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BJUI BJU INTERNATIONAL
Chemotherapy for advanced adrenal cancer: improvement from a molecular approach?
Renata Costa, Robert Wesolowski and Derek Raghavan*
Cleveland Clinic Taussig Cancer Institute, Ohio State University James Cancer Institute, Columbus, OH, and *Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC, USA Accepted for publication 11 March 2011
Advanced adrenal carcinoma remains a significant therapeutic challenge, with conventional approaches to systemic therapy having failed to achieve sustained objective remissions or major survival benefit in most instances. Several systemic therapies, including mitotane, suramin and gossypol, as well as cytotoxic agents, such as cisplatin and etoposide, have produced responses of =15-30%, with median survival figures of =6-15 months, depending on case selection bias, with only <10% 5-year survival rates. Recent preclinical and pathological studies have indicated a range of potential targets for drugs, including WNT/beta-catenin, epidermal growth factor receptor, RAF and k-RAS; similar applications in melanoma
What’s known on the subject? and What does the study add?
Adrenal cancer is classically a silent tumour that is often advanced at presentation. Conventional approaches to systemic therapy have been associated with relatively low objective tumour response rates, and modest survival benefit. More recent approaches have implemented targeted therapies focused on gene expression of these tumours, with some sustained remissions reported.
This review assesses the utility of conventional and novel systematic therapies for adrenal carcinoma, and points the way to future implementation of molecular biology in the design and execution of clinical trails for advanced adrenal carcinoma.
and renal carcinoma have achieved significant gains, and these targets are worthy of further, structured investigation. Advanced adrenal carcinoma constitutes an orphan disease, with a high mortality rate, and merits investment in clinical trials.
KEYWORDS
adrenal carcinoma, chemotherapy, targeted therapies, gene, cisplatin, mitotane
INTRODUCTION
Adrenocortical carcinoma (ACC) is one of the uncommon malignancies. Worldwide, the annual incidence is only 1-2 per million [1]. In the USA, it is estimated that =300 cases of ACC occur per year [1]. There is a slight predominance in women and the female: male ratio is approximately 4:3 [2,3]. A bimodal age distribution has been reported, with the first peak occurring before age 5, and the second one in the fourth to fifth decades. Geographical factors may also play a role. A higher incidence of ACC is found in certain regions, such as in southern and southwestern Brazil. This distribution may be related to rates of sporadic mutations such as the TP 53 tumour suppressor gene [4,5]. The contribution of genetic factors is also supported by the observation that familial conditions, such as Li-Fraumeni syndrome (mutation in p53 gene on 17p13), Beckwith- Wiedemann syndrome (mutation in IGF 2 on chromosome 11p15.5), multiple endocrine
neoplasia type I (mutation in MEN gene on chromosome 11q13) and Carney syndrome (loss of heterozygosity on 2p16) are associated with a higher predisposition to ACC [6] Environmental factors may also lead to an increase in the risk of developing this cancer. Smoking history, for example, has been suggested by some to be associated with a higher rate of ACC [1,7]. The majority of cases, however, are sporadic. The differentiation of ACC from the more common benign adenomas is achieved by using the Weiss criteria, a widely accepted multifactorial pathological scoring system. The score is based on nuclear grade, mitotic rate, atypical mitoses, clear cell component, diffuse architecture, tumour necrosis, invasion of venous or sinus structures, or tumour capsule. Benign adenoma is most likely in patients whose Weiss criteria score is <3 [8].
Adrenocortical carcinoma is notoriously silent in its initial presentation, probably owing to its anatomical site and the lack of
adjacent viscera that can be compressed or obstructed in the early stages, but =50% of patients with this disease oversecrete adrenal hormones. This often leads to corresponding clinical syndromes. The symptoms also correlate with the amount and type of overproduced hormone (cortisol, androgens and rarely aldosterone). Cushing’s syndrome is seen most commonly, followed by virilization [1]. Cortisol hypersecretion also leads to immunosuppression and increased risk of infections. Constitutional features and symptoms related to local effects of rapid tumour growth can also sometimes occur [9].
