Review
Current Evidence on Local Therapies in Advanced Adrenocortical Carcinoma
OPEN ACCESS
CC
=
Authors
Otilia Kimpel1, Ulrich Dischinger1, Barbara Altieri1, Carmina Teresa Fuss1, Bülent Polat2, Ralph Kickuth3, Matthias Kroiss1, 4, Martin Fassnacht1, 5
Affiliations
1 Division of Endocrinology and Diabetes, Department of Medicine, University Hospital, University of Würzburg, Würzburg, Germany
2 Department of Radiation Oncology, University Hospital, University of Würzburg, Würzburg, Germany
3 Institute of Diagnostic and Interventional Radiology, University Hospital, University of Würzburg, Würzburg, Germany
4 Department of Internal Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, München, Germany
5 Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany
Key words adrenal cancer, advanced disease, local therapies
received 19.06.2023 accepted after revision 25.09.2023
Bibliography Horm Metab Res 2024; 56: 91-98 DOI 10.1055/a-2209-6022 ISSN 0018-5043
@ 2024. The Author(s).
This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons. org/licenses/by-nc-nd/4.0/)
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany
Correspondence Dr. Otilia Kimpel Division of Endocrinology and Diabetes, Department of Medicine, University Hospital, University of Würzburg Oberdürrbacher Str. 6 97080 Würzburg
Germany Tel .: 0931 201 39885 Kimpel_o@ukw.de
ABSTRACT
International guidelines emphasise the role of local therapies (LT) for the treatment of advanced adrenocortical carcinoma (ACC). However, large studies are lacking in this field. Therefore, we performed a review of the literature to synthesise current evidence and develop clinical guidance. PubMed database was searched for systematic literature. We identified 119 potential- ly relevant articles, of which 21 could be included in our final analysis. All were retrospective and reported on 374 patients treated with LT for advanced ACC (12 studies on radiotherapy, 3 on transarterial chemoembolisation and radioembolisation, 4 on image-guided thermal ablation [radiofrequency, micro- wave ablation, and cryoablation, and two studies reporting treatment with several different LT]). Radiotherapy was fre- quently performed with palliative intention. However, in most patients, disease control and with higher dosage also partial responses could be achieved. Data for other LT were more lim- ited, but also point towards local disease control in a significant percentage of patients. Very few studies tried to identify fac- tors that are predictive on response. Patients with a dis- ease-free interval after primary surgery of more than 9 months and lesions <5 cm might benefit most. Underreporting of tox- icities may be prevalent, but LT appear to be relatively safe overall. Available evidence on LT for ACC is limited. LT appears to be safe and effective in cases with limited disease and should be considered depending on local expertise in a multidiscipli- nary team discussion.
Introduction
Adrenocortical carcinoma (ACC) is a rare malignant endocrine tu- mour with poor prognosis. Tumour stage, resection status and the proliferation index Ki67 are the most relevant prognostic factors, which are combined in the S-GRAS score together with age, symp- toms at diagnosis in patients undergoing primary tumour resec- tion [1]. The 5-year overall survival ranges from about 80 % in pa- tients with ACC stage I to less than 20% in stage IV disease [2-9]. However, even in stage IV some patients survive many years and cases with curable complete treatment responses have been re- ported [1, 10, 11].
International reviews and society guidelines recommend mito- tane alone or in combination with platinum-based chemotherapy as first-line treatment for recurrent or metastatic disease not amenable to complete resection [2,9, 12-15]. Surgery of metas- tases is usually the preferred option only if all tumoural lesions can be removed and the time interval to previous surgery is above 12 months [2, 16]. Despite limited evidence, local therapies (LT) should be considered in advanced ACC according to current rec- ommendations [2,9]. In these guidelines, the panellists agreed that local therapeutic measures [radiotherapy (RT), transarterial chemoembolisation (TACE), radiofrequency ablation (RFA), micro- wave ablation (MWA), and cryoablation (CA)] are relevant and sug- gested an individualised decision on which method to choose based on the localisation of the tumour lesion(s), local expertise, prog- nostic factors and patient’s preference [2,9]. LT may also be indi- cated for pain, prevention of imminent metastatic complications, severe mass effect or neurological symptoms. The aim of this re- view is to summarise data regarding the value of LT as alternative therapeutic option beside treatment with chemotherapy and/or surgery for advanced ACC.
