Adrenocortical Carcinoma
CrossMark
Eric Baudin, MD, PHD, Endocrine Tumor Board of Gustave Roussy (Department of Endocrine Oncology and Nuclear Medicine)® a,b,c,*
KEYWORDS
. Adrenocortical carcinoma . Prognosis . Predictors . Surrogate . Survival
. Metastasis . Mitotane . Chemotherapy
KEY POINTS
· Major breakthroughs have been achieved in the identification of relevant molecular alter- ations in adrenocortical carcinoma, but no simple actionable target has emerged.
· Progresses in the prognostic risk stratification constitute the basis of future stratified medical strategies and evaluations.
· Making therapeutic advances against adrenocortical carcinoma is a formidable challenge facing patients and clinicians with expert centers and networking as a basis of progress.
· RO surgery of more than 90% of localized ACC patients is a unmet need.
Adrenocortical carcinoma (ACC) originates from the adrenal cortex and is typically defined by positive immunostaining for steroidogenic factor 1 (SF1), melanA (Mart1) markers but without staining for cytokeratins and chromogranin A. 1-4 As for all endo- crine tumors, malignancy is ascertained by the presence of local or distant spread. No absolute criteria of malignancy exists for the diagnosis of ACC in those tumors confined to the adrenal gland, but a Weiss score of 3 or higher is generally considered to establish the diagnosis.3,4 In addition, several studies have shown that a Ki67 index higher than or equal to 2.5% to 5% was associated with an abnormal Weiss score or a higher risk of recurrence.5-9
The incidence of ACC is less than 0.7 to 1.5 per 1 million people per year. 10-12 Because of the low incidence of ACC, a limited number of prospective studies have investigated potential therapies. In addition, the use of mitotane, a major drug
Dr E. Baudin has received honoraria and grants from HRA Pharma. All other authors have nothing to disclose.
a Département de Médecine, Gustave Roussy, 114, rue Édouard-Vaillant, Paris South University, Villejuif Cedex 94805, France; b Département de Nucléaire et de Cancérologie Endocrinienne, Gustave Roussy, 114, rue Édouard-Vaillant, Paris South University, Villejuif Cedex 94805, France; ” Faculté de Médecine, INSERM UMR 1185, 63 rue Gabriel Péri, F-94276 Le Kremlin-Bicêtre, Université Paris Sud, Paris, France
* Gustave Roussy, 114, rue Édouard-Vaillant, Paris South University, Villejuif Cedex 94805, France.
E-mail address: eric.baudin@gustaveroussy.fr
Endocrinol Metab Clin N Am 44 (2015) 411-434
http://dx.doi.org/10.1016/j.ecl.2015.03.001
metabolism inducer but also a drug with delayed antitumor activity, in most patients with ACC makes the conclusions from previous trials uncertain. Thus, advances in the understanding and management of ACC largely depend on the history of mitotane prescription, findings in retrospective studies, expert consensus, and clinicians’ expe- rience from expert centers. The implementation of networks for ACC, such as the Eu- ropean Network for the Study of Adrenal Tumors (ENSAT), the demonstration of the feasibility of phase 3 trials but also recent recommendations, constitute major steps forward.3,4 This review focuses on the therapeutic management of adult patients with sporadic ACC.
CHARACTERIZATION BEFORE THERAPY
ACC must be precisely characterized according to standardized criteria as defined by ENSAT and the European Society for Medical Oncology recommendations. 4 Although the criteria are simple, lack of accurate characterization of patients with ACC in most retrospective studies, including absence of Weiss criteria, proliferative index, and resection status (R status), makes their final conclusions uncertain.
