Chemotherapy for Advanced Adrenal Cancer

Chemotherapy for advanced adrenal cancer: improvement from a molecular approach? BJUIBJU INTERNATIONAL 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 What ’ s known on the subject? and What does the study add? signifi cant therapeutic challenge, with Adrenal cancer is classically a silent tumour that is often advanced at presentation. conventional approaches to systemic Conventional approaches to systemic therapy have been associated with relatively low therapy having failed to achieve sustained objective tumour response rates, and modest survival benefi t. More recent approaches objective remissions or major survival have implemented targeted therapies focused on gene expression of these tumours, benefi t in most instances. Several systemic with some sustained remissions reported. therapies, including mitotane, suramin and gossypol, as well as cytotoxic agents, such This review assesses the utility of conventional and novel systematic therapies for as cisplatin and etoposide, have produced adrenal carcinoma, and points the way to future implementation of molecular biology responses of ≈ 15 – 30%, with median in the design and execution of clinical trails for advanced adrenal carcinoma. survival fi gures of ≈ 6 – 15 months, depending on case selection bias, with only < 10% 5-year survival rates. Recent and renal carcinoma have achieved KEYWORDS preclinical and pathological studies have signifi cant gains, and these targets are indicated a range of potential targets for worthy of further, structured investigation. adrenal carcinoma , chemotherapy , targeted drugs, including WNT/beta-catenin, Advanced adrenal carcinoma constitutes an therapies , gene , cisplatin , mitotane epidermal growth factor receptor, RAF and orphan disease, with a high mortality rate, k-RAS; similar applications in melanoma and merits investment in clinical trials.

INTRODUCTION neoplasia type I (mutation in MEN gene on adjacent viscera that can be compressed or chromosome 11q13) and Carney syndrome obstructed in the early stages, but ≈ 50% of Adrenocortical carcinoma (ACC) is one of (loss of heterozygosity on 2p16) are patients with this disease oversecrete the uncommon malignancies. Worldwide, associated with a higher predisposition to adrenal hormones. This often leads to the annual incidence is only 1 – 2 per million ACC [ 6 ] Environmental factors may also lead corresponding clinical syndromes. The [ 1 ] . In the USA, it is estimated that ≈ 300 to an increase in the risk of developing this symptoms also correlate with the amount cases of ACC occur per year [ 1 ] . There is a cancer. Smoking history, for example, has and type of overproduced hormone (cortisol, slight predominance in women and the been suggested by some to be associated androgens and rarely aldosterone). Cushing ’ s female: male ratio is approximately 4:3 [ 2,3 ] . with a higher rate of ACC [ 1,7 ] . The majority syndrome is seen most commonly, followed A bimodal age distribution has been of cases, however, are sporadic. The by virilization [ 1 ] . Cortisol hypersecretion reported, with the fi rst peak occurring differentiation of ACC from the more also leads to immunosuppression and before age 5, and the second one in the common benign adenomas is achieved by increased risk of infections. Constitutional fourth to fi fth decades. Geographical factors using the Weiss criteria, a widely accepted features and symptoms related to local may also play a role. A higher incidence of multifactorial pathological scoring system. effects of rapid tumour growth can also ACC is found in certain regions, such as in The score is based on nuclear grade, mitotic sometimes occur [ 9 ] . southern and southwestern Brazil. This rate, atypical mitoses, clear cell component, distribution may be related to rates of diffuse architecture, tumour necrosis, Adrenocortical carcinoma can be classifi ed sporadic mutations such as the TP 53 invasion of venous or sinus structures, or based on the TNM staging system. Lesions tumour suppressor gene [ 4,5 ] . The tumour capsule. Benign adenoma is most that are confi ned to the adrenal gland and contribution of genetic factors is also likely in patients whose Weiss criteria score < 5 cm (T1) defi ne stage I disease. Stage II supported by the observation that familial is < 3 [ 8 ] . tumours are > 5 cm but still confi ned to the conditions, such as Li-Fraumeni syndrome adrenal gland (T2). Stage III or locally (mutation in p53 gene on 17p13), Beckwith – Adrenocortical carcinoma is notoriously advanced adrenocortical carcinoma involves Wiedemann syndrome (mutation in IGF 2 on silent in its initial presentation, probably lesions that grow beyond the adrenal chromosome 11p15.5), multiple endocrine owing to its anatomical site and the lack of gland into the fat (T3) or invade adjacent

