URRENT PINION
Treatment of adrenocortical carcinoma: oncological and endocrine outcomes
Stephan Brönimann, Nathalie Garstka and Mesut Remzi
Purpose of review
Adrenocortical carcinoma (ACC) is a rare, aggressive disease with a paucity of data and great variability between published studies regarding its treatment. This review provides information on current clinical management and oncological and endocrine outcomes.
Recent findings
Complete surgical resection is the only potentially curative treatment for adrenocortical carcinoma (ACC). Adjuvant mitotane treatment is recommended in patients with favourable/intermediate prognosis. As part of the endocrine follow-up, steroid hormones and thyroid hormones may be decreased or increased and may need to be substituted or suppressed. Recurrences are common. If the disease-free interval is more than 12 months, surgery is a treatment if complete resection is feasible. In advanced/metastatic ACC patients, the prognosis is poor. Mitotane monotherapy is only appropriate for patients with low tumour burden and indolent disease. Patients with unfavourable prognosis should be treated with aggressive cytotoxic therapy. Patients requiring third-line treatment should be considered for clinical trials. Immunotherapy and targeted therapy are currently being investigated, but have so far yielded only unsatisfactory results.
Summary
There is scarce evidence for the treatment of ACC, which often complicates clinical decision-making. Patients who progress on EDP-M should be treated in clinical trials.
Keywords
adrenocortical carcinoma, endocrine, mitotane, oncologic, outcome, treatment
INTRODUCTION
Adrenocortical carcinoma (ACC) is a rare, in many cases, steroid hormone-producing aggressive malig- nant tumour. These tumours may be functional and induce Cushing’s syndrome and/or virilization, or may not be functional and manifest as an abdomi- nal mass or as an incidental mass. The purpose of this review is to provide evidence-based recommen- dations and information for the clinical manage- ment of this disease as well as information on the oncologic and endocrine outcome.
SURGICAL MANAGEMENT
Complete surgical resection is the sole potentially curative treatment for ACC. Because of the specific anatomy, the malignant nature of the disease and the potential need for en bloc resection of multiple organs, ACC surgery requires expertise in both, adrenal and oncologic surgery to optimize the likelihood of R0 resection and reduce the risk of complications.
Generally, ACC is rare; hence, there is a paucity of data comparing outcomes between high-volume and low-volume centres. Published studies from the UK, USA and Spain show an unacceptably low annual patient caseload for the majority of surgeons involved in adrenal surgery, with a median of one case per year [1-4]. This situation is considered to have a negative impact on patient care and is in marked contrast to the current state-of-the-art in other surgical specialties. As the diagnosis of ACC may not be established until histological analysis after the resection has taken place, it remains imper- ative to follow the principles of oncological surgery in patients with reasonable suspicion of ACC [5].
Department of Urology, Comprehensive Cancer Center, Medical Uni- versity of Vienna, Vienna, Austria
Correspondence to Mesut Remzi, MD, Department of Urology, Vienna General Hospital, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria. Tel: +43 1 40400 26150;
fax: +43 1 40400 32230; e-mail: mesut.remzi@meduniwien.ac.at
Curr Opin Urol 2023, 33:50-58
DOI:10.1097/MOU.0000000000001045
KEY POINTS
· Complete surgical resection is the only potentially curative treatment.
· Adjuvant mitotane treatment is recommended in patients with favourable/intermediate prognosis.
· Steroid hormones and thyroid hormones may be decreased or increased and may need to be substituted or suppressed.
· Surgery is a treatment option if the disease-free interval is more than 12 months, and complete resection is feasible.
· In advanced/metastatic ACC, mitotane monotherapy is only appropriate for patients with low tumour burden and indolent disease.
· Patients with unfavourable prognosis should be treated with aggressive cytotoxic therapy.
· Patients requiring third-line treatment should be considered for clinical trials.
Open surgery using a transperitoneal approach is the gold standard treatment for all patients with localized (stage I-II) and locally advanced (stage III) ACC whenever complete resection can be achieved. Any fragmentation of the tumour must be avoided to ensure that the pathologist is able to assess the completeness of resection. Moreover, intraoperative tumour rupture or spillage and R2 resections are associated with high recurrence rates and poor over- all survival (OS) [6,7].
Therefore, margin-free complete resection (R0 resection) is pivotal to long-term survival [8]. In this aspect, it is mandatory to perform a complete en bloc resection of the tumour, including the periadrenal adipose tissue and, if necessary, the adjacent organs, such as the wall of the vena cava, liver, spleen, colon, pancreas and stomach, if necessary to achieve a com- plete resection. However, for tumours that do not infiltrate the kidney, simultaneous nephrectomy does not appear to improve disease-free survival and OS and should, therefore, be omitted.
Although still controversial, laparoscopic adrena- lectomy in experienced hands appears to be a both well tolerated and effective procedure in a selected group of patients with small ACC and without evi- dence of local invasion [5]. In current clinical practice, adrenal masses, classified as only potentially malig- nant are commonly surgically resected by laparo- scopic adrenalectomy. Nonetheless, this procedure should only be performed in centres with profound experience in laparoscopic adrenal surgery, where the principles of oncological surgical treatment are
strictly followed [5]. Considering the approach, there is no evidence of superiority of the transperitoneal over the retroperitoneal approach. In case, any surrounding tissue involvement is detected during laparoscopic surgery or there is a risk of spillage, capsular damage or incomplete resection, conversion to an open approach is indicated [5].
Overall, approximately 15-25% of cases show an extension into the adrenal vein, renal vein or inferior vena cava [9-11]. In most cases, venous involvement consists of an intravenous tumour thrombus. In the absence of distant metastases, a 3-year overall survival rate of about 25% in a large series [12] argues in favour of performing venous resection in the presence of invasion of the vena cava or renal veins.