The minimum information that should be included in records of all patients with ACC is given in Box 1. Genetic disorders that affect less than 5% of adult patients with ACC are looked for in case of familial history or age younger than 40 years at diagnosis and have been extensively reviewed recently.13 Approximately 80% of pa- tients with ACC present with symptoms (tumor burden or hormone-related manifes- tations)14-19 and two-thirds of patients with ACC produce steroids.2º ACC hypersecretion can concern both active steroids (mainly glucocorticosteroids and
Box 1 Parameters to be characterized in patients with ACC at the time of therapeutic interventions
· Age and comorbidity, genetic background, performance status
· Weiss global score, including the precise count of mitosis/50 HPF
· Percentage of Ki 67 index in the most active regions (number of cells analyzed to be specified)
· Presence of tumor-related or hormone-related symptoms
· Secretory status: type and magnitude of secretions
· c/pTNM UICC and/or ENSAT staging including:
o Modality of imaging
o Disease-free interval
o Number and location of abnormal lymph nodes at imaging or positive at pathology
o Presence and type of venous invasion or adjacent organ invasion
o Number and type of tumor organs
· Resection status of the primary, number of lymph nodes resected, tumor spillage/ hemorrhage during surgery
. Mitotane history, highest plasma level reached in case of second-line therapy
· Signed informed consent for bioresource use when available
Abbreviations: c/p, clinical/pathological; HPF, high power field.
androgens but also estrogens or mineralocorticosteroids) and nonactive precursors with variable clinical impact. The presence of clinical symptoms should be recorded as well as the magnitude of hormone secretions.
At the time of diagnosis, based on thoracic and abdomen computed tomography (CT) and the analysis of multicentric studies, ACC patients typically present with a large primary tumor mass and are classified ENSAT stage I, II, III, or IV in 5% to 6%, 33% to 50%, 10% to 26% or 21% to 35% of cases, respectively.12,21-23 Frequent upstaging to stage III of patients preoperatively misclassified as stage II jus- tifies preoperative cautious radiologic analysis.24 Within the stage III ACC subgroup, the usual sites of local involvement include adipose tissue surrounding the tumor, adjacent organs, renal vein or vena cava, and lymph nodes in 39 (85.3%), 14 (20.6%), 19 (27.9%), and 7 (10.3%), respectively, in a recent study.22,25 The range of positive lymph nodes in patients with ACC varied between 20% and 50% in the absence or presence of routine lymph node dissection.26 Half of distant metastases are present initially and half occur during follow-up.27 The usual sites of metastatic involvement are mainly the liver and lungs, and less frequently, bone, peritoneum, and other sites. 16-18,27-29 At the time of the discovery of recurrences, local recur- rences are present in to 57% to 63% of cases and distant metastases in 27% to 36% of cases. 30-32
Routine use of [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) still needs validation.4,33,34 However, in our center, FDG-PET/CT is routinely performed at initial staging or at the time of recurrence when surgical resection is planned.
After surgery, the resection status and the Weiss score as well as the proliferative index are determined, including Ki67 measurements. Based on recommendations and the emerging role of the proliferative index as major diagnostic and prognostic tools in recent studies, standardization and the precise count of mitoses and the Ki67 labeling index should be included in the pathology reports.
The biology of ACC has recently been studied extensively.35 Although the clinical application of molecular alterations remains unknown, they constitute the cornerstone of future progress. The existence of several predisposition syndromes suggested the involvement of several driver genes in the pathogenesis of ACC: Li-Fraumeni syn- drome (TP53), Beckwith-Wiedemann syndrome (mapped to the 11p15.5 region con- taining genes coding IGFII, H19, and p57KIP2), familial adenomatous polyposis (Wnt/ B-catenin signaling APC), and Lynch syndromes (MSH2, MSH6, MLH3, PRS2). 13 Numerous genetic and molecular studies, combining several techniques (comparative genomic hybridization, transcriptome, miRNAome, methylome, exome sequencing) have recently been performed on adrenocortical tumors, including carcinoma. 35-39 These studies have confirmed the involvement of several key pathways, including the p53, Wnt/B-catenin, and IGFII pathways but also found that other driver genes such as CDKN2A, RB1, TERT, and MENIN can be involved in the control of the cell cycle or chromatin remodeling. Alteration in microRNA (miRNA) profiling or hyperme- thylation of the CpG island methylator phenotype in up to 50% of cases of ACC has also been described.37-39
PROGNOSIS: TOWARD PROGNOSTIC RISK STRATIFICATION
Although previously described as dismal, the prognosis of ACC is more heteroge- neous than previously believed and long-term survivors exist. Factors that have hampered a precise prognostic stratification of these tumors in the past include the scarcity of ACC, the absence of validated TNM classification, and the lack of strict
criteria of malignancy, which makes stage I or II ACC tumor behavior uncertain. His- torically, the presence of metastases and tumor resectability constituted the key- stones of prognostic stratification.10,40 More recently, the Union for International Cancer Control (UICC) and ENSAT established the first TNM stage classifications, and the resection status was implemented allowing for refined prognostica- tion.22,29,41,42 Within the TNM staging system, ENSAT classification has been found to more accurately predict the outcome of patients with ACC, but recent studies sug- gest that the N status or severe vena cava invasion may behave like stage IV ACC, suggesting that refinements in the stratification of TNM are still needed. 16,25,29,43,44 Also, the relevance of stage I or II ENSAT subcategories is debated. 15,17-19,22,23,42 Table 1 summarizes the evolution of TNM classifications in patients with ACC and new proposals based on recent studies.