organs (T4). T1 – 2 lesions with lymph node ROLE OF SYSTEMIC THERAPY IN was observed. Sixty-one percent of 75 involvement (N1) are also included in Stage ADVANCED ACC evaluatable patients had some tumour III. Patients with T3 or T4 tumours and regression. The median survival from the lymph node involvement, as well as those Haq et al . [ 16 ] performed an analysis of 27 onset of the study treatment was 5 months in whom metastases are present comprise ‘ trials ’ with 16 chemotherapy regimens used [ 21,22 ] . Overall response rates ranged Stage IV disease [ 10 ] . in 12 patients with metastatic ACC, nine between 25 and 32%, and the mean of whom progressed despite surgery and duration of the response was 5 – 24 months The 5-year survival rate in patients with ACC treatment with mitotane between 1960 [ 3,23,24 ] . Endocrine hypersecretion was depends on stage at presentation. It is and 1979. Both treatment with single agents shown to be controlled in 70 – 75% of ≈ 45 – 60% in patients with early stage as well as combinations were evaluated. patients in whom functional ACC was disease and 10 – 25% in patients with Only three patients were reported to have present [ 3,19,20 ] . No controlled trial has advanced stages [ 1 ] . Importantly, ≈ 70% of achieved true partial remission (all in the been completed to prove a survival benefi t cases present with spread of the tumour combination therapy group). Response of mitotane over best supportive care, but beyond the adrenal gland [ 3 ] . Completeness durations in those who responded were phase I – II studies have shown clear evidence of resection and stage of the disease have brief (3, 6 and 7 months, respectively). of symptomatic improvement and objective been considered important favourable The authors concluded that alkylating partial responses that are sustained, as prognostic factors [ 1 ] . Adverse prognostic agents and doxorubicin appear to have outlined above. In our experience, careful factors are tumour size and grade, presence some anti-tumour activity, but that monitoring of toxicity, with dose reduction of tumour necrosis, high Ki67 staining, no single agent or drug combination as necessary, will often allow the responding evidence of TP53 mutation and evidence showed consistent benefi t in this disease. patient to remain on treatment, with of cortisol secretion by the tumours Unfortunately, little progress has been made acceptable quality of life, for many months. [ 9,11 – 14 ] . Different outcomes based on gene since this publication, and the paucity of expression profi les have also been described high level information available from this Mitotane alone or in combination with other [ 15 ] . study indicates a great deal about the past cytotoxic drugs has been generally accepted state of the art. as the fi rst line therapy in patients with The rarity of ACC presents a challenge inoperable ACC, but no optimal dose has for studying the optimum management MONOTHERAPY been defi ned from the published trials of this disease. Complete surgical resection [ 25,26 ] . The measurement of plasma is considered to be the treatment of choice Mitotane mitotane concentration has been proposed for patients with non-metastatic disease as a method of predicting toxicity in and is believed to offer the best chance Mitotane (o,p′ -1,1- [ o,p′ -dichlorodiphenyl ] - patients on long-term therapy [ 27,28 ] . of cure. 2,2-dichloroethane; DDD) is an isomer of A serum concentration above 14 mg/L the insecticide p,p′ -DDD and a chemical has been found to correlate with higher Systemic treatment of advanced ACC has congener of DDT . It produces selective response rates, but at the expense of greater never been standardized because of a lack adrenocortical necrosis thought to be toxicity [ 27,29 ] . Drug levels > 20 mg/L of large randomized clinical trials. Although related to inhibiting conversion of usually