Several studies have shown that patients being operated on by surgeons performing more than six to seven cases per year have a shorter length of hospital stay and fewer complications [4,13]. However, although patients who were treated in high-volume centres in the USA and Italy had more radical surgery, a higher rate of lymph node dissection and more chemotherapy was used [14,15], no significant asso- ciation between OS and disease-free survival was found. Conversely, the establishment of national centres for adrenal surgery in the Netherlands resulted in significantly better disease-free survival of 93 vs. 78% after 1 year and 63 vs. 42% after 5 years [16,17].
A number of studies indicate that patients with stage III tumours and positive lymph nodes still have a 10-year OS rate of up to 40% after resection [9,18,19]. There is, however, a wide range of reported lymph node involvement in ACC from 4 to 73% [7,20,21], indicating that regional lymphadenectomy is neither formally performed by all surgeons nor accurately assessed. According to large American and French series, about 10-30% of patients with ACC under- went formal lymphadenectomy as part of tumour resection, revealing the heterogeneity of surgical management in this disease [21,22]. At a minimum, routine lymphadenectomy should constitute the periadrenal and hilar nodes, albeit the most appro- priate extent of lymphadenectomy has not been established [23]. In order to classify patients as lymph node-negative, at least four lymph nodes should be dissected [24]. Beyond this, the advantage of lympha- denectomy for OS persisted in a multivariable analysis of 120 cases from a multinational database. Similarly, resection of more than five lymph nodes also reduced the risk of local recurrence and cancer-related death in a multivariate analysis of the largest published series of 283 patients [23]. In case, lymphadenectomy has been omitted, for example, if a benign lesion was assumed, the Guidelines of the European Society of Endocrinology argue against a secondary lymphade- nectomy [25].
Concerning the benefit of re-resection in patients with R2 status, there is no prospective study evaluating this situation. That said, patients should be closely followed postoperatively and should undergo surgery with curative intent for local recur- rence without evidence of metastases if R0 resection appears feasible [25].
Adjuvant therapy
In one meta-analysis, the pooled hazard ratio for recurrence was 0.7 (95% CI 0.5-1.1), for mortality, the pooled hazard ratio was 0.7 (95% CI 0.5-0.9). However, all included studies were nonrandomized [25]. Adjuvant treatment may reduce this risk. It is sometimes difficult to determine whether a tumour is actually malignant. Given the fact that every adjuvant therapy is associated with potential tox- icity, adjuvant treatment should only be recom- mended in patients with a definitive diagnosis of ACC. In this regard, adjuvant mitotane treatment is recommended in patients who do not have macro- scopic residual tumour after surgery and are deemed to have a high risk of recurrence (stage III, or R1-Rx resection or Ki67 >10%) [25]. On the other hand, it is not possible to recommend either for or against adjuvant therapy in patients with low or intermedi- ate risk of recurrence (stage I-II, RO resection and Ki67 ≤10%). Ki67 has been found to be the strongest predictor of recurrence, and tumours with Ki67 10% or less may constitute a subgroup of patients with a favourable prognosis. In these patients, mitotane may potentially be regarded as overtreatment [25]. Regarding adjuvant mitotane treatment, two meta- analyses reported a decreased risk of recurrence and death [25,26]. The benefit associated with mitotane was significant for OS in both analyses, whereas it was significant for recurrence-free survival in only one.
The ideal point in time for starting adjuvant mito- tane treatment is unknown. There is, however, a recommendation to initiate therapy between 6 weeks and at the latest 3 months after the resection. With no recurrence, adjuvant therapy should be adminis- tered for 2-5 years in patients who tolerate mitotane with acceptable side effects. Relapse rate 5 years after surgery, however, may be too low to recommend continuing therapy beyond that time [25].
The pooled hazard ratio for local recurrence in three studies after treatment with radiotherapy was 0.3 (93% CI 0.1-1.9). In addition to being small with imprecise effect estimates, all of the studies were observational with the risk of residual confounding bias. Furthermore, radiotherapy appears to be able to reduce the risk for local recurrence but has not shown a significant impact on distant recurrence or OS [27-29], which constitutes roughly 40-60% of
tumour recurrences [30,31]. Adjuvant radiotherapy may be especially useful in patients with R1 resection [32]. In case of extensive tumour spillage during surgery, radiotherapy is not recommended. The com- bination of radiotherapy and mitotane is biologically useful ([33,34] and feasible, albeit at the cost of higher toxicity. The time of adjuvant radiotherapy should be as soon as possible after surgery and should be delivered at a dose of 50-60 Gy in fractionated doses of approximately 2 Gy each to the tumour bed.
Regarding the administration of adjuvant che- motherapy, this may be discussed in patients at high risk of recurrence, ideally in the context of clinical trials. Some centres use cisplatin with or without etoposide in patients suspected to be at very high risk of recurrence (e.g. Ki67 >30%, large tumour throm- bus in the vena cava, stage IV or R1 resection). Also patients with splenic and pancreatic involvement are at high risk of recurrence, and adjuvant mitotane treatment is, therefore, warranted [35]. The addition of cytotoxic drugs could be a possible option for these patients, although data on this are lacking.
ENDOCRINE OUTCOME
In cortisol-producing tumours, adrenal insufficiency might occur once the source of cortisol has been removed, even in patients with incompletely sup- pressed ACTH [36]. Accordingly, in all patients with evidence of potential autonomous cortisol secretion [postdexamethasone cortisol >50 nmol/l (>1.8 µg/dl)], there is a clear indication for intraoper- ative and postoperative glucocorticoid substitution, preferably with hydrocortisone. Postoperatively, the glucocorticoid dosage should be adjusted individu- ally [25]. In patients with a completely resected steroid hormone-producing ACC, some experts rou- tinely monitor for recurrent hormone excess every 3 months for 2 years using steroid tumour markers such as cortisol, dehydroepiandrosterone sulphate (DHEAS), androstenedione, testosterone, oestradiol or mineralocorticoid based on the steroid profile in the original tumour. Others do not routinely screen for recurrent hormone excess unless there is evidence of recurrent disease. Two distinct purposes are served by biochemical examination together with clinical assessment: it may allow early detection of recurrence in a minority of patients, and it may also identify patients who might benefit from early antihormonal therapy [25].
