Society for Endocrinology
Primary tumour resection in metastasised adrenocortical carcinoma
Charlotte L Viëtor(1,2, Ivo J Schurink1, Dirk J Grünhagen1, Cornelis Verhoef1, Gaston J H Franssen1, Richard A Feelders2,3 and Tessa M van Ginhoven 1
1Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands 2Department of Internal Medicine, Division of Endocrinology, Erasmus University Medical Center, Rotterdam, The Netherlands 3Division of Endocrinology, Diabetes and Metabolism, New York University Langone Medical Center, New York, New York, USA
Correspondence should be addressed to T M van Ginhoven: t.vanginhoven@erasmusmc.nl
Abstract
Up to 30% of adrenocortical carcinoma (ACC) patients have metastasised disease upon initial presentation, and systemic treatments currently fail to sufficiently improve survival. Palliative primary tumour resection can be considered for symptomatic relief, but its potential survival benefit remains a topic of debate. This systematic review therefore aims to assess the effect of primary tumour resection on overall survival in patients with metastatic ACC. A systematic review was performed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Relevant databases were searched from 2000 to 2024 for studies on primary tumour resection in metastatic ACC. Overall survival data were analysed. A total of 13 studies on primary tumour resection for metastatic ACC were included. All studies were retrospective and assessed as having a high risk of bias. Data regarding adequate patient characteristics and indications for surgery were missing in all studies. Hence, the current literature is hampered by both indication and selection biases to draw any conclusions on the survival benefit of primary tumour resection in patients with metastasised ACC. However, 12 out of 13 studies (92%) demonstrated longer overall survival after primary tumour resection compared to no surgery. Whereas this is in line with retrospective data on other cancers, randomised controlled trials in other tumours, such as breast and colorectal cancers, have failed to display survival benefits of primary tumour resection. These cancers are, however, relatively chemo-sensitive, unlike ACC. Primary tumour resection could therefore only be considered on an individual patient basis.
Keywords: adrenocortical carcinoma; primary tumour resection; palliative surgery; metastatic cancer; survival
Introduction
Adrenocortical carcinoma (ACC) is a rare malignancy with an estimated incidence between 0.5 and 2 cases per million population per year (Allolio & Fassnacht 2006). Up to 30% of the patients present with metastatic disease at the time of diagnosis (Wooten & King 1993, Kebebew et al. 2006, Fassnacht & Allolio 2009, Fassnacht et al. 2010). For those patients, current guidelines advocate systemic treatment, including mitotane monotherapy or combined with chemotherapy (Fassnacht et al. 2018). Disease response
rates with mitotane monotherapy are modest, ranging between 17 and 31% (Haak et al. 1994, Baudin et al. 2001, Hermsen et al. 2011, Reidy-Lagunes et al. 2017). Compared to mitotane monotherapy, combining etoposide, doxorubicine and cisplatin chemotherapy with mitotane showed superior disease response rates, progression-free survival and overall survival, yet overall survival remains limited to approximately 15 months (Fassnacht et al. 2012, Uchihara et al. 2021).
Given the disappointing outcomes of systemic treatments, there is a growing interest among clinicians to explore the role of surgery for the primary tumour in metastatic ACC patients in order to reduce symptoms and/or to improve survival. For symptomatic patients, who experience incapacitating complaints due to tumour mass effect or excessive hormone production, in particular cortisol leading to Cushing’s syndrome, palliative surgery can be considered to improve the symptomatic burden, as is incorporated in the current guidelines for metastatic ACC (Gaujoux et al. 2017, Sinclair et al. 2020). The role of surgery becomes less evident in (asymptomatic) patients with non-functional ACC, where it does not directly alleviate symptoms but may potentially influence survival outcomes. After the removal of the tumour bulk, often poorly vascularised, the remaining smaller, and probably better vascularised, lesions may be more responsive to systemic treatment (Megerle et al. 2018). Furthermore, tumour bulk removal may enhance anti- tumour immunity, which could improve treatment response or even lead to spontaneous metastasis regression, as has previously been reported after nephrectomy for stage 4 renal cell cancer (Masue et al. 2007). It is therefore hypothesised that surgical resection of the tumour bulk could enhance the effectiveness of systemic treatments and possibly reduce new metastatic seeding (Srougi et al. 2022).
