Keywords

15.1 Introduction

Mitotane is the main component of standard systemic therapy. It is recommended by the international guidelines [1] and can be administered either as monotherapy or in combination with cisplatin, doxorubicin, and etoposide (EDP-M regimen). The efficacy of systemic therapy for advanced ACC is limited, but about 15% of patients survive at 5 years [1, 2] and about 2% may be disease-free for more than 5 years [3], indicating a potential, albeit limited, curative role. In this chapter we will provide an overview of the efficacy of standard therapy and suggest strategies for its optimal use. Additionally, we will present and briefly discuss the available data on targeted therapies and immunotherapies.

15.2 Standard Systemic Therapy: Mitotane

Mitotane is the only pharmacological compound approved for ACC, both in the adjuvant and in the advanced setting [1]. The drug is a dichlorodiphenyltrichloroethane (DDT) derivative and has a cytolytic effect on ACC cells and an inhibitory effect on adrenal steroidogenesis. Indeed, to avoid adrenocortical insufficiency, patients receiving mitotane need steroid replacement therapy. To maximize the drug’s efficacy and tolerability, it is essential that its blood concentrations reach and maintain a therapeutic range of 14–20 mg/L. In the adjuvant setting, mitotane is indicated when the perceived risk of recurrence is high: stage III–IV and/or R1 and/or Ki67 >10%. If tolerated, the treatment should last for at least 2 years but no more than 5 years. In the advanced setting, mitotane is administered in monotherapy for indolent and oligometastatic disease [3]. It can be combined with all the different locoregional treatments [1].

A key factor for the success of mitotane is the patient’s compliance and active collaboration. In fact, this is a long-term treatment which may produce several side effects. For this reason, thorough counseling with clear explanations is mandatory, as is close medical monitoring and dose tailoring, as shown in Fig. 15.1.

Fig. 15.1
3 line graphs of serum mitotane versus time. Under normal conditions, the plot forms an overall increasing trend. During toxicity, the levels increase drastically forming multiple sharp peaks. During withdrawal at the post-optimum level, a bell-shaped curve is formed, and it later decreases steadily.

Three examples of variation in serum mitotane levels. The first case (a) describes the optimal situation, in which the serum concentration is reached and maintained in the therapeutic range. The second case (b) describes a patient who temporarily stopped the drug due to toxicity, causing the serum drug concentration to be inhomogeneous and well below the therapeutic range. The third case (c) describes a patient with poor compliance who reached the therapeutic range but spontaneously reduced the drug owing to the appearance of gynecomastia. All three patients with metastatic disease received mitotane for a long period of time. Noteworthy, in the last case, the patient was persuaded to increase the drug dosage after experiencing disease progression

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15.3 Combination Therapy: Chemotherapy plus Mitotane (EDP-M)

The combination of mitotane with etoposide, doxorubicin and cisplatin (EDP-M regimen) is recommended [1, 4] in the case of:

  • rapidly progressing disease;

  • high burden of disease, with metastases in different organs;

  • disease progressing during mitotane monotherapy, with mitotane blood levels in the therapeutic range, which means that mitotane alone is not enough to control the tumor growth.

The EDP regimen, which is usually administered for a maximum of 6–8 cycles, combines three effective cytotoxic compounds:

  • etoposide (or VP-16) that inhibits topoisomerase II, whose activity prevents DNA unwinding;

  • doxorubicin that inhibits DNA synthesis and transcription;

  • cisplatin that inhibits DNA synthesis and function as well as its transcription.

The recommendation for the use of EDP-M is supported by the FIRM-ACT trial, a multi-center prospective international study which enrolled 304 patients and compared the efficacy of the EDP-M regimen to the streptozotocin-mitotane regimen. Patients in the EDP-M arm had better median progression-free survival (mPFS) (5.0 months vs. 2.1 months; hazard ratio 0.55, 95% CI 0.43–0.69, p < 0.001) and longer median overall survival (mOS), which just failed to attain statistical significance (14.8 months versus 12.0 months; p = 0.07) [2]. In a retrospective trial performed at our Institution, we analyzed the data of 58 patients affected by advanced/metastatic ACC, who received a median of 5.5 EDP cycles. According to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, no complete response was achieved. Fifty percent of patients obtained a partial response and in 26% of cases a stability of disease was documented; mPFS and mOS were 10.1 (95% CI 8.1–12.8) and 18.7 (95% CI 14.6–22.8) months, respectively [5].

EDP-M therapy has the potential to be very effective in a minority of patients, leading to a limited number of disease responses [2]. For this reason, this chemotherapy regimen needs to be administered in the most efficient way. It is important to treat advanced ACC patients in oncologic referral centers with dedicated multidisciplinary teams and extensive experience in the treatment of ACC.

When monitoring a patient during EDP-M treatment, it should be kept in mind that its efficacy is influenced by the cytotoxic effects of both chemotherapy and mitotane, the latter being notoriously delayed. It is also important to note that an early radiological size increase EDP-M treatment does not necessarily correspond to disease progression. A multidisciplinary evaluation is necessary to assess the response to EDP-M, considering multiple parameters such as RECIST 1.1, the Choi criteria, and tumor volume [6]. In any case, EDP-M should not be withdrawn in cases of early progression if the mitotane blood level is below the therapeutic concentrations, unless new lesions appear [5].