Materials and Methods
We searched the PubMed database (https://pubmed.ncbi.nlm.nih. gov) for manuscripts published until May 2023. Search terms in- cluded: adrenocortical tumour, adrenocortical cancer/carcinoma, advanced disease, treatment, local therapies, radiotherapy, tran- sarterial chemoembolisation, transarterial radioembolisation, ra- diofrequency ablation, microwave ablation, cryoablation using “and” or “or”.
All abstracts were screened by O.K. and those reporting treat- ment with LT in advanced ACC were reviewed. Overall, we identi- fied 119 potentially relevant manuscripts. Duplicates and articles not relevant to this review (case reports, articles investigating ad- juvant therapy, reviews and guidelines) were excluded ( Fig. 1). Finally, data from 21 different full articles could be included in our analysis. In total, the analysed studies reported 374 patients with advanced ACC treated with one or more LT.
Local therapies in advanced adrenocortical carcinoma
Radiotherapy
Radiotherapy is an important modality used as curative or pallia- tive treatment in many different cancer types [17, 18]. The tech- nology developed in the past years leading to a more accurate and faster therapy with less adverse effects and improved treatment
Total number of publications identified by PubMed search n=119
Excluded studies
- on the basis of the abstracts n=71
- on the basis of full text screen n=27
Included studies n=21 with 374 patients
response. An emerging field in radiation oncology is the locally ab- lative treatment of all lesions in the so called oligo-metastatic dis- ease stage leading to improved survival in randomised trials [19]. In ACC, the evidence is much lower. Radiotherapy is recommend- ed as adjuvant therapy in patients with a high risk for local recur- rence (e. g., after R1 resection) [2,9]. Several studies suggested its efficacy in reducing the risk of local recurrence [12, 20-24], but data on improving recurrence-free and overall survival are conflict- ing. Furthermore, the current guidelines recommend RT as treat- ment option alone or in combination with mitotane and/or chemo- therapy in advanced ACC [2, 9]. However, evidence for treatment in advanced ACC is scarce.
Our literature search identified 13 studies reporting 200 pa- tients with advanced ACC treated with RT (> Table 1). All studies were retrospective analyses. In 9 studies the primary endpoint was palliation (e. g., pain), but 2 studies including 83 patients focused primarily on tumour control. In nine studies, RT was done as treat- ment of an irresectable or not completely resectable tumour, as pain therapy, or for the prevention of metastatic complications.
The exact localisation of RT treated lesions was not described in all studies. Most lesions were localised in bones, lung, liver, lymph nodes or an abdominal tumour mass (see > Table 1).
Reported doses of RT ranged from 10 to 60 Gray (Gy) (median 40 Gy). Only two studies reported the number of fractions and the type of RT. Ho et al. described a median of 15 fractions (5-31) [25]. In a previous study from our group, we reported four types of RT: conventional RT with a lower dosage (20-40 Gy) and a median of 12 fractions (1-28) with 3 Gy as median dose per fraction (1.2-8), conventional RT with a higher dosage (50-60 Gy) and a median of 27 fractions (15-30) with 2.1 Gy as median dose per fraction (1.8- 4), a third group with stereotactic body radiotherapy with a medi- an of 3.5 fractions (1-10) and 12.5 Gy as median dose per fraction (4-26) and a fourth group treated with single-dose brachytherapy with a median of 15 Gy (15-20) [26].
