ENDOCRINE TUMOURS Our experience with the management of patients with non-metastatic adrenocortical carcinoma
Massimo Terzolo DD1 and Martin Fassnacht12,3
1Internal Medicine, Department of Clinical and Biological Sciences, S. Luigi Hospital, Orbassano, University of Turin, Turin, Italy, 2Division of Endocrinology and Diabetes, Department of Internal Medicine, University Hospital, University of Würzburg, Würzburg, Germany, and 3Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany
Correspondence should be addressed to M Terzolo
Email massimo.terzolo@unito.it
Abstract
Adrenocortical carcinoma (ACC) accounts for a minority of all malignant tumors in adults. Surgery remains the most important therapeutic option for non-metastatic ACC. Whether a subset of patients with small ACC may benefit from minimally invasive surgery remains a debated issue, but we believe that surgeon’s expertise is more important than surgical technique to determine outcome. However, even a state-of-the-art surgery cannot prevent disease recurrence that is determined mainly by specific tumor characteristics. We consider that the concomitant presence of the following features characterizes a cohort of patients at low risk of recurrence, (i) R0 resection (microscopically free margin), (ii) localized disease (stage I-II ACC), and (iii) low-grade tumor (ki-67 <10%). After the ADIUVO study, we do not recommend adjuvant mitotane as a routine measure for such patients, who can be managed with active surveillance thus sparing a toxic treatment. Patients at average risk of recurrence should be treated with adjuvant mitotane. For patients at very high risk of recurrence, defined as the presence of at least one of the following: Ki67 >30%, large venous tumor thrombus, R1 resection or stage IV ACC, we increasingly recommend to combine mitotane with four cycles of platinum-based chemotherapy. However, patients at moderate-to-high risk of recurrence should be ideally enrolled in the ongoing ADIUVO2 trial. We do not use adjuvant radiotherapy of the tumor bed frequently at our institutions, and we select patients with incomplete resection, either microscopically or macroscopically, for this treatment. In the long-term, prospective multicenter trials are required to improve patient care.
European Journal of Endocrinology (2022) 187, R27-R40
Invited Author’s profile
Massimo Terzolo MD is Full Professor of Internal Medicine at the University of Turin, Italy. He is the Director of the Department of Clinical and Biological Sciences and Head of the Division of Internal Medicine at University Hospital San Luigi Gonzaga in Orbassano, Italy. He is a clinical and translational researcher in adrenal diseases and endocrine oncology, with major clinical expertise in the management of patients with adrenal tumors. His research enabled significant advances in diagnosing and treating patients with adrenal incidentaloma and patients with adrenocortical carcinoma.
Introduction
Adrenocortical carcinoma (ACC) is a very rare tumor sprouting from the adrenal cortex with an incidence estimated at about 0.7-1.3 per million population per year in population-based studies (1, 2). ACC has to be tackled with a limited arsenal of therapeutic options of which surgery remains the first choice (3, 4). The lack of significant improvement in treatment strategies for patients with ACC contrasts with the progress made in the treatment of many other solid tumors; however, this is not fully surprising given the rarity of the disease and the scarce resources that have been available to implement treatment. Despite great efforts of the scientific community that has organized international research networks, like the European Network for the Study of Adrenal Tumors (ENSAT) in 2002 and the American Australian Asian Adrenal Alliance (A5) in 2015, the search for emerging drugs remains almost vain (3, 4). After more than 50 years from its introduction in clinics, mitotane is still the only medication specifically approved for the treatment of ACC and is currently used either in adjuvant or advanced disease settings; in the last scenario, mitotane is usually combined with classic cytotoxic agents (5).
Preventing disease recurrence is a key to improve patient outcomes since treatment of advanced ACC comes with disappointing results (6). Moreover, ACC has a high propensity to relapse and in our experience about 60% of recurrences are detected as multiple lesions in different organs (7, 8). When ACC recurs, the disease usually becomes more aggressive and difficult to control (9). ACC recurrence has an important impact on survival as well as on patient-centered outcomes since it frequently impairs the quality of life and decreases the hope for a cure.
The scope of this paper is to present our personal approach to patients with non-metastatic ACC in the context of the more recent findings in the field. Potential therapeutic options are summarized in Table 1 and a flow- chart for the suggested treatment is given in Fig. 1.
Disease presentation
In our experience, ACC at diagnosis is localized to the adrenal gland in 50-60% of cases, at ENSAT stages I and II, while local tumor spread (ENSAT stage III) is found in about 20% and distant metastases (ENSAT stage IV) in 20-30% (6, 8). Treatment modalities discussed in the present paper encompass stage I-III ACC, although
some unresectable stage III tumors have to be treated as advanced diseases.