produce unacceptable toxicities. The many phase I – II trials in advanced ACC have cholesterol to pregnenolone as well as optimum duration of therapy has not been been reported, most of them have included conversion of 11-deoxycortisol to cortisol adequately established and published studies small numbers of patients, often from a [ 17 ] . It therefore has been viewed as an have varied in this respect. Most clinicians single institution. Most of these studies attractive therapeutic agent in ACC. One stop the drug when the disease progresses have been of single-arm, non-randomized of the fi rst reports that assessed the or when unacceptable toxicity develops. design, and many have included patients anti-tumour effects of this compound with different stages or extent of disease. was a study in 1960 by Bergenstal et al . Suramin Another problematic feature has been the [ 18 ] , who observed that mitotane lack of standardized criteria for reporting of produced objective responses and reduced Suramin, a polysulphonated naphthylurea, disease severity or response to treatment. corticosteroid secretion in 18 patients with has been used in the treatment of African Few, if any, of the available trials have ACC. Subsequently, 138 patients with ACC sleeping sickness since 1923. An adrenotoxic compared treatment with best supportive were enrolled to another similar trial [ 19 ] . effect of the drug leading to adrenal care. Accurate interpretation of these Thirty four percent of the 59 patients with insuffi ciency was reported in these early studies is therefore quite diffi cult, as the evaluatable disease had objective tumour studies, and it was therefore tested in documented outcomes are not robust. There regression with a median response duration patients with ACC. Individual case reports is scant level I evidence to provide defi nitive of ≈ 7 months. Decreased hormone secretion showing short partial responses were guidance on optimum systemic therapy, and was also reported. published in the 1980s [ 30 ] . Seventeen there has been uncertainty in the literature patients with metastatic ACC were treated about the respective merits of single-agent In a later single-arm study, 115 patients in a single-arm trial that tested clinical or combination therapy [ 7 ] . It is therefore with advanced ACC were treated with safety and activity of suramin, given at timely to review published evidence that increasing doses of mitotane until escalating doses [ 31 ] . A median survival of 7 examines the usefulness of systemic therapy unacceptable toxicities developed [ 20 ] . months was reported, with 4/16 evaluable in patients with unresectable ACC. Again, reduction in steroid hypersecretion patients showing partial responses. In

another trial of escalating doses of suramin, mitotane or in combination with other The treatment produced objective responses nine patients with metastatic ACC were chemotherapeutic agents. The rationale for in 8 of 22 patients with measurable disease treated [ 32 ] . Three partial responses were combining chemotherapy with mitotane defi ned by WHO criteria. The survival at 5 noted. All responders had serum suramin came from the in vitro observation that years was 35.2% , although this number also concentrations of ≥ 200 mg/L (target mitotane may inhibit the P-glycoprotein included patients who had early stage concentration). Unacceptable toxicities (P-gp) effl ux pump and so might potentially disease [ 46 ] . The regimen was associated without tumour responses occurred in reduce tumour resistance to with nausea in 11 patients . In addition, patients whose concentrations were above chemotherapeutic agents [ 42 ] . elevations in liver function tests were 300 mg/L. Other small studies with suramin reported in 62% of patients. Nevertheless, reported similar results [ 31,33 ] . Suramin COMBINATION CHEMOTHERAPY such favourable response rates and survival therefore has a narrow therapeutic window, made this an established treatment for which makes the use of this drug rather Cisplatin (CDDP) with mitotane patients with ACC. A phase III trial using this cumbersome with variable and unpredictable regimen is ongoing (see below). clinical benefi t. Bukowski et al . [ 43 ] reported results of the Southwest Oncology Group 8325 trial, that Cisplatin and etoposide Gossypol tested the combination of mitotane and cisplatin