In light of these considerations, this systematic review aims to offer a comprehensive overview of the existing literature on the effects of primary tumour resection on survival in metastatic ACC patients. Our objective is to provide evidence-based guidance to clinicians in their decision-making process regarding the treatment of patients with metastatic ACC. We will explore the role of primary tumour resection in the metastatic context of other cancer types to contextualise our findings on ACC within the broader landscape of oncological diseases.
Methods
This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Page et al. 2021). The research protocol is available online with PROSPERO registration number CRD42023390869.
Literature search
On 28 June 2024, a systematic literature search was performed in the databases Embase, MEDLINE via Ovid, Web of Science Core Collection, Cochrane Central Register of Controlled Trials and Google Scholar. The search strategy was created by a qualified librarian of the Erasmus Medical Centre, Rotterdam, and adapted for each database to obtain an optimal search strategy, as previously described by Bramer et al. (2018). Important keywords in our search included ACC, surgery, and stage
4 or metastatic. The full search strategy for each database is illustrated in Supplementary Table 1 (see section on Supplementary materials given at the end of the article).
Inclusion and exclusion criteria
Articles published from 2000 until the search date and articles written in English were considered. Articles on metastatic ACC, describing outcomes after primary tumour resection versus no surgery, were included. Articles were excluded if no original data were presented (e.g. reviews, editorial, and commentary), the study was not performed in humans, or the study consisted of a case report or case series of <3 patients. Conference abstracts were excluded. In case more than one publication was written based on partly but not completely similar study data, both publications were included.
Data extraction and quality assessment
Two reviewers (CLV and IJS) independently screened titles and abstracts of the found articles and subsequently assessed the full text of eligible articles based on the predefined inclusion criteria. We anticipated consulting a third reviewer (TMVG) in case of disagreement to make the final decision, but upon evaluation of the articles, there were no cases of disagreement between the first two reviewers. Hence, consultation of the third reviewer was not necessary. The following variables were extracted: year of publication, study country, study period, study design, inclusion and exclusion criteria, type of patients included, number of patients with metastatic or stage 4 ACC, outcome measurements and follow-up duration. Patient age, patient gender, hormonal excess, primary tumour side, tumour size and type of treatments received were assessed for both the group undergoing surgery and the control group. In case these variables were not provided in the original article, corresponding authors were contacted up to three times in order to obtain additional information regarding those patient characteristics. The quality of the included studies was assessed by both reviewers using the Newcastle- Ottawa scale (NOS), a tool developed specifically for quality assessment of non-randomised studies (https://www.ohri.ca/programs/clinical_epidemiology/ oxford.asp). We considered studies with a NOS score of ≥7 as high-quality studies, a NOS score of 4-6 as having a high risk of bias, and a NOS score of 0-3 as having a very high risk of bias.
Outcome
The outcome of this systematic review and meta-analysis was overall survival. We analysed survival data after primary tumour resection in metastatic ACC. Studies describing ‘adrenalectomy’, ‘adrenal surgery’,
| Study ID | Country | Study period | Patient sources | Stage 4 patients (n) | Follow-up (months); median (range) | Comparison(s) studied in article | Total score NOS |
|---|---|---|---|---|---|---|---|
| Dong et al. (2012) | China | 1984-2010 | Single centre | 23 | 7.17 (SD: 6.73)* | Palliative surgery versus nonsurgical treatment | (5) |
| Hermsen et al. (2012)+ | Netherlands | 1965-2008 | Multicentre | 75 | 25 (0-451)* | Surgery versus no surgery | (6) |
| Kerkhofs et al. (2013)+ | Netherlands | 1999-2008 | Dutch Cancer Registry | 72 | Min 12, max 75 | Surgery of the primary tumour versus no surgery/ unknown | (4) |
| Livhits et al. (2014) | USA | 1999-2008 | Cancer registry | 167 | 18.8 (max 156)* | Surgery versus no treatment, chemo- and/or radiotherapy or surgery + chemo- and/or radiotherapy | (5) |
| Ettaieb et al. (2016) | Netherlands | 2004-2013 | Multicentre | 50 | 17 (0-118)* | Adrenalectomy versus no adrenalectomy | (5) |
| Wang et al. (2017)5 | China | 1973-2014 | SEER database | 290 | Max 120 | Primary site surgery, versus no primary site surgery | (5) |
| Tella et al. (2018)|| | USA | 2004-2015 | National Cancer Database | 760 | Max 60 | Surgical resection primary tumour versus no surgery | (3) |
| Wu et al. (2021)s | China | 2010-2016 | SEER database | 202 | Max 60 | Adrenal surgery (radical + debulking) versus no adrenal surgery | (4) |
| Srougi et al. (2022) | Brazil | 1995-2019 | Multicentre | 239 | 67 (SD: 7)* | Primary tumour resection + systemic therapy versus systemic therapy alone | (6) |
| Passman et al. (2024)|| | USA | 2010-2019 | National Cancer Database | 556 | 7.2 (IQR: 3.1-20.7) | Primary tumour resection versus medical therapy | (6) |
| Debets et al. (2024) | Netherlands | 2005-2020 | IKNL database | 126 | Max 144 | Palliative adrenalectomy versus no adrenalectomy | (6) |
| Nakanishi et al. (2024) | Japan | 2009-2019 | Multicentre | 14 | Max 71 | Primary tumour resection versus no surgery | (5) |
| Yasar et al. (2024) | Turkey | Unknown | Multicentre | 55 | Max 125 | Surgery versus no surgery | (4) |
Abbreviations: IQR, interquartile range; NOS, Newcastle-Ottawa Scale; SD, standard deviation.
