REVIEW
Management of adrenal cancer: a 2013 update
M. Terzolo · F. Daffara . A. Ardito ·
B. Zaggia · V. Basile . L. Ferrari . A. Berruti
Received: 12 December 2013 / Accepted: 21 December 2013 @ Italian Society of Endocrinology (SIE) 2014
Abstract Adrenocortical carcinoma (ACC) is a devas- tating tumor for either patients or their families because of short life expectancy and severe impact on quality of life. Due to the rarity of ACC, with a reported annual incidence of 0.5-2 cases per million population, progress in the development of treatment options beyond surgery has been limited. Up to now, no personalized approach of ACC therapy has emerged, apart from plasma level-guided mitotane therapy, and no simple targetable molecular event has been identified from preclinical studies. Complete surgical removal of ACC is the only potentially curative approach and has the most important impact on patient’s prognosis. Despite the limits of the available evidence, adjuvant mitotane therapy is currently recommended in many expert centers whenever the patients present an ele- vated risk of recurrence. The management of patients with recurrent and metastatic disease is challenging and the prognosis is often poor. Mitotane monotherapy is indicated in the management of patients with a low tumor burden and/or more indolent disease while patients whose disease show an aggressive behavior need cytotoxic chemotherapy. The treatment of patients with advanced ACC may include loco-regional approaches such as surgery and radiofre- quency ablation in addition to systemic therapies. The present review provides an updated overview of the
management of ACC patients following surgery and of the management of ACC patients with advanced disease.
Keywords Adjuvant treatment . Adrenal cancer . Adrenocortical carcinoma · Chemotherapy · Cisplatin · Mitotane · Overall survival · Recurrence-free survival
Introduction
Adrenocortical carcinoma (ACC) is a devastating tumor for either patients or their families because of short life expectancy and severe impact on quality of life, that is severely affected by metastatic progression, associated endocrine syndromes and treatment-related side effects. The fact that ACC has a first peak of incidence in young children and frequently occurs in women of childbearing age makes the management of this aggressive tumor even more challenging. In addition, currently available treat- ments of advanced ACC have limited efficacy and relevant toxicity that concurs to reduce quality of life [1-3].
Due to the rarity of ACC, with a reported annual inci- dence of 0.5-2 cases per million population [4, 5], progress in the development of treatment options beyond surgery has been limited. Up to now, no personalized approach of ACC therapy has emerged, apart from plasma level-guided mitotane therapy, and no simple targetable molecular event has been identified from preclinical studies. Although generally regarded as one of the most aggressive endocrine tumors, ACC may present with a heterogeneous biological behavior ranging from almost indolent to extremely rapidly progressing tumors. Therefore, prognostic stratification of patients is of the utmost importance to tailor the treatment plan accordingly. However, we have limited knowledge of pathological and clinical criteria for risk stratification of
M. Terzolo · F. Daffara · A. Ardito · B. Zaggia · V. Basile Internal Medicine I, Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga Hospital, Regione Gonzole 10, 10043 Orbassano, Italy e-mail: terzolo@usa.net
L. Ferrari · A. Berruti Medical Oncology, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy
ACC patients and the identification of prognostic and predictive biomarkers has to be actively pursued.
Management of ACC patients is challenging and demanding because physicians have to deal with either oncological issues, concerning tumor progression and metastatic development, or endocrinological issues, related to tumor secretion or specific treatment (mitotane effects on the endocrine system). Treatment of ACC is multi- modal, including surgery (often repeated), mitotane, cyto- toxic agents, interventional radiology procedures and radiotherapy, and should be delivered by a multidisciplin- ary team within centers with adequate facilities [1-3, 6-8].
The objectives of this review are to provide an updated overview of the management of ACC patients (1) follow- ing surgery; (2) with advanced disease. It has to be pointed out that the recommendations of this review are generally based on a low level of evidence and may represent the personal view of the authors.
Management of ACC patients following surgery
Background
Complete surgical removal of ACC is the only potentially curative approach and has the most important impact on patient’s prognosis [1-3]. Whether surgery should be done as open adrenalectomy or whether laparoscopic adrenal- ectomy may be safely performed in selected patients is matter of an ongoing debate [9-12]. Despite this contro- versy, what is most important is that ACC surgery should be performed by experienced surgeons in referral centers with a high operation volume [7]. A common finding of all surgical series is that recurrence after apparently complete resection is frequent and may be found in up to 70-85 % of patients with high proliferation index or locally advanced disease [1-3, 8, 13-16]. This observation makes a strong case for post-operative adjuvant treatment in ACC management.