Median follow up time of all studies was 14 months ranging from 0.5 to 164 months. The results of these studies are very heteroge- neous. The reasons for this are very multifaceted. The main prob- lems are the heterogeneity of the patient groups, the site of the treated lesion and the very variable radiation doses, but above all also the different definitions of the endpoints investigated. Further-
| Authors [Ref] | Time frame | Patients n | Localisation of treated lesion | RT dose (Gy) | Reported endpoints | Response |
|---|---|---|---|---|---|---|
| Percarpio & Knowlton [30] | 1952-1975 | 7 | Bone, lymph node, LR, DR | 15-51 | Pain, intestinal obstruction | 7/7 |
| King & Lack [31] | 1956-1977 | 12 | Bone, bulky flank tumour | NG | Pain | 6/12 |
| Henley et al. [32] | 1960-1980 | 10 | Irresectable tumour | NG | Pain, tumour burden | 4/10 |
| Nader et al. [33]1 | 1944-1982 | 10 | Abdominal recurrence | NG | Tumour control and overall survival | 2/10 |
| Venkatesh et al. [34]1 | 1944-1987 | 19 | Abdominal recurrence | NG | Tumour control and overall survival | 3/19 |
| Magee et al. [35] | 1968-1981 | 1 | Cervical lymph node | NG | Palliation | 1/1 |
| Markoe et al. [36] | 1962-1991 | 5 | Irresectable tumour or DR, bone, lymph node | 30-50 | Pain | 5/5 |
| Pommier & Brennan [10] | 1980-1991 | 5 | Bone | NG | pain | 5/5 |
| Polat et al. [37] | 1986-2008 | 26 | Bone, LR, abdominal recurrence, | 10-60 | Pain (n=22) | 7/22 |
| lung | Control of CNS symptoms (n=6) | 3/6 | ||||
| Hermsen et al. [29] | 1990-2008 | 10 | Bone, DR | NG | Pain (n=6) Palliation (n=4) | 6/6 |
| 2/4 | ||||||
| Ho et al. [25] | 1997-2012 | 12 with 18 courses of RT | LR or DR | 17.5-60 | Pain, prevention of metastatic complications | 12/18 |
| Roux et al. [27] | 2008-2021 | 3 | LR or DR | NG | Tumour control | 3/3 |
| Kimpel et al. [26]2 | 2000-2022 | 80 | n=132 | 12-60 | Tumour control, overall | CR n=6 |
| LR n=22 or DR (bone n=46, lung | survival | PR n= 52 | ||||
| n= 32, liver n = 16, lymph node | SD n=60 | |||||
| n=3, soft tissue n=9, brain n=4) | PD n= 14 |
RT: Radiotherapy; n: Number; Gy: Gray; CR: Complete response; PR: Partial response; SD: Stable disease; PD: Progressive disease; LR: Local recurrence; DR: Distant recurrence; CNS: Central nervous system; NG: not given.1 Most likely there is an overlap of patients between the studies of Nader et al. [33] and Venkatesh et al. [34]. 2 One patient has also been reported by Polat et al. [37].
more, response to therapy was not uniformly defined. These points are probably also the reason why there are studies that reported a response rate of 100%, while others found only about 20% re- sponse. Our own study, which included cases from 2000 to 2022, is by far the largest study and here, among 132 irradiated tumour lesions, only 14 (11%) showed progression, while all other lesions showed at least stable disease or objective tumour response in 89%. In the subgroup of patients with conventional RT with a higher dos- age (50-60 Gy) or with stereotactic body radiotherapy the objec- tive response rate was even 95 and 100%, respectively.
Toxicities due to RT were described only in three studies [25- 27]. Ho et al. observed toxicities in 6 of 12 patients: three grade 1, three grade 2 and one grade 3 adverse events [25] according to the toxicity criteria of the Radiation Therapy Oncology Group (RTOG) [28]. In our study with 80 patients, we reported 43 grade 1 adverse events including fatigue, anaemia, skin, hepatic, renal, intestinal, and pulmonary toxicities. In addition, we observed 13 grade 2 ad- verse events with fatigue, musculoskeletal disorders, skin, pulmo- nary, and intestinal toxicities, and three grade 3 adverse events (with pulmonary and intestinal toxicities) (26). Both of these stud- ies reported no grade 4 or 5 adverse events. Roux et al. reported four grade 3 adverse events and also three grade 4 adverse events
in different LT. However, they did not provide information, which type of LT lead to these adverse events [27].
Some studies reported concomitant therapies with mitotane during RT [25-27,29]. We reported 38 (29%) patients with a mi- totane therapy and a mitotane level > 14 mg/l during RT. However, mitotane treatment had no significant influence on RT treatment response [26]. Roux et al. also included patients with mitotane treatment during RT. More than half of the patients achieved a ther- apeutic level > 14 mg/l. However, analysing a potential effect of mi- totane was not part of the study [27]. Hermsen et al. reported two patients treated with mitotane, but only one patient reached a ther- apeutic level [29]. Ho et al. reported seven patients receiving con- comitant chemotherapy, including mitotane (n=4). No further in- formation on chemotherapy or mitotane was available [25].