*Mean follow-up time. +Partially overlapping patient cohorts (48% of patients overlap). * All stages of ACC patients, not only stage 4 patients. $Partially overlapping patient cohorts (patients between 2010 and 2014 might overlap). |Potential of partially overlapping patient cohorts (patients between 2010 and 2015 might overlap).
‘palliative surgery’ or ‘cytoreductive surgery’ without further explanation of the extent and location of surgery were considered as focusing on primary tumour resection (Table 1).
Statistical analysis
We conducted a narrative synthesis of the results from all included studies. No additional survival analyses were performed with data from included studies. Descriptive statistics were presented as counts (numbers and percentages) and medians with range. Sample means with standard deviations were estimated from the median, range and sample size using Wan’s method (Wan et al. 2014). Median overall survival time and 1-, 2- and 3-year survival rates were extracted from the articles or were estimated using Kaplan-Meier curves, which were digitised using WebPlotDigitizer, version 4.6 (https://automeris.io/WebPlotDigitizer/). When both
univariable and multivariable analyses were presented within the included articles, we describe the results of the multivariable analysis in this review. When only univariable analyses results were presented in the included articles, we reported those data. Pooled means and pooled proportions were used as summary measures.
Results
Literature search
The literature search yielded a total of 6,164 articles. After the removal of duplicate articles, 3,046 records were screened on title and abstract, after which 40 full-text articles were assessed for eligibility. After careful selection, 13 articles were included in this systematic review (Fig. 1) (Dong et al. 2012, Hermsen et al. 2012, Kerkhofs et al. 2013, Livhits et al. 2014, Ettaieb et al. 2016,
Identification
Records identified from: Embase (n = 3022) Medline ALL (n = 1522) Web of Science (n = 1394) Cochrane (n = 26) Google Scholar (n = 200)
Records removed before screening: Duplicate records removed (n = 2814)
Records screened (n = 3350)
Records excluded (n = 3310)
Screening
Reports sought for retrieval (n = 40)
Reports not retrieved (n = 0)
Reports assessed for eligibility (n = 40)
Reports excluded: Not on impact of surgery on survival (n = 3) Not only initially metastasized ACC (n = 12)
Included
Conference abstract (n = 9)
Studies included in review (n = 13)
Not on primary site surgery (n = 3)
Wang et al. 2017, Tella et al. 2018, Wu et al. 2021, Srougi et al. 2022, Debets et al. 2024, Nakanishi et al. 2024, Passman et al. 2024, Yasar et al. 2024).
Study characteristics
Table 1 provides an overview of the study characteristics of the included articles, which were published between 2012 and 2024. All 13 articles were retrospective cohort studies, of which seven studies (54%) used data from existing national registries, five multicentre studies (38%) and one single-centre study (8%). Five studies (38%) originated from Europe, four (31%) from Asia, three (23%) from North America, and one (8%) from South America. Patient cohorts of the Dutch and Chinese studies, and possibly also from the American studies, will most likely partially overlap, since these studies contain data from similar sources (48% patient overlap in Dutch cohort; the extent of overlap in Chinese/ American studies unknown). As inclusion periods and patient selection strategies, however, differ between studies, the cohorts will not be completely similar.