In early years, many investigators considered the use of post-operative adjuvant therapy due to the high recurrence rate of ACC. The adrenolytic drug mitotane, an analog of the insecticide dichlorodiphenyltrichloroethane (DDT) widely used for advanced ACC since the sixties, was considered the reference drug also for adjuvant treatment. However, those studies provided conflicting results for a number of reasons, namely small patient numbers, lack of control groups, unclear specification of treatment outcome [17]. Given the lack of convincing evidence of the benefit of adjuvant mitotane, enthusiasm for this approach declined and no recommendation on post-operative adjunctive measures was released at the Ann Arbor Con- sensus Conference on ACC in 2003 [13].
In 2007, we published the results of a multicentric, retrospective analysis of post-operative management of 177 patients with ACC, who were recruited either at some centers in Italy where adjuvant mitotane was a standard following radical surgery or at other Italian centers where radical surgery was not followed by mitotane treatment. An independent cohort from Germany of patients who were not offered any post-operative treatment was also included. Recurrence-free survival (RFS) was significantly longer in the 47 patients treated with adjuvant mitotane, being 42 months versus 10 and 25 months, respectively, in the two groups of 55 and 75 patients who were left untreated after surgery [18]. Multivariate analysis confirmed that mitotane had an independent advantageous effect on RFS. The effect on overall survival (OS) was less apparent but nevertheless significant after adjusting for an imbalance of prognostic factors among the different groups [18]. An important finding of the study is the acceptable adverse event rate, a finding that was likely due to the use of low doses of mitotane (1-5 g per day). Conversely, employ- ment of high-dose mitotane in previous studies has been invariably accompanied by severe and disabling toxicity [17]. Strengths of our study are a large patient cohort, availability of well-matched contemporary control groups, and predefined treatment allocation independent from patient’s characteristics. Given its retrospective nature, however, this study cannot provide a high level of evidence in favor of adjuvant mitotane treatment. The publication of that study renewed interest on the use of mitotane in an adjuvant post-operative setting but raised also a fierce controversy based on the methodological flaws of that study [19].
Other adjunctive measures following surgical removal of ACC have received less attention. Cytotoxic agents have been rarely used in an adjuvant setting. The most inter- esting study is the one by Khan et al. [20], who reported that 17 patients treated with the association of streptozo- tocin and mitotane had a significantly better RFS than 11 patients who did not receive any treatment after surgery. However, the study does not allow to discriminate the relative contribution of each drug. Despite the historical view that ACC is a radio-resistant tumor, the adjuvant use of radiotherapy has been explored in recent years. The argument remains conflicting, since two initial studies showed a significant reduction of local recurrences with radiation therapy, although the impact on RSF and OS was not fully clear [21, 22], while a more recent study did not show any benefit of adjuvant radiotherapy [23]. Methodo- logical differences among studies and the inevitable limits inherent to their retrospective nature may offer a reason- able explanation of this discrepancy.
In recent years, the adjuvant use of mitotane has become increasingly popular and in current practice the
management of an ACC patient operated on certainly includes the option of giving mitotane. Therefore, the present review will focus on the use of mitotane as an adjuvant measure.
Selection of patients to adjuvant mitotane
Despite the limits of the available evidence, adjuvant mitotane therapy is currently recommended in many expert centers whenever the patients present an elevated risk of recurrence. Differences do exist in the criteria used to define a high-risk condition, as exemplified in a recent position of an international panel of experts who agreed on stage I-II, complete (RO) resection and ki-67 ≤10 % as markers of good prognosis, but a consensus was not found on stage III R0 ACC [24]. In patients with good prognostic markers, the decision on adjuvant mitotane therapy may be individual- ized, whereas adjuvant mitotane is mandatory in the high- risk category [24]. Following the ENS@T ACC staging system, stage III applies to locally invasive tumors char- acterized by infiltration in surrounding tissue, positive regional lymph nodes or a neoplastic thrombus in the vena cava or vena renalis [25]. It is biologically plausible that tumor spread in regional lymph nodes or in the vein system may portend to a higher risk of recurrence than local infil- tration and it is our opinion that subgroups at different risk of recurrence do exist among stage III ACC. Infrequently, a stage IV ACC, defined by presence of distant metastases [25], may be completely resected and has to be considered at a high risk of recurrence. The lowest risk applies to stage I and II ACC, being tumors localized in the adrenal gland with a size of ≤5 cm or >5 cm, respectively [25].