Only few studies investigated possible predictive factors influ- encing response to RT. We identified the absence of glucocorticoid excess and a Ki67 ≤ 15% as possible predictive factors [26]. Roux et al. could show that a maximum of five metastases or a maximum diameter below 3 cm were associated with higher rates of disease control [27]. No more predictive factors could be identified.
| Authors [Ref] | Time frame | Patients n | Lesions n | Reported endpoints | Response |
|---|---|---|---|---|---|
| Soga et al. [43]1 | 1995-2006 | 2 | 2 | Tumour control | CR=2 |
| Cazejust et al. [40] | 1995-2005 | 29 | 103 | Tumour control | PR =23 SD=67 PD=13 |
| Owen et al. [42] | 1997-2016 | Treatment with TACE n=2 Treatment with TARE n = 3 | NG | Tumour control | Presumably prolonged survival |
| Roux et al. [27] | 2008-2021 | 20 | 20 | Tumour control | Disease control rate 17/20 |
| Mauda-Havakuk et al. [41]2 | 1999-2018 | 12 | Tumour control | No details given |
n: Number; CR: Complete response; PR: Partial response; SD: Stable disease; PD: Progressive disease; NG: Not given; TACE: Transarterial chemoemboli- sation; TARE: Transarterial radioembolisation. 1Patients were treated with transarterial embolisation (TAE). 2 Twelve patients were treated with 35 transarterial embolisation sessions including 5 sessions with TAE and 30 sessions with chemotherapy.
Transarterial chemoembolisation (TACE) and transarterial radioembolisation (TARE)
Transarterial chemoembolisation is the most commonly used tran- sarterial therapy in oncology: Briefly, a mixture of iodised oil and cytotoxic agent (conventional TACE), drug-eluting beads and cy- totoxic agent (DEB-TACE) or degradable starch microspheres and cytotoxic agent (DSM-TACE) is administered intraarterially supply- ing the tumour to be targeted to avoid wash-out of the chemother- apeutic agent, potentiating local effectivity. Due to the limited sys- temic effect, the delivery of higher doses than in the context of sys- temic application is possible. In hepatocellular carcinoma (HCC), this treatment strategy has been proven to be beneficial, which has been shown also in randomised, controlled trials [38]. As a conse- quence, TACE is extensively used in HCC, as part of a curative ap- proach, in a palliative setting, or as a possible bridge to transplan- tation. With an overall mortality rate of < 1%, TACE is a very safe treatment option in HCC [39].
Data on TACE as treatment for patients with advanced ACC are very limited. Until now, there are only five studies (> Table 2), all reporting TACE of liver metastases. All studies are retrospective analyses. All reported patients presented with advanced disease and were treated with systemic chemotherapy concomitantly (mostly mitotane alone or in combination with etoposide, doxoru- bicin and platinum (EDP-M)). As an additional confounder, most studies summarise different methods in one report (e. g., cryother- apy, radiofrequency ablation, selective internal radiation therapy). For most of the reported patients, no further information on spe- cifics of the performed TACE is available, in some cases even the in- formation regarding the used cytotoxic drug is missing.
Until now, the largest number of patients (n=29) treated with TACE in advanced ACC was reported by Cazejust et al. in 2010. In this series a decrease in tumour size in 22% of 103 treated lesions was observed, an additional 65 % of lesions were stable in size after 3 months. In this study, higher response rates were observed in le- sions with a diameter < 3 cm [40]. Roux et al. reported a significant- ly longer time to second line treatments in 60 patients following loco-regional treatment (n = 20 treated with TACE) and a signifi-
cantly higher rate of disease control in a subgroup of cases (< = 5 metastases or maximum diameter <3 cm) (27). Mauda-Havakuk et al. stated a possible prolonged life expectancy in patients (n = 39) after loco-regional treatment (TACE: n = 12) [41].
None of the studies reported any high-grade adverse events, which is in line with the data of TACE in HCC.