in patients with ACC. Thirty-seven Another Southwest Oncology Group study Gossypol is a plant toxin derived from patients were stratifi ed into two groups, assessed response rates for cisplatin and cotton seed oil. Tso et al . [ 34 ] showed that defi ned as good-risk and poor-risk. These etoposide in advanced ACC, after the gossypol has potent spermatotoxic, categories were based on age (< or > 65 publication of several case reports describing anti-metabolic as well as anti-neoplastic years old), extent of prior radiation (< or purported partial responses in virtually all activity in vivo . Several investigators have > 30% of the bone marrow bearing areas) patients treated with the regimen [ 47,48 ] . examined its activity against ACC. Gossypol and tolerance of prior chemotherapy (poor Forty-fi ve eligible patients were allocated was tested in the SW-13 human ACC cells, vs good). Patients with good-risk disease into two groups: patients with no history of both in vitro and in xenografs, by Wu et al . were treated with cisplatin (100 mg/m2 prior mitotane therapy were scheduled to [ 35 ] . The drug appeared to be safe and every 3 weeks), concurrently with mitotane receive a combination of cisplatin (50 mg/m2 effective in delaying cancer growth. at 1000 mg four times per day. The poor risk on days 1 and 2) and etoposide (100 mg/m2 Subsequently, 21 patients with metastatic group received lower doses of CDDP (75 mg/ on days 1 – 3) every 21 days. Treatment was ACC that progressed on mitotane were m2 every 3 weeks) concurrently with the continued for a total of 6 months or until enrolled on a study evaluating the effi cacy same dose of mitotane. Toxicity was disease progression, at which time patients and toxicity of oral gossypol [ 36 ] . The moderate to severe, particularly with respect were treated with mitotane. Patients with doses were increased according to to gastrointestinal effects. Objective prior mitotane therapy were treated with tolerance (initial dose of 20 mg/day). A responses were reported in 11/37 eligible the same study regimen but were not partial tumour response was observed in patients for an overall response rate of 30% offered mitotane at the time of disease 3/18 patients that lasted several months (95% CI, 16.0 – 50%). The median (range) progression. The overall objective response to > 1 year. None of the patients had to response duration was 7.9 (1.4 – 36.1) rate was 11% and median survival was 10 discontinue gossypol because of side months. The median (range) survival was months [ 49 ] . No formal comparisons were effects, but three patients who died from 11.8 (0.2 – 51.2) months. This combination made between the two groups because of their disease were excluded from the above has therefore been used quite widely to the small overall numbers. In another study analysis [ 37 ] . In the ensuing decades, this treat advanced ACC. by Bonacci et al . [ 50 ] , CDDP (100 mg/m2 agent has not found its way into routine i.v. day 1) and etoposide (100 mg/m2 i.v. clinical practice. Streptozocin and mitotane days 1 – 3) every 4 weeks was used in 18 patients with ACC. Mitotane treatment Conventional chemotherapy The use of streptozotocin in advanced ACC was maintained in 14 patients. Complete was initially proposed based on animal response was observed in three cases and Treatment with single cytotoxic drugs has studies that showed that the drug was partial response in three cases . produced partial responses only in a preferentially taken up in the adrenal cortex minority of these patients, based on small, of mice [ 44 ] . Partial responses in patients Etoposide, doxorubicin cisplatin and single-arm trials, case series and case treated with this combination were reported mitotane reports. Cisplatin has been the most in single case reports and small case series extensively studied single agent, and has [ 45 ] . A single-arm, phase II study enrolled Given the responses seen in studies testing predominantly been found to produce 40 patients with local and advanced ACC regimens incorporating CDDP , etoposide and transient partial, or less than partial, to chemotherapy with mitotane at a dose mitotane, doxorubicin was added to create a responses [ 38,39 ] . Other agents, such as of 1– 4 g daily in combination with i.v. novel four-drug combination in the hopes doxorubicin or irinotecan, have also been streptozocin (1 g/day for 5 days, thereafter of further improving effi cacy. An Italian studied in small, single-arm phase II trials 2 g once every three weeks). Patients multicentre phase II trial tested the with variable results, none being particularly were treated until tumour recurrence or combination of mitotane at a starting dose impressive [ 16,40,41 ] . Chemotherapy is progression. Study subjects received a of 1g/day, doxorubicin 20 mg/m 2 on days 1 therefore more commonly used with median (range) number of 7 (1 – 23) cycles. and 8, cisplatin 40 mg/m2 on days 2 and 9,

