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REVIEW
Oncological Management of Adrenocortical Carcinoma: An Update and Critical Review
Nicholas P. Rowell ®
Received: December 5, 2024 / Accepted: January 27, 2025 / Published online: February 18, 2025 @ The Author(s) 2025
ABSTRACT
Adrenocortical carcinoma is a very rare cancer that commonly presents with hormonal abnor- malities or, more rarely, as an incidental finding of an adrenal mass. Following optimal surgical management, ideally in the form of open adre- nalectomy, meta-analyses show that adjuvant mitotane significantly increases recurrence-free and overall survival (HR 0.62 and 0.69 respec- tively) and tumour bed radiotherapy reduces locoregional recurrence and overall survival for higher risk cancers by at least 40-50%. Those with recurrent or metastatic cancers can be considered for the combination of etoposide, doxorubicin, cisplatin and mitotane (EDP-M) on the basis of results of a single randomised trial. There are significant pharmacological interactions within this regime that have yet to be satisfactorily addressed. Patients of borderline performance status may be treated with vari- ous modifications of this regime. More recent approaches with immune checkpoint inhibitors (ICI) and targeted therapy (TT), either alone or in combination, show some promise, but pro- gression-free survival for the majority of regimes
does not exceed 6 months. Cabozantinib or len- vatinib alone or in combination, show the great- est promise with disease control rates of 50% or greater, and progression-free survival in excess of 6 months. Studies combining ICIs and TT as a means of overcoming the immunosuppres- sive environment are ongoing. There are several ongoing clinical trials in this area although only a small proportion of patients may be able to access these. Local therapies with radiotherapy, thermal ablation or arterial embolisation may be helpful for selected patients, particularly those with oligometastatic disease or those with symp- tomatic metastases.
Keywords: Adrenocortical carcinoma; Mitotane; Radiotherapy; Immune checkpoint inhibitors; Targeted therapy
Key Summary Points
Adjuvant mitotane following surgery and adjuvant tumour bed radiotherapy, either alone or together, reduce recurrence in high- risk patients.
Etoposide, doxorubicin, cisplatin and mito- tane is standard first-line treatment for recur- rent or metastatic disease.
N. P. Rowell ( Kent Oncology Centre, Maidstone Hospital, Hermitage Lane, Maidstone, Kent ME16 9QQ, UK e-mail: nrowell@nhs.net
Though promising because of overexpression of MET and VEGF pathways, targeted therapy (TT) with kinase inhibitors has so far proved to have limited activity. Immunotherapy has proved less effective than in other solid tumours, but with the possibility of greater effectiveness when combined with TT. Stereotactic radiotherapy, thermal ablation or tumour embolisation can be helpful for patients with low volume metastatic disease, particularly in liver or lung while palliative radiotherapy can be helpful for those with symptomatic metastases.
INTRODUCTION
Adrenocortical carcinoma (ACC) is a rare can- cer, with an annual incidence of approximately one case per million population in the USA and Europe [1, 2]. Median age at diagnosis is 55 years, with a slight female preponderance, and approximately one-quarter of patients pre- sent with metastatic disease [1].
Adrenal masses are common incidental findings identified on routine cross-sectional imaging, most of which will prove to be small non-secretory adenomas, with larger masses (greater than 4 cm) more likely to be malignant [3]. Endocrine testing (which will also identify phaeochromocytomas) is recommended in all cases [4]. Cushing’s syndrome or an excess of sex hormones (producing a virilising syndrome, a feminising syndrome or a compound mixed syn- drome) may result from hormonal overproduc- tion by an adrenal adenoma or less commonly by an adrenocortical carcinoma. Of those with a final diagnosis of ACC, approximately one-third of cancers will be found to be non-secreting, which is associated with better overall survival [5, 6].
Adrenal metastases from an established meta- static cancer (most commonly breast, lung or melanoma) are found in up to 50% of patients with metastatic disease [7]. However, sarcomas, extension from a renal carcinoma or metastases from an unknown primary may present as an adrenal mass, although sarcomas in this region
typically arise retroperitoneally and extend to involve the adrenal rather than originating in the adrenal itself [8]
Following identification of a probable ACC, surgery is the treatment of choice without ini- tial biopsy because of the risk of tumour seeding along the biopsy track [9]. Open adrenalectomy has been associated with better outcomes than laparoscopic techniques [10, 11] and may need to include resection of adjacent organs (e.g. kid- ney, spleen, tail of pancreas) in order to achieve adequate clearance, although laparoscopic adre- nalectomy in the hands of those skilled in this approach may be considered for tumours <6 cm without local invasion [12]. An adrenal biopsy should only be considered in selected cases in which an adrenal metastasis of an extra-adrenal malignancy is suspected that precludes surgery, or in which the tumour is unresectable and where histopathologic confirmation is required to inform oncological management [12]. His- tological examination will confirm the diagno- sis. For ACC, prognosis depends on the Weiss score (a tumour grading system based on nine histological criteria applied to haematoxylin and eosin-stained slides, where a score of 1-3 is indicative of a benign tumour, 4-6 low-risk ACC and 7-10 high-risk ACC) [4]. Ki67 stain- ing likewise has prognostic significance with less than 10% of tumour cells staining being associ- ated with a slower rate of progression compared to tumours with Ki67 staining>20% [4, 13]. A proportion of ACC will prove to be unresectable, or operability may be limited by performance status or the presence of comorbidities. The prognosis is highly variable with complete sur- gical resection providing the only means of cure, with high Ki67 staining, high tumour grade and cortisol excess being independent adverse risk factors [4].