The use of transarterial radioembolisation (TARE) in patients with ACC and liver metastases is still under debate and restricted to case reports or smaller case series. Owen et al. reported three patients with ACC and liver metastases treated with TARE showing a longer overall survival in comparison to patients without TARE (32.4 months vs. 9.9 months, p=0.011) [42].
Image-guided thermal ablation: Radiofrequency ablation, microwave ablation and cryoablation
Radiofrequency ablation, microwave ablation and cryoablation are minimally invasive percutaneous thermal ablation therapies which are usually single examination procedures and may provide control of local disease in patients who cannot undergo surgery or refuse surgical treatment. RFA is a percutaneous treatment which gener- ates heat locally that leads to coagulation of the surrounding tissue. The needle and electrode are usually placed under guidance by com- puter tomography or ultrasound. Like RFA, MWA makes also use of electromagnetic energy causing rotation of water molecules and generates heat around the tip of the antenna causing denaturation of proteins and cell membranes of tumour cells. Cryoablation is a minimally invasive percutaneous technique to target tumour tissue and freeze it by extremely low temperatures resulting in cytotoxic effects and destruction of intracellular contents. It is used for treat- ing various solid tumours and showing a good tumour control [44].
To date, few studies presented data about these interventional treatment options in advanced ACC. All published studies togeth- er (n=6) covered 102 patients with ACC treated with at least one or more image-guided thermal ablation therapy (> Table 3).
All studies were retrospective analyses. All patients had an ad- vanced disease and intention to treat was palliative for local tumour control.
RFA was the most frequently used LT (n = 86), 24 lesions were treated with MWA and 10 lesions with CA. The localisation of the treated lesion was described in nearly all studies: liver n = 84, pul- monary n = 18, tumour bed n =6, bone = 4; retroperitoneum n = 5, subcutaneous n =2, intracaval= 1, respectively. Only few studies reported technical details on LT (see > Table 3).
Median follow up time was 26.5 months ranging from 5 to 164 months. Most of the patients showed a complete ablation after the treatment (see > Table 3).
Until now, the largest number of patients with advanced ACC treated with a thermal ablation therapy was reported by Mauda-Ha- vakuk et al. in 2020 and Roux et al. in 2022. Mauda-Havakuk et al. reported 39 patients treated with RFA, MWA, CA or a combination of LT. Complete ablation of the treated metastases was achieved in 61 % [41]. Roux et al. showed a similar response rate after treat- ment with a thermal ablation therapy. Nineteen out of 30 (63 %) patients showed a disease control after therapy [27].
Toxicities due to thermal ablation therapies were rarely report- ed but might not be sufficiently well documented. Roux et al. re-
ported four grade 3 adverse events consisting of two post-proce- dure bleedings with spontaneous haemostasis, one gastrointesti- nal fistula and one mild pancreatitis and also three grade 4 adverse events with two post-procedural adrenal insufficiencies and one pleural haemorrhage. However, they did not distinguish between the different LT [27]. Mauda-Havakuk et al. described two patients with greater than or equal grade 3 complications. One RFA session was complicated by an intrahepatic hematoma. Another patient developed transient atrial fibrillation and electrolyte imbalance. Three patients suffered grade 2 complications. One patient devel- oped an abscess after paraspinal ablation, and two patients devel- oped pneumothoraces [41]. Wood et al. had one patient with a multimicrobial abscess in a 90 mm lesion 11 weeks after his third RFA treatment session [45]. Veltri et al. observed a single major ad- verse event with an intrahepatic hematoma with subsequent haemothorax [46].