Adrenocortical carcinoma can be classified based on the TNM staging system. Lesions that are confined to the adrenal gland and <5 cm (T1) define stage I disease. Stage II tumours are >5 cm but still confined to the adrenal gland (T2). Stage III or locally advanced adrenocortical carcinoma involves lesions that grow beyond the adrenal gland into the fat (T3) or invade adjacent
organs (T4). T1-2 lesions with lymph node involvement (N1) are also included in Stage III. Patients with T3 or T4 tumours and lymph node involvement, as well as those in whom metastases are present comprise Stage IV disease [10].
The 5-year survival rate in patients with ACC depends on stage at presentation. It is =45-60% in patients with early stage disease and 10-25% in patients with advanced stages [1]. Importantly, =70% of cases present with spread of the tumour beyond the adrenal gland [3]. Completeness of resection and stage of the disease have been considered important favourable prognostic factors [1]. Adverse prognostic factors are tumour size and grade, presence of tumour necrosis, high Ki67 staining, evidence of TP53 mutation and evidence of cortisol secretion by the tumours [9,11-14]. Different outcomes based on gene expression profiles have also been described [15].
The rarity of ACC presents a challenge for studying the optimum management of this disease. Complete surgical resection is considered to be the treatment of choice for patients with non-metastatic disease and is believed to offer the best chance of cure.
Systemic treatment of advanced ACC has never been standardized because of a lack of large randomized clinical trials. Although many phase I-II trials in advanced ACC have been reported, most of them have included small numbers of patients, often from a single institution. Most of these studies have been of single-arm, non-randomized design, and many have included patients with different stages or extent of disease. Another problematic feature has been the lack of standardized criteria for reporting of disease severity or response to treatment. Few, if any, of the available trials have compared treatment with best supportive care. Accurate interpretation of these studies is therefore quite difficult, as the documented outcomes are not robust. There is scant level I evidence to provide definitive guidance on optimum systemic therapy, and there has been uncertainty in the literature about the respective merits of single-agent or combination therapy [7]. It is therefore timely to review published evidence that examines the usefulness of systemic therapy in patients with unresectable ACC.
ROLE OF SYSTEMIC THERAPY IN ADVANCED ACC
Haq et al. [16] performed an analysis of 27 ‘trials’ with 16 chemotherapy regimens used in 12 patients with metastatic ACC, nine of whom progressed despite surgery and treatment with mitotane between 1960 and 1979. Both treatment with single agents as well as combinations were evaluated. Only three patients were reported to have achieved true partial remission (all in the combination therapy group). Response durations in those who responded were brief (3, 6 and 7 months, respectively). The authors concluded that alkylating agents and doxorubicin appear to have some anti-tumour activity, but that no single agent or drug combination showed consistent benefit in this disease. Unfortunately, little progress has been made since this publication, and the paucity of high level information available from this study indicates a great deal about the past state of the art.
MONOTHERAPY
Mitotane
Mitotane (o,p’-1,1-[o,p’-dichlorodiphenyl]- 2,2-dichloroethane; DDD) is an isomer of the insecticide p.p’-DDD and a chemical congener of DDT. It produces selective adrenocortical necrosis thought to be related to inhibiting conversion of cholesterol to pregnenolone as well as conversion of 11-deoxycortisol to cortisol [17]. It therefore has been viewed as an attractive therapeutic agent in ACC. One of the first reports that assessed the anti-tumour effects of this compound was a study in 1960 by Bergenstal et al. [18], who observed that mitotane produced objective responses and reduced corticosteroid secretion in 18 patients with ACC. Subsequently, 138 patients with ACC were enrolled to another similar trial [19]. Thirty four percent of the 59 patients with evaluatable disease had objective tumour regression with a median response duration of =7 months. Decreased hormone secretion was also reported.
