6 Adrenocortical carcinoma: current treatment URRENT PINION options
Giuseppina De Filpo, Massimo Mannelli, and Letizia Canu
Purpose of review
In this article, we focus on the current and future treatment options for adrenocortical carcinoma (ACC).
Recent findings
Radical surgery remains the only curative treatment for ACC. Recent reports showed a longer overall survival (OS) in patients with high risk of recurrence treated with adjuvant mitotane; the time in target range (14-20mg/l) is related to low risk of relapse both in adjuvant and in palliative setting. In patients who experience disease progression after etoposide, doxorubicin, cisplatin with mitotane (EDP-M), gemcitabine and metronomic capecitabine, or the less used streptozotocin, represent a second-line chemotherapy option. Temozolomide can be employed as a third-line chemotherapy. To date, unsatisfactory results have been obtained on the efficacy of targeted therapies. Clinical trials are ongoing to evaluate the efficacy of tyrosine kinase and immune checkpoint inhibitors.
Summary
ACC is a rare disease with a poor prognosis. The main therapy is represented by radical surgery conducted by an expert surgeon. Adjuvant mitotane has to be started in patients with high risk of recurrence. In patients with inoperable disease, the scheme EDP-M is the most employed. Few data are available on second-line and third-line chemotherapy in patients with disease progression after EDP-M. Currently, the role of targeted therapies is under evaluation.
Keywords
adrenocortical carcinoma, chemotherapy, immunotherapy, mitotane, targeted therapy
INTRODUCTION
Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis and high mortality. In patients with metastatic disease, the 5-year sur- vival rate is less than 20%. Also localized disease has high risk of recurrence especially in the first 2 years after radical surgery (R0, microscopically free margins) (50-70%) [1]. ACC can be secreting in up to 60% of cases. The histopathological fea- tures with a Weiss score greater than 3 determine the diagnostic confirmation of ACC. Parameters, such as resection status, Ki67 proliferation index, ENS@T tumor stage, age at diagnosis, and the pres- ence of symptoms are useful to predict the clinical outcome [2].
SURGERY
Surgery represents the only curative treatment for patients affected by ACC. Recent guidelines recommend complete en bloc resection of adrenal lesions suspected to be ACC including peritumor/
periadrenal retroperitoneal fat [3]. Surgery for ACC requires expert adrenal surgeons to optimize the probability to obtain R0 resection and reduce complications. Open surgery is the standard procedure recommended in front of ACC suspi- cious. In addition, locoregional lymphadenectomy should be performed to improve survival outcome [4].
ADJUVANT THERAPY: MITOTANE
Mitotane (o,p’-DDD) is a steroidogenesis inhibitor and an adrenolytic drug; it is the only drug approved
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
Correspondence to Massimo Mannelli, MD, Department of Experimental and Clinical Biomedical Sciences, University Hospital of Florence, Viale Pieraccini, 6 50139 Florence, Italy. Tel: +0039 0552758241; e-mail: massimo.mannelli@unifi.it
Curr Opin Oncol 2021, 33:16-22 DOI:10.1097/CCO.0000000000000695
KEY POINTS
· Adrenocortical carcinoma is a rare aggressive disease.
. None of the tested drugs are curative.
· Metastases genetic profile increase the possibility of a better therapeutic choice.
· In patients with progressive disease, always consider clinical trials.
by the Food and Drug Administration (FDA) and by European Medicines Agency (EMA) for the treat- ment of metastatic ACC [5]. However, mitotane is considered also in an adjuvant setting as ACC is characterized by a strong risk of recurrence also after radical surgery. The European Society of Endocri- nology (ESE) - European Network for the Study of Adrenal Tumors (ENS@T) guidelines on the manage- ment of ACC in adults suggest mitotane adjuvant therapy in patients with a high risk of recurrence (stage III or R1 resection or Ki67 >10%), even if this recommendation is associated to a low level of evi- dence because of the lack of prospective randomized studies. On the other hand, in patients with a low/ moderate risk of recurrence (stage I-II, RO resection, Ki67 ≤10%) the adjuvant treatment should be eval- uated case by case [3].