Here again, only some studies investigated possible factors in- fluencing LT. Li et al. showed that microwave ablation can be suit- able for different adrenal tumours, especially those smaller than
| Authors [Ref] | Time frame | Patients n | Localisation and number of lesions | Lesion size (cm) | Type of local therapy | Technical details | Reported endpoints | Response |
|---|---|---|---|---|---|---|---|---|
| Wood et al. [45] | 1999-2001 | 8 | LR=5 DR=10 | Median 4.3 (1.5-9) | RFA n=15 | Ultrasound and/or CT scan guidance 200 Wt, 480 kHz alternating current radiofrequency generator | Tumour control | 3/15 (20%) PD 4/15 (27%) SD 8/15 (53%) decreased in size |
| Ripley et al. [48] | 1979-2009 | 8 | Liver n= 8 | NG | RFA n=8 | NG | Tumour control | 8-Jul |
| Li et al. [47] | 2007-2010 | 1 | LR=1 | 6.1 × 3.8 | MWA n=1 | 70 Wt, 15 Min | Tumour control | Necrotic tumour |
| Veltri et al. [46] | 2000-2017 | 16 | Liver n= 28 Lung n= 4 | Median 2.1 (0.6-7.5) | RFA MWA | US guidance for hepatic lesions CT guidance for lung lesions | Tumour control | Complete ablation 29/32 |
| Mauda-Havakuk et al. [41] | 1999-2018 | 39 | Liver n= 46 Lung n= 14 Retroperitone- um n=5 Bone n= 4 Subcutaneous n=2 Intracaval n= 1 | NG | RFA n=45 MWA n= 18 CA n=3 Combined n=3 | NG | Tumour control | Complete ablation in 52/84 |
| Roux et al. [27] | 2008-2021 | 30 | N= 30 LR or DR | 46 lesions with max diameter 3 cm | RFA n= 18 CA n=7 MWA n=5 | NG | Tumour control | Disease control rate 19/30 |
n: Number; Wt: Watt, kHz: Kilohertz; Min: Minute; cm: Centimetre; max: Maximum; NG: Not given; LR: Local recurrence; DR: Distant recurrence; US: Ultrasound; CT: Computer tomography; RFA: radiofrequency ablation: MWA: Microwave ablation; CA: Cryoablation.
5 cm in diameter [47]. Roux et al. showed that a maximum of five metastases or a maximum diameter below 3 cm were associated with higher rates of disease control [27]. Mauda-Havakuk et al. re- ported female gender and longer time from diagnosis to first ther- mal ablation as potential predictors of prolonged survival [41]. Vel- tri et al. also described size of metastases as predictive factor. Local tumour progress was significantly higher in larger metastases (20 mm vs. 34.5 mm; p= 0.009) [46]. Ripley et al. indicated that disease-free interval greater than 9 months after primary adrenal- ectomy was associated with longer survival (4.1 vs. 0.9 years; p=0.013) [48]. Wood et al. showed that RFA is most effective for tumours less than 5 cm [45].
Discussion
Despite the recommendation in the two international guidelines [2,9], it must be noted that the evidence on the effectiveness of local therapies in advanced ACC remains very limited. However, five studies with a total of 202 patients and 305 treated lesions, have been published in the last 5 years, leading to at least some improve- ment in data quality. In total, this allowed us to evaluate data from 374 patients. Prospective or even randomised studies were still completely missing, which prevented reliable recommendations. Overall, there are only a few studies that reported clearly negative results, although, a selection bias cannot be ruled out here. How- ever, from our point of view there are obvious explanations for these studies with disappointing results (e. g., outdated therapy, extremely advanced disease), we would actually attribute a certain effectiveness to all reported LT. Although toxicity appears to be lim- ited and most reported adverse events were mild or moderate, it must be acknowledged that retrospective studies tend to under- estimate negative effects. However, in this context results from other tumour entities can be extrapolated and these data suggest indeed acceptable toxicity for most local treatment modalities [18,49,50].
Treatment with RT was mostly (especially in the older publica- tions) used for palliative intention such as pain control and, there- fore, these studies did not report objective responses [25, 29, 36]. However, the more recent studies reported also on tumour re- sponse [26,27] and here tumour control was achieved in the vast majority of patients. As described above, toxicity data have to be judged with cautious, but in all studies that report adverse events these were manageable. Thus, we conclude that RT seems to be mostly well-tolerated and effective in the management of meta- static ACC, controlling local symptoms, and preventing complica- tions from large metastases. More recent data clearly suggest that higher radiation dosages (e. g., >50 Gy) or stereotactic body radi- otherapy might - not surprisingly - be more effective in achieving objective tumour response [26].