After adjustment for TNM classification, several studies claimed that age, 12,14,15,17-19,23,29,42 the presence of hormone-related symptoms or steroid bio- markers, 14,17-19 Weiss score and/or proliferative index and/or differentia- tion, 9,15,17-19,27,29,42,45-47 and the R status also play an important prognostic role.29,42,48 Recent publications based on a large number of patients and patients who were more precisely characterized enable elaboration of a prognostic stratifica- tion of patients with ACC in the adjuvant and palliative setting (Fig. 1).15,16
In patients with localized ACC, one recent study from the ENSAT group investi- gated the risk of recurrence and overall survival (OS) in 319 patients with stage I to III R0 ACC and in a validation cohort of 250 patients.15 This study identified younger age, stage III or less, and low Ki67 labeling as the most significant param- eters to predict recurrence-free survival. Based on these results and previous studies, 12,15,17,18,25,46,49 risk stratification in the management of these patients in the adjuvant setting can be envisaged based on a grading system that includes Weiss criteria and/or mitotic count and/or Ki67 analyses as well as the R status, age, and stage, as shown in Fig. 1A. This stratification is critical to adapt the adjuvant strategy in these patients.
In patients with ACC with advanced stage III to IV, another recent study of the ENSAT network, which analyzed 444 patients with advanced stage III to IV ACC, found that the stage as redefined by a new modified ENSAT (mENSAT) classification in which the presence of N positive moves from stage III to IV and which takes into account the number of tumor organs (see Table 1), has a major prognostic role together with 4 other parameters grouped together under the label GRAS.16 After adjustment for a new mENSAT TNM classifications, GRAS parameters, as defined by grade (Weiss score <6 or >6 or Ki67 <20% or >20%), resection status of the pri- mary, age younger than or older than 50 years, and absence or presence of tumor- related or hormone-related symptoms at diagnosis, were also found prognostic of OS. Similar parameters were previously found to play a major role in predicting recur- rence in patients with localized ACC. Based on these results, a risk stratification of the management of patients with stage III to IV ACC in the palliative setting can be envisioned based on mENSAT new TNM staging and GRAS parameters, as shown in Fig. 1B.
At the time of recurrence, the prognostic impact of disease-free interval as well as RO status was reported in several studies.32,40,50-52 In addition, another study30 suggested that feasaibility of complete surgery at the time of partial response (PR) to mitotane therapy may constitute another way to stratify the patients in terms of best first-line options, as shown in Fig. 2.
Similarly, molecular markers from genomic and epigenomic analyses are emerging and need to be applied to the aforementioned criteria. 35-39
| Table 1 TNM classifications in patients with ACC and proposals for new classifications | ||||
|---|---|---|---|---|
| Stage | UICC | ENSAT | mENSAT | mENSAT + GRASb |
| I | T1 (<5 cm) NO, MO | T1 (<5 cm) NO, MO | — | T1-2, favorable GRAS |
| II | T2 (>5 cm) N0, M0 | T2 (>5 cm) N0, M0 | — | II-A: T1-2, unfavorable GRAS II-B: T1-2, pejorative GRAS |
| III | T3N0 or, N1 | T3-T4 or, Any T-N1, M0 | T3, or T4, N0, M0 | III-A: mENSAT stage III and favorable GRAS III-B: mENSAT stage III and unfavorable GRAS III-C: mENSAT stage III and pejorative GRAS |
| IV | T3N1 or T4 or M1 | M1 | Any T-N1, M1 IV-A: 2 tumor organsª IV-B: 3 tumor organs IV-C: >3 tumor organs | IV-A: mENSAT stage IV-A or B and favorable GRAS IV-B: mENSAT stage IV-A or B and unfavorable GRAS IV-C: mENSAT IV-C or mENSAT-IV-A or B and pejorative GRAS |
mENSAT classification is based on the results of Ref.16 ENSAT-GRAS new proposal takes into account references listed in the section on prognosis.