Table 1 . At the time of disease progression, TABLE 1 Ongoing trials – chemotherapy patients are allowed to cross over to the other arm of the trial. The dose of mitotane Study Purpose Status will be adjusted to achieve plasma levels of Gossypol Acetic Acid in Treating This phase II trial is studying how well Recruiting the drug in the range of 14 – 20 mg/L in all Patients with Recurrent, Metastatic, gossypol acetic acid works in treating study subjects. The primary endpoint of the or Primary Adrenocortical Cancer patients with recurrent, metastatic, study is survival, but health-related quality that Cannot be Removed by or primary ACC that cannot be of life, time to progression, best overall Surgery. NCT 00848016 removed by surgery. response rate and duration of response are Suramin in Treating Patients with Phase II trial to study the effectiveness Active but not also measured as secondary endpoints. Stage III or Stage IV Adrenocortical of suramin in treating patients with recruiting FIRM-ACT is the fi rst large, phase III Cancer. NCT 00002921 stage III or stage IV ACC. randomized clinical trial with enough power Tariquidar, Mitotane, Doxorubicin, Phase II trial to study the effectiveness Active but not to provide level I evidence for most effective Vincristine, and Etoposide Plus of combining tariquidar with recruiting fi rst line therapy in patients with ACC. In Surgery in Treating Patients With combination chemotherapy and addition, the trial will study the usefulness Recurrent, Metastatic, or Primary surgery in treating patients who have of several biomarkers to predict response Unresectable Adrenocortical Cancer recurrent, metastatic, or primary to therapy and investigate whether NCT00073996 unresectable ACC. attempts to maintain mitotane levels Trial With Taxotere and Cisplatin in A phase II trial in ACC of which the Recruiting between 14 – 20 mg/L are important Non-operable Adrenocortical primary objective is to investigate [ http://clinicaltrials.gov/ct2/results?term= Carcinoma NCT00324012 response rate of taxotere and FIRM-ACT ]. cisplatin. Secondary endpoints are survival, time to progression, best Other regimens overall response rate and duration of response. Small single-arm studies using other Trial in Locally Advanced and Phase III trial to determine whether Recruiting combinations have also been published. One Metastatic Adrenocortical treatment with etoposide, of the largest of those was a phase II trial at Carcinoma Treatment (FIRM-ACT) doxorubicin, cisplatin and mitotane the National Cancer Institute. In this study, NCT00094497 (EDP/M) prolongs survival as 36 patients with advanced ACC received compared with streptozotocin and treatment with daily mitotane (mean dose mitotane (Sz/M) in patients with 4.6 g/day, dependent on serum levels) with 4 advanced ACC whose disease is not day infusion of doxorubicin (10 mg/m2 /day), amenable to complete surgical vincristine (0.4 mg/m2 /day), and etoposide resection. (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 and etoposide 100 mg/m2 on days 5 – 7 (6.9%) achieved a clinical complete response, treatment method in some patients. (EDP-M regimen). The cycle was repeated 20 (27.8%) had stable disease, while 16 Determination of eligibility for resection was every 4 weeks [ 51 ] . Attempts were made (22.2%) progressed. Time to progression of made by both the principal investigator and to maintain mitotane serum levels at 24 months was observed in patients who either one or two surgical consultants. An 14 – 20 mg/L. The primary aim of the study had objective response to treatment. The objective response was observed in 8/36 [ 51 ] was to defi ne effi cacy and toxicity of most frequent toxicities were haematological evaluatable patients (22%). The median this regimen as defi