Сurrent status of adrenocortical cancer therapy

Introduction

Adrenocortical cancer is a rare tumor of the adrenal glands with a morbidity of about 0.5–2.0 cases per million population per year [1][2]. The disease occurs somewhat more often in women (55%), and the age peaks of morbidity occur in childhood and 40–60 years [3]. An important feature of the tumor is the possible hormonal activity (approximately 55% of patients show the secretion of some hormone – cortisol, androgens, and less often estrogens and mineralocorticoids) [4].

Currently, the prognosis in patients suffering from adrenocortical cancer often remains unfavorable. With locally advanced tumors, the five-year survival rate is high enough (about 80%), whereas with a widespread unresectable or metastatic form, the indicator is less than 15% [4]. This difference in indicators is probably due to the fact that surgery is a reliable method of treatment, while drug therapy sometimes has a dubious effect. Interestingly, there are descriptions of cases of adrenocortical cancer with multiple metastases in the world, but with a very long survival (more than 10 years) [5][6].

The epidemiological data are discouraging, indicating the lack of significant progress in the treatment of adrenocortical cancer when comparing the results of the treatment of patients in the periods of 1993–1998 and 2005–2010 [3]. Only a few attempts to create a highly effective drug for the treatment of this disease have been successful. There are several possible reasons for this situation, including significant heterogeneity of adrenocortical cancer in sensitivity to drug therapy [7], possible interaction of drugs with mitotane, and others. The low prevalence of the tumor does not allow for large clinical trials; most of the few treatment recommendations are based on retrospective data or expert opinion.

Nevertheless, in oncology as a whole, a huge leap forward has been made in recent years, which has become possible due to the emergence of a huge number of new medicines, including so-called “target medications” that affect a specific target. Given the similarity of the etiology and pathogenesis of various malignant neoplasms, as well as the high unmet medical need in patients with adrenocortical cancer, the emergence of new therapy options for the treatment of the latter disease seems very likely. This article aims to highlight the status of existing methods of drug treatment of adrenocortical cancer, as well as an overview of promising directions in the development of medicines in this area.

Methods of academic literature search

The academic literature was searched in the bibliographic database of the Russian Scientific Citation Index according to the words “cancer”, “adrenal glands”, “adrenocortical”, “treatment” (the website https://www.elibrary.ru ), as well as in the database of medical and biological publications of the US National Center for Biotechnology Information according to the terms “cancer”, “adrenals”, “adrenocortical”, “treatment” (the website https://pubmed.ncbi.nlm.nih.gov): additionally the authors conducted a search for the specified words in the Google Academy search engine (the website https://scholar.google.com). Taking into account the rarity of publications on the problem under consideration, an analysis of sources over the past 10 years was carried out.

Additionally, a search was conducted in the database of clinical trials of the National Medical Library of the National Institutes of Health of the USA (the website https://clinicaltrials.gov), according to the disease “adrenocortical cancer”.

Mitotane

Mitotane is the only medicine in the world registered for the treatment of adrenocortical cancer. It appeared in the 1960s, after its selective cytotoxic effect on the bundle and mesh zones of the adrenal cortex was noted, it began to be used for the treatment of patients with widespread unresectable or metastatic tumors [8].

The cytotoxic mechanism of action of Mitotane is not completely clear. The most common view currently is that the medicine blocks sterol-O-acyltransferase 1 (SOAT1), which is widely expressed in adrenal cells. This effect leads to intracellular accumulation of free cholesterol, oxysterols, and fatty acids, which induce stress of the endoplasmic reticulum and thus cause cell apoptosis [9]. It is possible that the interaction of the drug with other proteins plays a role, since a number of studies indicate that there is no connection between the antitumor activity of Mitotane and the expression of SOAT1 [10].

An important aspect of Mitotane use is the pronounced induction of the CYP3A4 enzyme, which persists even for several months after drug withdrawal [11]. This effect significantly worsens the pharmacokinetic properties of many medications in patients, including glucocorticoids, statins, and antitumor drugs. This effect can be compensated for by increasing the dose of the medicine, and in some cases makes the use of it impractical.