In a later single-arm study, 115 patients with advanced ACC were treated with increasing doses of mitotane until unacceptable toxicities developed [20]. Again, reduction in steroid hypersecretion
was observed. Sixty-one percent of 75 evaluatable patients had some tumour regression. The median survival from the onset of the study treatment was 5 months [21,22]. Overall response rates ranged between 25 and 32%, and the mean duration of the response was 5-24 months [3,23,24]. Endocrine hypersecretion was shown to be controlled in 70-75% of patients in whom functional ACC was present [3,19,20]. No controlled trial has been completed to prove a survival benefit of mitotane over best supportive care, but phase I-II studies have shown clear evidence of symptomatic improvement and objective partial responses that are sustained, as outlined above. In our experience, careful monitoring of toxicity, with dose reduction as necessary, will often allow the responding patient to remain on treatment, with acceptable quality of life, for many months.
Mitotane alone or in combination with other cytotoxic drugs has been generally accepted as the first line therapy in patients with inoperable ACC, but no optimal dose has been defined from the published trials [25,26]. The measurement of plasma mitotane concentration has been proposed as a method of predicting toxicity in patients on long-term therapy [27,28]. A serum concentration above 14 mg/L has been found to correlate with higher response rates, but at the expense of greater toxicity [27,29]. Drug levels >20 mg/L usually produce unacceptable toxicities. The optimum duration of therapy has not been adequately established and published studies have varied in this respect. Most clinicians stop the drug when the disease progresses or when unacceptable toxicity develops.
Suramin
Suramin, a polysulphonated naphthylurea, has been used in the treatment of African sleeping sickness since 1923. An adrenotoxic effect of the drug leading to adrenal insufficiency was reported in these early studies, and it was therefore tested in patients with ACC. Individual case reports showing short partial responses were published in the 1980s [30]. Seventeen patients with metastatic ACC were treated in a single-arm trial that tested clinical safety and activity of suramin, given at escalating doses [31]. A median survival of 7 months was reported, with 4/16 evaluable patients showing partial responses. In
another trial of escalating doses of suramin, nine patients with metastatic ACC were treated [32]. Three partial responses were noted. All responders had serum suramin concentrations of ≥200 mg/L (target concentration). Unacceptable toxicities without tumour responses occurred in patients whose concentrations were above 300 mg/L. Other small studies with suramin reported similar results [31,33]. Suramin therefore has a narrow therapeutic window, which makes the use of this drug rather cumbersome with variable and unpredictable clinical benefit.
Gossypol
Gossypol is a plant toxin derived from cotton seed oil. Tso et al. [34] showed that gossypol has potent spermatotoxic, anti-metabolic as well as anti-neoplastic activity in vivo. Several investigators have examined its activity against ACC. Gossypol was tested in the SW-13 human ACC cells, both in vitro and in xenografs, by Wu et al. [35]. The drug appeared to be safe and effective in delaying cancer growth. Subsequently, 21 patients with metastatic ACC that progressed on mitotane were enrolled on a study evaluating the efficacy and toxicity of oral gossypol [36]. The doses were increased according to tolerance (initial dose of 20 mg/day). A partial tumour response was observed in 3/18 patients that lasted several months to >1 year. None of the patients had to discontinue gossypol because of side effects, but three patients who died from their disease were excluded from the above analysis [37]. In the ensuing decades, this agent has not found its way into routine clinical practice.
Conventional chemotherapy
Treatment with single cytotoxic drugs has produced partial responses only in a minority of these patients, based on small, single-arm trials, case series and case reports. Cisplatin has been the most extensively studied single agent, and has predominantly been found to produce transient partial, or less than partial, responses [38,39]. Other agents, such as doxorubicin or irinotecan, have also been studied in small, single-arm phase II trials with variable results, none being particularly impressive [16,40,41]. Chemotherapy is therefore more commonly used with
mitotane or in combination with other chemotherapeutic agents. The rationale for combining chemotherapy with mitotane came from the in vitro observation that mitotane may inhibit the P-glycoprotein (P-gp) efflux pump and so might potentially reduce tumour resistance to chemotherapeutic agents [42].
