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EXPERT OPINION
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Expert Opinion on Emerging Drugs
ISSN: 1472-8214 (Print) 1744-7623 (Online) Journal homepage: http://www.tandfonline.com/loi/iemd20
Emerging drugs for adrenocortical carcinoma
Alfredo Berruti, Anna Ferrero, Paola Sperone, Fulvia Daffara, Giuseppe Reimondo, Mauro Papotti, Luigi Dogliotti, Alberto Angeli & Massimo Terzolo
To cite this article: Alfredo Berruti, Anna Ferrero, Paola Sperone, Fulvia Daffara, Giuseppe Reimondo, Mauro Papotti, Luigi Dogliotti, Alberto Angeli & Massimo Terzolo (2008) Emerging drugs for adrenocortical carcinoma, Expert Opinion on Emerging Drugs, 13:3, 497-509
To link to this article: http://dx.doi.org/10.1517/14728214.13.3.497
Published online: 02 Sep 2008.
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Expert Opinion
1. Background
2. Medical need
3. Existing treatment
4. Therapeutic class review
5. Current research goals
6. Scientific rationale
7. Competitive environment and potential development issues
8. Conclusion
9. Expert opinion
informa healthcare
Oncologic, Endocrine & Metabolic
Emerging drugs for adrenocortical carcinoma
Alfredo Berruti+, Anna Ferrero, Paola Sperone, Fulvia Daffara, Giuseppe Reimondo, Mauro Papotti, Luigi Dogliotti, Alberto Angeli & Massimo Terzolo
*University of Turin, Department of Clinical and Biological Science, Orbassano, Italy
Background: Adrenocortical carcinoma (ACC) is an extremely rare aggressive disease. Few data are available on the efficacy of systemic antineoplastic treatments (mitotane and cytotoxic therapy) in the treatment of advanced disease. Objective/methods: this paper will review the existing treatment strategies and new perspectives in the management of ACC patients. Results/conclusion: An ongoing randomized international trial aims to define the best combination chemotherapy plus mitotane regimen. Based on the results of a case control study, mitotane is being explored as adjuvant therapy. Genetic and biological studies have identified molecular targets for specific targeted drugs such as IGF receptor inhibitors and antiangiogenetic drugs. Phase II trials are exploring the activity of these drugs either alone or in combination with chemotherapy.
Keywords: adrenocortical carcinoma, chemotherapy, mitotane, target therapies
Expert Opin. Emerging Drugs (2008) 13(3):497-509
1. Background
HO COLATE
Adrenocortical carcinoma (ACC) is an extremely rare disease, with an annual incidence of 0.5 - 2 cases per million people per year. ACC incidence has a bimodal age of distribution, with peaks in children aged < 5 years and adults in their fourth or fifth decades of life, respectively [1-3]. The disease is highly malignant and often difficult to treat; ACC patients have usually a poor prognosis. The 5-year survival rate after diagnosis in unselected cases is < 40% [1-4]. Approximately 50% of ACC in adults and 90% in pediatric patients are functioning and produce hormonal and metabolic syndromes leading to their discovery. Cortisol hypersecretion (Cushing’s syndrome) is the most common endocrine presentation. Less frequently, tumors produce androgens and/or steroid precursors. Co-secretion of androgens and cortisol is frequent and highly suggestive of a malignant adrenocortical tumor; feminizing tumors and aldosterone-secreting tumors are rare [5]. Among adult patients, 50% present a non-secretory mass, revealed incidentally or during evaluation for abdominal pain [5,6].
The cause of adrenal cancer remains elusive, but studies in the past 5 years suggest genetic mutations in the adrenal gland leading to the initiation of a malignant tumor [4,7]. Adrenal cancer occasionally develops in families with susceptibility for other types of cancer [4]. Environmental factors have been suggested to be implicated in southern Brazil, where the distribution of tumors seems to follow a regional rather than familial pattern [8]. It should be noted that a clear familial pattern of inheritance linked to the presence of a low-penetrance germline TP53 R337H mutation has been shown in Brazilian ACC patients, suggesting a genetic predisposition of Brazilian children to develop ACC [9].
Early diagnosis of a functional adrenal cancer is based on the prompt recognition of clinical manifestations of excessive hormone levels. Non-secreting tumors are
often discovered when they are large enough to produce localized abdominal symptoms, or when they metastasize [6]. The widespread use of imaging techniques such as ultrasonography, computed tomography and magnetic resonance imaging, however, has increased the incidental finding of non-functioning small adrenal tumors [6]. The most commonly used staging classification of ACC is that proposed by MacFarland and subsequently modified by Sullivan [10,11]. Patients with stage I disease have tumors that measure < 5 cm, and have no evidence of lymph node involvement or metastases; patients with stage II have tumors > 5 cm, but are also free of lymph node involvement or metastases. Patients in stage III exhibit tumors of any size with local lymph node invasion; patients in stage IV have distant metastases or locally advanced disease with lymph node metastases. This classification has a clear prognostic impact: in a French series including 253 patients, the 5-year survival rates were 60% for stage I, 58% for stage II, 24% for stage III and 0% for stage IV. The median survival in stage IV was 25 weeks only [12]. Similar results have been obtained by the Italian National Registry for Adrenal Cortical Carcinoma [13].