ACC has the potential to secrete a variety of steroid hormones and may be associated with different endocrine syndromes, of which Cushing syndrome is the most frequent (10). ACC may also be incidentally discovered or produce tumor-related symptoms like pain or abdominal discomfort. A detailed description of the clinical presentation is beyond the scope of this work and the reader is directed toward recent reviews of the topic (11).
In most cases, disease presentation does not alter referral to surgery, although in the case of severe Cushing syndrome, control of cortisol excess should be attempted with agents inhibiting glucocorticoid synthesis, or action, when the surgical risks are perceived to be exceedingly high (10). Cortisol replacement must be done following extirpation of cortisol-producing tumors, also when cortisol excess is minimal and not clinically apparent (autonomous cortisol secretion) (12).
Prognostication
Several clinical, pathological, and molecular characteristics have been associated with patient outcomes, and in this paper, we will focus on those factors that influence the risk of recurrence.
Tumor stage is an obvious factor influencing the survival, and the ENSAT staging system (in the meantime adapted by the AJCC and the World Health Organization) provides a simple and powerful tool to stratify prognosis by stage, with a 5-year survival dropping from 81% in stage I ACC to 61% in stage II and 50% in stage III (13). Stage influences prognosis also indirectly, as it affects the chance of successful tumor removal, and its effect may be less evident whenever radical surgery is attained (14). However, it is biologically plausible that stage III, characterized by the local spread of disease, may entail a worse prognosis than early stages even after complete ACC extirpation, as is the case for a few oligometastatic stages IV ACC that can be completely resected (5).
An incomplete resection after surgery impairs the definitive survival. In a large cohort of 3982 patients with ACC, either R1 (microscopically positive margins) or R2 (macroscopically positive margins) resections were associated with an increased risk of death compared to R0 (free margins) surgery (15). However, the exact quantification of the impact of R status on the risk of recurrence and death is difficult because, in our experience, R status is not accurately reported in a number of cases
Table 1 Treatment options for non-metastatic ACC.
| Treatment modality | Suitable for whom? | Treatment procedures | Adverse effects/ risk | Level of evidence | Other comments |
|---|---|---|---|---|---|
| Neo-adjuvant therapy | Selected patients bearing an invasive tumor with a high chance of not achieving an R0 resection | Two to six cycles of etoposide (100 mg/m2, d2-4), cisplatin (40 mg/m2, d3-4), doxorubicin (40 mg/m2, d1) and mitotane (with high starting dose) | In case of failure, surgery might not be possible anymore | Very low | |
| Open surgery | All patients with suspected locally invasive ACC | En bloc removal of the tumor and the periadrenal/ peritumoral retroperitoneal fat including lymphadenectomy | Good | ||
| Minimally-invasive surgery | Selected patients, in whom there is no evidence of local invasion and the tumor size is preferably <6 cm | En bloc removal of the tumor and the periadrenal/ peritumoral retroperitoneal fat including lymphadenectomy | In case of rupture of the capsule, risk of severe tumor spillage is increased | Moderate | In case of intraoperative evidence of invasiveness, converting to open surgery is recommended |
| Active surveillance | Patients at low risk of recurrence* | Follow-up visit including imaging assessment every 3 months for at least 2 years | Moderate | ||
| Adjuvant mitotane | All patients at high risk of recurrence ** | Either low or high-dose starting regimens allowed in the first months to build up therapeutic mitotane levels. Maintenance dose depending on tolerability and mitotane levels. | High-dose regimens may be less tolerable. | Moderate | High-dose regimens may fasten drug activity. |
| Adjuvant radiotherapy | Patients with incomplete resection (R1 resection) and no evidence of distant metastases | Aim at a total dose of 50-60 Gy to the previous tumor bed in fractionated doses of approximately 2 Gy each | Toxicity is increased if given with mitotane, potentially hampering up-titration of mitotane dose. | Low | Repeat surgery may be more difficult in irradiated areas. |
| Adjuvant cytotoxic therapy | Selected patients at very high risk of recurrence *** | Three to four cycles of etoposide (100 mg/m2, d1-3), cisplatin (60 mg/m2, d1) and mitotane (with high starting dose) | Toxicity may potentially hamper up-titration of mitotane dose. | Very low | A randomized study is currently ongoing. |
*Low risk of recurrence defined as R0 surgery, stage I-II, Ki-67 <10%; **High risk of recurrence defined as whatever does not apply to low and very high-risk categories; *** Very risk of recurrence defined as one of the following, R1 surgery, local invasion, Ki-67 >30%.
and an unknown margin status (RX) remains a frequent observation.