The EDP-M scheme can be burdened by significant toxicities and their correct management is recommended [7]. Neutropenia occurs in 77% of patients at nadir and in 53% of patients at recycling. Nevertheless, EDP efficacy depends on the correct administration of full doses. Granulocyte colony-stimulating factors (G-CSF) should be administered 24–48 h after every cycle. The presence of Cushing’s syndrome is the sole factor which may prevent the administration of EDP at full doses, due to the increased risk of infections and sepsis. Nausea and vomiting affect up to 90% of patients during chemotherapy administration and in the following days [7]. Asthenia is also a frequent symptom (70% of cases). The presence of mitotane-induced hypoadrenalism should be considered if patients experience nausea, vomiting and asthenia after EDP-M, since distinguishing between chemotherapy-induced nausea/asthenia and hypoadrenalism can be challenging [4, 7]. In cases of uncertainty, an extra dose of glucocorticoids is recommended.

Patients receiving EDP-M could develop neurological toxicity due both to cisplatin (peripheral) and mitotane (central). Since the mechanism of nerve damage is different, mitotane should not be withdrawn in the case of cisplatin-related neurotoxicity [7].

Furthermore, an ongoing trial (ACACIA, NCT03723941) is evaluating the efficacy of the addition of etoposide and cisplatin to mitotane therapy (EP-M regimen) in the adjuvant setting in resected patients at high risk of relapse.

15.4 Beyond EDP-M

The second-line treatments tested for patients who progress on EDP-M have not produced sufficient results to be considered standard therapy. The combination of gemcitabine plus capecitabine [8] or streptozocin [2] led to a limited response rate and poor PFS (between 2 and 4 months). Cabazitaxel was found to be totally inactive in a prospective phase II trial [9] and these results were in contrast with a previous in vitro experiment. Even though temozolomide was highly active in vitro, it obtained an objective response rate (ORR) of 36% and a mPFS and mOS of only 3.5 and 7.2 months, respectively [10].

Several trials have tested targeted drugs in advanced ACC. Results with anti-epidermal growth factor receptors (EGFR) and anti-angiogenic drugs, either alone or in combination with chemotherapy, have been disappointing [11]. Three cases of objective response and three of stable disease in 16 pretreated ACC patients described with cabozantinib, a tyrosine kinase inhibitor (TKI) targeting c-Met, vascular endothelial growth factor receptor-2 (VEGFR-2), AXL, and RET, are of some interest and deserve confirmation [12]. Dovitinib, a targeted therapy that inhibits the fibroblast growth factor receptor (FGFR), reached no objective response, but a clinical benefit longer than 6 months was achieved in 35% of patients, with long-lasting stable disease in 23% [13]. Moreover, thalidomide, with its anti-inflammatory and anti-angiogenetic properties, yielded poor results in a retrospective study: 7.5% stable disease, and no radiological response according to the RECIST criteria [14].

The overall disappointing results of these molecular target drugs can be partly explained by the fact that none of them interact with the three molecular pathways that are the basis of ACC pathophysiology: insulin-like growth factor, p53 and WNT/β-catenin. As regards the insulin-like growth factor pathways IGF1-IGF2, the IGF1 receptor inhibitor cixutumumab, combined with mitotane as a first-line treatment for advanced/metastatic ACC, led to a mPFS of 6 weeks (range 2.66–48) and a clinical benefit in 8 out of 20 patients (1 partial response, 7 stable disease) [15]. In a trial exploring cixutumumab plus the mTOR (mammalian target of rapamycin) inhibitor temsirolimus, 11 of 26 patients (42%) achieved stable disease for more than 6 months [16]. Linsitinib, an oral inhibitor of both the IGF1 receptor and the insulin receptor, failed to demonstrate any superiority over placebo in terms of both mPFS and mOS in heavily pretreated ACC patients [17].

Theragnostics is another modern therapeutic strategy in the treatment of cancer patients. Radionuclide therapy has also been tested in patients with ACC in small clinical trials. More than 50% of ACC cells have been found to express somatostatin receptors (SSTRs). A study [18] conducted on 19 pretreated metastatic ACC patients showed radiometabolic uptake of any intensity in 8 (42%) patients and a strong uptake in 2 (11%) patients; both patients were treated with 177Lu-DOTATATE obtaining a disease control of 4 and 12 months. The radionuclide molecule 131I-IMAZA, which targets 11-beta hydroxylase, has also been tested for ACC treatment [19]. Thirteen patients underwent a median dose of 25.7 GBq 131I-IMAZA (range 18.1–30.7 GBq) and follow-up data were available for 12 patients. Stable disease was obtained in five of them with a mPFS of 14.3 months (range 8.3–21.9). The mOS in the intention-to-treat population was 14.1 months (4.0–56.5). These results suggest that the theragnostic approach should continue to be tested in patients with ACC.

ACC has an intrinsic immunoresistance because of its pathophysiological pathways (β-catenin gene activation and TP53 mutation), which are also mechanisms of resistance to immunotherapy, and because of the frequent glucocorticoid hypersecretion which generates an immunosuppressive microenvironment. Despite ACC immunoresistance, many clinical trials testing PD1 (programmed death protein 1), PDL-1 (programmed death ligand-1) and CTLA-4 (cytotoxic T-lymphocyte antigen-4) inhibitors have been performed with interesting results, which appear more promising compared with those obtained with targeted molecules [11]. In a phase II trial, pembrolizumab obtained an ORR of 23%, with a mPFS of 2.1 months and a mOS of nearly 25 months. Nivolumab was tested in a phase II trial and an ORR of 10%, a mPFS of nearly 2 months and a mOS of 21 months were achieved. In a trial evaluating avelumab, the ORR was 6%, and the mPFS and mOS were 2.6 and 10.6 months, respectively. The CTLA-4 inhibitor ipilimumab was tested in combination with nivolumab in two phase II trials and the ORR was 6% and 33% [11, 20].

Many immunotherapy trials are currently enrolling patients with metastatic ACC, and this pharmacological approach could be one of the most important in the treatment of ACC.