TACE and TARE are two commonly used loco-regional therapies in several cancer types which aim to prolong survival by slowing tumour progression, or to bridge to more definitive therapies [51, 52]. TACE is extensively used in HCC, as part of a curative ap- proach, in a palliative setting, or as a possible bridge to transplan- tation. With an overall mortality rate of <1%, TACE is a very safe treatment option in HCC [39]. TACE also might be valuable in ACC patients with a small number of only hepatic metastases of limited
sizes, if surgical treatment is not possible. Although there are only few studies investigating treatment with TACE in advanced ACC, most of the reported studies showed a decrease in tumour size or achieved a disease control [27, 40]. In addition, TACE appeared to be a safe treatment option with few adverse events. With limited data available, the use of TACE remains a case-by-case decision to be made by an interdisciplinary tumour board.
Evidence for TARE in ACC is even more limited. Until now there are only some case reports and a case series of 3 patients treated with TARE in advanced ACC with liver metastases. However, this treatment was effective in most cases similar to TACE [42].
Similar to RT and TACE image-guided thermal ablation thera- pies are of use as curative and palliative cancer treatment.
RFA is an established therapeutic option in patients with lung cancer or metastatic lesions achieving good tumour control [42]. A meta-analysis comparing treatment with RFA versus surgery in non-small cell lung cancer showed similar results regarding overall survival [43].
Although RFA and MWA resemble, MWA showed advantages in larger tumours, in locations close to large vessels and in highly per- fused areas [53].
CA is used for treating various solid tumours and showing a good tumour control. Some studies in other tumour entities showed su- perior tumour response and quicker recovery compared to heat- based ablation therapies [44]. Image-guided thermal ablation ther- apies also might have an important role in palliative treatment of ACC.
These minimally invasive therapies achieve adequate local tu- mour control of ACC metastases, providing a safe and effective treatment option in the multidisciplinary management of ACC [27,41, 46]. Mauda-Havakuk et al. propose a combined use of LT, surgery and chemotherapy in advanced disease. Patients treated with a combination of therapies showed a longer 2 year- and 5 year-survival in comparison to patients with surgery and chemo- therapy or chemotherapy and RT [41].
Overall, the summarised studies suggest that most LT are effec- tive for palliative treatment, for example, for pain relief, but also for tumour control. Therefore, we are convinced that LT should be con- sidered more frequently as a treatment option alone or in combi- nation with chemotherapy and/or surgery in advanced disease, and not only in palliative care. Despite the limited number of studies, we believe that especially patients with oligo-metastatic ACC might benefit particularly from LT (either to defer the application of cy- totoxic therapy or to provide treatment options when standard sys- temic therapies have failed).
The most critical part in applying LT to patients with ACC is prob- ably the selection of the most adequate method to the “right” pa- tient. For some localisations certain methods seem to be more suit- able than others (e. g., RT for bone or cerebral metastases) and for some modalities the cumulative experience in certain organs is much higher than in other parts of the body (e. g., TACE for liver le- sions). However, at the end the indication for any given LT depends heavily also on local experience and expertise. Furthermore, not only the combination of different LT, but also treatment with sys- temic therapies might be reasonable in selected patients. Thus, the most important issue seems to be that all patients are discussed in
multidisciplinary team meetings as already strongly recommend- ed by the 2018 guidelines [9].
Finally, we would like to call for multi-institutional efforts to start prospective studies on LT in a rare disease like ACC. International networks like ENSAT or A5 are best suited to coordinate such stud- ies. These studies will also help to find factors that predict response to a given therapy or to identify constellation for which certain ther- apies are not suitable. In conclusion, LT are probably still un- der-used in ACC and treating physicians are encouraged to consid- er the different described modalities more frequently.
Funding Information
Clinician Scientist programme RISE funded by the Else Kroner- Fresenius-Stiftung & the Eva Luise und Horst Köhler Stiftung - German Research Foundation (DFG) project 314061271 (TRR-CRC 205) - project 314061271 (TRR-CRC 205)
Conflict of Interest
MF has served in an advisory board of HRA Pharma on the manage- ment of adrenocortical carcinoma. Remunerations paid to his university hospital. MK has received consultancy and speaker honoraria from HRA Pharma and Recordati, and research support from Ipsen, and Enterome (to institution). OK received speaker honoraria from HRA Pharma. UD, BA, CTF, BP, RK declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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