COMBINATION CHEMOTHERAPY
Cisplatin (CDDP) with mitotane
Bukowski et al. [43] reported results of the Southwest Oncology Group 8325 trial, that tested the combination of mitotane and cisplatin in patients with ACC. Thirty-seven patients were stratified into two groups, defined as good-risk and poor-risk. These categories were based on age (< or >65 years old), extent of prior radiation (< or >30% of the bone marrow bearing areas) and tolerance of prior chemotherapy (poor vs good). Patients with good-risk disease were treated with cisplatin (100 mg/m2 every 3 weeks), concurrently with mitotane at 1000 mg four times per day. The poor risk group received lower doses of CDDP (75 mg/ m2 every 3 weeks) concurrently with the same dose of mitotane. Toxicity was moderate to severe, particularly with respect to gastrointestinal effects. Objective responses were reported in 11/37 eligible patients for an overall response rate of 30% (95% CI, 16.0-50%). The median (range) response duration was 7.9 (1.4-36.1) months. The median (range) survival was 11.8 (0.2-51.2) months. This combination has therefore been used quite widely to treat advanced ACC.
Streptozocin and mitotane
The use of streptozotocin in advanced ACC was initially proposed based on animal studies that showed that the drug was preferentially taken up in the adrenal cortex of mice [44]. Partial responses in patients treated with this combination were reported in single case reports and small case series [45]. A single-arm, phase II study enrolled 40 patients with local and advanced ACC to chemotherapy with mitotane at a dose of 1-4 g daily in combination with i.v. streptozocin (1 g/day for 5 days, thereafter 2 g once every three weeks). Patients were treated until tumour recurrence or progression. Study subjects received a median (range) number of 7 (1-23) cycles.
The treatment produced objective responses in 8 of 22 patients with measurable disease defined by WHO criteria. The survival at 5 years was 35.2%, although this number also included patients who had early stage disease [46]. The regimen was associated with nausea in 11 patients. In addition, elevations in liver function tests were reported in 62% of patients. Nevertheless, such favourable response rates and survival made this an established treatment for patients with ACC. A phase III trial using this regimen is ongoing (see below).
Cisplatin and etoposide
Another Southwest Oncology Group study assessed response rates for cisplatin and etoposide in advanced ACC, after the publication of several case reports describing purported partial responses in virtually all patients treated with the regimen [47,48]. Forty-five eligible patients were allocated into two groups: patients with no history of prior mitotane therapy were scheduled to receive a combination of cisplatin (50 mg/m2 on days 1 and 2) and etoposide (100 mg/m2 on days 1-3) every 21 days. Treatment was continued for a total of 6 months or until disease progression, at which time patients were treated with mitotane. Patients with prior mitotane therapy were treated with the same study regimen but were not offered mitotane at the time of disease progression. The overall objective response rate was 11% and median survival was 10 months [49]. No formal comparisons were made between the two groups because of the small overall numbers. In another study by Bonacci et al. [50], CDDP (100 mg/m2 i.v. day 1) and etoposide (100 mg/m2 i.v. days 1-3) every 4 weeks was used in 18 patients with ACC. Mitotane treatment was maintained in 14 patients. Complete response was observed in three cases and partial response in three cases.