ned by WHO criteria. and included one death from septic shock in survival was 13.5 months, however, eight Interim analysis of 28 evaluatable patients a neutropenic patient. Other major toxicities patients who responded had a median showed that two (7.1%) had complete were gastrointestinal and neurological. The survival of 34.3 months measured from the responses and 13 (46.4%) had partial 5-year survival rate was 15%. The most time of initial evaluation of response at 4 responses, leading to an overall response severe and dose-limiting side effect was months until progression [ 53 ] . It was not rate of 53.5% (95% CI, 35– 72%). In addition, leucopenia [ 52 ] . clear what characteristics of disease could eight patients had stable disease (28.5%) have predicted response in those eight and fi ve experienced progression (17.8%). Given these somewhat promising results, a patients. Five patients (one parital response, four multinational effort, the First International stable disease) became disease-free after Randomized Trial in Locally Advanced and Van Slooten et al . [ 54 ] evaluated the use radical resection. The median time to Metastatic Adrenal Cancer Treatment of cyclophosphamide (600 mg/m2 i.v.), progression for the responding patients (FIRM-ACT), has been initiated and will doxorubicin (40 mg/m2 i.v.) and cisplatin was 24.4 months. In 2005, data for all 72 attempt to randomize 300 patients to either (50 mg/m2 i.v.) in advanced ACC in 11 patients became available. Objective tumour etoposide, doxorubin, cisplatin and mitotane patients. There were two partial responses regression was observed in 35/72 patients (an EDP-M regimen) or streptozocin and which lasted 6 – 9 months. There was an (48.6%; 95% CI: 37.1 – 60.3%). Five patients mitotane (an Sz-M regimen), as shown in objective response in two patients (90% CI

of 0 – 37%) and median survival was 10 TABLE 2 Ongoing trials that test tyrosine kinase inhibitors months. Ongoing trials – target therapy Another single-arm study enrolled 11 Study Purpose Status patients with locally recurrent or metastatic Sorafenib Plus Paclitaxel in Phase II trial, prospective, non randomized, Recruiting ACC, who had failed to respond to Adreno-Cortical Patients open label, single-arm, multicentre trial.The treatment with streptozocin and o,p′ -DDD, (PAXO). NCT 00786110 aim is to evaluate the clinical benefi t and to receive vincristine 1.5 mg/m2 on day 1, toxicity of this combination treatment in cyclophosphamide 600 mg/m2 on day 1, patients with advanced disease. cisplatin 100 mg/m2 on day 2, and A Study of IMC-A 12 in PhaseI/II study. The purpose is to fi nd out Not yet teniposide 150 mg on day 4 (OPEC regimen). Adrenocortical Cancer. what effects, good and/or bad, IMC A-12 recruiting Partial response and stable disease were NCT00810537 has on patients with ACC. IMC-A12 is a observed in two and seven patients, monoclonal antibody that was designed to respectively. The median overall survival was inhibit a protein called Type I IGF (IGF-1R). 21 months after the start of second line Cixutumumab in Treating This phase II trial is studying the side effects Recruiting treatment [ 55 ] . Patients with Relapsed or and how well cixutumumab works in Refractory Solid Tumours. treating patients with relapsed or refractory Other published small case series and NCT00831844 solid tumours, including ACC. some single case reports of various combinations of platinum drugs with etoposide, bleomycin, 5-fl uorouracil, cyclophosphamide or taxanes have identifi ed occasional responses [ 56 – 58 ] , but the case tumour response. The median survival in the A human, monoclonal antibody against numbers have been too small to lead to study population was 5.5 months after IGF-R1, Figitumumab, underwent phase I defi nitive recommendations regarding these starting erlotinib and gemcitabine. Small testing in ACC patients and was found to regimens. studies of this type preclude the ability to be safe at a dose of 20 mg/kg every 21 determine whether there may have been an days. Only one episode of grade 4 toxicity NOVEL APPROACHES unpredicted negative interaction between (hyperuricemia, proteinuria and elevated the targeted agent and the cytotoxic gamma-glutamyltransferase) was reported. Targeted therapy compound. Investigators in Germany studied Of 14 patients in this study, eight were bevacizumab, a