Therefore, all studies were included in this systematic review. The inclusion/registration of patients in some studies commenced multiple decades ago, with the earliest study period starting in 1965. Duration of the inclusion/registration periods ranged between 6 and 43 years, with a median of 10.5 years. Within the inclusion/registration period, the median number of patients included was 126 (range: 14-760). Scoring on the NOS, as a measure of study quality to answer our research question, ranged between 3 and 6 (Supplementary Table 2), which means that all studies can be regarded as having high risks of bias.
Table 2 summarises the patient characteristics of the patients included in the articles in this systematic review. The indication for surgery was not described in any of the articles. Seven articles (54%) described baseline characteristics per treatment group (Hermsen et al. 2012, Kerkhofs et al. 2013, Wang et al. 2017, Wu et al. 2021, Srougi et al. 2022, Debets et al. 2024, Passman et al. 2024). Propensity score matching was done in two studies with the aim to minimise selection biases (Srougi et al. 2022, Passman et al. 2024). In general, however, patients who underwent primary tumour resection were younger than patients who did not receive surgical treatment (pooled mean age: 51.3 years in operated patients vs 55.5 years in non-operated patients, P = 0.04, Supplementary Table 3). Furthermore, operated patients had on average larger tumours (14.1 vs 11.6 cm, P < 0.01) and were more likely to undergo additional local treatment for their metastasis (34 vs 6%, P < 0.01). No major differences regarding gender distribution, primary tumour side, amount and localisation of metastases and use of radio- or chemotherapy were seen between operated and non- operated patients. Three studies reported the percentage of patients with hormone excess. Nakanishi et al. (2024) stated that all operated and non-operated patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Measures of patient condition, such as American Society of Anaesthesiologists score, Charlson comorbidity index or Karnofski performance score, were not described for operated versus non-operated patients in any of the other articles.
Outcomes after primary tumour resection in ACC
In total, 1,220 patients underwent primary tumour resection for metastatic ACC compared to 1,410 patients who were not surgically treated. Twelve out of thirteen studies (92%) demonstrated significantly longer overall survival after primary tumour resection versus no surgical treatment at all (Dong et al. 2012, Hermsen et al. 2012, Kerkhofs et al. 2013, Livhits et al. 2014, Ettaieb et al. 2016, Wang et al. 2017, Tella et al. 2018, Wu et al. 2021, Srougi et al. 2022, Debets et al. 2024, Nakanishi et al. 2024, Passman et al. 2024, Yasar et al. 2024). Median overall survival in patients who
| Study ID | Comparison | Patients (n) | Age in years (mean + SD) | Gender (% male) | Hormone excess (% yes) | Tumour side (% left) | Tumour size (cm) (mean ± SD) | Metastasis treated (% yes) | RT (% yes) | Chemotherapy (% yes) |
|---|---|---|---|---|---|---|---|---|---|---|
| Dong et al. | PTR | 10 | – | - | - | - | – | - | - | – |
| (2012) | No surgery | 13 | ||||||||
| Hermsen | PTR | 52 | 43.5 ± 12.8+ | 40.4% | 71.2% | 48.1% | – | - | - | 30.8% |
| et al. (2012) | No surgery | 23 | 51.0 ± 15.6+ | 39.1% | 52.2% | 43.5% | 39.1% | |||
| Kerkhofs | PTR | 34 | 50.0 ± 11.0+ | 44.1% | – | 55.9% | – | – | 0% | 23.5% |
| et al. (2013) | No surgery | 38 | 59.5 ± 12.6+ | 36.8% | 52.6% | 0% | 21.1% | |||
| Livhits et al. | PTR | 69 | – | - | - | - | – | - | - | – |
| (2014) | No surgery | 98 | ||||||||
| Ettaieb et al. | PTR | 34 | – | - | - | - | – | - | - | – |
| (2016) | No surgery | 16 | ||||||||