The dependence of the Mitotane effectiveness on the dose used is rather weak. The reason is that the medicine is characterized by high variability of pharmacokinetics due to frequent genetic aberrations of P450-dependent enzymes that metabolize Mitotane [12]. It was found that there was a fairly narrow corridor of medicine concentrations (14–20 mg/l), at which the efficacy was higher and the toxicity was acceptable [2][12]. Puglisi et al. (2020) confirmed the importance of monitoring the content of Mitotane in the blood by detecting the effect of the length of time when concentrations were in a given range on the prognosis for the patient [13]. Cortisol secretion, which is often observed in adrenocortical cancer, is effectively inhibited by Mitotane and at lower concentrations [10].

Taking into account the fact that Mitotane is a derivative of the insecticide dichlorodiphenyltrichloroethane (DDT), it is not surprising that it causes many undesirable reactions in humans [8]. In publications of previous years, significant neurotoxicity of the medicine was noted in 40–60% of patients, it included lethargy, dizziness, and somnolence. After it was recommended to monitor the concentrations of the medicine in the blood during treatment, it turned out that this type of side effects is dose-dependent and is observed to a more pronounced extent in patients when the required dose is exceeded [8]. The most common reactions to Mitotane are nausea, vomiting, anorexia, diarrhea, rash, arthralgia, hypercholesterolemia, and gynecomastia [2]. Against the background of therapy, disorders of the endocrine glands may also appear (thyroid gland — in 36% of cases, hypogonadism — in 34% of men, ovarian cysts — in 50% of women). Mitotane may also have some effect on the glomerular zone of the adrenal cortex, causing a deficiency of mineralocorticoids [8].

Recommendations for the treatment of adrenocortical cancer suggest the use of Mitotane in the adjuvant mode in patients with a high risk of relapse (stage ENSAT III–IV, Ki67 > 10% or relapse with resection R0, or resection Rx/R1) [1, 2], however, indicate the controversy of this statement. The reason is that the efficacy data are collected retrospectively, are very heterogeneous from patient to patient and contradictory. The only prospective randomized trial (ADIUVO), which lasted from 2008 to 2021, included 91 of the planned 200 patients, no data on statistically significant differences between the Mitotane groups and observations regarding survival were obtained. Nevertheless, meta-analyses conducted in recent years generally indicate some improvement in relapse-free and overall survival with adjuvant use of Mitotane [14–16]. Currently, an ADIUVO-2 study has been initiated to compare the effectiveness of Mitotane in a group of high-risk patients when used in monotherapy and in combination with Cisplatin/Etoposide [17].

In common unresectable or metastatic disease, either Mitotane monotherapy or Mitotane in combination with chemotherapy (Etoposide, Doxorubicin, and Cisplatin) is often used [EDP-M] [1]. This recommendation is based on the results of the FIRM-ACT study, which included 304 patients with a common stage of the disease. In the group of patients treated according to the EDP-M scheme, the non-aggressive survival was significantly better than in the group treated according to the Mitotane + Streptozocin scheme (5.0 months vs. 2.1 months). Overall survival did not differ statistically significantly (14.8 months versus 12.0 months), probably due to the fact that patients whose disease progressed during treatment with Mitotane and Streptozocin were allowed to switch to the EDP-M group [18].

If the EDP-M scheme is poorly tolerated, it is possible to abandon Doxorubicin and replace Cisplatin with Carboplatin.

There are different positions in relation to the time of Mitotane cancellation. Some researchers recommend canceling it after the second progression [5], others — in patients with progression a year after the start of therapy [19]. The authors agree that it is necessary to take into account clinical features, such as the tolerability of the medicine, and make a decision to cancel Mitotane on an individual basis.

It is probably advisable to use Mitotane monotherapy in patients with metastatic disease with intolerance to chemotherapy to control symptoms caused by the hyperproduction of cortisol. At the same time, it should be noted that there are other steroidogenesis inhibitors, such as Methirapone or Ketoconazole, which have a better safety profile, so the relevance of Mitotane monotherapy in a patient with a common disease remains in doubt.

Chemotherapy

Chemotherapeutic medicines are traditionally used for adrenocortical cancer, taking into account their universal mechanism of action, which consists in blocking the main systems for ensuring the vital activity of cells. Adjuvant use of chemotherapy has not been sufficiently studied in this disease; however, some centers use such treatment (for example, Cisplatin + Etoposide) for patients with a very high risk of relapse; currently, a corresponding clinical trial is carried out (NCT03583710).

