2. harmonising different national ACC registries and thereby providing a multinational nucleus for a better understanding of the molecular pathogenesis of ACC; and
3. initiation of a second international trial to investigate adju- vant treatment options after complete surgery.
Undoubtedly, additional innovative treatment options urgently need to be developed based on a better understanding of the mo- lecular pathogenesis of ACC. At present, inhibition of IGF-II sig- nalling (e.g., by small molecule IGF-I receptor antagonists) may be a promising approach. In addition, antiangiogenic drugs and immunotherapy should be investigated for treatment of ACC.
In summary, the last five years have witnessed a dramatic change in the field of ACC with the creation of national and European in- itiatives which have already led to the start of a first large trial. For the first time, a perspective of continuous progress in the treatment of this dreadful disease has become realistic.
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