Adjuvant mitotane therapy should be started as soon as possible after initial surgery. Plasma drug levels should be monitored in order to reach and maintain a target range between 14 and 20mg/l (‘therapeutic window’) [5]. In our experience, a low-dose regimen with a starting dose of 1 g daily and increments of 0.5 g/day every 4 days until the maximal dose tolerated, allows to reduce toxicity and increase compliance. According to the
guidelines, mitotane therapy should be continued for at least 2 years to a maximum of 5 years, if adequately tolerated [3]. A periodic measurement of plasma mitotane is mandatory to prevent adverse effects. The most common adverse events are gas- trointestinal manifestations (i.e. nausea, vomiting), increase of hepatic enzymes (in particular. gamma glutamyl transferase (GGT), less frequently aspartate aminotransferase (GOT) and alanine aminotransfer- ase (GPT)), central hypothyroidism, hypercholester- olemia and hypertriglyceridemia. Hematological toxicity (i.e. anemia, leucopenia, thrombocytope- nia) and central nervous system (CNS) effects (i.e. somnolence, lethargy), mostly in cases of levels greater than 20 mg/l, can occur. Primary hypogo- nadism and gynecomastia can be observed in men.
Owing to its adrenolytic effect, all patients need a glucocorticoid supplementation to avoid adrenal insufficiency; on the contrary, mineralocorticoid supplementation is not always required as zona glo- merulosa is more resistant to mitotane toxicity [5].
To prevent and correctly manage these manifes- tations, a regular biochemical and hormonal moni- toring is needed (Table 1).
Calabrese et al. [6”] analyzed a retrospective series of 152 patients with nonmetastatic ACC divided into two groups: patients who underwent adjuvant mitotane therapy (n=100, mitotane group) and patients untreated after initial surgery (n=52, control group). The median recurrence-free survival (RFS) was 36.8 months (4-199) in the mito- tane-treated group and 21 months (4-180) in the untreated group (P<0.001). No difference in overall survival (OS) was observed between the two groups; however, adjuvant mitotane was asso- ciated with longer OS in patients with stage III and Ki67 greater than 10, features related to high risk of recurrence.
| Parameter | Interval |
|---|---|
| Mitotane blood level | Every 3-4 weeks and after reaching levels greater than 14 mg/l every 2-3 months |
| GOT, GPT, GGT, bilirubin | Initially every 3-4 weeks, after 6 months every 2-3 months |
| Blood count | Initially after 3-4 weeks, then after 3-4 months |
| ACTH | Suggested monitoring in suspected glucocorticoid deficiency or excess |
| TSH, FT4 | Every 3-4 months |
| Renin | Every 6 months |
| Cholesterol (HDL, LDL) | Every 3-4 months (in adjuvant setting) |
| Testosterone and SHBG in men | Every 3-4 months (in adjuvant setting) |
Adapted from [3]. ACTH, Adreno coricotropic hormone; GGT, glutamyl transferase; GOT, aspartate aminotransferase; GPT, alanine aminotransferase; HDL, high- density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol; TSH, Thyroid stimulating hormone.
In a recent retrospective Italian study on 110 patients affected by ACC treated with adjuvant mitotane for a median duration of 46 months (inter- quartile range, 28-42), multivariate analysis dem- onstrated that the time in the target range of plasma mitotane (14-20 mg/l) was associated with a signifi- cantly low risk of recurrence (hazard ratio=0.93; 0.88-0.98, P<0.01) [7”]. These results support the importance of reaching a therapeutic window of plasma mitotane and its monitoring.
The ADIUVO clinical trial, a phase III random- ized controlled study (ClinicalTrials.gov NCT00777244) promoted by ENS@T group, has been recently completed. The aim was to estimate the efficacy of adjuvant mitotane treatment in pro- longing the RFS in patients with low-risk/moderate- risk ACC. Results are not available at the time of drafting this review.
A phase III study (ADIUVO II, ClinicalTrials.gov NCT03583710) is ongoing to evaluate the effect of adjuvant mitotane alone and combined adjuvant mitotane with etoposide/cisplatin on RFS in patients with high-risk ACC after initial surgical resection.
MANAGEMENT OF RECURRENT/ METASTATIC ADRENOCORTICAL CARCINOMA
Surgery should be considered in cases of isolated or oligometastatic disease when complete resection (R0) seems obtainable, in order to improve disease control and survival. Data on local therapeutic mea- sures (e.g. radiation therapy, radiofrequency abla- tion, chemoembolization) in patients affected by advanced ACC are limited but these procedures could be helpful in lowering metastatic burden and slowing disease progression, in addition to sur- gery [8]. However, in all patients with recurrent/ metastatic disease, mitotane therapy should be started as soon as possible. In patients with high tumor burden and rapid disease progression, the combination of EDP-M is recommended [3].