Surgery is the mainstay of therapy in ACC patients [14,15]. The use of systemic therapies is confined to patients with advanced inoperable disease. In this setting, available systemic treatments (mitotane, cytotoxic drugs) have led as a whole to limited results [3,6]. Very recently, a retrospective clinical trial [15] has prompted interest in the use of mitotane after radical surgery, with the aim of prevening disease recurrence (adjuvant therapy). The extreme rarity of the disease, however, has so far impeded the development of any potentially effective single drug or therapeutic regimen. In the last 5 years, an international cooperation has been established, and the first worldwide randomized clinical trial is now being conducted [3]; this has attracted the interest of drug companies to partially support prospective studies in ACC patients. New insights into ACC pathophysiology suggest that the disease is a suitable candidate for testing drugs targeting epidermal growth factor receptor (EGFR), insulin growth factor receptor (IGF), vascular endothelial growth factor (VEGF) and the VEGF receptor; several studies with these drugs are currently underway.
2. Medical need
The mainstay of treatment for ACC patients is surgery [12-14]. Surgical resection, if feasible, should be always performed on either primary tumor or metastases [14] . An R0 resection is the most important prognostic factor, and represents the only chance for cure in ACC patients [12-14]. To attain radical resection, surgery often needs to be extensive, including extirpation of the adrenal gland, en-bloc resection of invaded organs, and lymphadenectomy [12-14].
Analysis of the surgical outcome of patients with ACC has underlined that about 25% of patientsz are left with residual disease after operation, and in > 50% of patients
submitted to a radical procedure the disease relapses, often with distant metastases [16-18].
The reasons why a significant number of patients with ACC in stages I - II are destined to relapse are actually unknown. Several potential predictive factors of recurrence in radically resected ACC patients have been identified [19,20], but the issue of defining prognostic factors is complicated by the great variability of clinical presentation and heterogeneity of biological behavior of the disease. The high relapse rate following radical operation offers a rationale for the use of adjuvant systemic therapies. Postoperative treatment with mitotane was associated with better outcome in a recently published case-control study [15]. The absence of randomization, however, hampers the generalization of the results.
Current data from the German ACC registry indicate that about 30% of patients are diagnosed in stage IV [21]. Patients with stage IV disease at diagnosis or with recurrent disease have a very poor prognosis when surgical removal of local relapse and distant metastases, or both, is not feasible [12-14,16,17]. Current systemic treatments for the disease at this stage (mitotane and cytotoxic chemotherapy) has led to unsatisfactorily results [3,6].
The interpretation of published results on systemic therapy, however, is difficult because most series are limited in the number of patients studied and there is a great variability in the drugs employed. Due to the rarity of the disease, no randomized trial results have yet been published. Though the efficacy of therapy for advanced ACC is generally poor, there are a number of patients in whom systemic therapy can extend life expectancy with acceptable side effects; but it is difficult to identify such patients in the absence of reliable predictive factors.
On the basis of these premises, the unmet medical needs regarding ACC can be defined as: i) new efficacious drugs in advanced inoperable patients; ii) assessment of the efficacy of adjuvant systemic therapy; and iii) predictive factors that enable treatment to be tailored to the individual patient.
3. Existing treatment
Patients in whom surgical approach is not possible are treated with mitotane therapy, cytotoxic chemotherapy, or a combination of both. As mentioned before, all these treatments have been mainly employed to treat patients with advanced/metastatic disease, and have shown limited efficacy. In the absence of randomized studies, it is not clear whether systemic therapy influences patient outcome. Moreover, since radically resected patients are at high risk of disease recurrence, there is a strong rationale for testing drugs as adjuvant therapy.
3.1 Mitotane
Mitotane (1,1 dichloro-2 ( o -chlorophenyl)-2-( p -chloro-phenyl) etane), an adrenolytic drug derived from the insecticide
| Study | Dosage (g/day) | Patients (n) | Response | Duration (months) |
|---|---|---|---|---|
| Venkatesh, 1989; retrospective [26] | NR | 72 | 21 PRs (29%) | NA |
| Luton, 1990; retrospective [27] | 3- 20 | 37 | 5 PRs (13%) | 5 - 25 |
| Decker, 1991; prospective [28] | 6 | 36 | 2 CRs, 6 PRs (22%) | 3- 82 |
| Pommier, 1992; retrospective [17] | NA | 29 | 7 PRs (24%) | NA |
| Haak, 1994; retrospective [29] | 4-8 | 55 | 8 CRs, 7 PRs (27%) | 2 - 190 |
| Barzon, 1997; retrospective [30] | 4-8 | 11 | 2 PRs (18%) | 40 - 64 |
| Williamson, 1999; II line [31] | 4 - 10 | 16 | 2 PRs (13%) | NA |
| Baudin, 2001; prospective [32] | 6 - 12 | 13 | 1 CR, 3 PRs (33%) | 10 - 48 |
CR: Complete response; NA: Not available; NR: Not reported; PR: Partial response.