| Wang et al. | PTR | 118 | 52.15 ± 13.96 | 43.2% | – | 48.3% | 13.56 ± 6.42 | 27.1% | 17.8% | 63.6% |
| (2017) | No surgery | 172 | 56.45 ± 15.37* | 41.8% | 58.1% | 11.33 ± 4.94* | 4.6%* | 17.4% | 57.0% | |
| Tella et al. | PTR | 325 | – | - | - | - | – | - | - | – |
| (2018) | No surgery | 435 | ||||||||
| Wu et al. | PTR | 76 | 53.8 ± 14.9 | 46.1% | – | 56.6% | 13.5 ± 7.0 | 31.6% | 19.7% | 68.4% |
| (2021) | No surgery | 126 | 55.8 ± 15.6 | 37.3% | 47.6% | 10.9 ± 4.4* | 3.2%* | 19.0% | 57.9% | |
| Srougi et al. | PTR | 128 | 52.3 ± 13.0+ | 41.4% | 64.1% | 57.8% | 14.9 ± 4.9+ | 35.9% | 27.3% | – |
| (2022) | No surgery | 111 | 52.3 ± 13.2+ | 45.0% | 62.2% | 51.4% | 12.4 ± 3.9*,+ | 0.9%* | 9%* | |
| Passman | PTR | 278 | 53.8 ± 15.8 | 38.5% | – | 50.7% | 65.1% >10 cm | – | 55.0% | 62.6% |
| et al. (2024) | No surgery | 278 | 54.1 ± 14.7 | 39.9% | 49.3%* | 64.4% >10 cm | 64.0%* | 76.6%* | ||
| Debets et al. | PTR | 60 | 53.13 ± 15.36 | 43.3% | 21.7% | – | – | 45.0% | 5.0% | 30.0% |
| (2024) | No surgery | 67 | 58.19 ± 12.91* | 40.3% | 32.8% | 22.4%* | 4.5% | 22.4% | ||
| Nakanishi | PTR | 5 | – | - | - | - | – | - | - | – |
| et al. (2024) | No surgery | 9 | ||||||||
| Yasar et al. | PTR | 31 | – | - | - | - | – | - | - | – |
| (2024) | No surgery | 24 |
Abbreviations: PTR, primary tumour resection.
*Difference between groups is statistically significant. +Mean and SD calculated by Wan’s method.
underwent surgery ranged between 4.8 and 26.4 months, whereas median overall survival in non-operated patients ranged between 1.2 and 9.0 months (Table 3). Seven studies reported that primary tumour resection was associated with prolonged overall survival in a multivariable regression analysis, after adjustment for other known or suspected predictors for survival (Hermsen et al. 2012, Livhits et al. 2014, Wang et al. 2017, Wu et al. 2021, Srougi et al. 2022, Debets et al. 2024, Passman et al. 2024). Four studies adjusted for chemotherapy administration, and five studies corrected for local treatment of metastatic lesions. It is likely that patients who are eligible for chemotherapy are fitter or that patients who are also locally treated for metastases have a lesser disease extent, and therefore, such patients might have a better prognosis irrespective of primary tumour resection. Although it is impossible in a multivariable analysis to correct for all potential factors that influence a patient’s prognosis, it is remarkable that after controlling for such other treatments, the association of primary tumour resection with longer survival still remains significant. Taking into account only the studies in which multivariable analyses have been performed, survival of patients who underwent
primary tumour resection was on average 9.5 months longer than patients who did not undergo surgery. One study investigated both survival after surgery versus no surgery and survival after surgery combined with chemo- and/or radiotherapy versus chemo- and/or radiotherapy alone (Livhits et al. 2014). For both comparisons, patients who underwent primary tumour resection had four times longer overall survival. No data are available on whether the effect of surgery on survival differs in ACC patients with hormonal overproduction compared to patients with non-functional ACCs.
Discussion
This systematic review aimed to assess whether resection of the primary tumour in the setting of metastasised ACC could improve survival. The available literature is only retrospective and lacks information regarding patient characteristics and indications for surgery. Nevertheless, these studies almost uniformly demonstrated increased overall survival after resection of the primary tumour, also after adjusting for other predictors of survival.