The potential effect of chemotherapy in the first-line therapy of common tumors is clearly demonstrated by the above results of the FIRM-ACT study. The short-term non-aggressive survival of patients using Mitotane in combination with Streptozocin (2.1 months) indicates the limited effectiveness of the first component of therapy. In this regard, chemotherapy according to the EDP scheme (without Mitotane) can also be used in the first line of therapy.

There is practically no reliable information about the effectiveness of any therapeutic options in the second line of therapy for adrenocortical cancer; in such circumstances, as a rule, it is chemotherapy that is used. A small study showed moderate antitumor activity of a combination of Gemcitabine and Capecitabine/5-Fluorouracil in pretreated patients. After 4 months of therapy, 46.3% of patients had disease control [20].

Under certain circumstances, it is possible to use Streptozocin monotherapy or this medicine in combination with Mitotane in the second/third line of therapy [1][18].

Despite the fact that the expression of vascular endothelial growth factor (VEGF) by adrenocortical cancer cells was shown, the combination of Capecitabine with Bevacizumab (an antibody to VEGF) did not lead to a response in any of the ten patients [21].

Another chemotherapeutic agent, Trophosfamide, was tested in adrenocortical cancer as part of a clinical trial. Therefore, among 21 treated patients, 8 patients demonstrated disease progression based on clinical signs, and among 13 patients with an estimated response according to RECIST 1.1 criteria, 3 ones patients disease stabilization. One of the stabilizations was long-lasting – 479 days [22].

Medicines affecting the signaling pathway of insulin-like growth factor

Since insulin-like growth factor-2 (IGF2) is overexpressed in about 80% of adrenocortical cancers [23], many attempts have been made to use appropriate medicines to treat the disease.

There are quite a few medicines registered or at the stage of clinical development that affect the IGF signaling pathway. Among them, there are IGF1R blockers (Figitumumab, Cycsutumumab, Lincitinib) and mTOR inhibitors (Everolimus, Temsirolimus, etc.).

Cycsutumumab is a blocking antibody to IGF1R, which also has antibody-dependent cellular cytotoxicity. The medicine in combination with Mitotane caused a response in only one patient out of fifteen; this result was considered unsatisfactory, and the study was completed ahead of schedule [24]. Negative results were also demonstrated by Figitumumab, which is a blocking antibody to IFG1R without significant antibody-dependent cellular cytotoxicity [25].

Lincitinib in a fairly large study also demonstrated ineffectiveness in terms of improving non-aggressive and overall survival [26]. However, it should be noted that 4 out of 90 patients taking Lincitinib had long-term disease control (from 23 to 45 months), and one patient had a complete response, he stopped treatment 75 months after its start, and 111 months after the start of therapy he still demonstrated no signs of the disease [27].

Then, mTOR inhibitors (blocking the IGF1R signaling pathway) have shown their antitumor activity against adrenocortical cancer in a number of preclinical experiments. There are descriptions of responses when using drugs in humans, but at present, it seems unlikely that this class of medicines can be used in patients in monotherapy [28][29].

Interestingly, Metformin, which inhibits mTOR, had antitumor activity in an experiment with adrenocortical cancer cells [30]. Given the low toxicity and availability of the medicine, the expediency of its use in combination with other therapy is not excluded.

Multikinase inhibitors

The experience of using multikinase inhibitors, such as Sunitinib, Axitinib, and Sorafenib, blocking several cellular receptors at once, also proved unsuccessful. As part of the clinical study of Sunitinib, among 29 pretreated patients who could assess the response to therapy, five had stabilization of the disease [31]. It should be noted that the induction of CYP3A4 by Mitotane could lead to negative results in this case, which significantly worsened the pharmacokinetic profile of sunitinib [31].

Axitinib did not elicit responses in 13 patients; however, a decrease in the rate of progression was noted in 4 patients [32]. When Sorafenib was combined with Paclitaxel, no responses were observed [33].

Immunotherapeutic medicines

Immunotherapeutic medicines are a group of various drugs that act on various targets that provide antitumor immune responses. The undoubted leaders in this group are currently antibodies to the programmed cell death receptor (PD-1) or its ligand (PD-L1). These medicines prevent the binding of PD-1 on T-lymphocytes and PD-L1 on tumor cells, which activates antitumor cytotoxic reactions of T-lymphocytes.