DDT, is the only adrenal-specific drug approved for the treatment of advanced ACC [22]. Mitotane treatment controls hormone secretion in most patients with functioning ACC [23], and also exerts a specific, direct cytotoxic effect on cells deriving from the fascicular and reticular zones of the adrenal gland, although the exact mechanism of action has not been elucidated [24].
Mitotane has been widely employed in the medical treatment of advanced ACC, but it is difficult to critically appraise the evidence of its efficacy from published studies. Early studies, performed before the era of modern imaging techniques, adopted different criteria to define disease response; many included hormonal amelioration as an indicator of clinical response [24,25]. In more recent reports that include > 10 patients and use strict response criteria, partial responses were found in 13 - 33% of cases (median 24%), whereas complete responses were rarely observed (Table 1) [17,26-32].
Duration of tumor regressions was variable (2 - 190 months). The most common confounding factors in mitotane studies is that most of them were retrospective, employed different dosages of mitotane (in the range 3 - 20 g/day) and used two different formulations: Lysodren® (o,p’DDD alone) and the so-called ‘French mitotane’ (o,p’DDD mixed with enteric gastro-resistant coated granules of cellulose acetylpthalate), respectively.
The drawback of mitotane is its toxicity, the most common side effects being gastrointestinal and neurological. Neurological toxicity may be disabling, but reverses completely after mitotane withdrawal. Other common side effects include liver toxicity and increased cholesterol serum levels, so that liver function tests and cholesterol levels should be monitored during mitotane treatment [25]. Due to the adrenolytic activity of the drug, glucocorticoid supplementation is mandatory during mitotane treatment. Some patients may require also mineral corticoid supplementation (Florinef) [24].
A number of limited experiences have recently correlated mitotane activity and toxicity with the drug concentration achieved in the blood [29,32]. These studies have shown that
most severe adverse effects of this drug become manifest for blood levels > 20 mg/l, while disease response is mainly confined to patients achieving blood levels > 14 mg/dl [29,32-34]. Though these cutoffs are defined arbitrarily, these data indicate that mitotane has a narrow therapeutic index and that it is essential to monitor circulating mitotane levels in order to optimize treatment efficacy and to limit side effects.
The optimal mitotane schedule still remains a matter of controversy. High mitotane doses may rapidly achieve the therapeutic range, at the price of a substantial toxicity [32]. Low doses are better tolerated, but usually achieve the therapeutic range after some months, and this time lag may pose a problem when treating patients with rapidly progressive disease [33].
It is not clear how many patients are able to attain, and maintain over time, mitotane serum levels in the therapeutic range. In a French study, using French mitotane, therapeutic concentrations of mitotane were reached in about 50% of patients [32]; in an Italian series (using Lysodren®), 100% of the patients reached the therapeutic levels after 3 - 5 months [33]. Both studies, however, are too small to allow generalization of the results.
3.2 Cytotoxic chemotherapy with or without mitotane
The use of chemotherapy in metastatic unresectable ACC has generally led to modest results. Cisplatin has been the most widely used drug, either alone or in combination with other agents [35,36]. Table 2 summarises the prospective studies testing cytotoxic agents in series of > 10 patients with unresectable ACC (either metastatic or locally advanced). In the different multiple-agent regimens, cisplatin was mainly employed in combination with etoposide and doxorubicin. Taken together, these regimens led to an overall response rate in about 30% of cancers.
Mitotane was combined with conventional cytotoxic agents in about half of the studies. The rationale for combining mitotane with classic cytotoxic drugs is based on the finding that mitotane is able to reverse multi-drug
| Cytotoxic agent | Mitotane | n | Response | Ref. | ||
|---|---|---|---|---|---|---|
| CR (n) | PR (n) | Total (%) | ||||
| D, V, E | + | 36 | 1 | 4 | 14 | [38] |
| S | + | 22 | 1 | 7 | 36 | [39] |
| P, E | – | 45 | – | 5 | 11 | [40] |
| E, D, P | + | 72 | 5 | 30 | 49 | [41,42] |
| P, E | + | 18 | 3 | 3 | 33 | [43] |
| P | + | 37 | 1 | 10 | 30 | [44] |
| D | – | 16 | 1 | 2 | 19 | [27] |
| D, P, 5-FU | – | 13 | 1 | 2 | 23 | [45] |
| C, D, P | – | 11 | – | 2 | 18 | [46] |
| P, E | – | 11 | – | 6 | 46 | [47] |
| P, G | – | 18 (13 pretreated) | – | 2 | 11 | [48] |
| Total | 299 | 13 | 73 | 29 | ||
| Chemotherapy alone | 113 | 2 | 19 | 18 | ||
| Chemotherapy + mitotane | 186 | 11 | 54 | 35 | ||
C: Cyclophosphamide; CR: Complete response; D: Doxorubicin; E: Etoposide; 5-FU: 5-fluorouracil; G: Gemcitabine; P: Cisplatin; PR: Partial response; S: Streptozocin; V: Vincristin.
resistance mediated by P-glycoprotein expression in vitro, thus enhancing the effects of doxorubicin, vincristine and etoposide [37,38].