METHODS
This review seeks to aid clinicians in making treatment decisions, pointing out limitations of the current evidence and directions of current clinical trials. Given the very disparate nature of the evidence, much of this review is narrative in
nature. A systematic review was undertaken for the effects for radiotherapy using search terms adrenocortical carcinoma and radiotherapy, excluding studies or case reports where fewer than ten patients had received radiotherapy. Meta-analysis, using a fixed effects model, was undertaken using RevMan software [Ver- sion 8.9.0. The Cochrane Collaboration, 2024. Available at revman.cochrane.org]. This review focuses on treatment of adults with ACC over the age of 18 years.
Ethical approval was not sought as this review is based on previously conducted studies and does not contain any new studies with human participants or animals performed by the author.
ADJUVANT TREATMENT
Mitotane, a parent compound of the insecti- cide DDT (dichlorodiphenyltrichloroethane), has direct effects on adrenal cells leading to reduced steroidogenesis and cell death. Mito- tane has a long half-life (ranging from days to weeks) and a high volume of distribution, bind- ing extensively, particularly to adipose tissue [14]. Side effects, including nausea, vomiting, diarrhoea and fatigue along with ataxia, depres- sion and memory loss, increase in proportion to plasma mitotane levels. Mineralocorticoid defi- ciency and hypothyroidism may also occur [15]. The combination of side effects and complex pharmacokinetics result in a narrow therapeu- tic window and routine measurement of plasma levels is recommended, aiming for plasma mito- tane concentrations in the range 14-20 mg/l [16]. Stabilisation of levels generally takes about eight weeks, whether starting gradually or with a rapid escalation approach. Levels should be monitored at 4-weekly intervals until the desired level is reached, then at intervals of 4-12 weeks [14]. Mitotane is a potent enzyme inducer, par- ticularly of cytochrome CYP3A4, with signifi- cant effects on co-administered drugs [16].
In a meta-analysis of five retrospective studies of non-metastatic ACC, adjuvant mitotane pro- longed both overall survival (HR 0.69; P<0.05) and recurrence-free survival (HR 0.62; P<0.05) [17]. Some studies included patients with R2
resection, and most allowed radiotherapy. In the ADIUVO study of low to intermediate risk ACC, defined as those with an R0 resection and Ki67 less than 10%, there was an overall 5-year recurrence-free survival rate of 75% and no benefit from 2 years adjuvant mitotane [18]. On this basis, following resection, adjuvant treatment with mitotane may be considered for those considered to be at higher risk of recur- rence, namely those with R1 or R2 resection and/or Ki67>10% (Table 3). Optimal duration of treatment remains uncertain although one retrospective study found no clear evidence of benefit beyond 2 years [19].
Alongside mitotane, external beam radio- therapy (EBRT) may be considered as adjuvant treatment for selected patients. A systematic review was undertaken and identified nine single or multicentre retrospective studies in which EBRT had been given following surgery with curative intent [20-28] (Table 1). As four reports [22, 24, 26, 28] originate from the same centre, the intermediate studies [23, 28] have been excluded from further analysis to reduce the amount of overlap, leaving a total of 1338 patients in the seven studies, of which 147 received EBRT. The use of matched controls in some studies reduces the size of the unirradi- ated group but does reduce the impact of con- founding variables. The control group therefore comprised 214 patients. In a meta-analysis, the risk of locoregional recurrence was reduced from 56.5% in the unirradiated patients to 36.1% in those receiving EBRT (relative risk 0.59; 95% CI 0.46-0.74; P<0.00001; Fig. 1). Likewise, the risk of death was reduced from 45.8 to 23.4% (relative risk 0.49; 95% CI 0.33-0.72; P=0.0003; Fig. 2). In one of the excluded studies, there was evidence of a positive interaction between EBRT and mitotane resulting in a greater reduction in the risk of recurrence in those receiving both treatments (HR 0.42; 95% CI 0.18-0.93) [28]. While evidence from these studies shows that EBRT may be beneficial in the populations of patients treated, the question as to whether par- ticular subgroups might benefit from EBRT to a greater or less extent is not really addressed.