| Study ID | Indication for surgery and/or baseline data available | Patients (n) | OS (months); median (95% CI) | 1-YSR | 2-YSR | 3-YSR | HR (95%CI) of multivariable analysis | P value | |
|---|---|---|---|---|---|---|---|---|---|
| Dong et al. (2012) | No | No | 10 | 10.04 (SD: ± 8.95) | – | - | - | – | >0.05 |
| 13 | 4.96 (SD: ± 1.86) | – | - | - | – | ||||
| Hermsen et al. (2012) | No | Yes | 52 | 11 | 48%* | 33%* | 19%* | 0.46 (0.27-0.77)a | 0.002 |
| 23 | 4 | 17%* | 4%* | 4%* | |||||
| Kerkhofs et al. (2013) | No | Yes | 34 | 10 (4-16) | 47% | 29% | – | – | <0.001 |
| 38 | 2 (1-3) | 5% | 0% | 0% | |||||
| Livhits et al. (2014) | No | No | 25 | 4.8 | 17%* | 8% | 8%* | 0.52 (0.28-0.97)b | 0.0394 |
| 48 | 1.2 | 10%* | 8% | 8%* | |||||
| Livhits et al. (2014)+ | No | No | 44 | 13.2 | 52%* | 34% | 22%* | 0.31 (0.17-0.55)b | <0.001 |
| 50 | 3.6 | 14%* | 6% | 4%* | |||||
| Ettaieb et al. (2016) | No | No | 34 | 16.6 (range: 0-113.8) | 50%* | 30%* | 19%* | – | <0.001 |
| 16 | 1.8 (range: 0-16.5) | 12%* | 0%* | 0%* | |||||
| Wang et al. (2017) | No | Yes | 118 | 12 (8-16) | 53%* | 33%* | 17%* | 0.41 (0.30-0.57)c | <0.01 |
| 172 | 4 (3-4) | 19%* | 8%* | 5%* | |||||
| Tella et al. (2018) | No | No | 325 | 19 | 61%* | 43%* | 34%* | – | <0.001 |
| 435 | 6 | 28%* | 14%* | 10%* | |||||
| Wu et al. (2021) | No | Yes | 76 | 13 | 52%* | 34%* | 32%* | 0.64 (0.45-0.92)d | 0.017* |
| 126 | 4 | 25%* | 12%* | 5%* | |||||
| Srougi et al. (2022) | No | Yes | 128 | 25.2 (21.0-29.5) | 77% | 54% | 38%* | 0.31 (0.23-0.43)e | <0.001 |
| 111 | 9.0 (6.7-11.3) | 34% | 15% | 5%* | |||||
| Passman (2024) | No | Yes | 278 | 15.9 (11.0-18.9) | 55%* | 35%* | 25%* | 0.59 (0.49-0.72f | <0.001 |
| 278 | 6.0 (4.8-7.5) | 29%* | 16%* | 11%* | |||||
| Debets et al. (2024) | No | Yes | 60/345 | 11.2/155 | 48%* | 31%* | 27%* | 0.23 (0.11-0.46)g | <0.001 |
| 67/285 | 3.2/25 | 15%* | 11%* | 7%* | |||||
| Nakanishi et al. (2024) | No | No | 5 | – | 100%* | 100%* | 67%* | – | 0.0262 |
| 9 | 13%* | 13%* | – | ||||||
| Yasar et al. (2024) | No | No | 31 | 26.4 (10-42.8) | – | 52.6% | – | – | 0.006 |
| 24 | 8.4 (3.1-13.7) | 9.1% | |||||||
All studies compared primary tumour resection (PTR, upper row) to no surgery (lower row). Livhits et al. (2014) also compared PTR + chemoradiotherapy (CRT) to CRT only. YSR: year survival rate.
*Survival rates extracted from Kaplan-Meier curves. +PTR + CRT vs CRT only. * Except for subgroup analysis of patients with liver metastases; they do not have a survival benefit from surgery (median OS: 5 vs 7 months, HR = 1.16, 95% CI: 0.57-2.38, P = 0.670). Numbers given on the left are all synchronously metastasised ACC patients included, and numbers given on the right are a subgroup analysis of patients treated after 2014.
These patients are included in the multivariable cox regression analysis: aAdjusted for age, gender, stage at diagnosis, hormonal function and treatment in specialised adrenal centre in multivariable analysis; bAdjusted for age, gender, comorbidities, socio-economic status, hospital type and presence of Cushing syndrome in multivariable analysis; cAdjusted for age, size, surgical treatment of metastases and chemotherapy in multivariable analysis; dAdjusted for age, location of metastasis, surgical treatment of metastases and chemotherapy in multivariable analysis; eAdjusted for age, size, hormonal function, presence of liver metastases, local treatment of metastasis, radiotherapy and chemotherapy in multivariable analysis; fAdjusted for age, gender, race, comorbidities, number of metastases and chemotherapy in multivariable analysis; gAdjusted for local treatment of metastases and Ki67 in multivariable analysis.
This trend is also seen in other tumour types, such as breast, colorectal, gastric and renal cell cancers, regarding retrospective data (Fig. 2; Supplementary Table 4). Dependent on the type of cancer, 67-100% of retrospective studies demonstrated significantly longer survival after primary site surgery in all or at least in a subset of patients (Haugstvedt et al. 1989, Hartgrink et al. 2002, Sarela et al. 2007, Blanchard et al. 2008, Culp et al. 2010, Stillwell et al. 2010, Choueiri et al. 2011, Verhoe et al. 2011, You et al. 2011, Cirocchi et al. 2012, Park et al. 2013, Abern et al. 2014, Heng et al. 2014, Tarantino et al. 2015, De Groot et al. 2016, Hanna et al. 2016, Klatte et al. 2018, Li et al. 2019, Simillis et al. 2019, Yang et al. 2019, Palumbo et al. 2020, Peng et al. 2020, Cowling et al.