Along with mitotoane, adjunctive treatment with hydrocortisone 20 mg/day should be initiated on the first day of treatment. As an alternative, patients may be started on hydrocortisone later, since impairment of glucocorticoid effectiveness is seldom seen within the first few weeks. As a result of
the increased steroid clearance and the rise in corti- sol-binding globulin induced by mitotane, at least twice the standard substitution dose is usually required [37-39]. Furthermore, the increase in cor- tisol-binding globulin induced by mitotane may compromise the interpretation of serum cortisol measurements. A sign of an inadequate dose may be ACTH levels that are more than two times the upper limit of normal. Nevertheless, there is no reliable laboratory marker to determine the optimal hydrocortisone dose [40,41]. The dose must, there- fore, be based on clinical assessment, comparable to the treatment of patients with adrenal insufficiency [42]. In acute adverse events, patients need to be treated with high-dose hydrocortisone (e.g. 100 mg t.i.d) intravenously until symptoms resolve.
In some patients, mitotane may also cause aldos- terone deficiency. In this case, despite full-dose substitution with hydrocortisone, symptoms and signs of inadequate mineralocorticoid activity (hypotension, hyponatremia or hyperkalaemia and elevation in plasma renin activity) are then seen. In such patients, the additional administration of fludrocortisone is indicated. Clinical assessment, electrolytes and plasma renin concentration should guide the decision on whether to start fludrocorti- sone [37,43].
After discontinuing mitotane, hydrocortisone therapy should be maintained but progressively tapered to more physiological doses. Assessment for possible recovery of adrenal insufficiency should be carried out every 6 months by measuring morn- ing serum cortisol levels before taking hydrocorti- sone. Depending on the duration of mitotane therapy, adrenal insufficiency may remain persis- tent in some patients, whereas in others, adrenal function may recover. This was shown in a study of 23 patients who were treated for at least 2 years. The hypothalamic-pituitary-adrenal axis recovered completely in 18-23 patients (78%) within a median period of 2.7 years after stopping the adjuvant treat- ment [44”].
It is also possible for patients to develop hyper- cortisolism, with symptoms such as immunosup- pression, diabetes and muscle weakness, which may have a significant negative impact on the qual- ity of life [45]. In a recently published analysis, eight patients (47%) had autonomous hormone produc- tion, of whom most suffered from hypercortisolism [45]. Medical therapy is recommended to control the overproduction of hormones. Mitotane is usu- ally effective in reducing steroid excess, but its effect is often several weeks delayed. In such circumstan- ces, potent steroidogenic enzyme inhibitors, like metyrapone, may be of value. Metyrapone tends to be a well tolerated drug in which metabolism
and excretion are not altered by the concomitant intake of mitotane. Hence, it can be administered safely in combination with mitotane and cytotoxic therapy [46]. Although ketoconazole is effective in benign adrenal disease, it is unlikely to control hypercortisolism in ACC. However, in case eucortis- olism is not achieved with metyrapone, combina- tion therapy with ketoconazole can be useful.
A small percentage of ACC patients show virili- zation. The best approach to treat virilization is specific androgen blockade with androgen receptor inhibitors (e.g. bicalutamide at 50 mg per day) or 5- alpha reductase inhibition (e.g. finasteride at 5 mg per day). For women with androgen excess as a result of benign disease, spironolactone is often used to control androgen effects, whilst this approach is often ineffective in ACC with exceedingly high- serum androgen concentrations.
On the other hand, hypogonadism is common in men receiving mitotane therapy, which frequently requires testosterone substitution. In addition to its effect on corticosteroid-binding globulin, mitotane increases serum concentrations of sex hormone- binding globulin as well [37,47]. In addition, poten- tially reducing free testosterone levels, mitotane causes a severe inhibition of the 5-alpha-reductase activity [38]. Therefore, serum testosterone should be routinely measured in men receiving mitotane.
In female individuals, the effects of mitotane on the reproductive function are less evident. Elevation of both luteinizing hormone (LH) and follicle-stim- ulating hormone (FSH) have been reported, possibly causing the development of large ovarian cysts in some premenopausal women [48].
Additionally to its effect on corticosteroid-bind- ing globulin and sex hormone binding globulin, mitotane elevates serum concentrations of thyroid hormone binding globulin. Hence, serum concen- trations of free thyroxine may be decreased [37]. Recent studies indicate that mitotane has a direct inhibitory effect on thyroid-stimulating hormone (TSH) secretion. Given that patients on mitotane therapy often present with fatigue, thyroid hor- mones should be regularly monitored. Replacement of thyroid hormone is advised in all patients pre- senting with clinical symptoms of hypothyroidism and low free T4 levels [37].
ONCOLOGIC OUTCOME
Despite the fact that resection is feasible in the majority of patients with stage I-III disease, it is often not curative, probably because of the existence of occult micrometastases, even in stage I disease [49]. As an example, in a single-centre study, 27, 46 and 63% of patients with stage I, II and III disease,
respectively, developed distant metastases within 2 years of diagnosis [50].
The most important prognostic factor after com- plete resection is whether tumour recurrence occurs [25]. After complete resection, radiological imaging is recommended every 3 months for 2 years and then every 3-6 months for a subsequent 3 years. After curative initial surgery, recurrences are rare after more than 5 years and, therefore, imaging follow-up is individualized thereafter [25]. A large number of recurrences and disease progression occur either locally-regionally or with metastases in the lungs or liver. Bone metastases are seen rarely and cerebral involvement is the exception [19,51]. At the time of recurrence, the most important prog- nostic factors are the time interval between initial resection and recurrence, tumour burden and resect- ability [52-54]. Further prognostic factors are age and sex [7,9,25,55].