M1; presence of distant metastasis; N1, positive lymph nodes; T1, <5 cm; T2, <5 cm; T3, infiltration of surrounding tissue; T4, invasion of adjacent organs or renal vein/vena cava.
a Tumor organ counts include the primary and lymph nodes if not resected.
GRAS parameters are considered favorable if grading defined by Ki67 is <20%, primary RO resection status performed, age <50 y and absence of symptoms at diagnosis. GRAS parameters are classified unfavorable in case of age >50 y, or presence of symptoms at diagnosis. GRAS parameters are classified as pejorative in case of: grading as defined by Ki67 >20% and/or primary R1-2 resection status.
A
Stage I-III ACC
RO and Ki67 2-5% (?)
RO and Weiss Score> 2 and Ki67 5-10%
RO and Weiss score >2 and Ki67>10-20%
Weiss score >2 and: Ki67>20% or, stage III or, R1
Low
Intermediate 3-yr RFS : >50 % No adjuvant therapy
High 3-yr RFS : ⇐ 50 % Adjuvant therapy
Very high 3-yr RFS : ⇐ 30% Adjuvant therapy
3-yr RFS : >90%
No adjuvant therapy
B
mENSAT Stage III-IV GRAS parameters
Stagel-III and GRAS favorable or unfavorable
Stage I-III and GRAS pejorative IV-AB GRAS favorable
III and GRAS pejorative or, IV-AB and GRAS unfavorable
IV-C or, IV-AB and GRAS pejorative
Favorable 5-yr OS >50%y
Intermediate OS 5-yr OS : 25-50%
Low OS 5-yr OS : 10-25 %
Very low OS 5-yr OS <10%
Improved OS in case of partial response to systemic therapy
Surgery in ACC
Stage I-III Resectable
Stage I-III not resectable
Recurrence
Metastatic
Surgery
Surgery if partial response to neoadjuvant therapy
Surgery if DFI>6-12 months and RO or partial response and RO
Surgery of primary if good prognosis
Surgery of metastases if : DCR>6 months and RO or, partial response and RO
Hypermethylation status, miRNA profile, or p53 mutations constitute valuable candi- dates that could integrate a future clinicomolecular prognostic classification of pa- tients with ACC.35,53
TREATMENT
Tumor growth is the main cause of death in patients with ACC, and there has been no major breakthrough in recent decades. In addition, no shift toward lower stage at the discovery of the disease has been observed.12,18,23 However, emerging standardiza- tion of ACC management throughout the world through recommendations, emergent targets, and the recent demonstration of the feasibility of phase 3 trials within net- works constitute remarkable keystones for the future. During the last decade, the role of mitotane in the management of patients with ACC has been reinforced, the combination of mitotane with etoposide-doxorubicin-cisplatin (MEDP) has been selected as the standard treatment for patients with advanced ACC; preliminary tar- geted therapy approaches have failed and future targets for ACC management have emerged. The therapeutic options for patients with advanced ACC remain limited and mostly palliative. New protocols including phase 1 trials, even as first line, are urgently needed.