The tumor proliferation activity, expressed by the Ki-67 index, is currently in clinical practice the strongest predictor of recurrence after R0 surgery. An ENSAT retrospective multicenter study demonstrated on more than 500 patients with completely resected ACC that a Ki-67 value at 10%, or less, qualified patients at a better prognosis (median recurrence-free survival of 53 months), while a Ki-67 value at 20%, or more, qualified the worst
prognosis group (median recurrence-free survival of 9.4 months) (16). Ki-67 is in the meantime also the most accepted tool for pathological grading of ACC (3, 17). The drawback of Ki-67 analysis is that it is operator-dependent and influenced heavily by the inclusion of hot spots of proliferation in the analysis (18). This is an additional reason to have patients with ACC operated on at reference centers with access to expert pathologists.
The ESE-ENSAT guidelines have adopted a stratification of the risk of recurrence to inform patient management
ACC amenable to complete resection1
Complete resection (RO)
Rx or R1 resection
Low risk2
Standard risk3
Very high risk4
Active surveillance or consider mitotane
Adjuvant mitotane
Adjuvant mitotane and consider addition of EP
Adjuvant mitotane and consider addition of RT
Follow-up every 3 months5
that is based on tumor stage, resection status, and Ki-67 index, implying that a low-risk condition is defined by stage I-II, RO surgery, and a Ki-67 value of 10%, or less (3).
Another characteristic influencing outcome is the capability of the tumor to secrete steroids. Several studies demonstrated that hypercortisolism is an independent predictor of ACC recurrence and death in patients with localized disease (19, 20, 21). It is conceivable that cortisol- secreting ACCs are more aggressive, as demonstrated by higher Ki-67 values of these tumors (8), or that the immunosuppressive effects of hypercortisolism may facilitate recurrence after surgery (10). Although secreting tumors are more frequently found in women, sex per se does not seem to be of prognostic relevance (22, 23).
In 2015, a comprehensive score was developed including all the most relevant prognostic parameters in a single prognosticator tool named GRAS score, from Grade, Resection status, Age, and Symptoms. The GRAS score has been introduced in patients with stage III-IV ACC (24) and then extended also to patients with localized ACC, in which a higher GRAS score was associated with worse outcomes (25).
More recently, the ENSAT stage has been included in a new version of the score, which has been named as S-GRAS, since it includes also the stage in addition to the other parameters (26). By applying the S-GRAS score,
patients could be stratified into four different groups that were found to be associated with increasingly worse prognosis in a multicenter ENSAT study including 942 operated patients. In that study, the S-GRAS score was superior in predicting prognosis to both tumor stage and Ki-67 index (26).
In addition to the evaluation of the classic clinical and pathological factors, new approaches have been increasingly pursued thanks to the advancement in molecular techniques, including genomics platforms to assess gene expression and epigenetic alterations, with the aim to identify molecular markers of prognostic significance. Targeted molecular markers, such as the differential expression of BUB1 and PINK1 genes (27, 28), overexpression of SF-1 (29), VAV2 (30), and the histone methyltransferase EZH2 (31) have been found to predict poor prognosis. Furthermore, gene methylation pattern holds promise as a predictive tool to differentiate subsets of patients with different prognoses. This is true for genome-wide methylation analysis (32) as well as a more targeted approach (e.g. analyzing the methylation of the CpG islands in four genes (PAX5, PAX6, PYCARD, and GSTP1) (33) or the hypermethylation just of a single gene G0S2 (34). Studies employing a pan-genomic approach including multiple omic technologies (targeted gene expression and sequencing, targeted methylation)
suggested that the combined assessment of a set of molecular markers may stratify patients into three groups with different prognoses (35, 36). Not surprisingly, the combined assessment of targeted molecular markers with tumor stage and tumor proliferation provided the best prognostic assessment in patients with stage I-III ACC following surgery (37).
With the advent of immunotherapeutic approaches, immune cell infiltration has been investigated. Patients with CD4+ and CD8+ T cells infiltration (especially in the absence of glucocorticoid excess) have a significantly better prognosis than patients with ‘immunologically cold’ tumors and cortisol excess (38). More recently, studies have tried to introduce the concept of ‘liquid biopsy’, which is increasingly considered in other solid tumors, by the assessment of circulating microRNA (miRNA), tumor DNA (ctDNA), and tumor cells (CTC) (39, 40, 41). Based on these preliminary findings, ctDNA and CTC seem to be potentially useful for prognostication and disease monitoring, although larger experience is needed.
Despite these advances, the translation in clinics of the aforementioned biomarkers remains limited. Therefore, we have to acknowledge that in our daily practice, we mostly rely on the classic prognostic factors: stage, grade, resection status, and secretion for the decision whether or not adjuvant therapy should be instituted and what type (see following sections). However, we hope evidence for simplified tools (that can be executed in paraffin- embedded tissue or in the blood) will soon become available and path the way toward clinical application.