2021, Kamarajah et al. 2021, Chakiryan et al. 2022, Bakouny et al. 2023, Liu et al. 2023). However, as opposed to the retrospective data, in prospective randomised controlled trials (RCTs), primary site surgery is not associated with improved survival in case of metastatic disease. RCTs on the impact of primary site surgery on survival have, to the best of our knowledge, been performed for a few types of cancer, including the aforementioned tumour types: breast, colorectal, gastric and renal cell cancer. For all four malignancies, the survival benefits related to primary site surgery could not, or only in a small subset of trials, be validated (Fig. 2; Supplementary Table 4). Regarding breast cancer, one of the four RCTs
Breast cancer
Colorectal cancer
Gastric cancer
Renal cell cancer
1
15
1
2
Retrospective data
27
103
134
9
Prospective data
1
0
0
1
3
3
1
2
Longer survival after surgery
Similar survival after surgery
on breast cancer demonstrated improved median overall survival after mastectomy compared to no surgery (Badwe et al. 2015, Soran et al. 2018, Fitzal et al. 2019, Khan et al. 2020). In colorectal cancer, two RCTs did not report improved survival with primary tumour resection and chemotherapy compared to chemotherapy alone (Park et al. 2020, Kanemitsu et al. 2021). Accordingly, results of the SYNCHRONOUS trial pooled with the CCRe-IV trial did not show improved survival after primary tumour resection compared to chemotherapy alone (Rahbari et al. 2024). An additional study even reported a higher 60-day mortality rate after primary tumour resection (Van Der Kruijssen et al. 2021). The only RCT performed on gastric cancer is the REGATTA trial (Fujitani et al. 2016); in this study, no survival benefit of palliative gastrectomy was found compared to systemic therapy alone. In contrast to these malignancies, in renal cell cancer, two out of three RCTs demonstrated survival benefits of palliative nephrectomy (Flanigan et al. 2001, Mickisch et al. 2001). Nevertheless, these were both studies from the early 2000s, whereas the more recent CARMENA trial (Méjean et al. 2018) found that sunitinib treatment alone was non-inferior compared to nephrectomy combined with sunitinib. A survival benefit from nephrectomy was only seen in a subgroup of patients having one International Metastatic Renal Cell Carcinoma Database Consortium risk factor.
The discrepancies between the findings of the retrospective literature and the subsequent RCTs can be explained by indication and selection bias in retrospective data. More than half of the included articles are based on data from existing registries. Those registries may lack enough detail about individual patient characteristics to report all factors that influence survival or the chance to undergo surgery. Many of the included studies did not present any patient characteristics for operated and non- operated patients separately, so comparability of those groups before surgery remains unknown. In the articles
that did provide some patient characteristics for operated and non-operated patients, selection bias is evident. Patients who underwent primary site surgery were younger, had larger tumours and more frequently received metastasis treatment compared to non- operated patients. Differences between operated and non-operated patients were even evident in the studies that had performed propensity score matching in an attempt to minimise selection biases. Nevertheless, after controlling for these factors in multivariable regression models performed in a substantial part of the included studies, improved survival after primary tumour resection is consistently reported. As for all articles in this systematic review, however, the absence of indication details complicates understanding whether surgery was aimed at symptom relief or survival prolongation. For the patients not operated on, it remains unknown whether this was because they were asymptomatic or because their general condition disqualified them from being candidates for surgical treatment at all. Although patient condition scores were hardly described in any of the studies, it is very likely that individual patient performance has resulted in biases. Both the indication and selection bias hinder drawing conclusions on the survival benefits of surgery in metastatic ACC.