These studies are not randomized, so that caution should be adopted in the generalization of the results. These limitations notwithstanding, chemotherapy plus mitotane- containing regimens seemed to obtain better objective responses than chemotherapy alone (35 vs 18%) [28,39-48], although the association also increases gastrointestinal and neurological toxicity.
The highest response rate has been obtained with combination regimen using low-dose mitotane with etoposide, doxorubicin and cisplatin (EDP scheme). This led to an overall response rate of 48.5%, with a median time to disease progression of 28 months [41,42]. A combination of mitotane and streptozotocin has been proposed [40]. Complete or partial responses were observed in 36% of patients with measurable disease. The International Consensus Conference on Adrenal Cancer, held in Ann Arbor, USA, in September 2003 [22] recommended these two regimens as best choices of treatment for advanced ACC, leading to the first randomized controlled multicenter Phase III trial in this disease (FIRM-ACT trial) [3] (for more details, see below).
3.3 Adjuvant therapy
As mentioned earlier, the high recurrence rate of radically operated ACC has generated interest in examining the use of adjuvant systemic therapy.
With regard to adjuvant mitotane, small retrospective studies have provided insufficient and controversial results. Some did not include a control arm [49]. Table 3 outlines all retrospective studies with a control arm; in most of them, mitotane treatment failed to be associated with a disease- free or overall survival benefit. As a consequence, no recommendation regarding adjuvant treatment was made at the 2003 consensus conference on ACC held in Ann Arbor, MI [22].
Very recently, however, the results of a retrospective analysis involving a relatively large sample of patients with ACC, who were followed for up to 10 years at different institutions in Italy and Germany, have been published [15]. Adjuvant therapy was given to 47 Italian patients after radical surgery, and recurrence-free survival in these patients was compared to that of two independent groups of 55 Italian and 75 German patients whose surgery was not followed by mitotane treatment. Recurrence-free survival was significantly prolonged in the mitotane group, as compared with the two groups of untreated patients. The patients who were left untreated after radical resection of primary tumor had a significantly higher risk of recurrence than those receiving mitotane.
Although also this study was retrospective, the mitotane group and the Italian control group were highly comparable for the clinical characteristics known to affect outcome, while the control group from Germany had better prognostic factors, making mitotane effects even more impressive. Indeed, multivariate analysis confirmed that mitotane
| Study | Treatment | Patients (n) | Disease-free survival | Overall survival |
|---|---|---|---|---|
| Bodie et al., 1989 [78] | Mito | 21 | Not reported | Mito = Control |
| Control | 25 | |||
| Pommier et al., 1992 [17] | Mito | 7 | Mito = Control | Mito = Control |
| Control | 43 | |||
| Vassilopoulu-Sellin et al., 1994 [90] | Mito | 8 | Mito < Control | Mito < Control |
| Control | 6 | |||
| Haak et al., 1994 [29] | Mito | 11 | Not reported | Mito < Control |
| Control | 15 | |||
| Barzon et al., 1997 [30] | Mito | 7 | Mito < Control | Mito < Control |
| Control | 11 | |||
| Khan et al., 2000 [40] | Mito-STZ | 17 | Mito-STZ > Control | Mito-STZ > Control |
| Control | 11 | |||
| Terzolo et al., 2007 [15] | Mito | 47 | Mito > Control | Mito > Control* |
| Control | 130 | |||
| Bertherat et al., 2007 [50] | Mito | 162 | Not reported | Mito > Control |
| Control | 40 | Cortisol-secreting+ |
*Multivariate analysis after adjusting for age and prognostic parameters.
+Trend not significant.
Mito: Mitotane; STZ: Streptozotocin.
treatment gave a significant advantage for recurrence-free survival. Similarly, overall survival appeared to be superior in patients receiving adjuvant mitotane [15]. In a further retrospective study [20], no significant advantage was observed with adjuvant mitotane after complete removal of ACC. In a cohort of 166 patients who underwent complete tumor removal, mitotane use was not associated with any improve- ment in disease-free survival. These authors, however, found a significant benefit of adjuvant mitotane in the subset of patients with cortisol-secreting tumors. An update of this series has been recently published, confirming a trend (not significant) of survival benefit in favor of adjuvant mitotane therapy in the subset of cortisol-secreting tumors [50].
Taken together, these results look promising, but should be considered only as a hypothesis that warrants further exploration in randomized trials. There are also several issues against the use of adjuvant mitotane. Mitotane therapy is complex due to the long half-life of the drug and the need for careful steroid replacement therapy. Moreover, the narrow therapeutic index of this drug introduces additional uncertainties in its use as postoperative treatment, in terms of cost versus benefits, particularly before the widespread use of serum level monitoring. This treatment should be prescribed only in referral centers that have considerable experience in this setting [51]. Though the widespread availability of serum concentration data makes it possible to guide dose adjustments and prevent severe toxicity no prospective data on long-term toxicity and drug efficacy are yet available in serum mitotane monitored patients. These concerns are particularly important in the adjuvant setting, where apparently disease-free patients are treated, some of whom will not relapse.
The great majority of researchers involved in this disease agree on the need for a prospective randomized adjuvant study.