Neo-adjuvant therapy
Neo-adjuvant therapy is a well-established concept in oncology; however, it is - from our perspective - still underused in the management of ACC. The rationale behind neoadjuvant therapy is to increase the probability of R0 resection and minimize the need for extensive organ resections to achieve this goal (42). Primary ACC often shows the involvement of blood vessels and lymph nodes with the invasion of neighboring organs that challenges the technical feasibility of a complete resection. In addition, synchronous metastases may be present at diagnosis, and tumor-related factors or hormone excess may result in a poor performance status that makes an initial surgical approach unattractive (43). Patients with locally advanced ACC are less likely to undergo an operation, in particular when managed outside high- volume surgical centers (44), and may be a candidate for
a neo-adjuvant approach whose aim is to downstage the tumor. Patients who have responded to induction therapy and are then submitted to surgery may attain a better control of the disease (43, 45). Another potential advantage of neoadjuvant therapy is that it gives the possibility of administering nephrotoxic systemic therapy prior to possible nephrectomy. Moreover, neoadjuvant therapy may allow assessing the effectiveness of chemotherapy and select patients who can further benefit from systemic therapy following surgery (42).
Neo-adjuvant therapy has been introduced at MD Anderson, and a recent study from this center reported on the outcome of 29 patients with borderline resectable ACC who have been treated pre-operatively with systemic therapy including a combination of mitotane and platinum-based chemotherapy. Recurrence-free survival of such patients was 60.1% at 1 year, 36.1% at 3 years, and 27.1% at 5 years, and the authors concluded that this approach contributed to the better outcome of patients with ACC treated in recent years at their center (5, 45).
In summary, experience with neo-adjuvant therapy is still preliminary even if this approach has the potential to reduce the risk of incomplete removal of ACC, one of the worst predictors of survival. In our experience, we consider neo-adjuvant therapy on an individual basis and we try to balance the risk of extensive (and still incomplete) resection with that of delaying surgery and impairing patient conditions in case of lack of efficacy.
Surgery
There is no doubt that surgery is the only chance and the prerequisite for long-term cure in patients with localized ACC. However, there is an ongoing debate on the best surgical approach for these patients. While there is consensus that evidence of invasive disease on imaging prior to surgery should prompt surgeons to an open approach, there is conflicting data on the role of minimal-invasive surgery in non-invasive tumors. Meta- analyses in the last years on this topic do not report an adverse outcome in tumors resected by laparoscopic or retroperitoneoscopic surgery (12, 46, 47, 48), although in some (but not all) studies laparoscopic surgery has been associated with a higher frequency of R1 surgery and peritoneal carcinomatosis. However, our personal experience clearly tells us that laparoscopic surgery is efficacious only if the surgeon has a long-lasting experience in adrenal surgery and is respecting the principles of oncological surgery. From our perspective, these two
points are probably the most important for the individual patient and are more relevant than the question on open or minimal-invasive surgery. Having said this, open surgery should be regarded as the standard of care for surgery on tumors suspected to be ACC, and this is particularly true if the surgeon does not have extensive expertise. Therefore - despite the lack of published evidence - we would extend the vague recommendations of the recent guidelines (3, 4) and refer patients, who are asking us personally for advice, only to centers with a minimal annual workload of at least 20-30 adrenalectomies per year, of which at least 6 should be for ACC and significant experience in oncological abdomen surgery. However, for the best clinical outcome, the entire perioperative team (including a radiologist, anesthesiologists, a endocrinologist, and an oncologist) should be well trained in treating patients with adrenal tumors. This is particularly true for cortisol- producing tumors, which come with an increased risk for perioperative complications and postoperative adrenal insufficiency.
Regarding the extent of surgery, we clearly recommend a complete en bloc resection of the tumoral mass including periadrenal fat to avoid tumor rupture or spillage that will come with deleterious outcomes (15). The removal of the kidney or other adjacent organs should be avoided if there is no evidence of invasion (49). Since locoregional lymphadenectomy improves tumor staging and seems to lead to a favorable oncological outcome (50), it is advisable to perform in all patients with suspected ACC a lymphadenectomy that includes at least the periadrenal and hilar nodes, although the best extent of lymphadenectomy is still unknown (51, 52).
Adjuvant mitotane therapy
‘Mitotane, 1,1-(o,p’-dichlorodiphenyl)-2,2-dichloroethane (o,p’-DDD)’, is the only available drug approved for the treatment of advanced ACC; therefore, its use as an adjunctive measure has to be considered off label. Mitotane is acting primarily on the adrenal cortex leading to cell destruction and impairment of steroidogenesis. Mitotane action involves the deregulation of cytochromes P450 enzymes, depolarization of mitochondrial membranes, and accumulation of free cholesterol, leading to cell death. However, its exact mechanism of action remains poorly defined at a molecular level due to controversial results generated by in vitro studies (53).