Etoposide, doxorubicin cisplatin and mitotane
Given the responses seen in studies testing regimens incorporating CDDP, etoposide and mitotane, doxorubicin was added to create a novel four-drug combination in the hopes of further improving efficacy. An Italian multicentre phase II trial tested the combination of mitotane at a starting dose of 1g/day, doxorubicin 20 mg/m2 on days 1 and 8, cisplatin 40 mg/m2 on days 2 and 9,
| TABLE 1 Ongoing trials - chemotherapy | ||
|---|---|---|
| Study | Purpose | Status |
| Gossypol Acetic Acid in Treating | This phase II trial is studying how well | Recruiting |
| Patients with Recurrent, Metastatic, or Primary Adrenocortical Cancer | gossypol acetic acid works in treating patients with recurrent, metastatic, | |
| that Cannot be Removed by | or primary ACC that cannot be | |
| Surgery. NCT 00848016 | removed by surgery. | |
| Suramin in Treating Patients with | Phase II trial to study the effectiveness | Active but not |
| Stage III or Stage IV Adrenocortical | of suramin in treating patients with | recruiting |
| Cancer. NCT 00002921 | stage III or stage IV ACC. | |
| Tariquidar, Mitotane, Doxorubicin, | Phase II trial to study the effectiveness | Active but not |
| Vincristine, and Etoposide Plus | of combining tariquidar with | recruiting |
| Surgery in Treating Patients With | combination chemotherapy and | |
| Recurrent, Metastatic, or Primary | surgery in treating patients who have | |
| Unresectable Adrenocortical Cancer | recurrent, metastatic, or primary | |
| NCT00073996 | unresectable ACC. | |
| Trial With Taxotere and Cisplatin in | A phase II trial in ACC of which the | Recruiting |
| Non-operable Adrenocortical | primary objective is to investigate | |
| Carcinoma NCT00324012 | response rate of taxotere and cisplatin. Secondary endpoints are survival, time to progression, best overall response rate and duration of response. | |
| Trial in Locally Advanced and | Phase III trial to determine whether | Recruiting |
| Metastatic Adrenocortical | treatment with etoposide, | |
| Carcinoma Treatment (FIRM-ACT) | doxorubicin, cisplatin and mitotane | |
| NCT00094497 | (EDP/M) prolongs survival as compared with streptozotocin and mitotane (Sz/M) in patients with advanced ACC whose disease is not amenable to complete surgical resection. | |
and etoposide 100 mg/m2 on days 5-7 (EDP-M regimen). The cycle was repeated every 4 weeks [51]. Attempts were made to maintain mitotane serum levels at 14-20 mg/L. The primary aim of the study [51] was to define efficacy and toxicity of this regimen as defined by WHO criteria. Interim analysis of 28 evaluatable patients showed that two (7.1%) had complete responses and 13 (46.4%) had partial responses, leading to an overall response rate of 53.5% (95% CI, 35-72%). In addition, eight patients had stable disease (28.5%) and five experienced progression (17.8%). Five patients (one parital response, four stable disease) became disease-free after radical resection. The median time to progression for the responding patients was 24.4 months. In 2005, data for all 72 patients became available. Objective tumour regression was observed in 35/72 patients (48.6%; 95% CI: 37.1-60.3%). Five patients
(6.9%) achieved a clinical complete response, 20 (27.8%) had stable disease, while 16 (22.2%) progressed. Time to progression of 24 months was observed in patients who had objective response to treatment. The most frequent toxicities were haematological and included one death from septic shock in a neutropenic patient. Other major toxicities were gastrointestinal and neurological. The 5-year survival rate was 15%. The most severe and dose-limiting side effect was leucopenia [52].
Given these somewhat promising results, a multinational effort, the First International Randomized Trial in Locally Advanced and Metastatic Adrenal Cancer Treatment (FIRM-ACT), has been initiated and will attempt to randomize 300 patients to either etoposide, doxorubin, cisplatin and mitotane (an EDP-M regimen) or streptozocin and mitotane (an Sz-M regimen), as shown in
Table 1. At the time of disease progression, patients are allowed to cross over to the other arm of the trial. The dose of mitotane will be adjusted to achieve plasma levels of the drug in the range of 14-20 mg/L in all study subjects. The primary endpoint of the study is survival, but health-related quality of life, time to progression, best overall response rate and duration of response are also measured as secondary endpoints. FIRM-ACT is the first large, phase III randomized clinical trial with enough power to provide level I evidence for most effective first line therapy in patients with ACC. In addition, the trial will study the usefulness of several biomarkers to predict response to therapy and investigate whether attempts to maintain mitotane levels between 14-20 mg/L are important [http://clinicaltrials.gov/ct2/results?term= FIRM-ACT].