4. Therapeutic class review
Since ACC is an extremely rare disease, it is estimated that 400 - 1500 new cases are diagnosed in Europe every year and 150 - 600 patients diagnosed in the United States. Due to the high aggressiveness of the disease, it is expected that most ACC patients are destined to receive some form of systemic treatment. The drug most frequently used in the management of the disease is mitotane, produced by Bristol- Myers Squibb and distributed in Europe by HRA Pharma. The market for this drug in the United States and Europe is approximately 20 - 40 million/year (author’s estimation). With the increasing interest in the postoperative use of systemic therapy, the number of patients eligible to receive mitotane treatment is destined to increase steadily over the next few years. Systemic chemotherapy is increasingly prescribed, but this approach has only a marginal impact on the global market due to the relatively low cost of the drugs used and the short time period of administration (4 - 6 months for each patient, on average).
5. Current research goals
Current research goals are:
· to define standards for systemic treatment in the management of advanced disease
· to overcome chemotherapy resistance
· to identify predictive factors for treatment efficacy
· to improve therapeutic outcomes in advanced disease by introducing new targeted drugs, based on an improved understanding of disease genomics and proteomics
· to assess the efficacy of systemic therapy in the adjuvant setting in order to reduce the proportion of patients who are likely to relapse.
6. Scientific rationale
The scientific rationale for each of the research goals is outlined below.
6.1 Define standards for treating advanced disease
Due to the rarity of the disease, we currently do not know which is the best systemic treatment for advanced ACC. A randomized prospective study is therefore mandatory, and international cooperation is required.
6.2 Overcome chemotherapy resistance
ACC is commonly recognized as a chemoresistant disease. Normal adrenocortical tissue produces high levels of the multi-drug resistance protein MDR1 (also known as P-glycoprotein). This protein functions as an ATP-dependent drug efflux pump, transporting hydrophobic cytotoxic agents (such as doxorubicin, vinblastine, and paclitaxel) out of the cell. High MDR1 expression is retained in ACC [37,38]. ACC may also express MDR1-independent drug resistance mechanisms, which could account for the ineffectiveness of cisplatin. Pathway nucleotide excision repair is a key pathway involved in mediating resistance or sensitivity to platinum chemotherapeutic agents [53]; research is underway to assess the role of excision repair cross-complementation group 1 (ERCC1) protein in ACC as a predictive factor of resistance to cisplatin-based chemotherapy.
6.3 Rationale for target therapies
Genetic abnormalities associated with ACC development are mutations in various chromosomal regions (2,11p15,11q,17p13) and genes (IGF-II, p53, ß-catenin, adrenocorticotropic hormone [ACTH] receptor) [4,54]. Overexpression of the IGF gene is probably the most frequent genetic alteration. Both IGF-1 and IGF-2 are involved in tumorigenesis and dedifferentiation from normal cortex gland.
The IGF system is well-characterized for its contribution to normal and pathological adrenocortical growth. The IGF pathway is composed of two receptors (IGF1R and IGF2R) with their respective ligands (IGF-I and IGF-II). Following binding of either ligand, the IGF1R efficiently engages the cell to proliferate, differentiate, and survive. IGF1R is a receptor tyrosine kinase composed of two heterodimeric chains with intrinsic tyrosine kinase activity that is responsible for mediating IGF ligand (both IGF-I and IGF-II)-dependent intracellular action [55,56]. Transduction of signals through
IGF1R leads to multiple intracellular phosphorylation events and the activation of several signaling pathways. The two predominant effectors for this are the PI3K/Akt and MAPK pathways [54].
Various growth factors and cytokines other than IGFs have been shown to regulate adrenal tumor growth. These include basic fibroblast growth factor (FGF-2), transforming growth factor-o. (TGF-a) and transforming gowth factor-ß1 (TGF-ß1), VEGF, and interleukins [55-63]. Potential targets for specific drugs are therefore EGFR, FGR1, IGF1-2, K-Ras, VEGF and PI3K/AKT/m-TOR and MAPK pathways. Metabolic pathways involved in ACC are depicted in Figure 1.
Angiogenesis plays a major role in cancer growth and metastasis, and the assessment of VEGF expression is a way to quantify the angiogenic status of a tumor. VEGF is more frequently overexpressed in ACC by comparison with adrenal adenoma [59,63]. However, a low vascularization was observed in ACC as opposed to adrenal adenoma, suggesting a dissociation between the angiogenic status and the neo- angiogenic capabilities of these tumors [64]. Furthermore, no data are yet available on the prognostic role of VEGF in ACC. These limitations notwithstanding, drugs targeting angiogenesis are considered very promising in the management of ACC.
6.4 Predictive factors of treatment efficacy
The identification of predictive factors of efficacy is of paramount importance in the management of cancer patients, since it allows treatment to be tailored to suit individual patients. Few data are available on predictive factors in ACC patients. In a series of advanced ACC patients uniformly treated with etoposide, doxorubicin and cisplatin, an Italian cooperative group showed that tumors secreting androgens or precursors alone have a better time to progression and overall survival than tumors secreting cortisol alone or with androgens [42]. The predictive role of secretion was maintained in multivariate analysis, including after adjustment for commonly recognized prognostic factors such as disease extent, disease-free survival and patient performance status. The negative prognostic role of cortisol hypersecretion was also observed in a French series involving 202 consecutive ACC patients at various stages of disease [20]. These data provide some evidence that the secretory status of tumors may have a predictive role in specific antineoplastic treatments and should be considered in the treatment decision-making process.