Whether adjuvant mitotane treatment is able to extend survival after surgical extirpation of an ACC remains
a debated issue. The main reason for this uncertainty is the lack of prospective studies and this represents an important knowledge gap with direct consequences on patient management. Following the early work of Schteingart (54), adjuvant mitotane treatment has been around for more than 50 years in clinical practice. However, the retrospective, non-randomized design of published studies implies that they were heterogeneous in treatment modalities (i.e. mitotane dose and treatment duration) and patient characteristics. Studies are generally skewed to the selection of patients with worse prognostic characteristics for the treatment. Moreover, many studies included small patient groups and were uncontrolled (5).
All clinical guidelines published by the European Society of Endocrinology and the European Society of Medical Oncology, while recognizing the low level of existing evidence, recommend adjuvant mitotane in patients who are considered to be at high risk of recurrence following surgery (3, 4, 55). This recommendation was supported by two meta-analyses that concluded a beneficial effect of adjuvant mitotane despite some heterogeneity between studies (3, 56).
A breakthrough in the treatment of patients with ACC may come from the ADIUVO study, an international, multicentric, investigator-initiated, randomized, clinical trial conducted within the ENSAT, whose preliminary results have been recently presented (57).
The concept of the ADIUVO study was born in 2007, and after that, there was increasing evidence that adjuvant mitotane had a beneficial effect on the survival of patients with ACC (14). Due to the retrospective nature of that study, however, we could not definitively assume that treatment was effective. Since it was obvious that a subgroup of patients with localized ACC had a better prognosis than the majority of patients, the ADIUVO study was conceived to answer the key question of whether such patients may benefit from postoperative adjuvant treatment. Given the toxicity and complexity of mitotane treatment, adjuvant treatment could be perceived as questionable in low-intermediate risk patients, while there was general consensus on its use in patients at high risk of recurrence (9).
Based on the knowledge available when the study was designed, we set the main inclusion criteria on the contemporary presence of three characteristics: (i) localized disease, defined by a stage I-III ACC; (ii) complete resection, defined by microscopically clean margins (R0 surgery); (iii) low-grade tumor, defined by a Ki-67 value ≤10%. As discussed above, the proliferation rate is an important determinant of prognosis for non-metastatic
ACC. Data from the German ACC registry suggested that a cutoff level of 10% for Ki67 could differentiate between low-risk and high-risk ACC patients who have undergone R0 surgery independently on other parameters (58). Overall, the study population was assumed to be at ‘low- intermediate risk’ of recurrence, and the randomization process was done with the stratification of stage III vs stage I-II patients. The primary endpoint of the study was to compare the efficacy of adjuvant mitotane treatment vs active surveillance in prolonging recurrence-free survival (RFS) following complete removal of ACC in the study population (Fig. 2). Patients were randomly assigned 1:1 to receive mitotane treatment or observational follow-up for a period of 2 years with follow-up visits including thorax and abdominal cross-sectional imaging every 12 weeks after randomization in both study arms. From March 2008 to December 2018, a total of 91 patients (instead of the targeted 200) were enrolled in the study.
The preliminary analysis of this randomized clinical trial showed that patients allocated to receive mitotane as an adjuvant measure or surveillance alone following surgery demonstrated no significant difference in the primary outcome, namely recurrence of ACC. However, the beneficial effect of mitotane could not be ruled out because the sample size was not attained.
An important piece of information provided by the trial is that survival of patients at low risk of recurrence is excellent, with a 2-year RFS of approximately 80%, clearly better than what was observed in a comparable cohort of patients analyzed retrospectively by Beuschlein et al. (16). The survival of the ADIUVO cohort was dramatically different from what is currently observed in the published series of patients with ACC, who were reported of having a 2-year RFS of 50%, or even lower (8, 21, 22, 59). However, low-risk patients represent a minority of all patients with ACC referred after surgery (3, 8) and this is the key justification for the slow patient recruitment in the trial in addition to the refusal of a number of patients
to be randomized. Insufficient recruitment is indeed frequently observed in investigator-initiated clinical trials proposing randomization between active treatment and surveillance (60)
The ADIUVO study establishes a simple prognostication scheme based on clinical and pathological characteristics that can be used in clinical practice to select patients for treatment. This is the first prospective demonstration of markers that may be used to individualize treatment. Several explanations might account for the lack of efficacy of adjuvant mitotane, including the limited potential for tumor recurrence and progression of this subset of ACC. The findings of this clinical trial, however, cannot be generalizable to the majority of patients with ACC, who are at high risk of recurrence after surgery, for which mitotane is currently recommended (3, 4).
Given the ADIUVO findings, we do not routinely recommend adjuvant mitotane treatment after R0 resection of low-grade, stage I-II tumors. Given that very few patients with stage III ACC were included in ADIUVO, in such patients the decision to use adjuvant mitotane is taken on an individual basis (Fig. 1).