Recent data suggest that the proliferation activity of the tumor is the most important factor predicting risk of recur- rence following R0 surgery. Assessment of the proliferation index Ki-67 is currently used to assess proliferation, despite some problems to harmonize immunohistochemical read- ings among different pathologists. In a European multicen- tric study, a threshold value at 10 % was found to separate patients at good or worse prognosis with a hazard ratio of recurrence of 1.042 per each % increase [26]. Although the results of this study have still to be considered as preliminary, the availability of a large patient cohort totaling more than 500 patients represents a solid database to confirm the view that tumor proliferation is a strong determinant of patient survival. The value of ACC proliferation has been already appreciated in smaller series by the use of mitosis count [27, 28], that is likely the single most predictive factor of Weiss score. Conversely, Weiss score as a whole does not clearly indicate the probability of tumor recurrence [28, 29].
Resection status is another established adverse risk factor, being Rx (unknown), R1 (microscopically positive margins) and R2 (macroscopically positive margins)
associated with progressively reduced RFS irrespectively of other risk factors [2-8].
A number of molecular markers, like matrix metallo- proteinase type 2 [30], glucose transporter GLUT1 [31], SF1 [32], BUB1B and PINK1 [33], might potentially emerge in the future as powerful outcome predictors, but none of them has yet found a place in current management of ACC.
Management of patients on adjuvant mitotane treatment
No results from randomized controlled trial on adjuvant mitotane treatment are available. We have recently laun- ched the first prospective randomized study-the ADIUVO trial (NCT00777244)-which is currently recruiting at different European and North-American centers. The aim of this trial, whose results are not expected before 2016, is to compare the results of adjuvant mitotane with a strategy of no treatment on RFS (the study primary endpoint) in patients at low-intermediate risk of recurrence, defined by stage I-III ACC, RO and Ki-67 ≤10 % (http://www. adiuvo-trial.org). At our center, we are currently recom- mending low-risk patients to enter the trial while the remainders are offered adjuvant mitotane (Fig. 1). Most patients seen in our practice actually belong to the high-risk category and are candidate to mitotane, which is an off- label prescription in adjuvant setting.
Whenever the decision of giving mitotane is taken, monitoring of plasma mitotane levels is currently consid- ered a standard in the management of ACC patients treated adjuvantly because mitotane is known to have a narrow therapeutic window [1-3, 6, 17]. The concept that plasma levels of mitotane matter for both therapeutic efficacy and drug-related toxicity has been developed in the clinical
Localized ACC
Surgery
High risk of recurrence
Low risk of recurrence
Adjuvant Mitotane
ADIUVO Trial
scenario of advanced ACC [34-36]. Mitotane concentra- tion should be kept above 14 mg/l to achieve the most from treatment [36]. The same target of 14 mg/l has been pur- sued by many experts also when using mitotane as an adjuvant measure, despite the lack of specific data in dis- ease-free patients [1-3, 17]. Results of a very recent ret- rospective analysis provided evidence that this strategy is sound also in the adjuvant setting [37]. Of 122 ACC patients who were radically resected, 63 patients reached and maintained target mitotane concentrations during fol- low-up. They had a significantly lower rate of recurrence than 59 patients who failed to keep mitotane levels as high. Mitotane was an independent factor influencing RFS at a multivariate analysis while the prolongation of OS did not reach levels of statistical significance [37]. This may be due to the relatively short follow-up duration and should not downplay the effect of mitotane. The study actually provided a further, although indirect, evidence in favor to adjuvant mitotane.
What is the best dosing regimen to initiate mitotane therapy is currently debated and either high- or low-dose regimens are employed. A high-dose regimen has the merit of inducing a faster rise of plasma mitotane that may translate in a more rapid action of the drug [38, 39]. It is concerning that several weeks of treatment are needed to attain blood drug levels conferring therapeutic efficacy [1- 3, 17, 40], since this may cause a window of under-treat- ment following surgery during which tumor remnants may grow and progress. With a low-dose regimen, a longer time needed to achieve therapeutic concentrations may be anticipated. However, RFS did not differ between patients attaining target mitotane concentrations within 3 months and patients who did not underwent a monitored mitotane treatment in a retrospective study of 122 patients [37]. Exposure to mitotane concentrations at target over an extended period of time is likely more important to prevent recurrence than a fast attainment of target mitotane con- centrations. Furthermore, a high-dose regimen requires an intensive follow-up and may be more frequently associated with side effects, while a low-dose regimen is better tol- erated and easier to manage in an outpatient setting [1, 17].