Regarding surgical resection vs. systematic ther- apy for recurrent or advanced disease, there are major variations in disease extent, indication and concur- rent treatment between published studies. The reported benefit of surgery is affected by the different indications for surgery, which do not allow clear conclusions to be made. Hereby, an influential factor in the case of recurrence is the disease-free interval preceding the recurrence. As it has been shown that patients have a significantly better prognosis and long-term disease control is achievable, it is recom- mended that surgery or alternatively other local therapies are used in patients with recurrent disease and a disease-free interval of at least 12 months, in whom complete resection/ablation appears feasible [52,53]. After resection, mitotane treatment should be started as early as possible. Furthermore, in patients with local recurrence, adjuvant radiation therapy after resection should be considered.
Patients with a disease-free interval of greater than 12 months, where complete resection or locore- gional therapy is not possible and who are currently not treated with mitotane, are advised to be treated with mitotane monotherapy [56]. If the time interval from the latest surgery and recurrence is shorter than 6 months, doxorubicin, cisplatin, etoposide and mitotane (EDP-M) is preferred as first-line treatment instead of repeated locoregional interventions, as patients who develop early recurrence usually suffer from a very aggressive tumour that most likely may not be controlled by surgery or locoregional thera- pies. For all other patients with recurrent disease, an individualized approach is required. However, one exception may be patients in whom incomplete initial surgery is the most probable cause of early disease progression. For these selected individuals, re-operation could be a viable option.
In metastatic ACC, there is no curative therapy. Moreover, the general prognosis of advanced/meta- static ACC patients is poor, with a 5-year OS of about less than 15%. A study by the ENSAT network has identified prognostic factors in advanced disease patients. They found that stage, as redefined by a modified ENSAT classification, which takes into account the number of organs affected by the malig- nancy, plays an important prognostic role along with other four parameters known as GRAS: tumour grade, resection status of the primary tumour, age, and tumour-related or hormone-related symptoms [19]. A risk stratification was introduced on the basis of these findings [57]. This new risk classification needs to be confirmed in further studies before it can be fully applied in the clinical setting.
The observed correlation between stage and prognosis was robust, although different staging systems have been used in the studies. However, the ENSAT staging [9] was found to be slightly superior to the UICC staging [18] in a formal com- parison. Furthermore, the association between hypercortisolism and mortality was consistent. A positive hazard ratio (1.71, 95% CI 1.18-2.47) [58] was found to persist even after adjustment for tumour stage. Likewise, Ki67 was assessed and all studies showed a worse prognosis with elevated Ki67 levels. Other molecular markers were only studied in some small cohorts. Moreover, numerous studies have attempted to find biomarkers that predict response to cytotoxic therapy in ACC [59-61]. Still, no robust biomarker has been found. Moreover, it must be mentioned that relative risks, even if stat- istically significant, cannot provide clinical decision support unless they are integrated into predictive models. In this respect, so far, only one formal prediction model was published (including tumour size, stage, mitotic index, venous invasion and endocrine activity variables), which showed a sen- sitivity of 0.91 and a specificity of 0.90 [62]. Another study published nomograms to aid prognostication in individual patients [63]. However, none of these models has been externally validated.
As not curative, the aim of any therapy in advanced disease is to alleviate symptoms and pro- long survival. Patients who have a limited number of intra-abdominal metastases may be referred for surgical therapy if complete resection of all lesions appears achievable. Complete surgical resection is the most promising way to achieve long-term dis- ease control, even though the likelihood of com- plete tumour eradication in advanced ACC is low. Complete resection is important, as shown in a trial of 47 patients with ACC who underwent resection for locally recurrent metastatic disease. The 5-year survival rate was 57 and 0% for patients with
completely and incompletely resected locally recur- rent disease, respectively [64]. In all of these patients, mitotane therapy should be initiated as soon as possible.
In patients with unresectable indolent disease, mitotane is the currently recommended first-line treatment. The available literature on mitotane monotherapy is of poor quality, and results are highly inconsistent. Most studies were conducted in early years without adequate follow-up of tumour response with appropriate imaging. Additionally, mitotane was administered frequently in a subopti- mal regimen. Hence, subtherapeutic serum concen- trations may have accounted for much of the variability. The importance of therapeutic plasma levels was recently published by Puglisi et al. [65""]. In general, the duration of treatment response is generally short and survival is not uniformly pro- longed. Although there are isolated case reports of long-term disease control and even rarer cases of prolonged complete remission in patients with unresectable or metastatic disease, these are almost always patients with low-grade disease [66,67]. An analysis of nine prospective trials constituting a total of 246 patients with advanced ACC estimated a mean objective response rate of as low as 26% [47]. In addition, some patients who responded objec- tively to mitotane had to discontinue the treatment because of the side effects of the drug [68].
In patients progressing on mitotane monother- apy, the addition of doxorubicin, cisplatin, etopo- side (EDP) is recommended. Given the latency of mitotane to reach therapeutic range, mitotane monotherapy is only appropriate in patients with low tumour burden and indolent disease. Patients with unfavourable prognostic parameters, like high tumour burden, uncontrolled symptoms, high pro- liferation index and clinical evidence of a rapidly growing tumour should be started on aggressive therapy, with a combination of EDP-M being the best validated regimen [69]. However, it must be emphasized that progression-free survival (PFS) was the only outcome that was significantly improved compared with the alternative therapy (in this case, streptozotocin and mitotane; 5.0 vs 2.1 months; hazard ratio 0.55; 95% CI 0.43-0.69; P <0.001)), while for OS, the crossover design may have skewed the outcomes (14.8 vs. 12 months, hazard ratio 0.79; 95% CI 0.61-1.02; P= 0.07). In a recently published study including 58 patients with stage III-IV ACC, a partial response was reached in 50% of cases and a stable disease in 26% of cases. However, no complete response was observed. The PFS was 10.1 months (95% CI 8.1-12.8) and OS was 18.7 months (95% CI 14.6-22.8) [70""]. These data support the limited efficacy of the EDP-M regimen, which is, however,
currently the most effective therapy in the treat- ment of advanced ACC.