Other regimens
Small single-arm studies using other combinations have also been published. One of the largest of those was a phase II trial at the National Cancer Institute. In this study, 36 patients with advanced ACC received treatment with daily mitotane (mean dose 4.6 g/day, dependent on serum levels) with 4 day infusion of doxorubicin (10 mg/m2/day), vincristine (0.4 mg/m2/day), and etoposide (75 mg/m2/day). Cycles were repeated every 3 weeks. Interestingly, surgical resection of the primary tumour, as well as metastases, was sometimes performed as an integral treatment method in some patients. Determination of eligibility for resection was made by both the principal investigator and either one or two surgical consultants. An objective response was observed in 8/36 evaluatable patients (22%). The median survival was 13.5 months, however, eight patients who responded had a median survival of 34.3 months measured from the time of initial evaluation of response at 4 months until progression [53]. It was not clear what characteristics of disease could have predicted response in those eight patients.
Van Slooten et al. [54] evaluated the use of cyclophosphamide (600 mg/m2 i.v.), doxorubicin (40 mg/m2 i.v.) and cisplatin (50 mg/m2 i.v.) in advanced ACC in 11 patients. There were two partial responses which lasted 6-9 months. There was an objective response in two patients (90% CI
of 0-37%) and median survival was 10 months.
Another single-arm study enrolled 11 patients with locally recurrent or metastatic ACC, who had failed to respond to treatment with streptozocin and o,p’-DDD, to receive vincristine 1.5 mg/m2 on day 1, cyclophosphamide 600 mg/m2 on day 1, cisplatin 100 mg/m2 on day 2, and teniposide 150 mg on day 4 (OPEC regimen). Partial response and stable disease were observed in two and seven patients, respectively. The median overall survival was 21 months after the start of second line treatment [55].
Other published small case series and some single case reports of various combinations of platinum drugs with etoposide, bleomycin, 5-fluorouracil, cyclophosphamide or taxanes have identified occasional responses [56-58], but the case numbers have been too small to lead to definitive recommendations regarding these regimens.
NOVEL APPROACHES
Targeted therapy
A review of 41 pathological specimens of ACC and 54 specimens of adrenocortical adenoma found that the epidermal growth factor receptor (EGFR) immunoreactivity was significantly more abundant in ACC than in adrenal adenoma or normal adrenal glands [59,60]. Vascular endothelial growth factor A immunoreactivity was significantly higher in tumours with higher Weiss criteria scores (P < 0.01), and in those with a high frequency of mitotic figures, atypical mitosis, or venous invasion (P < 0.05, P < 0.05, P < 0.01, respectively). Such preclinical data provided the rationale for development of novel systemic therapy regimens for ACC that incorporate tyrosine kinase inhibitors [60-62]. Most such trials are still ongoing (Table 2). Only results of small non- randomized studies have been published to date, and these have predominantly shown very limited anticancer efficacy. For example, one study enrolled 10 patients with heavily pretreated advanced ACC to treatment with EGFR inhibitor, erlotinib (100 mg/day) and gemcitabine (800 mg/m2 i.v. every 2 weeks) [63]. Immunohistochemical evidence of EGFR expression was found in nine patients. Only one of 10 patients experienced a minor
| Ongoing trials - target therapy | ||
|---|---|---|
| Study | Purpose | Status |
| Sorafenib Plus Paclitaxel in | Phase II trial, prospective, non randomized, | Recruiting |
| Adreno-Cortical Patients | open label, single-arm, multicentre trial.The | |
| (PAXO). NCT 00786110 | aim is to evaluate the clinical benefit and toxicity of this combination treatment in patients with advanced disease. | |
| A Study of IMC-A 12 in | PhaseI/II study. The purpose is to fi nd out | Not yet |
| Adrenocortical Cancer. | what effects, good and/or bad, IMC A-12 | recruiting |
| NCT00810537 | has on patients with ACC. IMC-A12 is a monoclonal antibody that was designed to inhibit a protein called Type I IGF (IGF-1R). | |
| Cixutumumab in Treating | This phase II trial is studying the side effects | Recruiting |
| Patients with Relapsed or | and how well cixutumumab works in | |
| Refractory Solid Tumours. | treating patients with relapsed or refractory | |
| NCT00831844 | solid tumours, including ACC. | |
tumour response. The median survival in the study population was 5.5 months after starting erlotinib and gemcitabine. Small studies of this type preclude the ability to determine whether there may have been an unpredicted negative interaction between the targeted agent and the cytotoxic compound. Investigators in Germany studied bevacizumab, a monoclonal antibody directed functionally against some of the determinants of angiogenesis, at a dose of 5 mg/kg every 21 days and capecitabine at 950 mg/m2 twice daily for 14 days, given in a 21 days cycle. Ten patients, who failed prior systemic therapy, were enrolled. None of the patients had objective responses or stable disease as defined by Response Evaluation Criteria In Solid Tumours (RECIST) criteria. In addition, two patients discontinued therapy owing to hand-foot syndrome and the median survival was only 4 months [64]. Another phase II trial (NCT00215202) employed treatment with gefitinib, another targeted therapy against the EGF receptor, in patients with previously treated unresectable ACC. The study has been completed, but results are not yet available.