The literature search identified seven popu- lation studies based on the US National Can- cer Database (NCDB) or the Surveillance,
| Study | Centre | Years | Num- ber of patients | Radiation dose (Gy); median (range) | Median follow-up (months) | Control group |
|---|---|---|---|---|---|---|
| Wu 2023 [20] | Shanghai | 2015-2021 | 105 | 45 (30-50.4) | 36.5 | |
| Zhu 2020 [21] | Peking | 1994-2014 | 75 | Not stated | 30 | Propensity-score matched |
| Gharzai 2019 [22] | Michigan | 2003-2017 | 424 | 55 (45-60) | 50.5 | Propensity-score matched |
| Srougi 2017 [23] | Sao Paulo | 1994-2014 | 61 | 54 (45-54) | 33.5 | Paired compari- son |
| Sabolch 2015 [24] | Michigan | 1991-2011 | 360 | 55 (45-60) | 34 | Matched con- trols |
| Else 2013 [28] | Michigan | 1979-2013 | 389 | Not stated | Not stated | |
| Habra 2013 [25] | MD Anderson | 1998-2011 | 330 | 50.4 (36-59.4) | 27.6 | |
| Sabolch 2011 [26] | Michigan | 1989-2008 | 58 | 53.4 (45-57) | 72 | |
| Fassnacht 2006 [27] | German ACC Registry | Not stated | 285 | Not stated | 37 | Matched controls |
| Study or Subgroup | Surgery + Events | Radiotherapy Total | Surgery Events | only Total | Weight | Risk ratio M-H, Fixed, 95% CI | Risk ratio M-H, Fixed, 95% CI |
|---|---|---|---|---|---|---|---|
| Fassnacht 2006 | 2 | 14 | 11 | 14 | 10.8% | 0.18 [0.05, 0.68] | |
| Gharzai 2019 | 13 | 39 | 28 | 39 | 27.6% | 0.46 [0.29 , 0.75] | |
| Habra 2013 | 7 | 16 | 10 | 32 | 6.6% | 1.40 [0.66 , 2.98] | |
| Sabolch 2011 | 2 | 10 | 16 | 48 | 5.4% | 0.60 [0.16 , 2.21] | |
| Srougi 2017 | 4 | 10 | 6 | 10 | 5.9% | 0.67 [0.27 , 1.66] | |
| Wu 2023 | 23 | 46 | 46 | 59 | 39.7% | 0.64 [0.47 , 0.88] | |
| Zhu 2023 | 2 | 12 | 4 | 12 | 3.9% | 0.50 [0.11 , 2.23] | |
| Total | 147 | 214 | 100.0% | 0.59 [0.46 , 0.74] | |||
| Total events: | 53 | 121 | |||||
| Test for overall effect: Z = 4.45 (P < 0.00001) Test for subgroup differences: Not applicable Heterogeneity: Chi2 = 9.45, df = 6 (P = 0.15); 12 = 37% | 0.01 | 0.1 1 10 100 | |||||
| Favours Surgery + | Radiotherapy Favours Surgery only | ||||||
Epidemiology and End Results (SEER) database [29-35] (Table 2). These seven studies cover overlapping time periods and can reasonably be reduced to two [29, 30]. The main concern with population studies is that as treatment strategies differ across many centres, irradiated patients are likely to have been those considered
at greater clinical risk, and simple compari- son with those not irradiated will likely show worse outcomes (particularly with respect to survival) in those at greater risk (i.e. those for whom EBRT was advised). There needs therefore to be some means of addressing the confound- ing variables and eliminating this as a source of
| Study or Subgroup | Surgery + Events | Radiotherapy Total | Surgery Events | only Total | Weight | Risk ratio M-H, Fixed, 95% CI | Risk ratio M-H, Fixed, 95% CI |
|---|---|---|---|---|---|---|---|
| Gharzai 2019 | 8 | 39 | 24 | 39 | 45.7% | 0.33 [0.17, 0.65] | |
| Srougi 2017 | 7 | 10 | 7 | 10 | 13.3% | 1.00 [0.56, 1.78] | |
| Wu 2023 | 5 | 46 | 20 | 59 | 33.4% | 0.32 [0.13, 0.79] | |
| Zhu 2023 | 5 | 12 | 4 | 12 | 7.6% | 1.25 [0.44 , 3.55] | |
| Total | 107 | 120 | 100.0% | 0.49 [0.33 , 0.72] | |||
| Total events: | 25 | 55 | |||||
| Test for overall effect: | Z = 3.62 (P = 0.0003) | 0.01 | 0.1 1 10 100 | ||||
| Test for subgroup Heterogeneity: Chi2 = | differences: Not applicable 11.23, df = 3 (P = 0.01); 12 = | Favours Surgery + | Radiotherapy Favours Surgery only | ||||
| 73% | |||||||
| Study | Database | Years | Number of patients | Note |
|---|---|---|---|---|
| Abdel-Rahman 2022 [29] | SEER | 2010-2015 | 294 | |
| Wu 2021 [30] | SEER | 2004-2016 | 365 | |
| Ginsburg 2021 [31] | NCDB | 2004-2017 | 1433 | Treated surgically with at least one risk factor |
| Thomas 2021 [32] | SEER | 1988-2015 | 865 | Controls propensity-score matched |
| Nelson 2018 [33] | NCDB | 2004-2013 | 1184 | |