Prospective trials are lacking due to ACC’s rarity and are unlikely to be conducted for the same reason. As mentioned earlier, existing RCTs in other cancers often do not show surgery’s survival benefit over systemic therapy alone, while retrospective studies in these other cancers also display survival benefit. A critical consideration is the advancement in systemic therapy across these other cancer types in recent years, leading to improved disease survival in general. Systemic treatment options for ACC, however, remain limited, and the results are disappointing. While immunotherapy has emerged as a promising treatment strategy for many other cancer types, the few trials on immunotherapy in ACC patients showed low response
rates and poor survival (Georgantzoglou et al. 2021). More research is needed to understand the low response rates to systemic therapies in ACC and to potentially overcome this problem in the future. Until then, the lack of effective alternative treatments may justify consideration of surgery in metastatic ACC specifically. It is, however, essential to recognise that the delay of systemic therapy initiation due to postoperative recovery after surgery can be detrimental for the subgroup of patients that do benefit from systemic therapy. This is in addition to the general surgical risks of major abdominal surgery in patients with metastasised disease who often suffer from conditional losses, rendering them prone to a complicated postoperative course. Hence, the decision to operate in the metastatic setting should be well weighed, acknowledging the complex interplay between surgery, systemic therapy and the unique characteristics of ACC.
For symptomatic patients, surgery may be appropriate as it can provide relief irrespective of its impact on survival. Some experts state that debulking of cortisol-producing ACC is the fastest way to provide relief of hypercortisolism, which poses a serious threat to a patient’s overall condition (Fassnacht et al. 2018, Mihai et al. 2024). Steroid synthesis inhibitors, such as metapyrone, ketaoconazole or osilodrostat, might serve as alternative treatments to timely control hypercortisolism in patients not undergoing surgery (Fassnacht et al. 2018, Feelders et al. 2019). In patients in whom surgery would solely be performed in an attempt to prolong life, for example as they are asymptomatic, decision-making is more complex, demanding careful selection of patients with the smallest risks and the largest benefits to undergo surgery. For instance, patients in whom resection of all disease is possible might benefit more from surgery. Complete resection of both the primary tumour and all metastases might exclude the need for chemotherapy or mitotane treatment in some patients. Not treating patients with chemotherapy or mitotane spares them the side effects and could thereby enhance quality of life. Whether the ability to perform either an incomplete debulking surgery or a complete resection of all disease impacts survival remains, however, a topic of debate. Whereas two studies have shown longer survival after complete versus incomplete debulking surgery (Dy et al. 2015, Prendergast et al. 2020), others demonstrated similar survival rates after (in)complete surgery (Libé et al. 2015, Wu et al. 2021).
Selection of patients is crucial to avoid invasive treatments, such as surgery, in patients who will experience early postoperative disease progression causing significant morbidity, as in those cases, the harm of treatment most likely outweighs the benefits. A neoadjuvant approach could present a potential solution by allowing clinicians to assess the patient’s response to
systemic treatment before deciding on surgery, although it is critical to acknowledge that the disappointing results of systemic treatment in ACC can complicate such an approach. Nevertheless, Bednarski et al. (2014) showed in 15 patients with borderline resectable ACC that 86.7% of the patients proceeded to surgical resection of their tumour and that disease-free survival was longer after neoadjuvant chemotherapy compared to direct surgery. Besides facilitating patient selection for surgery, neoadjuvant treatment offers the advantage of addressing the potential delay in systemic therapy inherent in a surgery-first approach. Moreover, by downsizing the disease, neoadjuvant treatment enhances the likelihood of achieving complete resection and reduces the surgical burden by minimising the extent of the operation required.
Conclusion
The current literature in this systematic review is hampered by both indication and selection biases to draw strong conclusions on survival benefits of primary tumour resection in patients with metastasised ACC. However, data do show longer survival rates after primary tumour resection of metastatic ACC. Decision- making should still take place on an individual patient basis, keeping symptomatic burden in mind. Future studies should provide adequate patient characteristics in order to enable interpretation of their results for clinical use. Moreover, research should explore the possibilities to improve patient selection for surgery, for instance based on the ability to completely remove all disease or response to neoadjuvant treatment.
Supplementary material
This is linked to the online version of the paper at https://doi.org/10.1530/ERC-24-0056.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the work reported.
Funding
This research received no external funding.
Author contribution statement
Conceptualization, CLV, TMVG, DJG and CV; methodology, CLV, IJS and TMVG; article selection, CLV and IJS; data extraction, CLV and IJS, writing - original draft preparation, CLV, IJS and TMVG; writing - review & editing, CLV, IJS, TMVG, DJG, CV, GJHF and RAF; supervision, TMVG, DJG, CV and RAF.
Registration
This study was registered on PROSPERO on 16 January 2023, with registration number CRD42023390869.
Acknowledgements
The authors wish to thank Dr M F M Engel from the Erasmus MC Medical Library for developing and updating the search strategies.
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