In case of concerns about using doxorubicin, cisplatin with or without etoposide (EP or P) may be an alternative option. Nevertheless, the evidence for etoposide + cisplatin or cisplatin alone is based only on small phase II trials [71-73]. Carboplatin may be an alternative to cisplatin, particularly if cardiac or renal function is compromised.
For patients who initially appear inoperable and respond well to systemic therapy, surgery should be considered, particularly if complete resection is achievable, which can be considered a neoadjuvant approach. However, there is little published evi- dence for such an approach [25].
Another indication for surgical resection may be selected cases of patients with severe hormone excess, although antihormonal medication as described above should be considered in these cases. Surgery may be particularly useful in these patients if removal of more than 80% of the tumour burden can be achieved safely [25].
The majority of patients with progressing, advanced ACC are in good clinical condition and, therefore, urgently seeking therapy. As no estab- lished regimen exists, patients should be considered for further therapy in clinical trials. If there are no trials available, two fairly well studied cytotoxic regimens are gemcitabine + capecitabine (+/- mito- tane) [74,75] and streptozotocin + mitotane [69,76]. However, the objective response rates are well below 10%, and the median PFS is usually less than 4 months.
A number of new therapeutic approaches are currently being investigated for the treatment of advanced ACC. Up until now, these therapies have only been evaluated in clinical trials, often after dis- ease progression has occurred on standard therapies.
Compared with the primary tumour, in meta- static disease, a 2.8-fold higher mutation rate was demonstrated in primary tumour [77]. Insulin-like growth factor II (IGF-II) represents the most over- expressed gene in 70-90% of ACC. Roughly 80% of ACCs overexpress insulin-like growth factor type 2 (IGF-2), which is known to primarily signal through the IGF-1 receptor (IGF1R). A randomized trial was conducted comparing linsitinib, an IGF1R inhibitor, with placebo and demonstrated no significant ben- efit on PFS (hazard ratio 0.83, 95% CI 0.56-1.21; P=0.30) or OS (hazard ratio 0.94; 95% CI 0.61-1.44; P=0.77) [78].
Programmed cell death ligand (PD-L1) is expressed in some ACCs, which has raised interest in checkpoint inhibitors. Overall, 39 patients with advanced ACC were treated with pembrolizumab in a single-arm phase II open-label study. The majority
Special commentary
had previously received systemic therapy. During a median follow-up of around 18 months, the objec- tive response rate was 23%, while median PFS and OS were 2 and 24 months, respectively [79""].
The vascular endothelial growth factor (VEGF) is up-regulated in ACCs, and it has been shown that circulating VEGF levels are significantly elevated in patients with ACC compared with patients with adre- nal adenomas. However, phase II studies conducted so far have shown limited efficacy of VEGF inhibitors as both single agents, like axitinib [80], sunitinib [81] and in combination with chemotherapy [82].
Given the fact that more than 80% of ACCs express the epidermal growth factor receptor (EGFR) [83], EGFR has been targeted as well. Unfortunately, salvage therapy with erlotinib in combination with gemcitabine was of limited benefit in a trial involv- ing 10 patients with advanced ACC who had failed at least two other systemic chemotherapies [84].
CONCLUSION
ACC is a rare and aggressive disease. None of the drugs tested to date have been found to significantly improve clinical outcome in advanced stage disease. For patients with progression after first-line treat- ment, there are no robust data on second-line and third-line options. The most commonly used second- line chemotherapy is a combination of gemcitabine and capecitabine. Also targeted and immunotherapy has not been a game changer in the natural course of the disease. Advances in the treatment of advanced ACC have been severely limited, mainly because of the rarity of the disease. Nevertheless, multicentre trials are ongoing for recurrent and advanced disease, several of which are investigating immunotherapy and targeted therapies.
Acknowledgements
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Conflicts of interest
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REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
of special interest
of outstanding interest
1. Park HS, Roman SA, Sosa JA. Outcomes from 3144 adrenalectomies in the United States: which matters more, surgeon volume or specialty? Arch Surg 2009; 144:1060-1067.
2. Villar JM, Moreno P, Ortega J, et al. Results of adrenal surgery. Data of a Spanish National Survey. Langenbeck’s Arch Surg 2010; 395:837-843.
3. Lindeman B, Hashimoto DA, Bababekov YJ, et al. Fifteen years of adrena- lectomies: impact of specialty training and operative volume. Surgery 2018; 163:150-156.
4. Palazzo F, Dickinson A, Phillips B, et al. Adrenal surgery in England: better outcomes in high-volume practices. Clin Endocrinol (Oxf) 2016; 85:17-20.
5. Gaujoux S, Mihai R. European Society of Endocrine Surgeons (ESES) and European Network for the Study of Adrenal Tumours (ENSAT) recommenda- tions for the surgical management of adrenocortical carcinoma. Br J Surg 2017; 104:358-376.
6. Crucitti F, Bellantone R, Ferrante A, et al. The Italian Registry for Adrenal Cortical Carcinoma: analysis of a multiinstitutional series of 129 patients. The ACC Italian Registry Study Group. Surgery 1996; 119:161-170.
7. Bilimoria KY, Shen WT, Elaraj D, et al. Adrenocortical carcinoma in the United States: treatment utilization and prognostic factors. Cancer 2008; 113:3130-3136.
8. Kebebew E, Reiff E, Duh Q-Y, et al. Extent of disease at presentation and outcome for adrenocortical carcinoma: have we made progress? World J Surg 2006; 30:872-878.
9. Fassnacht M, Johanssen S, Quinkler M, et al. Limited prognostic value of the 2004 International Union Against Cancer staging classification for adreno- cortical carcinoma: proposal for a Revised TNM Classification. Cancer 2009; 115:243-250.
10. Chiche L, Dousset B, Kieffer E, Chapuis Y. Adrenocortical carcinoma ex- tending into the inferior vena cava: presentation of a 15-patient series and review of the literature. Surgery 2006; 139:15-27.
11. Turbendian HK, Strong VE, Hsu M, et al. Adrenocortical carcinoma: the influence of large vessel extension. Surgery 2010; 148:1057-1064.