In our practice, we start mitotane treatment as soon as possible after surgery with two tablets (1 g) daily. The patient is instructed to add one tablet every 4-7 days, depending on drug tolerability, targeting a dose of 6-8 g daily, or the maximum tolerated dose. We try to accom- modate mitotane schedule to patient’s tolerance with the aim of increasing compliance with treatment and minimizing the impact on patient’s quality of life. However, we are strongly committed to target serum mitotane concentrations of 14-20 mg/l. Monitoring of mitotane concentrations is done on a regular basis, after 4-6 weeks from treatment start and thereafter every 4-8 weeks until target levels are reached to
adjust dosage accordingly. Then, mitotane dose can be usually reduced and monitoring is done less frequently. We manage mitotane toxicity by reducing the daily dose to the previously tolerated one, or discontinuing treatment for a while allowing resolution of complaints.
Mitotane monitoring is a key for the management of patients treated adjuvantly to guide dose adjustments with the aim of targeting mitotane concentrations of therapeutic relevance while avoiding severe toxicity. Experience with mitotane before availability of drug monitoring was afflicted by severe and disabling toxicity [15]. In Europe, mitotane monitoring is readily available as a free service provided by the company distributing mitotane (info@lysodren-europe.com). Thus, this is no longer a barrier to optimal practice.
Mitotane is a toxic drug and unwanted effects are observed in almost all patients, but toxicity is usually mild and tolerable, if managed properly, with a low-dose sche- dule. Most commonly, patients complain of gastrointestinal manifestations, such as nausea and diarrhea, early in the course of treatment. These unwanted effects occur inde- pendently on mitotane levels. They can be managed with temporary dose reduction, or delay of dose increments, and symptomatic therapy [1, 17].
Clinically significant liver toxicity is characterized by a marked increase in transaminases and bilirubin, but is infrequently observed although predisposing conditions are present. Conversely, elevation in GGT levels is a universal finding without any clinical impact unless values are exceedingly elevated. Central neurologic toxicity is more closely associated with mitotane concentrations >20 mg/l but subtler symptoms, such as memory impairment or attention deficit, may be observed in some patients at lower concentrations [1, 17]. A great individual variability in the susceptibility to mitotane-related unwanted effects is apparent for causes that are still unknown [1-3, 17, 40]. Recent data from our group suggest that individual response to mitotane, in terms of circulating drug levels, is at least partially genetically determined [41]. Evaluation of gene polymorphisms involved in mitotane metabolism, like CYP2B6 and ABCB1 genes, may allow predicting which patients may be more responsive and/or more prone to unwanted effects.
Because of the adrenolytic effect of mitotane, all patients should receive glucocorticoid replacement to pre- vent adrenal insufficiency. Hydrocortisone (Cortisone acetate) is used at doses that are almost double than in Addison’s disease, due to an enhanced metabolic clearance rate of glucocorticoids induced by mitotane [1-3]. Mito- tane enhances cytochrome P450 3A4 enzyme activity resulting in rapid inactivation of more than 50 % of administered hydrocortisone [42]. An inadequate treatment of adrenal insufficiency increases mitotane-related toxicity,
particularly gastrointestinal side effects, and reduces tol- erance. Adequacy of replacement has to be judged mostly on clinical grounds and routine biochemical tests; hormone monitoring is of limited utility [17]. Mineralocorticoid supplementation is not mandatory in all patients because mitotane has only a limited effect on the zona glomerulosa. Frank elevation of PRA heralds mineralocorticoid insuffi- ciency [17, 40]. In mitotane-treated patients, a derange- ment in thyroid function characterized by low FT4 levels without a compensatory rise in TSH is frequently observed early in the course of treatment. This finding usually prompts thyroxin replacement [40]. In vitro evidence that mitotane is able to inhibit TSH secretion at the pituitary level, thus explaining a hormone pattern alike central hypothyroidism, has been published [43].
Gonadal function is also compromised during mitotane treatment by mechanisms that are still to be completely elucidated. Most women maintain regular cycles and may even become pregnant on treatment. However, some women develop ovarian cysts and oligomenorrhea with possible vaginal bleedings. In treated men, sexual dys- function is more common due to inhibition of testosterone and DHT synthesis [40, 42]. Gynecomastia is also fre- quently seen and may be partially due to the weak estro- gen-like activity of mitotane [40]. Sex steroid replacement may become necessary to treat erectile dysfunction in some patients but may worsen gynecomastia. However, the best way to replace gonadal steroids remains disputed [42].
Patients should be carefully informed of the goals of treatment, including the importance to target mitotane con- centrations of 14-20 mg/l, to motivate them to cope with unwanted effects and to remain compliant with a cumber- some poly-pharmacologic regimen. To this aim, it is impor- tant the establishment of a close patient-physician relationship to induce and maintain adherence to treatment. Patients may seek advice frequently and their local physicians are usually unfamiliar with mitotane; thus, it is necessary to give timely counseling to keep patients on treatment.