Currently, immunotherapy is considered a fairly universal method of treating malignant neoplasms, while it has radically changed approaches to the treatment of some “difficult” diseases, such as melanoma. At the same time, this class of medicines is characterized by good tolerability. The effectiveness of immunotherapeutic medicines may vary significantly depending on the status of PD-L1 expression by the tumor and the presence of microsatellite instability. Adrenocortical cancer may be resistant to immunotherapy due to the relatively low expression of PD-L1, a frequent increase in the activity of glucocorticoids that are secreted by the tumor and can inhibit immune responses, Wnt-activation, and possible inactivating TP53 mutations [23][34].

Nowadays, the results of several studies of anti-PD-1/PD-L1 medicines have been published. A relatively large study of Avelumab included 50 patients who did not respond to treatment with a platinum-containing drug. The overall response rate was only 6%, and the median non-aggressive survival was 2.6 months. At the same time, it should be noted that in the subgroup of patients with a positive PD-L1 status (≥5%), the response rate reached 16.7% (two out of twelve participants) [35].

The results of the monotherapy use with Pembrolizumab in the framework of a clinical trial of the second phase are also interesting. Among 14 patients who were able to assess the response to therapy, two patients demonstrated a partial response. Stabilization of the disease was noted in seven participants; moreover, in six of them, it lasted more than 4 months [36]. In another study of Pembrolizumab, out of 39 patients (including both pretreated and untreated), the response was noted in nine (23%), the median duration of responses was not reached. The frequency of disease control was 52%. Among six patients with microsatellite instability, two responded to therapy [37].

In the study of Nivolumab, two of ten patients showed stabilization, and one patient had an unconfirmed response [38].

These data make it possible to be cautiously optimistic about the possibility of using anti-PD-1/PD-L1 medicines, especially in patients with microsatellite instability of the tumor. Confirmatory clinical studies are needed. The possibilities of combining this class of drugs with other therapy options are interesting, such as chemotherapy, which can increase the expression of PD-L1, or Mitotane, which can inhibit the secretion of glucocorticoids by the tumor. These effects may increase the sensitivity of adrenocortical cancer to immunotherapy.

Currently, several prospective clinical studies of immunotherapy in patients with adrenocortical cancer are ongoing, among them studies of Pembrolizumab (NCT02673333, NCT02721732), Pembrolizumab in combination with Relakorilant (glucocorticoid receptor antagonist) (NCT04373265), and combinations of Nivolumab and Ipilimumab (immunotherapy medicine, antibodies against CTLA receptor -4) (NCT02834013, NCT03333616).

Discussion

Despite the efforts expended by many researchers to find an effective medicine for the treatment of adrenocortical cancer, as well as a high unmet medical need, modern international standards of therapy are based on the use of Mitotane and chemotherapy according to the EDP scheme. Many attempts to use other anticancer medicines have not led to success. There are several reasons for this.

First, the rarity of adrenocortical cancer does not allow for large prospective studies, which is a significant limitation for the development of new medicines. This circumstance can be solved by routing patients with adrenocortical cancer to large specialized centers and scientific cooperation of such institutions.

Second, as the example of Sunitinib clearly shows, the widespread use of Mitotane in clinical practice imposes an additional requirement for drugs based on small molecules — they should not be metabolized by CYP3A4.

Third, adrenocortical cancer, apparently, is an extremely heterogeneous disease, which is illustrated by the high interindividual variability of survival and sensitivity of patients to therapy. The works by Zheng et al. (2016) and Assie et al. (2014) are curious (based on genome sequencing and studies of individual polymorphisms in tumor samples), which showed the possibility of isolating separate groups of patients with radically different prognoses [39][40]. In this regard, it seems advisable to search for new markers that would determine the prognosis for the patient and/or his/her sensitivity to a particular type of therapy. Currently, genetic testing methods are being used more and more widely, which will definitely contribute to solving the task. Mutations in genes such as BRAF, BRCA1, BRCA2, as well as microsatellite instability and PD-L1 status, which are often found in adrenocortical cancer, can determine the results of therapy with a particular medicine.

Conclusions

Despite the fact that progress in the treatment of adrenocortical cancer is slow, and a large number of negative results of clinical studies have been obtained, new medicines are emerging that can potentially be tested for the treatment of patients with adrenocortical cancer, among them Wnt-signaling inhibitors, cyclin-dependent kinase inhibitors (CDK), serine-threonine-kinase inhibitors BRAF, poly (ADP-ribose) inhibitors-polymerases (PARP), and many others [27].