12. Mihai R, Iacobone M, Makay O, et al. Outcome of operation in patients with adrenocortical cancer invading the inferior vena cava-a European Society of Endocrine Surgeons (ESES) survey. Langenbeck’s Arch Surg 2012; 397:225-231.
13. Gallagher SF, Wahi M, Haines KL, et al. Trends in adrenalectomy rates, indications, and physician volume: a statewide analysis of 1816 adrenalec- tomies. Surgery 2007; 142:1011-1021.
14. Lombardi CP, Raffaelli M, Boniardi M, et al. Adrenocortical carcinoma: effect of hospital volume on patient outcome. Langenbeck’s Arch Surg 2012; 397:201-207.
15. Gratian L, Pura J, Dinan M, et al. Treatment patterns and outcomes for patients with adrenocortical carcinoma associated with hospital case volume in the United States. Ann Surg Oncol 2014; 21:3509-3514.
16. Kerkhofs TMA, Verhoeven RHA, Bonjer HJ, et al. Surgery for adrenocortical carcinoma in The Netherlands: analysis of the national cancer registry data. Eur J Endocrinol 2013; 169:83-89.
17. Hermsen IGC, Kerkhofs TMA, den Butter G, et al. Surgery in adrenocortical carcinoma: importance of national cooperation and centralized surgery. Surgery 2012; 152:50-56.
18. Lughezzani G, Sun M, Perrotte P, et al. The European Network for the Study of Adrenal Tumors staging system is prognostically superior to the international union against cancer-staging system: a North American validation. Eur J Cancer 2010; 46:713-719.
19. Libé R, Borget I, Ronchi CL, et al. Prognostic factors in stage III-IV adreno- cortical carcinomas (ACC): an European Network for the Study of Adrenal Tumor (ENSAT) study. Ann Oncol 2015; 26:2119-2125.
20. Harrison LE, Gaudin PB, Brennan MF. Pathologic features of prognostic significance for adrenocortical carcinoma after curative resection. Arch Surg 1999; 134:181-185.
21. Icard P, Goudet P, Charpenay C, et al. Adrenocortical carcinomas: surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons study group. World J Surg 2001; 25:891-897.
22. Nilubol N, Patel D, Kebebew E. Does lymphadenectomy improve survival in patients with adrenocortical carcinoma? A population-based study. World J Surg 2016; 40:697-705.
23. Reibetanz J, Rinn B, Kunz AS, et al. Patterns of lymph node recurrence in adrenocortical carcinoma: possible implications for primary surgical treat- ment. Ann Surg Oncol 2019; 26:531-538.
24. Panjwani S, Moore MD, Gray KD, et al. The impact of nodal dissection on staging in adrenocortical carcinoma. Ann Surg Oncol 2017; 24:3617-3623.
25. Fassnacht M, Dekkers O, Else T, et al. European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol 2018; 179:G1-46.
26. Tang Y, Liu Z, Zou Z, et al. Benefits of adjuvant mitotane after resection of adrenocortical carcinoma: a systematic review and meta-analysis. Biomed Res Int 2018; 2018:9362108.
27. Else T, Williams AR, Sabolch A, et al. Adjuvant therapies and patient and tumor characteristics associated with survival of adult patients with adreno- cortical carcinoma. J Clin Endocrinol Metab 2014; 99:455-461.
28. Fassnacht M, Hahner S, Polat B, et al. Efficacy of adjuvant radiotherapy of the tumor bed on local recurrence of adrenocortical carcinoma. J Clin Endocrinol Metab 2006; 91:4501-4504.
Oncologic and endocrine outcome in adrenocortical carcinoma Bronimann et al.
29. Habra MA, Ejaz S, Feng L, et al. A retrospective cohort analysis of the efficacy of adjuvant radiotherapy after primary surgical resection in patients with adrenocortical carcinoma. J Clin Endocrinol Metab 2013; 98:192-197.
30. Amini N, Margonis GA, Kim Y, et al. Curative resection of adrenocortical carcinoma: rates and patterns of postoperative recurrence. Ann Surg Oncol 2016; 23:126-133.
31. Berruti A, Grisanti S, Pulzer A, et al. Long-term outcomes of adjuvant mitotane therapy in patients with radically resected adrenocortical carcinoma. J Clin Endocrinol Metab 2017; 102:1358-1365.
32. Nelson DW, Chang S-C, Bandera BC, et al. Adjuvant radiation is associated with improved survival for select patients with nonmetastatic adrenocortical carcinoma. Ann Surg Oncol 2018; 25:2060-2066.
33. Cerquetti L, Bucci B, Marchese R, et al. Mitotane increases the radiotherapy inhibitory effect and induces G2-arrest in combined treatment on both H295R and SW13 adrenocortical cell lines. Endocr Relat Cancer 2008; 15:623-634.
34. Cerquetti L, Sampaoli C, Amendola D, et al. Mitotane sensitizes adrenocor- tical cancer cells to ionizing radiations by involvement of the cyclin B1/CDK complex in G2 arrest and mismatch repair enzymes modulation. Int J Oncol 2010; 37:493-501.
35. Wängberg B, Khorram-Manesh A, Jansson S, et al. The long-term survival in adrenocortical carcinoma with active surgical management and use of mon- itored mitotane. Endocr Relat Cancer 2010; 17:265-272.
36. Eller-Vainicher C, Morelli V, Salcuni AS, et al. Accuracy of several parameters of hypothalamic-pituitary-adrenal axis activity in predicting before surgery the metabolic effects of the removal of an adrenal incidentaloma. Eur J Endocrinol 2010; 163:925-935.
37. Daffara F, De Francia S, Reimondo G, et al. Prospective evaluation of mitotane toxicity in adrenocortical cancer patients treated adjuvantly. Endocr Relat Cancer 2008; 15:1043-1053.
38. Chortis V, Taylor AE, Schneider P, et al. Mitotane therapy in adrenocortical cancer induces CYP3A4 and inhibits 5x-reductase, explaining the need for personalized glucocorticoid and androgen replacement. J Clin Endocrinol Metab 2013; 98:161-171.