There are insufficient data to define what is the optimal duration of adjuvant mitotane treatment. In our practice, we are currently recommending longer periods of treatment, at least in patients showing a good compliance, the minimal duration of treatment being 2 years. Since most ACC recurrences occur within 5 years from surgery, this period is considered as a landmark to consider discontinuation of treatment.
Management of ACC patients with advanced disease
Background
The management of patients with recurrent and metastatic disease is challenging and the prognosis is often poor.
However, a minority of patients with metastatic disease may show a rather indolent disease course. Several prog- nostic factors such as time since diagnosis, presence of hepatic or bone metastases, number of metastatic lesions and number of tumoral organs involved, high mitotic rate (20 per 50 high-power field), and atypical mitoses in the primary tumor have been found to predict survival in patients with metastatic ACC [44, 45]. Two previous reports identified cortisol secretion as a negative prognostic factor in metastatic ACC patients. In a large single-insti- tution French series including 202 patients with different disease stages, cortisol excess was found to be an inde- pendent prognostic factor for OS and was predictive of subsequent metastatic disease in the subset of patients with stages I-III [46]. Similar results were obtained from a series of 72 Italian patients with metastatic ACC submitted to chemotherapy with EDP (etoposide, doxorubicin and cisplatin) plus mitotane [47].
The treatment of advanced/metastatic patients includes loco-regional approaches such as surgery, radiofrequency ablation (RFA) and chemoembolization in addition to systemic therapies. In presence of isolated loco-regional recurrence or oligo-metastatic disease, surgery can lead to improved survival [14], so an aggressive surgical approach to achieve complete resection (R0) may be advisable. Conversely, tumor debulking offers little benefit and may be considered in patients with functional tumors not con- trolled by medical treatment.
In patients who are not candidates for surgery, percu- taneous image-guided RFA is a locally effective treatment. RFA was well tolerated in a small series of 15 ACC recurrences, with 53 % of patients demonstrating decrease in tumor size or loss of enhancement on imaging [48]. RFA in combination with surgical resection may allow better disease control in the setting of oligo-metastatic disease. Chemoembolization is another possibility to treat liver metastases, particularly when they are multiple [49]. Chemoembolization may be used in combination with systemic treatment (mitotane) when liver is the only met- astatic organ, or after chemotherapy when disease is pro- gressing only at liver being stable at other sites.
Chemotherapy and mitotane in the management of metastatic ACC
Systemic treatments in the management of patients with metastatic disease include mitotane alone or mitotane in combination with chemotherapy. Single agent mitotane has a modest activity and response rates between 13 and 31 % have been reported (Table 1). Most of the responses are of limited duration, and complete responses rarely occur. Monitoring mitotane serum levels is mandatory since it was demonstrated that disease responses are mainly
| References | Daily dose (g) | Patient no | OR (no, % and CI) | CR (no, % and CI) | Duration (months) |
|---|---|---|---|---|---|
| Retrospective studies | |||||
| Henley et al. [65] | NR | 24 | 6 OR (25 %, 7-43) | None | 3-24 |
| Venkatesh et al. [66] | NR | 72 | 21 OR (29 %, 18-40) | None | NA |
| Luton et al. [67] | 3-20 | 37 | 5 OR (13 %,2-24) | None | 5-25 |
| Pommier et al. [68] | NA | 29 | 7 OR (24 %, 8-40) | None | NA |
| Haak et al. [34] | 4-8 | 55 | 15 OR (27 %, 15-39) | 8 CR (15 %, 5-25) | 2-190 |
| Barzon et al. [69] | 4-8 | 11 | 2 OR (18 %, 0-41) | None | 40-64 |
| Williamson et al. [70] | 4-10 | 16 | 2 OR (13 %, 0-30) | None | NA |
| Total | 244 | 58 OR (24 %, 18-30) | 8 CR (3 %, 1-5) | ||
| Prospective studies | |||||
| Decker et al. [71] | 6 | 36 | 8 OR (22 %, 8-36) | 2 CR (6 %, 0-14) | 3-82 |
| Baudin et al. [35] | 6-12 | 13 | 4 OR (33 %, 7-59) | 1 CR (8 %, 0-23) | 10-48 |
| Total | 49 | 12 OR (24 %, 12-36) | 3 CR (6 %, 0-13) |
OR overall response, CR complete response, NA not available, NR not retrieved
confined in patients attaining and maintaining over time serum levels within the therapeutic range (14-20 mg/l) [34, 35]. Mitotane serum levels within the therapeutic range are also predictive of prolonged survival [36].