Approximately 90% of ACCs over-express IGF-2, and preclinical studies have suggested that IGF-2 functions in an autocrine fashion to stimulate proliferation of ACC cells [65]. Inhibitors of IGF-2 receptor, IGF-R1 reduced proliferation and cell viability in cultures [66]. This has provided a rationale for testing novel anti-IGF agents in patients with ACC.
A human, monoclonal antibody against IGF-R1, Figitumumab, underwent phase I testing in ACC patients and was found to be safe at a dose of 20 mg/kg every 21 days. Only one episode of grade 4 toxicity (hyperuricemia, proteinuria and elevated gamma-glutamyltransferase) was reported. Of 14 patients in this study, eight were found to have stable disease, although it should be noted that the significance of so-called stable disease in ACC can be very difficult to interpret, given the indolent nature of this disease in many cases. A phase II trial is warranted to further assess the efficacy of this agent in ACC [67].
Other strategies
Gene therapy involves manipulation of expression of specific genetic material in tumour cells by use of vectors such as adenoviruses or retroviruses. Such treatment may affect cell cycle and lead to inhibition of tumour growth. Some gene therapies showed promising results in vitro. These approaches are yet to be tested in clinical settings [68,69].
Immune therapy is also being explored. The goal of this approach is to stimulate the patient’s own immunity to produce antitumour effects. This could be achieved by DNA vaccination or stimulation of antigen-presenting dendritic cells. Recent efforts to identify immunogenic targets in adrenal tumours are ongoing. Some proteins, such as 11 ß-hydroxylase,
21-hydroxylase, cytochrome P450, steroidogenic acute regulatory protein and DAX-1, are more abundant in adrenocortical tissues and they may serve as specific antigens for cytotoxic immune response [70]. One study that uses this approach, NCT 00457587, is presently recruiting patients.
FUTURE APPROACHES - MOLECULAR CHARACTERIZATION
The quality of the information available on systemic therapy of ACC continues to be inadequate, predicated mostly on the lack of well powered controlled trials, and the profusion of case reports and anecdotal small case series. In North America, the National Cancer Institute Cancer Therapy Evaluation Program bears some responsibility for its lack of interest in allowing the cooperative groups to develop studies focused on this important, but narrow, domain; however, in reality, it comes down to an issue of investment vs potential return, and government funds everywhere are somewhat limited, requiring difficult and draconian decisions.
In vitro studies have shown that ACC cells can be killed by several known cytotoxic drugs [71]. Paclitaxel, 2-methoxyestradiol, cytosine arabinoside, cisplatin and etoposide show potent growth inhibitory effects on SW-13 human ACC cells in culture. Etoposide and cisplatin has been shown to be the most potent combination in vitro, and 2-methoxyestradiol has had the most rapid onset of inhibitory activity. Conversely, mitotane, 5-fluorouracil or suramin have not shown significant effect on the survival of the studied ACC cells in vitro, although these drugs have produced sustained responses in patients in clinical trials.