CONTROL OF HORMONE-RELATED SYMPTOMS
In many patients with ACC, steroid hypersecretion may be reduced by the administra- tion of mitotane as monotherapy.3,4 This compound, through its combined antitumor and antisecretory effects, reduces steroid production by tumor cells. 13,54-56 However, in some patients with ACC, major cortisol secretion may rapidly compromise short- term survival, and the use of metyrapone, ketoconazole, or etomidate, administered either alone or in combination, as a complement of mitotane is effective in rapidly blocking hypercortisolism.57
CONTROL OF TUMOR GROWTH
Current recommendations for the treatment of patients with ACC are based on retrospective studies but also 10 single-arm phase 2 and 2 phase 3 studies (Tables 2-4). Stratification of therapeutic management has recently been imple- mented.4 Mitotane therapy and the combination of mitotane with locoregional ther- apies or cisplatinum-based cytotoxic chemotherapy remain the basis for the therapeutic management of these patients. Surgery remains the only curative treat- ment modality. There is no demonstration that median OS has improved in the past decades. 12,23
SURGERY
tions, 3,4,58,59 surgery should respect the rules of oncologic surgery and be performed within expert centers by expert surgeons and through laparotomy. In European guide- lines, laparoscopy is accepted in cases of tumors smaller than 8 to 10 cm with no evidence of invasion. In all cases, not only expert surgeons but also expert multidisci- plinary teams and active prospective registration of patients within dedicated data- bases are mandatory. Retrospective studies that compared the risk of recurrence in patients operated on by laparotomy or laparoscopy have shown comparable60-63 or higher risk of recurrence after laparoscopy.45,64,65 The absence of clear pathologic definitions of so-called stage I to II ACC in these studies as well as potential biases
| Table 2 Tumor response rate to monotherapy in patients with ACC | |||||
|---|---|---|---|---|---|
| Author, Year; Design (n) | Drug/Line | Dosage (g/d) | World Health Organization/ RECIST Criteria | Response (%) | Duration (mo) |
| Venkatesh et al,81 1989; retrospective (72) | M/1 | NR | No | 21 (29) | NA |
| Luton et al,82 1990; retrospective (37) | M/1 | 3-20 | No | 5 (13) | 5-25 |
| Decker et al,83 1991; prospective (36) | M/1 | 6 | Yes | 8 (22) | 3-82 |
| Pommier et al,84 1992; retrospective (29) | M/1 | NA | No | 7 (24) | NA |
| Haak et al,85 1994; retrospective (55) | M/1 | 4-8 | Yes | 15 (27) | 2-190 |
| Barzon et al,86 1997; retrospective (11) | M/1 | 4-8 | Yes | 2 (18) | 12-21 |
| Williamson et al,87 2000; prospective (16) | M/2 | 4-10 | Yes | 2 (13) | NA |
| Baudin et al,88 2001; prospective (13) | M/1 | 6-12 | Yes | 4 (33) | 10-48 |
| Gonzalez et al,3º 2007; retrospective (52) | M/1 | NA | No | 13 (19) | NA |
| Decker et al,83 1991; phase 2 (16) | D/1 | 60 mg/m2 | No | 3 (19) | 3-51 |
Abbreviations: D, doxorubicin; M, mitotane.
in all series constitute significant limitations that preclude definitive conclusions. Pre- selection of R0 patients likely occurs in studies on laparoscopy as well as an increased number of patients referred at the time of recurrences for studies on laparotomy. To date, only half of all patients with ACC have been potentially resectable at diagnosis, 42 and the rate of R0 resection ranges between 53% and 58% in most modern se- ries 18,29,31,60,66 but reached 76% to 89% in tertiary referral centers.31,65 Thus, the increased rate of R0 resection at first surgery of adrenal tumors should be considered as the primary objective of all centers and networks worldwide. Tracks toward this objective encompass the restriction of adrenal surgery for suspected adrenal tumors to expert centers as well as better selection of resectable tumors. In addition, although the added value and definition of expert centers is still debated, 12,62,66,67 it is common sense to state that only such centers offer expert surgeons within a multidisciplinary team as well as adequate follow-up and registration.