ERCC1 protein in tumor tissues has been assessed in a series of ACC patients undergoing cisplatin-based chemotherapy in multiple centers in Germany. The results showed a clear survival advantage of ERCC1-negative patients compared with control groups, in both univariate and multivariate analyses [65].
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7. Competitive environment and potential development issues
7.1 Efforts to identify a standard therapy for advanced disease
The international consensus conference on adrenal cancer, held in Ann Arbor, United States in September 2003, recommended both etoposide, doxorubicin and cisplatin in combination with mitotane, and streptozotocin in combination with mitotane, as therapeutic options in advanced ACC [22].
On this basis, the Collaborative Group for Adrenocortical Cancer (COACT) has been established, with the aim of setting up a large international study: FIRM-ACT (First International Randomised Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment) [66]. FIRM- ACT is a Phase III, randomized, open-label, crossover trial involving Australia, France, Germany, Italy, The Netherlands, Sweden, the United Kingdom and the United States. This trial compares the efficacy (in terms of survival prolongation) of etoposide, doxorubicin, cisplatin and mitotane (EDP/M)
with streptozotocin and mitotane (Sz/M) (Figure 2). In total, 300 patients will be randomized in approximately 5 years. The final results of this trial are expected around 2011. The main eligibility criteria are histological diagnosis of ACC and stage III - IV disease.
Secondary end points are disease response, response duration, quality of life and time to progression. Any correlation between plasma levels of mitotane and overall survival will be determined for both treatment groups. In case of unacceptable toxicity or progression of underlying disease, patients will be treated according to the treatment regimen of the other group, so that second-line treatment data will become available for both treatment regimens.
7.2 Efforts to circumvent resistance to cytotoxic treatments
Several agents have been tested with the aim of circumventing the cytotoxic drug resistance induced by MDR1 expression. In vitro studies have shown that mitotane is able to target MDR1 [38,39]. This may be a mechanism by which combination chemotherapy regimens containing mitotane
Randomization
EDP + mitotane
Streptozotocin + mitotane
Evaluation every 56 days In case of progressive disease switch the regimen
EDP + mitotane
Streptozotocin + mitotane
have seemed to be more active than those not containing mitotane. Other agents such as PSC833 (valspodar™), a second-generation competitor, have been attempted without success [67]. A current Phase II study (Table 4) is evaluating the effect of chemotherapy plus tariquidar (XR9576), a third-generation noncompetitive inhibitor of the MDR1 efflux pump [68-70].
7.3 New target therapies
Target drugs against EGFR have so far provided disappointing results when used as second-line therapy in advanced ACC. In a Phase II trial conducted at the MD Anderson Cancer Center in the United States found no activity for single- agent gefitinib in 19 ACC patients previously treated with mitotane or chemotherapy [71].
The activity of erlotinib, an oral tyrosine kinase inhibitor targeting EGFR, has been tested in combination with gemcitabine in a small series of advanced-ACC patients in Germany [72]. Only 1 of 10 patients enrolled experienced a minor response (progression-free survival: 8 months), whereas 8 patients had progressive disease at the first staging. The authors’ conclusion was that salvage chemotherapy using erlotinib plus gemcitabine has very limited to no activity in patients with advanced, pretreated ACC.
A novel EGFR inhibitor, BMS-690514, is currently under investigation in a multicenter Phase I study enrolling patients with advanced/metastatic solid tumors (including ACC) (Table 4).
Two studies are being conducted in Europe with antiangiogenetic drugs. Both trials have a similar study design and are enrolling patients with similar tumor characteristics. The primary aim of these two studies is not (as in most Phase II trials) the response rate, but
progression-free survival after 3 or 4 months. Antiangiogenetic drugs, as well as most targeted drugs, are not very active in inducing tumor shrinkage; so durable disease stabilization is a reasonable effect. In both trials patients should have advanced disease, having previously been treated with one or two chemotherapy regimens plus mitotane.
The first trial, being conducted in Germany, is testing the activity of sunitib, an orally available multitargeted thyrosine kinase inhibitor that inhibits the receptors for VEGF and PDGF, KIT, FLT-3 and RET. The second European trial currently open for accrual in Italy is testing the activity of the association of sorafenib to weekly metronomic paclitaxel. Sorafenib is an orally available multitarget serin/thyrosine kinase inhibitor that inhibits RAF-1, a key enzyme in the RAS/RAF/MEK/ERK signaling pathway leading to cell proliferation, and VEGFR-2 and PDGFR-ß involved in angiogenesis. Metronomic chemotherapy is the frequent administration of cytotoxic drugs at doses that are low enough to avoid myelosuppression and other dose-limiting side effects that otherwise necessitate a rest period. This treatment modality may not target tumor cells directly (as is the aim of approaches that seek to determine the maximum tolerated dose), but indirectly, inhibiting angiogenesis and vasculogenesis by continuously exposing the more slowly proliferating tumor endothelial cells to the damaging action of the cytotoxic therapy [73]. Low-dose metronomic chemotherapy may offer several advantages over the MTD approach, including reduced toxicity and treatment response irrespective of the resistance profile of the tumor cell population. Theoretically, a metronomic schedule is the best way to introduce a cytotoxic drug in heavily pretreated cancer patients, and metronomic chemotherapy may have a synergistic effect with antiangiogetic drugs [73].