| Tella 2018 [34] | NCDB | 2004-2015 | 3185 | |
| Luo 2017 [35] | SEER | 1973-2013 | 530 | Controls propensity-score matched |
NCDB National Cancer Database, SEER Surveillance, Epidemiology and End Results database
selection bias. However, this bias may be con- sidered predominantly unidirectional, meaning that potential treatment benefit in a higher risk group is likely to be underestimated rather than overestimated. The NCDB study [31] included 1433 patients treated surgically with at least one risk factor (tumour size greater than 6 cm, high-grade histology or positive surgical margin) and showed that in the whole group there was no survival benefit from EBRT (perhaps unsur- prisingly), but when individually risk categories were examined, overall survival was improved by radiotherapy for each risk factor (HR 0.47 for positive surgical margin; 0.69 for tumours>6 cm and 0.61 for high-grade disease). In the SEER study [32], after propensity-score adjustment, there was improved overall survival in those
with stage III disease but who were node-neg- ative (HR 0.42; 95% CI 0.21-0.83) amounting to 65.5% versus 37.9% 3-year overall survival. ENSAT stage III includes T3 and T4 cancers (i.e. those extending into surrounding fat or into adjacent organs or structures) with or without regional lymph node involvement [36]. One of the excluded SEER studies [30] did identify age over 55 as a risk factor on multivariate analysis.
From these studies, we can conclude that EBRT significantly improves overall survival by reducing locoregional recurrence and that radi- otherapy should be considered for those with tumours>6 cm, positive surgical margins or high-grade disease (Table 3). Age over 55 might be considered an additional factor, though with less weight.
| Risk factor | Adjuvant mito- tane | Adjuvant EBRT |
|---|---|---|
| Tumour size | >6 cm | |
| Histology | High-grade | |
| Ki67 | > 10% | |
| Stage | Node-negative stage III (T3_4No) | |
| Microscopic margins | Positive* | Positive* |
| Age | > 55 ** |
*i.e. following R1 or R2 resection
** Age as a risk factor identified in only one study
RECURRENT OR METASTATIC DISEASE
Cytotoxic Chemotherapy
Although only a minority have metastases at diagnosis, 30-50% may develop distant metas- tases subsequently. There had been early reports of responses to streptozotocin with an objective response rate of 36% in 22 patients with meas- urable disease [37], while an Italian multicen- tre phase II study conducted between 1993 and 2003 found a response rate of 49% in 72 patients with recurrent or metastatic ACC with a median duration of response of 18 months in respond- ing patients [38]. This paved the way for the FIRM-ACT randomised controlled trial of EDP-M versus streptozotocin and mitotane (SzM) [39]. This, however, demonstrated an objective response rate of 23% in the EDP-M arm but only 9% in the SzM arm with median progression-free interval (PFS) of 5.0 versus 2.1 months (HR 0.55, P≤0.001). The improvement in overall survival was less convincing (14.8 versus 12.0 months; HR 0.79; P=0.07), probably because crossover to the other arm was permitted at progression.
In a population-based study of EDP-M, mul- tivariate analysis identified mitotane only as being associated with better overall survival, but not EDP-M [40]. Three separate retrospec- tive studies identified complete plus partial response rates of 50%, 12% and 18% to EDP-M with progression-free survival rates of 10.0, 6.2 and 6.5 months respectively [41-43], with the first study using post-treatment surgery as a means of enhancing response rates. An earlier phase II study using just etoposide and cispl- atin (with mitotane on progression) reported only an 11% response rate in 45 patients and concluded that “the combination of cispl- atin and etoposide has minimal activity in advanced and metastatic ACC” [44].