Oncologic surgical resection standards (en bloc adrenal gland resection, margin- free resection, no tumor spillage, conversion to laparotomy in case of difficult dissec- tion) must be strictly respected. For some patients with locally advanced tumor, the surgery requires en bloc resection of surrounding peritoneal tissue and adjacent or- gans. However, routine nephrectomy is not recommended in all patients. A lymphade- nectomy may improve the prognosis or the staging, but its extent remains to be specified.26 ACC with extension into the renal vein, vena cava, or right atrium may require thrombectomy, cardiopulmonary bypass, hepatectomy for local spread or exposure, and vena cava reconstruction. 43,44,68,69
At the time of recurrence, surgery is recommended for patients with favorable prognostic factors, including a disease-free interval from previous surgery that is
| Table 3 Tumor response rate to first-line cytotoxic chemotherapy in patients with ACC | |||||
|---|---|---|---|---|---|
| Author, Year; Design (n) | Drugs | ACC Stage IV (%) | WHO/ RECIST Criteria | Response (%) | Disease Control Rate Duration (mo) (Range) |
| Williamson et al, 87 2000; phase 2 (45) | E, P | 94 | SWOG | 11 | NA |
| Van Slooten et al,96 1983; retrospective (11) | (M)C, D, P | 100 | WHO | 18 | (6-9) |
| Bukoswski et al,97 1983; phase 2 (37) | M, P | 100 | No | 30 | Median 7.9 (1.4-36) |
| Khan et al,98 2000; phase 2 (22) | M, S | Not all | No | 36 | Median 7 (3-13) |
| Fassnacht et al,28 2012; phase 3 (153) | M, S | 99 | RECIST | 9 | Median 2.1 |
| Schlumberger et al,99 1991; retrospective (14) | M, F, D, P | 100 | WHO | 23 | NA (4-42) |
| Bonacci et al, 100 1998; retrospective (18) | M, E, P | 88 | WHO | 33 | NA (8-26) |
| Berruti et al,70 2005; phase 2 (72) | M, E, D, P | 87 | WHO | 55 | Median 9 |
| Abraham et al, 101 2002; phase 2 (36) | M, E, D, V | 100 | WHO | 14 | Median 12 |
| Urup et al, 102 2013; phase 2 (21) | M, Doc, P | 100 | RECIST | 21 | Median 3 |
| Fassnacht et al,28 2012; phase 3 (151) | M, E, D, P | 100 | RECIST | 23 | Median 5 |
| Lerario et al, 107 2014; phase 1 (19) | M, Cixutumumab | 100 | RECIST | 5 | Median 1.5 (2.6-48) |
Series are classified as a function of mitotane prescription, number, and type of drugs. Duration is expressed in median and ranges when available or percentage of control at a fixed date.
Abbreviations: C, cisplatin; D, doxorubicin; Doc, docetaxel; E, etoposide; F, 5-fluorouracil; M, mitotane; (M), signifies that mitotane was not given in all patients; NA, not available; P, paclitaxel; S, streptozotocin; SWOG, Southwest Oncology Group; V, vincristine; WHO, World Health Organization.
longer than 6 to 12 months, and achievable RO resection.31,32,40,50-52 If not possible, surgery may be reconsidered at the time of objective response. 30,70,71 In the palliative setting, surgery of the primary is also recommended in patients with favorable prognostic parameters if an R0 resection can be achieved.16 Surgery of metastases is considered on a case-by-case basis and performed mainly in pa- tients with favorable prognostic factors, sustained PR, and long-term survival with R0 resection expectations.51,52 In all cases, postoperative mortality less than 5% is expected. Fig. 2 recapitulates the use of ACC surgery in patients with ACC.
LOCOREGIONAL GUIDED THERAPY
Interventional radiology techniques may offer an alternative approach to surgery to control tumor growth and to improve secretory status in the palliative setting. They are recommended in combination with mitotane therapy in patients with advanced
| Table 4 Tumor response rate to post-first-line cytotoxic chemotherapy in patients with ACCª | |||||
|---|---|---|---|---|---|
| Author, Year; Design (n) | Drugs/Line | ACC Stage IV (%) | WHO/ RECIST Criteria | Response (%) | Disease Control Rate Duration (mo) (Range) |
| Baudin et al, 105 2002; retrospective (12) | M, I | 81 | RECIST | 0 | NA (1.5-4) |
| Khan et al, 103 2004; retrospective (9) | M, Cy, V, T, C | 18 | WHO | 11 | Median 6.7 (3-11) |
| Sperone et al, 104 2010; retrospective (29) | M, F, G | 87 | RECIST | 7 | Median 5.3 (1-43) |
| Fassnacht et al, 28 2012; phase 3 (86) | M, S | 100 | RECIST | NA | Median 2.2 |
| Fassnacht et al,28 2012; phase 3 (101) | M, E, D, P | 100 | RECIST | NA | Median 5.5 |
| Quinkler et al, 112 2008; retrospective (10) | (M)G-Erlotinib | 100 | RECIST | 0 | NA (8) |
| Wortmann et al, 116 2010; retrospective (10) | (M)Ca-Avastin | 100 | RECIST | 0 | Median 2.1 |
| Kroiss et al,90 2012; phase 2 (35) | (M)Sunitinib | NA | RECIST | 0 | Median 2.9 (6-11) |
| Berruti et al,4 2012; phase 2 (9) | Paclitaxel- Sorafenib | 20 | RECIST | 0 | — |
| Sullivan et al, 115 2014; phase 2 (13) | Axitinib | 100 | RECIST | 0 | Median 5.5 (1.8-10.9) |
| Haluska et al, 108 2010; phase 1 (14) | (M)Figitumumab | NA | RECIST | 0 | 43%-3 mo |
| Naing et al,110 2013; phase 1 (26) | (M)Cixutumumab- Temsirolimus | NA | RECIST | 5 | 42%-6 mo |
| Fassnacht et al, 109 2015; phase 3 (90) | Linsatinib | NA | RECIST | 3 | Median 1.5 |
Series are classified as a function of mitotane prescription, number, and type of drugs. Duration is expressed in median and ranges when available or percentage of control at a fixed date. (M) sig- nifies that most patients, but not all, received concomitant mitotane therapy.