Besides its antitumor effect, mitotane is a strong inhib- itor of adrenal steroidogenesis and it has a compelling indication in patients with endocrine symptoms, although the rate of success in controlling hormone excess is not well known [2, 3]. Owing to the latency of mitotane to attain the therapeutic range, mitotane monotherapy is indicated in the management of patients with a low tumor burden and/or more indolent disease. For patients whose disease show an aggressive behavior, cytotoxic chemo- therapy is required (Fig. 2).
Whether cytotoxic chemotherapy is effective or not in the management of ACC was a matter of debate for a long time. The results of several small studies have demon- strated that chemotherapy administered alone has a limited activity and the combination of chemotherapy with mito- tane seems to increase the response rate (Table 2). Mito- tane may have a synergistic effect on chemotherapy activity thanks to the ability to reverse multidrug resistance mediated by P-glycoprotein expression. ACC produces high levels of the multidrug resistance protein MDR1 (also known as P-glycoprotein) which functions as an ATP- dependent drug efflux pump, transporting out of the cell hydrophobic cytotoxic agents such as doxorubicin, vin- blastine, and paclitaxel. However, the effect of mitotane on multidrug resistance has been questioned [50].
The efficacy of chemotherapy was demonstrated by the results of a large prospective multicenter multinational phase III study (FIRM-ACT) that compared the efficacy of two chemotherapy regimens: etoposide, doxorubicin, cis- platin, and mitotane (EDP-M) and streptozotocin and
Stage IV ACC
Low tumor burden, slowly progressing
High tumor burden, rapidly progressing
Mitotane monotherapy
EDP-M
mitotane (Sz-M) [51]. Three hundred and four patients were prospectively enrolled in about 6 years. Patients with disease progression to the first-line treatment received the alternate regimen. EDP-M was superior to Sz-M both in terms of disease response rate and progression-free survival (PFS). Analysis of OS also favored patients initially ran- domized to receive EDP-M but the difference just failed to attain statistical significance. The explorative analysis performed in the subset of patients that crossed to the alternative regimen upon progression showed a significant improvement of PFS and OS in patients receiving EDP-M in second line as opposed to those receiving Sz-M. Therefore, the efficacy of EDP plus mitotane as second-line therapy attenuated its advantage as first-line therapy and affected the OS results. These limitations notwithstanding; it should be noted that the 5-year survival increased from
about 7 % in patients initially randomized to receive Sz-M to about 15 % in patients receiving EDP-M. Based on the results of this trial, the European Society for Medical Oncology guidelines recommends EDP-M as the first-line therapy for ACC requiring cytotoxic therapy [6]. The EDP- M regimen however is quite toxic and the combination of cisplatin plus mitotane may constitute a reasonable alter- native for patients that appear to be not fit for EDP-M.
The efficacy of chemotherapy plus mitotane is overall modest but highly variable among patients. At our center, we treated with chemotherapy plus mitotane (mainly EDP- M) 180 metastatic ACC patients over 20 years, and 4 of them (2.2 %) obtained an extremely favorable outcome. All of them had a PFS >5 years and only one had a disease progression after 6.5 years, the remaining patients are still alive and disease free after 11, 5 and 6 years, respectively. Two patients attained a complete response and the remainders attained a partial response and then became disease free after surgical removal of the residual disease [52]. These data suggest that cytotoxic therapy plus mito- tane could potentially cure few metastatic ACC patients. These data underline the importance of identifying factors that may predict chemotherapy efficacy to select patients for this aggressive strategy and avoid unhelpful toxicity in patients not destined to obtain any benefit.
The results of second-line therapy in patients with dis- ease progression to platinum-containing regimens plus mitotane were as a whole modest and in most studies disappointing (see the following chapter).