In a retrospective single institution study, 15/53 patients who were considered to be of borderline resectability received preoperative treatment with EDP-M (or EDP alone in one and mitotane only in two patients). A partial response was seen in 5/12 (39%) with 13 subse- quently undergoing surgical resection [45].
From this series of results, it is difficult to conclude definitively which are the more active components of the EDP-M regime, though mitotane does appear to be a key component. Because of enzyme induction by mitotane (par- ticularly via CYP3A4), concurrent administra- tion of mitotane reduces etoposide levels and AUC (area under the time-concentration curve) by about 50% [46]. In this study of five patients who progressed on EDP-M, there were two fur- ther responses resulting from subsequent etopo- side dose escalation, consistent with evidence that, as in other cancers, response is related to etoposide AUC. Whether the EDP-M regime as currently formulated is the optimal means of delivering these drugs remains unclear.
A variation of the EDP-M regime using a novel 96-h infusion of doxorubicin, etoposide and vincristine with a dose escalation plan for etoposide according to neutrophil counts saw a 22% response rate in 36 patients with four patients able to undergo surgery [47]. High lev- els of P-glycoprotein within tumours were seen in the nine patients in whom this was measured, but in vivo P-glycoprotein inhibition could not be demonstrated despite mitotane levels in the therapeutic range.
There is also evidence that this enzyme induction reduces the effectiveness of doxoru- bicin [48, 49]. On the other hand, there is some evidence that mitotane enhances the effects of doxorubicin on ACC cells in vitro where these displayed chemoresistance due to raised P-gly- coprotein levels [50].
Other cytotoxic agents have been assessed but results have been disappointing. In a sys- tematic review of phase II/III trials of systemic therapy, most were early trials with EDP-M or variations [51]. This review identified a single study using irinotecan but with no responders in 12 previously treated patients [52]. Despite encouraging in vitro results with paclitaxel [53], there were no objective responders and a disease-control rate (DCR) of 24% at 4 months and a median PFS of 1.5 months in a phase II study of cabazitaxel [54], and disease progres- sion in all nine patients in a phase II study of paclitaxel and sorafenib [55]. There was a 21% response rate in 19 patients treated with docetaxel and cisplatin with a median PFS of 3 months [56], somewhat less than that seen in studies with EDP-M. Similarly, the combi- nation of gemcitabine and 5-flurouracil or capecitabine (again as second/third-line treat- ment) showed just a 7% response rate (though with disease stabilisation in 39%) and a median PFS of 5.3 months [57]. A subsequent multi- centre study of 145 patients (all but 12 receiv- ing second-line or subsequent treatment) using the same gemcitabine and capecitabine regime reported a partial response rate of 5% and a DCR of 34% [58]. The authors regarded this regime as “moderately active” and well toler- ated. Better outcomes were observed in those continuing mitotane.
An earlier systematic review also identified small series and case reports that had found limited evidence of response to thalidomide, trofosfamide and temozolomide [59]. In a ret- rospective study of 28 patients receiving temo- zolomide as second-line treatment, there were six objective responses (21%) and DCR of 36% with a median PFS of 3.5 months [60]. It is dif- ficult to conclude whether any of these agents might usefully be considered as second-line
therapy, although temozolomide might be worth considering.
Immunotherapy
A systematic review and meta-analysis of 20 studies using immune checkpoint inhibitors (ICI) alone or in combination found an overall response rate of 14% in one or more arms with a DCR of 43% and median PFS of 2.8 months, with a range in the eight studies reporting it of 1.4-6.3 months [61]. The included studies con- sisted of ten phase I/II trials, four retrospective studies or case series and six case reports, with a total of 248 patients. Treatment was generally well tolerated with grade 3/4 reactions in less than 4%. These small studies hamper definite conclusions but there was no clear difference between use of single agent therapy or com- binations. Studies did not record the concur- rent use of corticosteroids which might have reduced the effectiveness of ICI, and in some studies patients continued to take mitotane. Response was unrelated to programmed death ligand 1 (PD-L1) expression or microsatellite instability. The reasons for the relative ineffec- tiveness of ICI, in contrast to other cancers, are unclear. In a study of tissue samples from 56 patients with ACC, 15 (44%) stained posi- tive for programmed death ligand 2 (PD-L2) and just one (2%) for PD-L1 [62]. An earlier study demonstrated PD-L1 positivity in only 11% of 28 patients with ACC [63]. This might account for the lower response rate with the PD-L1 inhibitor avelumab [64] compared to PD-1 inhibitors in general [61]. In the JAVELIN study, the objective response rate to avelumab was 6% (DCR 48% and median PFS 2.6 months) in 50 patients who had previously received platinum-based chemotherapy and where 50% continued mitotane [64]. A more recent study demonstrated an association between positive PD-1 expression and longer PFS which was not seen in relation to PD-L1 or CTLA-4 [65].