Abbreviations: C, cisplatin; Ca, capecitabin; Cy, cyclophosphamide; D, doxorubicin; E, etoposide; F, 5-fluorouracil; G, gemcitabine; I, irinotecan; M, mitotane; NA, not available; S, streptozotocin; T, teniposide; V, vincristine; WHO, World Health Organization.
a All patients received previous chemotherapy with at least mitotane and cisplatinum or strep- tozotocin except for Naing and Fassnacht, in which series only 50% of patients with ACC previously received cisplatinum therapy.
ACC with favorable prognostic factors.4 The local rate of tumor control provided by these tools is superior to systemic options, justifying the increasing use of these mo- dalities in patients with ACC.
Thermal ablation techniques, namely radiofrequency ablation and cryotherapy, are effective for curing small (<3 cm) metastatic lesions in the liver, lung, and bone. Min- imal morbidity, short recovery time, and repeatability in the same organ are major ad- vantages of these techniques.72-74 Transarterial chemoembolization (TACE) consists of the injection of an emulsion of lipiodol (Guerbet, Aulnay sous Bois, France) and chemotherapy directly into the liver arterial supply. In one retrospective study using
platinum-based TACE as second-line treatment,75 an 83% rate of liver tumor control was reported at 3 months, and this was observed especially in patients with small me- tastases (≤3 cm).
RADIOTHERAPY
Radiotherapy (RT) is recommended in patients with ACC in the adjuvant setting in case of R1 resection in the European guidelines or in all stage III patients in the French guidelines.4 In the palliative setting, RT is recommended to control bone or brain metastases. Proximity of the adrenals to critical organs, such as the kidney, stomach, intestine, and spinal cord, and radioresistance of ACC were supposed to argue against the use of RT in the setting of ACC. Recent technical improvements in RT techniques include stereotactic RT, intensity-modulated radiation therapy, and breathing motion monitoring techniques. Data from the German ACC registry also suggest a role for adjuvant RT after a macroscopically complete resection. Median dose was 50.4 Gy (range, 41.4-56 Gy), given in 1.8-Gy to 2.0-Gy daily frac- tions. Local recurrence appeared in 2 of 14 patients in the RT group and in 11 of 14 patients in the control group.76 These recurrences developed in the adrenalectomy bed and the adjacent ipsilateral and contralateral interaortocaval lymph nodes. These results were confirmed in only 1 of 2 recently published studies, but none of these studies reported an improved OS rate.77,78 Stereotactic RT was shown to provide a favorable effect when used for the management of metastasis to the adrenals with limited toxicity and in the palliative setting, showing a 27% response rate according to RECIST (Response Evaluation Criteria In Solid Tumors) in selected patients.79 These results suggest an increasing role of RT in the future to control unresectable primary ACC, local recurrence, and the treatment of liver or lung metas- tases in patients with ACC.