Recently, the data of 80 patients with advanced ACC were retrospectively analyzed [9”] to assess the impact of time in the target range of mitotane levels (14-20 mg/l) on the patients’ response to therapy and outcome. At baseline evaluation, mitotane monotherapy was employed in 56.2% of cases, whereas mitotane with a combination of chemo- therapy, in most cases, EDP, was started in 43.8% of patients. Median follow-up was 33 months (22- 51.2). During the entire follow-up, 68 patients received mitotane including at least one chemother- apy treatment. Patients with progression disease had a lower time target range, that was confirmed as an
independent predictor of OS at multivariate analy- sis. These results support the importance to main- tain a ‘therapeutic window’ for plasma mitotane in advanced ACC [9”]. Laganà et al. [10""] evaluated the efficacy of the EDP-M scheme in 58 patients with stage III-IV ACC. The median follow-up was 34 months (12-145) and median administered EDP cycles were 5.5 (1-8). Half of the enrolled patients completed the treatment plan (at least six cycles). The most frequent adverse events were asthenia (53%), nausea and vomiting (40%), hema- tological toxicity (31%). One patient died for a hemorrhagic shock because of massive gastric bleed- ing, potentially related to the treatment scheme. A partial response was reached in 50% of cases and a stable disease in 26% of cases. No complete response was observed, whereas a progression disease was reported in 24% of patients. The progression free survival (PFS) was 10.1 months (95% confidence interval (CI) 8.1-12.8) and OS was 18.7 months (95% CI 14.6-22.8). Patients who underwent sur- gery after a disease response to EDP-M had a better PFS (median 13.1 vs. 7.4 months, P=0.053) and OS (median 29.8 vs. 10.8 months, P≤0.0001) com- pared with those who did not [10""]. This report confirms the limited efficacy of the EDP-M scheme but it currently remains the most effective therapy in the management of advanced ACC.
OTHER CHEMOTHERAPY OPTIONS
No robust data on second-line and third-line che- motherapy is available for patients treated with mitotane with EDP and progression disease. The most used second-line chemotherapy is a combined gemcitabine and metronomic capecitabine. A mul- ticenter phase II study was conducted in 145 patients with advanced ACC. The scheduled therapy consisted of 800 mg/m2 intravenous gemcitabine on days 1 and 8 every 21 days with oral capecitabine (1500 mg daily). Partial response and stable disease were achieved in 4.9 and 25%, respectively, with PFS and OS for 3 and 10 months, respectively [11].
Alternatively, a second-line therapy may be rep- resented by streptozotocin every 3 weeks (1g on days 1-5 in cycle 1; 2g on day 1 in subsequent cycles), which in FIRM-ACT study demonstrated no significant difference in OS as compared with EDP [12].
The third-line chemotherapy is represented by temozolomide at the dose of 220 mg/m2/day for five consecutive days every 28 days. A recent study including 28 patients demonstrated one complete response, five partial response and four stable dis- ease with a median PFS and OS of 3.5 and 7.2 months, respectively. Temozolomide was more
| Study title (identifier number) | Interventions | Locations |
|---|---|---|
| Cabazitaxel Activity in Patients With Advanced AdrenoCortical-Carcinoma Progressing After Previous Chemotherapy Lines (CabACC) (NCT03257891) | Cabazitaxel | Azienda Ospedaliera Spedali Civili di Brescia, Brescia, Italy |
| Cabozantinib in Advanced Adrenocortical Carcinoma (CaboACC) (NCT03612232) | Cabozantinib | University Hospital Würzburg, Würzburg, Germany |
| Cabozantinib in Treating Patients With Locally Advanced or Metastatic Unresectable Adrenocortical Carcinoma (NCT03370718) | Cabozantinib | M D Anderson Cancer Center, Houston, Texas, United States |
| Cabozantinib-S-Malate in Treating Younger Patients With Recurrent, Refractory, or Newly Diagnosed Sarcomas, Wilms Tumor, or Other Rare Tumors (NCT02867592) | Cabozantinib | Children's Hospital of Alabama Birmingham, Alabama, United States Providence Alaska Medical Center Anchorage, Alaska, United States Arkansas Children's Hospital Little Rock, Arkansas, United States And more other centers |
| Pembrolizumab in Treating Patients With Rare Tumors That Cannot Be Removed by Surgery or Are Metastatic (NCT02721732) | Pembrolizumab | M D Anderson Cancer Center, Houston, Texas, United States |
| Nivolumab and Ipilimumab in Treating Patients With Rare Tumors (NCT02834013) | Nivolumab, Ipilimumab | University of Alabama at Birmingham Cancer Center Birmingham, Alabama, United States And more other centers |
| Nivolumab Combined With Ipilimumab for Patients With Advanced Rare Genitourinary Tumors (NCT03333616) | Nivolumab, Ipilimumab | University of California, San Diego Moores Cancer Center La Jolla, California, United States Winship Cancer Institute, Emory University Atlanta, Georgia, United States Beth Israel Deaconess Medical Center Boston, Massachusetts, United States And other three centers |
| A Novel Therapeutic Vaccine (EO2401) in Metastatic Adrenocortical Carcinoma, or Malignant Pheochromocytoma/Paraganglioma (NCT04187404) | Biological: EO2401 | MD Anderson Cancer Center Houston, Texas, United States Rigshospitalet Copenhagen, Denmark Centre Léon Bérard Lyon, France And other six centers |
Available at: www.ClinicalTrial.gov.