39. Kerkhofs TMA, Derijks LJJ, Ettaieb H, et al. Development of a pharmacokinetic model of mitotane: toward personalized dosing in adrenocortical carcinoma. Ther Drug Monit 2015; 37:58-65.
40. Reimondo G, Puglisi S, Zaggia B, et al. Effects of mitotane on the hypotha- lamic-pituitary-adrenal axis in patients with adrenocortical carcinoma. Eur J Endocrinol 2017; 177:361-367.
41. Alexandraki KI, Kaltsas GA, le Roux CW, et al. Assessment of serum-free cortisol levels in patients with adrenocortical carcinoma treated with mitotane: a pilot study. Clin Endocrinol (Oxf) 2010; 72:305-311.
42. Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2016; 101:364-389.
43. Terzolo M, Daffara F, Ardito A, et al. Management of adrenal cancer: a 2013 update. J Endocrinol Invest 2014; 37:207-217.
44. Poirier J, Gagnon N, Terzolo M, et al. Recovery of adrenal insufficiency is
frequent after adjuvant mitotane therapy in patients with adrenocortical carcinoma. Cancers (Basel) 2020; 12:639.
In this study, patients with stage I-III ACC were retrospectively reviewed at two referral centres in Canada and Italy. Data from 23 patients treated with adjuvant mitotane for at least 2 years were analysed. After discontinuation of mitotane, 18 of 23 (78.3%) patients achieved complete recovery of the hypothalamic-pituitary- adrenal axis, while 3 of 23 (13.0%) could not tolerate glucocorticoid withdrawal despite normal hormonal test values and 2 of 23 (8.7%) did not achieve recovery. The median time interval between mitotane discontinuation and hypothalamic- pituitary-adrenal axis recovery was 2.7 years. What is significant about this study is that adrenal function fully recovers in most patients, although often with a delay of up to 2.5 years.
45. Uchihara M, Tanioka M, Kojima Y, et al. Clinical management and outcomes associated with etoposide, doxorubicin, and cisplatin plus mitotane treatment in metastatic adrenocortical carcinoma: a single institute experience. Int J Clin Oncol 2021; 26:2275-2281.
46. Claps M, Cerri S, Grisanti S, et al. Adding metyrapone to chemotherapy plus mitotane for Cushing’s syndrome due to advanced adrenocortical carcinoma. Endocrine 2018; 61:169-172.
47. Allolio B, Fassnacht M. Clinical review: adrenocortical carcinoma: clinical update. J Clin Endocrinol Metab 2006; 91:2027-2037.
48. Salenave S, Bernard V, Do Cao C, et al. Ovarian macrocysts and gonadotrope- ovarian axis disruption in premenopausal women receiving mitotane for adreno- cortical carcinoma or Cushing’s disease. Eur J Endocrinol 2015; 172:141-149.
49. Stojadinovic A, Ghossein RA, Hoos A, et al. Adrenocortical carcinoma: clinical, morphologic, and molecular characterization. J Clin Oncol 2002; 20:941-950.
50. Abiven G, Coste J, Groussin L, et al. Clinical and biological features in the prognosis of adrenocortical cancer: poor outcome of cortisol-secreting tumors in a series of 202 consecutive patients. J Clin Endocrinol Metab 2006; 91:2650-2655.
51. Burotto M, Tageja N, Rosenberg A, et al. Brain metastasis in patients with adrenocortical carcinoma: a clinical series. J Clin Endocrinol Metab 2015; 100:331-336.
52. Datrice NM, Langan RC, Ripley RT, et al. Operative management for recurrent and metastatic adrenocortical carcinoma. J Surg Oncol 2012; 105:709-713.
53. Erdogan I, Deutschbein T, Jurowich C, et al. The role of surgery in the management of recurrent adrenocortical carcinoma. J Clin Endocrinol Metab 2013; 98:181-191.
54. Lo WM, Kariya CM, Hernandez JM. Operative management of recurrent and metastatic adrenocortical carcinoma: a systematic review. Am Surg 2019; 85:23-28.
55. Berruti A, Fassnacht M, Haak H, et al. Prognostic role of overt hypercortiso- lism in completely operated patients with adrenocortical cancer. Eur Urol 2014; 65:832-838.
56. Megerle F, Herrmann W, Schloetelburg W, et al. Mitotane monotherapy in patients with advanced adrenocortical carcinoma. J Clin Endocrinol Metab 2018; 103:1686-1695.
57. Baudin E. Adrenocortical carcinoma. Endocrinol Metab Clin North Am 2015; 44:411-434.
58. Vanbrabant T, Fassnacht M, Assie G, Dekkers OM. Influence of hormonal functional status on survival in adrenocortical carcinoma: systematic review and meta-analysis. Eur J Endocrinol 2018; 179:429-436.
59. Ronchi CL, Sbiera S, Kraus L, et al. Expression of excision repair cross complementing group 1 and prognosis in adrenocortical carcinoma patients treated with platinum-based chemotherapy. Endocr Relat Cancer 2009; 16:907-918.
60. Malandrino P, Al Ghuzlan A, Castaing M, et al. Prognostic markers of survival after combined mitotane- and platinum-based chemotherapy in metastatic adrenocortical carcinoma. Endocr Relat Cancer 2010; 17:797-807.
61. Laufs V, Altieri B, Sbiera S, et al. ERCC1 as predictive biomarker to platinum- based chemotherapy in adrenocortical carcinomas. Eur J Endocrinol 2018; 178:181-188.
62. Freire DS, Siqueira SAC, Zerbini MCN, et al. Development and internal validation of an adrenal cortical carcinoma prognostic score for predicting the risk of metastasis and local recurrence. Clin Endocrinol (Oxf) 2013; 79:468-475.
63. Kim Y, Margonis GA, Prescott JD, et al. Nomograms to predict recurrence- free and overall survival after curative resection of adrenocortical carcinoma. JAMA Surg 2016; 151:365-373.