Our group has developed a metronomic schedule of cytotoxic drugs to overcome drug resistance and limit
patient toxicity. Metronomic chemotherapy is the admin- istration of cytotoxic drugs at low doses, on a frequent or continuous schedule, with no extended interruption. This approach can target tumor cells indirectly, since it can affect the endothelium of the growing tumor vasculature and stimulates anticancer immune response. One multi- center Italian study assessed the activity of the combination of gemcitabine administered on days 1 and 8 in association with fluoropyrimidines, such as 5-fluorouracil and cape- citabine, administered on a metronomic schedule [53]. Since the main goal of metronomic approach is to induce tumor dormancy, both tumor response and disease stabil- ization (the so called clinical benefit) were considered. Among the 28 patients who entered the study, 13 (46.4 %) obtained a clinical benefit lasting 4 months at least. Two patients attained a tumor response according to RECIST criteria, one of them a complete response. The patient who attained a complete response remained free from progres- sion for 48 months, then tumor progressed and the patient died 6 months later. These data suggest that this combi- nation regimen may have some efficacy, at least in a subset of patients. Since all patients had progressive ACC to platinum-containing regimens plus mitotane, gemcitabine plus capecitabine could be potentially considered non- cross-resistant to cisplatin-containing regimens. Despite all patients included in the trial had disease progression on mitotane, the drug was not interrupted. Patients who had serum mitotane above the therapeutic threshold had a better time to progression than those who did not. These data suggest that the synergism between mitotane and chemo- therapy can persist when further chemotherapeutic agents
| References | Drug regimen | Patient no | OR (no, % and CI) | CR (no, % and CI) |
|---|---|---|---|---|
| Chemotherapy without mitotane | ||||
| Van Slooten et al. [72] | CDDP + DOXO + CTX | 11 | 2 OR (18 %, 0-41) | None |
| Decker et al. [71] | DOXO | 16 | 3 OR (19 %, 0-38) | 1 CR (6 %, 0-18) |
| Schlumberger et al. [73] | CDDP + DOXO + 5FU | 13 | 3 OR (23 %, 5-54) | 1 CR (8 %, 0-23) |
| Burgess et al. [74] | CDDP + VP16 | 13 | 6 OR (46 %, 18-74) | None |
| Williamson et al. [70] | CDDP + VP16 | 45 | 5 OR (11 %, 4-24) | None |
| Urup et al. [75] | CDDP + TAX | 19 | 4 OR (21 %, 3-39) | None |
| Total | 117 | 23 OR (20 %, 13-27) | 2 CR (2 %, 0-5) | |
| Chemotherapy with mitotane | ||||
| Bukowski et al. [76] | CDDP + MIT (4 g/day) | 37 | 11 OR (30 %, 16-50) | 1 CR (3 %, 0-9) |
| Bonacci et al. [77] | CDDP + VP16 + MIT (3-9 g/day) | 18 | 6 OR (33 %, 11-55) | 3 CR (17 %, 0-35) |
| Berruti et al. [78] | CDDP + DOXO + VP16 + MIT (1-4 g/day) | 28 | 15 OR (53 %, 35-72) | 2 CR (7 %, 0-17) |
| Khan et al. [20] | STZ + MIT (1-4 g/day) | 22 | 8 OR (36 %, 16-56) | 1 CR (5 %, 0-14) |
| Abraham et al. [79] | VP16 + DOXO + VCR + MIT (6 g/day) | 36 | 5 OR (22 %, 8-36) | 1 CR (3 %, 0-9) |
| Total | 141 | 45 OR (32 %, 24-40) | 8 CR (6 %, 2-10) | |
OR overall response, CR complete response, CDDP cisplatin, CTX cyclophosphamide, DOXO doxorubicin, 5FU 5 fluorouracil, TAX docetaxel, MIT mitotane, VP16 etoposide, STZ streptozotocin, VCR vincristine
| References | Drug | Target | Setting | Phase | Patients no | Results |
|---|---|---|---|---|---|---|
| Samnotra et al. [55] | Gefitinib | EGFR | Advanced pre-treated ACC | II | 19 | No response |
| Quinkler et al. [56] | Erlotinib + gemcitabine | EGFR | Advanced pre-treated ACC | II | 10 | 1 minor response |
| Wortmann et al. [57] | Bevacizumab capecitabine | Angiogenesis | Advanced ACC | II | 10 | No response |
| Berruti et al. [58] | Sorafenib weekly paclitaxel | Angiogenesis | Advanced pre-treated ACC | II | 10 | PD in all cases |
| Kroiss et al. [59] | Sunitinib | Angiogenesis | Advanced pre-treated ACC | II | 36 | SD > 4 months in 5 cases |
| Haluska et al. [62] | Figitumumab | IGF-1R | Advanced pre-treated ACC | I/II | 14 | SD ≥ 3 months in 6 cases |
| Naing et al. [63] | Cixutumumab temsirolimus | IGF- 1R + mTOR | Advanced ACC | I/II | 10 ACC | SD ≥ 8 months in 4 cases |
| Naing et al. [64] | Cixutumumab temsirolimus | IGF- 1R + mTOR | Advanced pre-treated ACC | II | 26 | SD > 6 months in 11 cases |
PD progressive disease, SD stable disease
are introduced. This hypothesis deserves further study because practice varies as to continuing mitotane after progression to this treatment.
Metronomic chemotherapy may be occasionally active also when administered after several treatment lines. We recently described two cases with metastatic ACC with a rather long disease history that attained a durable disease response with oral cyclophosphamide and oral etoposide, respectively, both administered on a metronomic schedule [54]. These data suggest that metronomic chemotherapy may be active in patients bearing a rather indolent disease.