Adjuvant radiotherapy
Local recurrence is a frequent mode of disease relapse in ACC after complete recurrence (8). Thus, adjuvant radiotherapy of the tumor bed is a very plausible concept. Indeed, almost all studies could demonstrate the efficacy of radiotherapy to reduce the risk of local recurrence. However, overall recurrence-free and overall survival data are more conflicting. One reason might be that there are several publications using the same database and have, therefore, significantly overlapping cohorts. Here, we mention only the largest report of each series to reduce the likelihood of overemphasis of a certain series. Whereas the series from Ann Arbor, the SEER database in the United
Recurrence-free survival
Stage I-III RO surgery Ki67 ≤10%
Primary endpoint:
R*
A
Active surveillance
O Q
Adjuvant mitotane, for at least 2 yrs (targeting 14-20 mg/L)
M
*Randomization stratified for stage (I-II vs. III)
Figure 2 ADIUVO study design.
States, and China suggest a benefit in recurrence- and overall survival (61, 62, 63), the cohorts from Germany, MD Anderson, and Brazil do not confirm this observation (64, 65, 66). All these studies were retrospective and prone to bias due to non-randomized control groups. Therefore, an objective judgment of the pros and cons of adjuvant radiotherapy is very difficult and more studies (ideally randomized trials) are needed to define the role of radiation therapy in the adjuvant setting. From our perspective, radiotherapy is particularly interesting for patients with microscopically (or macroscopically) incomplete resection without evidence of distant metastases (Fig. 1). These patients suffer obviously from extremely high risk of local recurrence/residual disease and represent the candidates that most likely benefit from radiotherapy, although studies focusing on these specific subgroups are missing yet.
Adjuvant cytotoxic chemotherapy treatment
In comparison to adjuvant radiotherapy and even more to adjuvant mitotane, data on adjuvant therapy with cytotoxic drugs are extremely scarce. Until recently, only two publications were available. Hovi et al. reported no evidence for recurrence in five patients with ACC aged 1-21 years treated adjuvantly with the combination of cisplatin and etoposide (67). The second study analyzed 17 patients treated with streptozotocin plus mitotane after complete resection and suggested a prolonged disease-free survival compared to a non-randomized control cohort of 11 patients without adjuvant therapy (68). However, the panelist of both the ESE-ENSAT and the European Society of Medical Oncology (ESMO) guidelines based their recommendations mainly on personal experience and suggested to consider treatment with cisplatin and etoposide in addition to mitotane in patients with very high risk of recurrence (3, 4). In the meantime, we have published the first larger retrospective multicenter study on this topic (69) including 31 patients with very high risk of recurrence (e.g. median Ki67: 30%) who were treated with a platinum-based therapy and compared with 31 matched controls. Median recurrence-free and overall survival were significantly longer in the chemotherapy group. In a second statistical approach including a total of 299 patients and using propensity score matching, also overall mortality was clearly reduced with a hazard ratio of 0.25 (95% CI: 0.09-0.69; P=0.007). Of note, a recent prospective single-arm study in children demonstrated
also beneficial effects of adjuvant platinum-based chemotherapy in patients with stage III (70). However, all these data are only a hint that adjuvant cytotoxic therapy might be of benefit in a subset of adult patients with ACC. The currently running randomized ADIUVO2 trial (NCT03583710) will hopefully provide a more definitive answer. Thus, we encourage all clinicians to enroll suitable patients in this trial or transfer them to centers who are participating in ADIUVO2. Major inclusion criteria of the ADIUVO2 study are stage I-III ACC, either complete resection (R0), microscopically positive margins (R1), or unknown resection margin (RX), and -Ki67>10%. However, if enrollment in this trial is not possible, we suggest to offer patients at very high risk of recurrence four cycles of cisplatin and etoposide in addition to mitotane (Fig. 2). A very high risk may be arbitrarily defined as the presence of at least one of the following characteristics: Ki67 >30%, large tumor thrombus in the vena cava, R1 resection, or complete resection in stage IV ACC.
Surveillance after surgery
The ESE-ENSAT guidelines recommend active surveillance after surgery with follow-up visits every 3 months for the first 2 years and then every 3-6 months for the next 3 years (3). The loosening of the follow-up schedule reflects the progressively decreasing risk of recurrence with time. After 5 years, the modality of follow-up has to be discussed individually since there is no evidence that a long-term surveillance is useful. At our centers, we keep patients engaged in some form of follow-up since it is our experience that most patients prefer not to be dismissed and, in few patients, recurrence occurs as late as 10 years after primary surgery.