A Phase I trial recently open for accrual at the MD Anderson Cancer Center is testing the activity and feasibility of the association of sorafenib with tipifarnib, a farnesyl transferase inhibitor targeting the RAS in advanced cancer patients with various malignancies, including ACC.
Since IGFs are very frequently overexpressed in ACC, there is a strong rationale to test drugs targeting IGFRs. A Phase I study has been recently conducted in the United States, testing the feasibility and activity of CP-751,871 and IGF-1 inhibitors in patients with various solid tumors, including ACC. This trial has completed the accrual, and the results will be available soon [74].
7.4 Randomized trial of adjuvant therapy in radically resected ACC
Since ACC is a very aggressive disease, whenever the tumor is completely removed, and there is no evidence of residual disease, physicians must resolve a number of clinical dilemmas. Should patients simply be followed-up without further treatment, or is adjuvant therapy required? If so, which adjuvant therapy? And which patients are destined to obtain the most benefit from this approach? As previously
| Principal investigators | Phase | Drugs | Category | Patients |
|---|---|---|---|---|
| Daugaard D Rigshospitalet - Copenhagen University Hospital, Denmark | II | Docetaxel Cisplatin | Chemotherapy | Advanced ACC first-line approach |
| Fojo T | II | Doxorubicin Vincristine Etoposide Mitotane Tariquidar | Chemotherapy MDR1 revertant drugs | Advanced ACC first-line approach |
| National Cancer Institute, Bethesda, USA | ||||
| Samnotra V Cotton Cancer Center Darmouth-Hitchcock Medical Center, New Hampshire, USA | II | Bevacizumab | Angiogenesis inhibitor | Advanced ACC first-line approach |
| Fassnacht M Dept. of Internal Medicine, University of Wuerzburg, Germany | II | Sunitinib | Angiogenesis/multitarget inhibitor | Advanced ACC second-line approach |
| Berruti A Dept. of Clinical and Biological Sciences University of Turin, Orbassano, Italy Baudin E Dept. of Nuclear Medicine and Endocrine Oncology Institut Gustave-Roussy, Villejuif, France | II | Sorafenib Weekly paclitaxel | Antiangiogenesis/ multitarget inhibitor Chemotherapy | Advanced ACC second-line approach |
| MD Anderson Cancer Center Trial Office, Houston, USA | I | Tipifarnib Sorafenib | Antiangiogenesis; farnesyl transferase inhibitors | Various advanced solid tumors, including ACC |
| Kohn E National Cancer Institute, Bethesda, USA | I | Sorafenib Bevacizumab | Angiogenesis; multitarget inhibitors | Various advanced solid tumors, including ACC |
| Pfizer Company, USA | I | CP-751,871 | IGF-1 inhibitor | Various advanced solid tumors, including ACC |
ACC: Adrenocortical carcinoma.
mentioned, there are potential advantages but also dis- advantages in using adjuvant therapy in ACC patients. On the basis of the limited evidence already available, most ACC experts agree that mitotane can be recommended in radically resected patients who are considered at high risk of disease relapse [75]. There is general agreement that in these patients, it is not ethical to design a prospective randomized trial that includes a no-treatment arm. By contrast, considerable uncertainty persists regarding the patient subset with a low risk of recurrence, in which any treatment benefits should be weighted against the risks of long-term toxicity.
The problem is: how do we define low- and high-risk patients? As mentioned in the introduction, stage of disease and radical surgery are the most important prognostic factors; but in a combined Italian and German series [15] of radically resected patients, disease stage was no longer predictive for disease-free survival, though it retained prognostic significance in multivariate analysis. Age was the only independent variable inversely associated with either disease-free or overall survival. These latter data, however, are in contrast with the bulk of previous evidence to suggest that age does not play a major role in prognosis [19,23,76,77]. The majority of publications have reported no correlation
between sex and survival [12,17,18,78], whereas few reports suggested better survival in women [23,27]. The functional status of the tumor was usually found to be unrelated to prognosis [1,16,23,26-28,77], although some reports indicated a longer survival in patients with androgen- secreting tumors [12]. In patients with advanced disease, it is biologically plausible that hypercortisolism may contribute to an unfavorable prognosis because of its negative effects on health status [43].
On the basis of these observations, it is clear that the issue of defining prognostic factors by clinical parameters is complicated by the heterogeneity of the biological behavior of ACC, so that histological and biological parameters should theoretically be preferred. The traditional features used for a morphological characterisation of ACC include architectural and cytological data, together with information on the invasive properties of the tumor. Nine of these have been combined in the Weiss system [79], which includes three issues related to tumor structure (‘dark’ cytoplasm, diffuse architecture, necrosis), three related to cytological features (atypias, mitotic count, atypical mitotic figures), and three related to invasion (of sinusoids, veins and tumor capsule).