It has been argued that such a discrepancy may be attributable to the fact that ACC has multiple resistance mechanisms in vivo, which may be inherent to adrenal tissue. For example, adrenal cells have a high rate of P-gp expression, a product of mdr-1 gene. This 130-180-kDa membrane glycoprotein functions as an ATP-dependent efflux pump that removes a variety of toxins from the intracellular compartment, including anthracyclines, epipodophyllotoxins and vinca alkaloids, leading to resistance [72,73]. Flynn et al. [74] have reported strong immunoreactivity of P-gp in pathology
specimens from 11 study patients with ACC. Another study evaluated P-gp expression in adrenocortical tumours of 15 patients. The P-gp was overexpressed in eight tumours and did not relate to clinical symptoms or prognosis [26]. Others have confirmed that P-gp is expressed at very high levels on the ACC cells even in patients without previous exposure to chemotherapy [42]. In vitro studies suggest that mitotane is not affected by P-gp and in fact may potentially inhibit P-gp. This provided a rationale for combining mitotane with chemotherapy [54]. Unfortunately, the effect of mitotane on inhibition of P-gp is not as evident in vivo [54]. Overexpression of P-gp is not enough to account for the poor response of ACC to chemotherapy. For example, cisplatin does not appear to be affected by P-gp, yet only a minority of patients treated with cisplatin experience significant tumour shrinkage. Improved understanding of the molecular biology of ACC, and particularly the expression or mutation of genes that code for resistance factors relevant to key cytotoxic and targeted agents, could therefore help us devise more effective treatment strategies, similarly to the advent of better therapies for renal cell carcinoma, breast and prostate cancers.
It seems more likely that a dramatic shift in the theoretical approach to the management of ACC will be required if real progress is to be made. For example, new mechanistic approaches to unravel the patterns of innate resistance to chemotherapy will be essential. Schteingart et al. [75] have shown that it is possible to predict the potential of some of the above listed agents to induce apoptosis, based on the expression of bcl-XL. There are now preliminary data to suggest that measurement of excision repair enzyme pathways, such as ERCC1, may help to refine treatment selection for such combination regimens as mitotane- cisplatin [76].
Disparate preclinical and clinical data sets now suggest that the WNT/beta catenin pathway may regulate the control of ACC, and may thus be a useful target for drug action [77,78]. Similarly, mutations of BRAF, k-RAS and EGFR have been identified in cell lines and human specimens of ACC, presenting other potential targets that might be addressed by currently available clinical inhibitors of gene function [79] (Table 2).
Treatment of ACC has not changed dramatically in the last decades and novel, more effective chemotherapy regimens are still needed. A very low incidence of ACC presents a major challenge in performing randomized clinical trials with enough power to study the effect of systemic treatment on clinically important endpoints such as survival, palliation of symptoms and improvement in health-related quality of life. Perhaps one of the most important imperatives will be to develop a mechanism to allow collaborative studies to be completed and published in a timely fashion, reflecting phase II-III design in the current, statistically acceptable fashion. The European Network for the Study of Adrenal Tumours is a potentially important effort to accrue pertinent information [12]. In addition, the FIRM-ACT trial is the first phase III randomized trial in advanced ACC. To achieve real progress in this complex and challenging area, clinicians must avoid pointless, under-powered phase II studies that are inconclusive, recycling of conventional cytotoxic regimens that have achieved only small gains, and should begin to collaborate in well structured clinical trials with well defined, reproducible endpoints, perhaps focused on some of the novel molecular targets that have been so helpful in defining effective new treatments in old adversaries, such as malignant melanoma and RCC.
CONFLICT OF INTEREST
Derek Raghavan is on the advisory boards for Sanofi and Lilly.
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Correspondence: Derek Raghavan, Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC, USA. e-mail: derek.raghavan@carolinashealthcare. org
Abbreviations: ACC, adrenocortical carcinoma; CDDP, cis- diaminedicholorplatinum-II ; DDT , dicholordiphenyltrichloroethane; FIRM-ACT, First International Randomized Trial in Locally Advanced and Metastatic Adrenal Cancer Treatment; EGFR, epidermal growth factor receptor; P-gp, P-glycoprotein.