Overall, ICI as a group have so far exhibited relatively low response rates and short progres- sion-free survival times.
Targeted Therapy
Preclinical studies have identified a number of potential targets in ACC [66]. However, despite approximately 80% of ACC expressing epider- mal growth factor receptor (EGFR), two early studies of EGFR inhibitors, erlotinib (in com- bination with gemcitabine) [67] and gefitinib [68], failed to produce any objective responses. Likewise, there were no objective responses seen in studies with the tyrosine kinase inhibi- tors sunitinib and sorafenib [55, 69]. A nega- tive correlation was seen between mitotane and sunitinib concentrations resulting in a higher odds ratio for progressive disease in those tak- ing mitotane [69].
A randomised controlled trial of linsitinib (an inhibitor of both insulin receptor and insu- lin-like growth factor receptor, IGF-1R) versus placebo showed no advantage for linsitinib but for comparative purposes (which is helpful in putting results of other studies in perspective), there was a 3% objective response rate with linsitinib and a DCR of 32% (versus 35% in the control group) and a median PFS of 1.4 months (versus 1.5 months in the control group) [70]. Similarly, there were no objective responses in 14 patients treated with a similarly targeted approach with figitumumab, an anti-IGF-1R monoclonal antibody (DCR 57%, median PFS not reported and six patients received concom- itant mitotane) [71]. However, the combina- tion of another IGF-1R-antibody cixutumumab and mitotane as first-line treatment only pro- duced one objective response in 20 patients (DCR 40%, median PFS 1.4 months) [72]. A similar study, using the combination of cixutu- mumab and the mTOR inhibitor temsirolimus in previously treated patients, saw no objective responses in 26 patients but disease stabilisa- tion in 42% and median PFS of 9 months [73].
A phase II trial of dovitinib, an inhibitor of fibroblast growth factor (FGF), produced just one objective response in 17 patients (DCR 30%, median PFS 1.8 months) [74].
Multikinase inhibitors (MKI), acting against a range of targets, have proven slightly more effective. Cabozantinib, an inhibitor of
vascular endothelial growth factor (VEGF), cMET and RET, produced an objective response rate of 19% with a DCR of 50% and median PFS of 3.7 months when used as a second-line (or greater) treatment in a retrospective cohort study of 16 patients [75]. Mitotane was discon- tinued in advance to ensure there was no inter- action between this and cabozantinib. Treat- ment was on the whole well tolerated but grade 3 adverse events were noted in 19%. A subse- quent single-centre phase II study using cabo- zantinib which recruited 18 patients, again fol- lowing discontinuation of mitotane, recorded a median PFS of 6 months (95% CI 4.3 months to not reached) [76]. Objective responses were seen in only two (11%) but there was a DCR of 78%. Grade 3 or worse adverse effects were seen in 61%, though with a preponderance of ele- vated liver enzymes or lipase concentrations. Cabozantinib levels were shown to be lower during the first month of treatment in those having received mitotane, even up to 6 months previously, despite the study requiring mito- tane levels to have fallen to less than one-tenth of the generally accepted therapeutic level for mitotane. A small study of salvage therapy included seven patients treated with another MKI, lenvatinib (an inhibitor of VEGF, FGF and RET), with two achieving partial responses (DCR 57% and median PFS 6 months) [77]. There is an ongoing phase II trial of cabozan- tinib in Germany (NCT03612232). The anti- VEGF antibody bevacizumab (plus capecit- abine), however, produced no responses in 10 patients [78]. Likewise, a further VEGF inhibi- tor, axitinib, produced no objective responses in a study of 13 patients though with some evidence of disease control in four (31%) and median PFS of 5.5 months [79].
In summary, MKIs can produce a small num- ber of objective responses, seemingly greater than with other types of targeted therapy, with DCR greater than 50% and PFS exceed- ing 6 months, though at the expense of some increase in toxicity. Though not directly com- pared and with evidence limited to small stud- ies, these results appear better than what has been achieved so far with immunotherapy approaches.
Combinations of Targeted Therapy with Immunotherapy
One approach to improve response rates has been to combine targeted therapy and immu- notherapy. Based on preclinical studies, there is potential synergy between MKIs and ICI due to the blockade of the VEGF receptor which may result in a more immune-responsive tumour microenvironment [80]. A retrospective case series of eight patients treated with lenvatinib and pembrolizumab reported partial responses in two and stable disease in one (DCR 38%, median PFS 5.5 months) [81]. In this study, six patients had received prior treatment with a PD-1 inhibitor as a single agent and five with an MKI. A further retrospective study of 17 patients treated with various ICI/MKI combinations reported an objective response rate of 13% with DCR of 59% and median PFS on 7.1 months [82].