effective in patients with methylation of O6-methyl- guanine-DNA methyltransferase (MGMT) gene [13]. A trial with a taxoid cabazitaxel is ongoing (CabACC ClinicalTrials.gov NCT03257891) (Table 2).
RADIOMETABOLIC THERAPY
Data regarding 11 patients treated with 123 iodine metomidate (IMTO) are available (ORR 9%). It rep- resents a possible therapeutic option in selected patients [8].
In-vitro and in-vivo studies have demonstrated a high somatostatin receptor (SSTR) expression in ACC cells and tissues but no trials have been con- ducted so far. Data in only two treated patients are available (overall disease control for 4 and 12
months, respectively) [14]. SSTR-targeted radiome- tabolic therapy could represent a future option for patients with a positive immunohistochemistry and/or 68Ga-DOTATOC PET [8].
TARGETED THERAPY
In the last decade, many molecular alterations were identified in ACC. In 2014, was conducted the first comprehensive molecular analysis of ACC: some driver genes were identified, including ZNRF3, CTNBB1, TP53, RB1, CDKN2A, MEN1, DAX, ATRX, TERT, TERF2, RPL22, PRKAR1A [15""]. On the basis of the combined expression of PINK1 with DLG7 or BUB1B, a classification in two different classes was obtained: C1A cluster - including aggressive ACC -
and C1B cluster - including indolent forms [15""]. DNA methylation was also investigated in ACC: the presence of hypermethylated CpG island in the promoter of tumor suppressor genes (CpG Island Methylator Phenotype, CIMP) was observed. A reclassification in three classes with different out- comes was obtained (CIMP high, CIMP low, non- CIMP). Recently, in CIMP-high patients, the pres- ence of G0S2 hypermethylation as a single marker of aggressive disease was demonstrated [16""].
Moreover, in a recent study, a 2.8-fold higher mutation rate was demonstrated in metastatic tumor than in primary tumor [15""]. Insulin-like growth factor II (IGF-II) represents the most overexpressed gene in 70-90% of ACC. Linsitinib, an inhibitor of IGF-IR, was tested in a double-blinded, randomized, phase III study at a dose of 150 mg twice daily. Unfor- tunately, no differences in OS and in RFS between treated and untreated patients were observed (P=0.77 and P=0.30, respectively). Out of 90 patients included in the linsitinib group, three patients (3%) obtained a partial response and 14 (15.6%) showed a stable disease [17]. Moreover, many tyrosine kinase inhibitors have been evaluated with- out obtaining good results. In a phase II clinical trial, sunitinib was administered to 35 patients. The start- ing dose was 50 mg/day for 4 weeks on and 2 weeks off. Only five patients obtained a stable disease. The median PFS and OS were 83 days and 5.4 months, respectively. The combined mitotane therapy seems to have a negative effect on the response to sunitinib, because of its CYP3A4-inducing action [17,18]. In 2020, Kroiss et al. [18] published a study conducted on 16 patients with progressive ACC treated with a multityrosine kinase inhibitor, cabozantinib (CABO), without associated mitotane therapy. The starting dose was different, ranging from 20 to 140 mg and the median maximum dose reached was 80 mg (60-140). Three patients obtained a partial response and five a stable disease with a median PFS and OS of 16 and 58 weeks, respectively. mTOR is a protein kinase involved in proliferation control mod- ulating the effects of growth factors, such as IGFs. Recently, a combined treatment with linsitinib and the mTOR inhibitor sirolimus, was tested in vitro [19]. Many studies have been conducted to evaluate the efficacy of targeted therapies but to date no satisfac- tory results have been obtained.