Molecular target agents in the management of metastatic ACC
Several oncogenes, growth factors and tumor suppressor genes have been implicated in ACC tumorigenesis. The most important genomic alterations involve the p53 sys- tem, the insulin growth factor receptor (IGFR) and the Wnt/B-catenin signaling pathway. In addition, also the epidermal growth factor receptor (EGR) and neoangio- genesis are considered potential targets.
As outlined in Table 3, several small phase II trials have tested the efficacy of molecular agents targeting EGFR, angiogenesis, IGFR, and mTOR pathways. These treat- ments were administered in pre-treated patients. The molecular agents employed were tested alone, in combi- nation with chemotherapy, or with other molecular target agents. As a whole, these trials obtained poor results. EGFR target agents (gefitinib and erlotinib) either admin- istered alone, or in combination with gemcitabine, were not active [55, 56]. Three trials tested anti-angiogenic drugs,
two of them testing the association of bevacizumab with capecitabine [57] and sorafenib with weekly paclitaxel [58], respectively, led to negative results. In a multicenter prospective phase II German trial, sunitinib obtained dis- ease stabilization lasting more than 4 months in 5 patients out of the 36 consecutively enrolled (13.8 %); 4 of them showed a modest increase of ACC lesions <20 % and therefore below the threshold for progression according to the RECIST criteria and only one a decrease of tumor burden (below the threshold of response) [59].
The reasons why these trials were substantially negative are not clear and several hypotheses can be raised. First, poor patients selection, because of (1) inclusion of heavily pre-treated cases that may have led to emerging of multi- resistant tumor clones, or (2) inclusion of tumor that do not express the molecular target. As an example, EFR muta- tions in ACC are extremely rare and this may have accounted for the poor response obtained with the EGFR inhibitors in unselected ACC patients. It has been shown that these drugs are active in the small subset of patients whose non-small-cell lung cancers harbor EGFR mutation [60]. Second, the patients included in molecular target therapy trials were pre-treated with mitotane, a drug with a very long half life (more than 40 days) and whose bio- logical activity usually persists for months after drug withdrawal. Many small molecular target agents are sub- strates of the p450-dependent enzyme CYP3A4 that is induced by mitotane [61]. Therefore, pretreatment with mitotane may have reduced the antitumor efficacy of these agents.
Better results were obtained by figitumumab, a mono- clonal antibody against IGFR-1, either administered alone
[62] or in combination with the mTOR inhibitor temsirol- imus [63, 64]. As shown in Table 3, durable disease sta- bilizations were obtained in a relevant proportion of patients. In our opinion, figitumumab deserves to be further explored in the management of advanced ACC. Being a monoclonal antibody, this drug is not metabolized by the CYP3A4 enzyme and its pharmacokinetic may be not negatively influenced by mitotane. A prospective phase II trial testing the activity of figitumumab in association with mitotane in ACC relapsed/refractory or primary not removable by surgery is currently recruiting in USA (Trial No NCT00778817).
The most important study in this arena was a multi- center, multinational, prospective, randomized, placebo- controlled clinical trial recently conducted aimed to test the efficacy of OSI 906-301, a small molecule IGFR inhibitor, as second-/third-line approach in advanced/metastatic ACC patients (Trial No: NCT00924989). This trial has com- pleted patient accrual in June 2011 and the final results are expected in 2014.
Conclusion
Our current policy is to recommend adjuvant mitotane after extirpation of ACC. Patients at low risk of recurrence (R0, stage I-II, Ki-67 ≤10 %) are offered to participate in the ADIUVO trial and are randomized between mitotane treat- ment and observation. A monitored mitotane treatment is followed targeting levels between 14 and 20 mg/l. Minimal duration of treatment for high-risk patients is 2 years, but we strive continuing for 4-5 years in most cases.
The strategy of treatment of advanced ACC is chosen considering a number of prognostic factors (tumor burden, type of progression, secretion, proliferation index) and the clinical conditions. If a patient is fit and carries bad prog- nostic factors, we recommend the polychemotherapy reg- imen EDP + mitotane. In case of compromised conditions, platinum + mitotane is an alternative. Patients at per- ceived good prognosis may be treated with mitotane monotherapy and EDP is added on in case of disease progression. As a second-line therapy, we use gemcitabine plus capecitabine while continuing mitotane.
Conflict of interest M. Terzolo received research grants and advi- sory honoraria by HRA Pharma. F. Daffara, A. Ardito, B. Zaggia, V. Basile, L. Ferrari and A. Berruti declare that they have no conflict of interest.
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