Visits should include a careful history and physical examination, laboratory evaluation, and high-resolution cross-sectional imaging of the thorax and whole abdomen and pelvis, while brain evaluation is not mandatory. This suggestion takes into consideration the fact that ACC recurs beyond the adrenal region in more than 50% of cases (7) while brain localization is usually a late event in the course of the disease (71). Whether CT remains the standard, we increasingly use 18-FDG-PET/CT and MRI, particularly in specific scenarios (i.e. peritoneal carcinomatosis, liver metastases). The most appropriate imaging study for a given patient should be decided by a multidisciplinary team. Laboratory workup should include routine biochemistry, hormonal assessment, and measurement of mitotane plasma levels in patients on
treatment (Table 2). Measurement of plasma mitotane can be attained as a free service in most European countries and gives the possibility to guide dose adjustments and prevent severe toxicity.
Toxicity of mitotane
Mitotane holds the reputation of being a toxic drug that is unbearable for most patients; however, in our practice, the rate of patients who have to discontinue permanently mitotane for toxicity is below 20%. That said, it is plainly evident that adjuvant mitotane treatment may be associated with a variety of unwanted effects, and most patients experience different effects. For the patients to be able to cope with mitotane toxicity, it is key to explain carefully the potential toxicity of the drug and the plan to tackle it. Furthermore, regular laboratory monitoring is recommended (Table 2). It is also important to underline how many adverse effects, particularly gastrointestinal manifestations, will wane with time.
The efficacy of mitotane has been traditionally linked to the existence of a therapeutic range of the circulating concentrations of the drug. This concept has been more validated in the treatment of patients with advanced/ metastatic ACC, where objective disease responses are mainly observed in patients whose plasma mitotane concentrations are above 14 14 mg/L (72, 73). Evidence that the efficacy of adjuvant mitotane is restricted to patients with blood mitotane levels higher than 14 mg/L
is more controversial in the adjuvant setting (8, 74). In our opinion, also mitotane levels in the range of 10-14 mg/L if maintained consistently during the course of adjuvant treatment may be tied with drug activity. The concept of the importance of chronic exposure to mitotane over time is at the basis of the time in the therapeutic range (i.e. the time spent with mitotane concentrations of 14 mg/L, or more) that has been introduced recently to assess the impact of mitotane levels on prognosis (75).
The optimal duration of mitotane therapy in adjuvant setting is not known and practice is heterogeneous. The ESE/ENSAT guidelines suggest to give mitotane for at least 2 years, but no longer than 5 years (3). A recent multicenter study found that extending an adjuvant mitotane treatment over 2 years was not associated with superior benefit (76). After this study, we currently do not prolong adjuvant mitotane treatment beyond 2 years; however, if the risk of recurrence is perceived to be very high, or tolerability has been very good, we continue for up to 3-4 years.
During follow-up, close contacts by the use of text messages, emails, and video calls, which have been increasingly used during the SARS-CoV-2 pandemic, are important to provide guidance and reassurance to patients. They should not feel to be left alone with their disease or that they are managed by local physicians who do not have personal expertise in the management of patients with ACC. The management of mitotane toxicity entails experience, patience, and clinical judgment to avoid a premature interruption of treatment, which is
| Parameter | Interval | Comment |
|---|---|---|
| Mitotane blood level ACTH | Every 6-9 weeks1 Suspected glucocorticoid deficiency or excess | Target: 14-20 mg/L Glucocorticoid status is difficult to determine Target: ACTH in the normal range or slightly above (e.g. < 2 times the ULN) |
| GOT, GPT, bilirubin, GGT | Initially every 4 weeks, after 6 months every 8 weeks | GGT is invariably elevated without clinical consequences. If other liver enzymes are rapidly increasing (>3 times of baseline), there is an increasing risk of liver failure: Interrupt mitotane |
| TSH, fT4 | Every 3-4 months | Reduction of fT4 is frequent. Thyroid hormone replacement is a debated issue |
| Renin | Every 6 months | If renin 11 and K in the high normal range, add fludrocortisone Target: renin two to three times the normal range |
| Cholesterol (HDL, LDL), triglycerides | Every 3-4 months | If total and LDL cholesterol 11, consider treatment with statins not metabolized by CYP3A4 |
| Blood count | Every 3-4 months | Check for rare (and in only few cases severe) leucopenia, thrombocytopenia, and anemia |
| LH, testosterone, SHBG2 | In case of symptoms of hypogonadism | Reduction of testosterone levels may be masked by increased SHBG and calculation of free testosterone is recommended. Testosterone replacement is a debated issue |
1In the first 3 months, mitotane blood levels should be checked more frequently. Additional measurements may be needed in case of severe toxicity (in particular, neurological toxicity). 2In male patients.
obviously the simplest choice. In most cases, temporary dose adjustments, and sometimes brief ‘drug holidays’, along with correct symptomatic treatment may resolve toxicity. Mitotane management is a demanding art that should be reserved for experienced physicians who have treated a significant number of patients, not differently from what we expect from surgeons. Reference centers may guide and coordinate physicians in the community to offer adequate advice to limit health journeys. However, a close patient-physician contact is required in the early phase of treatment - more frequently than the classic 3-month schedule.