Disappointingly, a recently reported prospec- tive multicentre phase II study in Spain with the combination of cabozantinib and atezolizumab (an antibody targeting PD-L1) produced only two partial responses in 24 patients (response rate 8.3%, median PFS 2.9 months, DCR not reported) [83].
There are ongoing trials with lenvatinib plus pembrolizumab in South Korea (NCT05036434) and with cabozantinib plus atezolizumab in USA (NCT06006013) which should help assess the potential of this approach.
LOCAL THERAPIES
Local therapies include radiation therapy (prin- cipally EBRT but also including peptide recep- tor radionuclide therapy), different techniques of thermal ablation, and arterial embolisation with a variety of drugs and particles.
Radiotherapy
As well as its indications as adjuvant treatment, conventional EBRT can be helpful as a pallia- tive treatment, as in other cancers. A systematic
review identified five studies of 209 patients [26, 84-87], undergoing 223 courses of treatment (Table 4) to a variety of sites, including bone, in over one half of instances, and the primary site, either for recurrent disease or in the pres- ence of metastatic disease, in approximately one quarter. One study [87] included a systematic review of 65 patients reported in earlier stud- ies. Overall, objective responses were observed in 33% (37/112), with 65% (77/118) reporting symptomatic benefit. Median time to progres- sion at the irradiated site was 7.6 months [84].
One study separately reported the use of stere- otactic ablative radiotherapy (SABR; 16 patients, 36 irradiated sites) [84]. This resulted in objec- tive responses in 24/36 (67%) with a median time to progression of 19.3 months. This study had also shown a higher response rate (65% ver- sus 26%) and longer time to progression in those treated with EBRT to a higher dose (50-60 Gy compared to less than 50 Gy). With increasing biologically effective dose, there is therefore a gradation in benefit from lower dose EBRT to higher dose EBRT to SABR. This study confirms the relative radiosensitivity of ACC and also records that higher dose treatments were, in general, delivered to smaller volumes. In this study, over one-half were also taking mitotane.
Thermal Ablation and Transarterial Embolisation
A recent review by Kimpel et al. [88] reported that local thermal ablation techniques (predomi- nantly image-guided radiofrequency ablation but including some studies using microwave or cryoablation) in 84 treated lesions resulted in a 32% complete response rate, with partial responses in 16% and stable disease in 32% (effectively a DCR of 80%) and a median time to progression (of the treated lesion) of greater than 22 months. Transarterial embolisation with lipiodol, chemotherapeutic agents or yttrium-90 glass microspheres yielded lower response rates (no complete responses but partial responses in 29% and DCR 52%) and shorter median time to lesion progression (8 months). However, these techniques are not directly comparable as the median size of treated lesions was 20 mm
| Study | Centre | Num- ber of patients | Total number of irradiated sites | Irradiation of bony sites | Irradiation of primary site* | Radiation dose (Gy) | Objective responses (CR+PR) (%) | Symp- tomatic improve- ment (%) |
|---|---|---|---|---|---|---|---|---|
| Kimpel | 5 European | 80 | 89 | 46 | 16 | 20-60 | 31/89 (35) | |
| 2023 [84] | centres | |||||||
| Ho 2013 | Bethesda | 12 | 15 | 6 | 8 | 17.5-60 | 4/13 (31) | 12/15 |
| [85] | (80) | |||||||
| Sabolch | Michigan | 16 | 16 | 11 | 5 | Not stated | ||
| 2011 [26] | ||||||||
| Hermsen | Dutch ACC | 10 | 10 | 6 | 4 | Not stated | 2/10 (20) | 8/10 |
| 2010 [86] | registry | (80) | ||||||
| Polat 2009 | German | 26 | 28 | 22 | 10-60 | 20/28 | ||
| [87] | ACC | (71) | ||||||
| registry | ||||||||
| Polat 2009 | Review of | 65 | 65 | Not stated | 15-51 | 37/65 | ||
| [87] | earlier | (57) | ||||||
| studies | ||||||||
| Total | 209 | 223 | 91/158 | 33/130 | 37/112 | 77/118 | ||
| (58%) | (25%) | (33%) | (65%) |
*Primary site irradiated for recurrent disease or in the presence of metastatic disease
with thermal ablation compared to 49 mm and 62 mm with transarterial radioembolisation and chemoembolisation respectively. Lesions treated were most commonly liver (86/132 lesions treated), with just four treated for local recur- rence. Other sites included lung (21), soft tissue (15), bone (5) and lymph node (1). Given the problems associated with systemic therapy, these techniques may be of particular value as first- line therapy for low volume oligometastatic dis- ease. Median overall survival was 33 months in those treated with thermal ablation techniques but 15-19 months in those treated with embo- lisation techniques, more reflecting the use of thermal ablation for those with lower tumour volumes and less advanced disease. A further retrospective study of treating 86 lesions in 26 patients with a range of thermal ablation and embolisation techniques saw complete responses in 66% and a DCR of 81%. Control rates at 1 and 2 years were 73% and 63% respectively [89].