Three trials with CABO are ongoing (Clinical- Trials.gov NCT03612232, NCT03370718, NCT02867592) (Table 2).
IMMUNOTHERAPY
Currently, the role of immune checkpoint inhibi- tors (ICI) in ACC tumors is still unclear. The
programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway is modulated by cancer cells inducing an immunosuppressive environment that allows tumor growth. Many different monoclo- nal antibodies target the PD1/PD-L1 pathway. In ACC tumors, the PD-L1 expression has been observed. A high expression of Fetal and Adult Testis Expressed 1 (FATE1) gene in adult ACC tissues has been demonstrated to be associated with worse prognosis [20].
Recently, a review of the literature was con- ducted to evaluate the effectiveness of immunother- apy. One hundred and fifteen patients were treated with an ORR from 30 to 64%, PFS and OS from 1.8 to 2.6 and from 10.6 to 24.0 months, respectively [21].
In 2018, a single-arm phase Ib study with ave- lumab was conducted in 50 metastatic ACC (10 mg/ kg intravenously every 2 weeks). Twenty-five patients also started mitotane therapy. The primary endpoint was ORR as evaluated by RECIST criteria. Three patients obtained partial response and 21 stable disease. PFS and OS were 2.6 and 10.6 months, respectively [22].
In 2019, a single-arm multicenter phase II study was conducted with nivolumab (240 mg intrave- nously every 2 weeks) in 10 patients affected by metastatic ACC. The primary endpoint was ORR evaluated by RECIST criteria. Two out of eight patients showed stable disease and six progressive disease. The PFS was 1.8 months [23].
A phase II trial, involving 29 patients with advanced ACC treated with AT-101 (20 mg oral daily dose, 21 out of 28 days), was considered ineffective and was closed [24].
The results of two single-center phase II clinical trials in advanced ACC have been published in the last 2 years. In both studies, pembrolizumab 200 mg intravenously every 3 weeks without concomitant mitotane therapy was administered. Habra et al. [25] in their study included 16 patients. The primary endpoint was no progression rate (NPR) after 27 weeks of treatment. Five out of 14 patients evaluated after 27 weeks were progression free. At the radiological evaluation, 14 patients experimented with partial response, 7 stable disease, and 5 progressive disease with an ORR of 14% [25]. Three out of seven patients affected by a cortisol producing ACC presented stable disease, one partial response and three progressive disease. The second study included 39 patients [24]. The primary endpoint was ORR, as evaluated by RECIST criteria. Nine out of 39 patients presented a partial response and 7 a stable disease. Two patients had a mixed response with a positive effect on lung metastases and progression on liver lesions. PFS was 2.1 months and OS was 24.9 months [26]. A correla- tion between response to pembrolizumab and PD-L1
status and tumor-infiltrating lymphocytes (TIL) was not demonstrated in both studies.
Unfortunately, immunotherapy leads to modest results in ACC for many reasons; PDL-1 expression is present in few cases of ACC and the presence of TP53 mutations and WNT-B-catenin amplification are responsible for a decreased production of CD8+ required for responding to immunotherapy [27”]. Moreover, many patients present a glucocorticoid- secreting ACC with an immunosuppressive action [28].
Contrary to what happens in patients treated with targeted therapy, the combination of mitotane with immunotherapy seems to have a synergistic effect [29”].
Trials with combined therapy with nivolumab and ipilimumab (ClinicalTrials.gov NCT02834013 and NCT03333616) and one with pembrolizumab (ClinicalTrials.gov NCT02721732) are ongoing (Table 2).
CONCLUSION
ACC is a rare aggressive tumor. To date, none of the tested drugs significantly improved disease outcome, except in rare cases. Drug interactions with mitotane may play an important role in the therapy failure. However, different pathways can act in synergy; hence, the use of combined therapies represents an important therapeutic option. The study of the genetic expression and the methylation profile seems to be promising for prognosticating ACC. The possi- bility of carrying out analysis of a single marker makes this evaluation useful in clinical management. In this perspective, it is necessary to implement the charac- terization of patients affected by advanced disease also considering the metastasis tissue analysis.
Acknowledgements
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Conflicts of interest
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REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
of special interest
of outstanding interest
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