Emerging drugs for adrenocortical carcinoma
The Weiss score is widely recognized as the best way to morphologically discriminate ACCs from the corresponding adenomas. However, controversy remains around its use in prognostic assessment. Some Weiss criteria are far from being reproducible by different pathologists, and this may have accounted, at least in part, for the controversial results [80]. The prognostic role of each Weiss indicator has been evaluated separately, and many papers conclude that the mitotic count is the most reliable [80]. In our personal experience in a series of radically operated ACC patients, mitotic count was independently associated with poor survival after adjustment for clinical (age, stage) and biological (Weiss) parameters (unpublished data). Similar results have been obtained in a large German series [81]. Assessment of the expression of the proliferative antigen Ki67 may be a valid prognostic alternative to the mitotic count [81-87]. On the basis of these data, proliferative activity can be considered to be the most potent prognostic marker in radically operated patients.
A randomized prospective multicenter trial has recently been designed to compare the efficacy and toxicity of adjuvant mitotane treatment versus no treatment in prolonging relapse-free survival (RFS) in patients with low- risk ACC submitted to radical surgery. Low-risk patients are defined as having ACC with Ki67 expressed in ≤ 10% of malignant cells. This trial is now ready for accrual in Italy, but will soon become a multinational trial, since many countries are interested in participating. In high-risk patients (defined as having Ki67 expressed in > 10% of ACC cells), a randomized trial comparing mitotane versus mitotane plus chemotherapy is in preparation.
8. Conclusion
Adrenocortical cancer is an extremely rare disease in which systemic treatment has so far obtained unsatisfactory results. An improved understanding of the molecular pathways that underlie development and progression of this aggressive disease has provided the rationale for testing new target drugs in its management [88]. Recent international collaboration means that multinational trials are now feasible. This has attracted the interest of drug companies in testing new drugs for this disease.
Due to the rarity of ACC, only relatively small trials can be conducted, even on a multicenter basis; hence the rationale for new prospective trials should have a strong biological basis. Tumor biology (molecular alterations) may be a key in determining response to treatment and, in future, the molecular approach will help in the selection of patients who could benefit from specific therapies [88]. Translational research is therefore mandatory to improve our knowledge of tumor biology and identify new predictive markers of treatment efficacy. Future studies should be designed to search for a strong difference between the standard approach and the experimental one, with the aim
of obtaining useful results through the involvement of relatively few patients. This can be achieved only through careful patient selection.
9. Expert opinion
Adrenocortical carcinoma is commonly believed to be a disease that responds poorly to available systemic anti- neoplastic treatments. In the authors’ opinion, however, the extreme rarity of this disease has hindered the development of efficacious treatment strategies. The choice of treatment available, in fact, is based on the results of retrospective studies and small prospective clinical trials that have enrolled few patients over a rather long time period.
The establishment of an international cooperative group for the treatment of ACC, involving referral centers in most countries in the world, represents an important step forward in achieving high-quality research. This group has demonstrated that randomized trials, never previously attempted, are feasible with multinational cooperation. The first randomized trial in patients with advanced disease, the FIRM-ACT trial, has accrued > 160 patients in just a few years. It will soon define the standard combination regimen to be used routine in clinical practice and as the comparator for future randomized trials.
ACC is an aggressive disease with a high recurrence rate in radically resected patients. Adjuvant therapy, by destroying micrometastases, can prevent disease recurrence and improve the survival of ACC patients. This treatment modality offers therefore the best chance to significantly change the natural history of the disease. As repeatedly observed in other malignancies, drugs or combination regimens with a limited activity in advanced patients can be more efficacious if used as adjuvant therapy. The next task of the international cooperative group will be to test the drugs or combination regimens already available in metastatic disease, such as mitotane or mitotane plus chemotherapy, as adjuvant therapy.
The problem is, which patients are suitable for adjuvant therapy? Since ACC is an aggressive disease with a high recurrence rate, virtually all patients might benefit from an adjuvant treatment. However, the clinical behavior of ACC is notoriously heterogeneous: some patients with rather indolent disease may not require adjuvant treatment. Conversely, patients with highly aggressive disease may require a very aggressive treatment. The international panel is planning to determine the appropriate strategy for adjuvant treatment, based on individual risk of relapse: mitotane therapy versus nothing in low-risk patients, and mitotane versus chemotherapy plus mitotane in high-risk patients. This is the first step. The second step will be to tailor the treatment strategy to each patient, on the basis of biological predictive factors of responsiveness to a particular therapy, independent of individual risk of relapse.
With clinical researchers and drug companies showing increasing interest in this potentially devastating disease, it is to be hoped that we will soon see improved outcomes in ACC patients receiving systemic treatments.
Declaration of interest
Supported in part by: MURST (Ministero dell’Università e della Ricerca Scientifica e Tecnologica), Rome, Italy and by Regione Piemonte, Ricerca Sanitaria, bando 2008.
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