64. Schulick RD, Brennan MF. Long-term survival after complete resection and repeat resection in patients with adrenocortical carcinoma. Ann Surg Oncol 1999; 6:719-726.
65. Puglisi S, Calabrese A, Basile V, et al. Mitotane concentrations influence outcome in patients with advanced adrenocortical carcinoma. Cancers (Basel) 2020; 12:740.
There is limited evidence on the influence of mitotane plasma levels on treatment outcome. Therefore, the authors studied 80 patients treated with mitotane. Patients with progression had a lower time in the mitotane plasma target range and an unfavourable outcome. Multivariate analysis showed that clinical benefit after the first treatment and longer plasma target range were favourable predictors of OS. In conclusion, the results highlight the importance of mitotane monitoring and reinforce the concept of a therapeutic window for mitotane.
66. Ilias I, Alevizaki M, Philippou G, et al. Sustained remission of metastatic adrenal carcinoma during long-term administration of low-dose mitotane. J Endocrinol Invest 2001; 24:532-535.
67. El Ghorayeb N, Rondeau G, Latour M, et al. Rapid and complete remission of metastatic adrenocortical carcinoma persisting 10 years after treatment with mitotane monotherapy: case report and review of the literature. Medicine (Baltimore) 2016; 95:e3180.
68. Hoffman DL, Mattox VR. Treatment of adrenocortical carcinoma with o,p’- DDD. Med Clin North Am 1972; 56:999-1012.
69. Fassnacht M, Terzolo M, Allolio B, et al. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med 2012; 366:2189-2197.
70. Laganà M, Grisanti S, Cosentini D, et al. Efficacy of the EDP-M scheme plus
adjunctive surgery in the management of patients with advanced adrenocor- tical carcinoma: the Brescia experience. Cancers (Basel) 2020; 12:94.
In this study, the outcome of 58 patients with advanced/metastatic ACC treated with EDP-M was published. EDP-M showed a partial response in 50% of patients; median PFS and OS were both 10.1 months. Twenty-six patients who responded to treatment underwent surgery for residual disease, and 13 of them became disease-free. Surgery identified a pathological complete response in 7%. Overall, EDP-M therapy was confirmed to have limited efficacy. Moreover, early progres- sion of the disease does not mean that the treatment is ineffective.
71. Williamson SK, Lew D, Miller GJ, et al. Phase II evaluation of cisplatin and etoposide followed by mitotane at disease progression in patients with locally advanced or metastatic adrenocortical carcinoma: a Southwest Oncology Group Study. Cancer 2000; 88:1159-1165.
72. Bukowski RM, Wolfe M, Levine HS, et al. Phase II trial of mitotane and cisplatin in patients with adrenal carcinoma: a Southwest Oncology Group study. J Clin Oncol 1993; 11:161-165.
73. Bonacci R, Gigliotti A, Baudin E, et al. Cytotoxic therapy with etoposide and cisplatin in advanced adrenocortical carcinoma. Br J Cancer 1998; 78:546-549.
74. Henning JEK, Deutschbein T, Altieri B, et al. Gemcitabine-based chemother- apy in adrenocortical carcinoma: a multicenter study of efficacy and predictive factors. J Clin Endocrinol Metab 2017; 102:4323-4332.
75. Sperone P, Ferrero A, Daffara F, et al. Gemcitabine plus metronomic 5- fluorouracil or capecitabine as a second-/third-line chemotherapy in advanced adrenocortical carcinoma: a multicenter phase II study. Endocr Relat Cancer 2010; 17:445-453.
Special commentary
76. Khan TS, Imam H, Juhlin C, et al. Streptozocin and o,p’DDD in the treatment of adrenocortical cancer patients: long-term survival in its adjuvant use. Ann Oncol 2000; 11:1281-1287.
77. Crona J, Beuschlein F. Adrenocortical carcinoma - towards genomics guided clinical care. Nat Rev Endocrinol 2019; 15:548-560.
78. Fassnacht M, Berruti A, Baudin E, et al. Linsitinib (OSI-906) versus placebo for patients with locally advanced or metastatic adrenocortical carcinoma: a double-blind, randomised, phase 3 study. Lancet Oncol 2015; 16:426-435.
79. Raj N, Zheng Y, Kelly V, et al. PD-1 blockade in advanced adrenocortical carcinoma. J Clin Oncol 2020; 38:71-80.
This is one of the few studies investigating immunotherapy in ACC. This phase II study reports the results of treatment with pembrolizumab in 39 patients with advanced ACC after a median follow-up of 17.8 months. The objective response rate was 23%. The median progression-free survival was 2.1 months and the median OS was 24.9 months. Tumour programmed death ligand 1 expression, mismatch repair protein deficiency and high microsatellite instability status were not associated with objective response.
80. O’Sullivan C, Edgerly M, Velarde M, et al. The VEGF inhibitor axitinib has limited effectiveness as a therapy for adrenocortical cancer. J Clin Endocrinol Metab 2014; 99:1291-1297.
81. Kroiss M, Quinkler M, Johanssen S, et al. Sunitinib in refractory adrenocortical carcinoma: a phase II, single-arm, open-label trial. J Clin Endocrinol Metab 2012; 97:3495-3503.
82. Wortmann S, Quinkler M, Ritter C, et al. Bevacizumab plus capecitabine as a salvage therapy in advanced adrenocortical carcinoma. Eur J Endocrinol 2010; 162:349-356.
83. Edgren M, Eriksson B, Wilander E, et al. Biological characteristics of adrenocortical carcinoma: a study of p53, IGF, EGF-r, Ki-67 and PCNA in 17 adrenocortical carcinomas. Anticancer Res 1997; 17(2B): 1303-1309.
84. Quinkler M, Hahner S, Wortmann S, et al. Treatment of advanced adreno- cortical carcinoma with erlotinib plus gemcitabine. J Clin Endocrinol Metab 2008; 93:2057-2062.