monoclonal antibody found to have stable disease, although it A review of 41 pathological specimens of directed functionally against some of the should be noted that the signifi cance of ACC and 54 specimens of adrenocortical determinants of angiogenesis, at a dose so-called stable disease in ACC can be very adenoma found that the epidermal growth of 5 mg/kg every 21 days and capecitabine diffi cult to interpret, given the indolent factor receptor (EGFR) immunoreactivity was at 950 mg/m 2 twice daily for 14 days, nature of this disease in many cases. A signifi cantly more abundant in ACC than in given in a 21 days cycle. Ten patients, phase II trial is warranted to further assess adrenal adenoma or normal adrenal glands who failed prior systemic therapy, were the effi cacy of this agent in ACC [ 67 ] . [ 59,60 ] . Vascular endothelial growth factor enrolled. None of the patients had objective A immunoreactivity was signifi cantly responses or stable disease as defi ned by Other strategies higher in tumours with higher Weiss Response Evaluation Criteria In Solid criteria scores (P < 0.01), and in those with Tumours (RECIST) criteria. In addition, two Gene therapy involves manipulation of a high frequency of mitotic fi gures, atypical patients discontinued therapy owing to expression of specifi c genetic material in mitosis, or venous invasion (P < 0.05, P < hand-foot syndrome and the median tumour cells by use of vectors such as 0.05, P < 0.01, respectively). Such preclinical survival was only 4 months [ 64 ] . Another adenoviruses or retroviruses. Such treatment data provided the rationale for development phase II trial (NCT00215202) employed may affect cell cycle and lead to inhibition of novel systemic therapy regimens for ACC treatment with gefi tinib, another targeted of tumour growth. Some gene therapies that incorporate tyrosine kinase inhibitors therapy against the EGF receptor, in patients showed promising results in vitro . These [ 60 – 62 ] . Most such trials are still ongoing with previously treated unresectable ACC. approaches are yet to be tested in clinical ( Table 2 ). Only results of small non- The study has been completed, but results settings [ 68,69 ] . randomized studies have been published to are not yet available. date, and these have predominantly shown Immune therapy is also being explored. very limited anticancer effi cacy. For example, Approximately 90% of ACCs over-express The goal of this approach is to stimulate one study enrolled 10 patients with heavily IGF-2, and preclinical studies have suggested the patient ’ s own immunity to produce pretreated advanced ACC to treatment with that IGF-2 functions in an autocrine fashion antitumour effects. This could be achieved EGFR inhibitor, erlotinib (100 mg/day) and to stimulate proliferation of ACC cells [ 65 ] . by DNA vaccination or stimulation of gemcitabine (800 mg/m2 i.v. every 2 weeks) Inhibitors of IGF-2 receptor, IGF-R1 reduced antigen-presenting dendritic cells. [ 63 ] . Immunohistochemical evidence of proliferation and cell viability in cultures Recent efforts to identify immunogenic EGFR expression was found in nine patients. [ 66 ] . This has provided a rationale for testing targets in adrenal tumours are ongoing. Only one of 10 patients experienced a minor novel anti-IGF agents in patients with ACC. Some proteins, such as 11 β -hydroxylase,

21-hydroxylase, cytochrome P450, specimens from 11 study patients with ACC. Treatment of ACC has not changed steroidogenic acute regulatory protein and Another study evaluated P-gp expression in dramatically in the last decades and novel, DAX-1, are more abundant in adrenocortical adrenocortical tumours of 15 patients. The more effective chemotherapy regimens are tissues and they may serve as specifi c P-gp was overexpressed in eight tumours still needed. A very low incidence of ACC antigens for cytotoxic immune response and did not relate to clinical symptoms or presents a major challenge in performing [ 70 ] . One study that uses this approach, NCT prognosis [ 26 ] . Others have confi rmed that randomized clinical trials with enough 00457587, is presently recruiting patients. P-gp is expressed at very high levels on the power to study the effect of systemic ACC cells even in patients without previous treatment on clinically important endpoints exposure to chemotherapy [ 42 ] . In vitro