Precise adjustment of steroid coverage, including a stepwise increase in glucocorticoid dose (especially in the first months) and - in some patients - addition of mineralocorticoid replacement, is beneficial for many manifestations, such as anorexia, depression, fatigue, to nausea.
Clinically relevant hepatic toxicity is rare while (very) elevated gamma glutamyl transferase (GGT) levels are almost universally found; however, this biochemical alteration does not require any specific measure, although we have seen recommending improper treatment discontinuation for this reason (5).
Of particular concern are the unwanted neurological manifestations that could be subtle, such as disturbance of memory and impairment of attention and concentration capability, or more frightening, such as impairment of speech and mentation, and dizziness, with altered balance and walking. Although these effects are frequently observed when plasma mitotane levels are elevated, usually higher than 20 mg/L, they can be found even in patients exposed to lower concentrations. In our experience, neurological manifestations are the most difficult to combat and frequently mitotane has to be interrupted for some days.
Mitotane has multiple effects on the endocrine system beyond the expected hypoadrenalism, which makes steroid replacement therapy mandatory. While glucocorticoids should be given at higher doses than that used in Addison disease, fludrocortisone is only needed in about 30% of patients, and it is likely underused (77, 78). In male patients, mitotane-induced secondary hypogonadism might be considered as it might have subtle but detrimental clinical manifestations beyond impairment of sexual function. Hypogonadism is often underestimated since mitotane induces an increase in SHBG levels leading to normal or even increased total testosterone levels (17, 77, 79). In our practice, we have different approaches concerning testosterone replacement.
This reflects a difficulty in the assessment of the benefits of treatment. In fertile women, menstrual cycle and ovarian function are often preserved, but ovarian cysts are frequently detected in surveillance studies. These cysts are often asymptomatic or paucisymptomatic and, in our experience, do not need specific therapy in most cases (3, 5). A disturbance of thyroid function is apparent in about 40% of patients; however, our practice concerning the need for replacement with thyroxine differs. Again, this reflects a difficulty in the assessment of the benefits of treatment.
Mitotane has also a profound impact on lipid levels, causing a marked increase in total, LDL, and HDL cholesterol levels in more than 50% of patients (78). Patients are often worried by these alterations and we treat most of them with statins, paying attention to drug interactions, although it is presently unknown if this therapeutic measure will reduce the risk of future cardiovascular events.
In most cases, mitotane-related endocrine and metabolic alterations appear to be reversible at the suspension of treatment; however, the time needed for a complete return to normalcy may be very long, at least for cortisol secretion (80).
Conclusions/perspective
In the last 15 years, we have witnessed continuous progress in the therapy of non-metastatic ACC. Our knowledge about the importance of primary surgery is robust, although it is still uncertain if a subgroup of patients may benefit from minimally invasive adrenalectomy. Adjuvant mitotane was introduced in 2007, but currently, we are defining two additional subgroups; one that may not require mitotane and another that may require additional measures on top of mitotane. The first randomized trial in the adjuvant setting, ADIUVO, is completed and the final results will be published soon and a second randomized trial, ADIUVO2, comparing mitotane alone with mitotane plus cisplatin and etoposide, started recruitment. These trials were only possible due to unprecedented international collaborative efforts. About 20 years ago, the ENSAT (www.ensat.org) has been founded and has been complemented in 2015 by its sister society, the American Australian Asian Adrenal Alliance (A5). These networks support not only clinical trials but also standardized tumor registries and tumor bank protocols allowing for the exchange of data and high-quality biological material. These cooperative efforts are predicted to significantly
enhance basic and clinical research in ACC and to further facilitate progress in the treatment of this rare disease.
To conclude, the first steps toward personalization of therapy of non-metastatic ACC have been done and we propose here a stratification of patients into three groups at different risk of recurrence that need different levels of treatment. We believe that the application of the most recent research findings may improve either patient- centered outcomes or treatment efficacy.
Declaration of interest
Massimo Terzolo has received advisory board honoraria and speaker honoraria from HRA Pharma Rare Diseases; Martin Fassnacht is an investigator of a clinical trial sponsored by Enterome and his institution has received honorarium for co-organizing a meeting by HRA Pharma. Martin Fassnacht is a senior editor of the European Journal of Endocrinology and will not be involved in the peer review or editorial process for this paper on which he is listed as an author.
Funding
Deutsche Forschungsgemeinschaft (DFG) project number 314061271 (CRC/Transregio 205/1 ‘The Adrenal: Central relay of health and disease’, grant to Martin Fassnacht); ‘Associazione Italiana per la Ricerca sul Cancro’ (AIRC), grant number IG2019-23069 to Massimo Terzolo.
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Received 24 March 2022 Revised version received 15 May 2022 Accepted 13 June 2022