These therefore are mostly techniques for treating smaller isolated metastatic lesions, typi- cally in liver or lung, whereas EBRT may be pre- ferred for soft tissue or bony lesions, particularly where these are larger or multiple.
Peptide Receptor Radionuclide Therapy
This is an appealing technique but limited by the relatively small numbers of patients who take up sufficient labelled compound to allow delivery of a therapeutically meaningful radia- tion dose. In 19 patients with metastatic ACC, the presence of somatostatin receptors was assessed by PET/CT imaging with gallium-68 labelled dodecanetetraacetic acid Tyr3-octreo- tide (DOTATOC) [90]. Ten (53%) showed some uptake but only two had sufficient uptake to jus- tify therapy with yttrium-90 and lutetium-177 labelled DOTATOC. These two patients achieved
partial responses with control of disease for 4 and 12 months.
DISCUSSION
The potential benefits or mitotane and EBRT as adjuvant treatment following surgical resec- tion have been clearly demonstrated. Addi- tionally, there is in vitro evidence that mito- tane might potentiate the effect of radiation by inducing G2-arrest [91], so that treatment with both together, where appropriate, might be considered of greater benefit. In the absence of evidence that mitotane affects radiotherapy side effects, maintaining therapeutic levels of mitotane during EBRT would be appropriate.
In advanced disease, however, treatment options are not so clearly defined. While the EDP-M regime is clearly beneficial, how best to deliver this to those of borderline performance status is less clear, with the inference from ret- rospective studies being that mitotane is the more active constituent of the regime. Enzyme induction causes problems for etoposide and there is no agreed strategy for optimising etopo- side delivery. At progression, the challenge is whether to continue the mitotane in the hope that some tumour retarding effect might persist, but given its very long half-life this can have a detectable, and possibly detrimental, effect on the pharmacokinetics of drugs delivered subse- quently. Despite preclinical evidence supporting use of IGFR and FGFR inhibitors, results have been disappointing. MKIs have shown greater promise, while ICIs delivered as single agents or in combination have been disappointing. Combinations have fared little better thus far, with DCR less than 50% and median PFS less than 6 months in the majority of studies. At this point, combinations of lenvatinib or cabozan- tinib with an ICI hold the best hope of improved outcomes.
The reasons for the relative resistance of ACC to treatments that appear more effective in other solid tumours remain unclear. Further research is clearly required with new approaches to treat- ment [92]. Identification of new molecular tar- gets may result from other approaches which
include studies of circulating cell-free DNA- based biomarkers [93], identifying differentially expressed genes between ACC and adrenal ade- nomas [94] and exploring targets in the Wnt signalling pathway [95]. In the meantime, the emphasis must be on encouraging recruitment into appropriately designed trials to which most patients have access.
CONCLUSIONS
Mitotane and EBRT have a proven role (either alone or together) as adjuvant therapy following potentially curative surgery, as shown by a previ- ous meta-analysis of the effects of mitotane and the new meta-analysis of EBRT contained within this review. The EDP-M regime remains stand- ard first-line treatment for recurrent or meta- static ACC despite the uncertainties surround- ing optimal scheduling and drug interactions. As yet, there are no forms of immunotherapy or targeted therapy licensed for ACC reflecting relatively low response rates of limited duration. Combinations of ICI and TT (particularly with MKIs cabozantinib and lenvatinib) hold prom- ise for the future. Further exploration of new molecular pathways is required to generate new therapeutic avenues.
Author Contributions. Nicholas Rowell was responsible for all stages of this review.
Funding. No funding or sponsorship was received for this study or publication of this article.
Declarations
Conflict of Interest. Nicholas Rowell has no conflict of interest.
Ethical Approval. This article is based on previously conducted studies and does not con- tain any new studies with human participants or animals performed by the author.
Open Access. This article is licensed under a Creative Commons Attribution-NonCommercial
4.0 International License, which permits any non-commercial use, sharing, adaptation, distri- bution and reproduction in any medium or for- mat, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indi- cated otherwise in a credit line to the material. If material is not included in the article’s Crea- tive Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain per- mission directly from the copyright holder. To view a copy of this licence, visit http://creativeco mmons.org/licenses/by-nc/4.0/.
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