such as survival, palliation of symptoms FUTURE APPROACHES – MOLECULAR studies suggest that mitotane is not and improvement in health-related quality CHARACTERIZATION affected by P-gp and in fact may potentially of life. Perhaps one of the most important inhibit P-gp. This provided a rationale for imperatives will be to develop a mechanism The quality of the information available on combining mitotane with chemotherapy to allow collaborative studies to be systemic therapy of ACC continues to be [ 54 ] . Unfortunately, the effect of mitotane completed and published in a timely inadequate, predicated mostly on the lack on inhibition of P-gp is not as evident in fashion, refl ecting phase II-III design in the of well powered controlled trials, and the vivo [ 54 ] . Overexpression of P-gp is not current, statistically acceptable fashion. The profusion of case reports and anecdotal enough to account for the poor response of European Network for the Study of Adrenal small case series. In North America, ACC to chemotherapy. For example, cisplatin Tumours is a potentially important effort the National Cancer Institute Cancer does not appear to be affected by P-gp, yet to accrue pertinent information [ 12 ] . In Therapy Evaluation Program bears some only a minority of patients treated with addition, the FIRM-ACT trial is the fi rst responsibility for its lack of interest in cisplatin experience signifi cant tumour phase III randomized trial in advanced ACC. allowing the cooperative groups to develop shrinkage. Improved understanding of the To achieve real progress in this complex studies focused on this important, but molecular biology of ACC, and particularly and challenging area, clinicians must narrow, domain; however, in reality, it comes the expression or mutation of genes that avoid pointless, under-powered phase II down to an issue of investment vs potential code for resistance factors relevant to studies that are inconclusive, recycling of return, and government funds everywhere key cytotoxic and targeted agents, could conventional cytotoxic regimens that have are somewhat limited, requiring diffi cult and therefore help us devise more effective achieved only small gains, and should begin draconian decisions. treatment strategies, similarly to the advent to collaborate in well structured clinical of better therapies for renal cell carcinoma, trials with well defi ned, reproducible In vitro studies have shown that ACC cells breast and prostate cancers. endpoints, perhaps focused on some of the can be killed by several known cytotoxic novel molecular targets that have been so drugs [ 71 ] . Paclitaxel, 2-methoxyestradiol, It seems more likely that a dramatic shift in helpful in defi ning effective new treatments cytosine arabinoside, cisplatin and etoposide the theoretical approach to the management in old adversaries, such as malignant show potent growth inhibitory effects of ACC will be required if real progress is melanoma and RCC. on SW-13 human ACC cells in culture. to be made. For example, new mechanistic Etoposide and cisplatin has been shown to approaches to unravel the patterns of be the most potent combination in vitro , innate resistance to chemotherapy will CONFLICT OF INTEREST and 2-methoxyestradiol has had the most be essential. Schteingart et al . [ 75 ] have rapid onset of inhibitory activity. Conversely, shown that it is possible to predict the Derek Raghavan is on the advisory boards mitotane, 5-fl uorouracil or suramin have not potential of some of the above listed agents for Sanofi and Lilly. shown signifi cant effect on the survival of to induce apoptosis, based on the expression the studied ACC cells in vitro , although these of bcl-XL. There are now preliminary data drugs have produced sustained responses in to suggest that measurement of excision REFERENCES patients in clinical trials. repair enzyme pathways, such as ERCC1, may help to refi ne treatment selection for 1 Katz MD , Imperato-McGinley J . It has been argued that such a discrepancy such combination regimens as mitotane- Adrenal cancer – endrocinology, may be attributable to the fact that ACC cisplatin [ 76 ] . diagnosis and clinical staging . In has multiple resistance mechanisms in vivo , Raghavan D , Scher HI , Leibel SA , Lange which may be inherent to adrenal tissue. 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