MITOTANE THERAPY
Mitotane constitutes the most studied and specific systemic option for patients with ACC, but the mechanism of its antitumor action remains unknown.80 Mitotane therapy is recommended in both the adjuvant setting in patients with ACC at high risk of recur- rence and in the palliative setting in all patients, in combination with locoregional or other systemic options.4 Mitotane is the only drug approved in Europe for the treat- ment of advanced ACC.
In the palliative setting, 6 retrospective and 3 prospective studies have analyzed the antitumor role of this drug as monochemotherapy in patients with unresectable ACC.30,81-88 As described in Table 2, various dosages of the drug were used in a minimum of 11 to a maximum of 72 patients as first-line therapy in most cases. PRs were reported in 13% to 33% of cases, with response duration of 2 to 190 months. In the absence of placebo-controlled randomized trials, the real benefit of mitotane therapy on OS remains unknown. In addition, the delayed modality of ac- tion of this drug makes the feasibility of such a trial questionable in the future. Based on these results and progress in the prognostic stratification of patients with ACC with unresectable stage III to IV advanced disease, current recommendations sug- gest the use of mitotane in all patients in combination with either locoregional ther- apies or other systemic options in patients with favorable or poor prognostic parameters, respectively.4
The side effects of mitotane are diverse and target mainly the digestive (nausea, vomiting, diarrhea) and neurologic systems (vertigo, dizziness, somnolence, blurred vision, poor verbalization, and slow ideation). Awareness of these side effects is
critical and requires dedicated education of patients and providers. Digestive sec- ondary effects occur early and are believed to be related to a direct effect of the drug on the digestive mucosa. Because of its cytotoxic effect on the adrenals and the inhibitory effect on steroidogenesis, adrenal insufficiency is a logical conse- quence of mitotane therapy that requires both glucocorticoid and mineralocorticoid substitution. As a rule, the appearance of digestive cytotoxic effects requires an in- crease in cortisol supplementation both to control the stress and as a diagnostic test to diagnose insufficient replacement of cortisol. Mitotane is a strong inducer of liver enzyme activity, including CYP3A4, with major relevance regarding concomitant therapy such as cortisol replacement, vitamin K antagonist, oral contraception, and combined antitumor therapies. 13,54-56,89,90 As a practical consequence of this mitotane induction of CYP3A4 activity, the routine cortisol replacement dosage is folded by 2 or 3 compared with patients treated for primary adrenal insufficiency; in addition, heparin and mechanical contraception methods are favored. Blood moni- toring of mitotane should include electrolyte measurements, liver tests, and blood cell measurements, because their respective alterations constitute rare but poten- tially severe cytotoxic targets of the drug. The relevance of monitoring gonadal ste- roids or thyroid function tests remains debatable in the absence of related symptoms.91 Dyslipidemia should be treated with drugs that do not interfere with CYP3A4 liver enzyme activity.
Eight retrospective studies have explored the role of mitotane therapy in the adju- vant setting14,15,17,21,88,92-95 but no single trial has been performed. Compared to historical controls, improved recurrence-free survival was reported in 4 and improved OS in 3, and was restricted to patients with cortisol secretion in 1. Based on these limited results and the progress on prognostic stratification, mitotane adju- vant therapy is recommended in patients with ACC at high risk of recurrence as defined by Ki67 higher than 10% or R1 resection.4 Because of the high risk of recur- rence of stage III ACC, adjuvant mitotane therapy is also recommended in these pa- tients in the French guidelines. Patients with ACC with Ki67 less than 10% should be enrolled in the ongoing ADIUVO (Efficacy of Adjuvant Mitotane Treatment) trial, which is investigating the role of mitotane in patients with stage I to III ACC after R0 resection on recurrence-free survival in the prospective setting.
CYTOTOXIC CHEMOTHERAPY
Apart from mitotane, only doxorubicin has been tested as monochemotherapy in first- line or post-first-line patients with stage IV ACC (see Table 2). With doxorubicin used in first line, a 19% objective response rate was reported in 1 study.83 No confirmatory study has been published.
Apart from the 2 studies mentioned earlier, mitotane therapy has been combined with a cytotoxic agent in all studies but two that analyzed the results of first-line cyto- toxic chemotherapy (see Table 3). In addition, no randomized trial comparing the anti- tumor role of mitotane combined or not with other chemotherapy has been published. Therefore, in 2015, the benefit of combining mitotane with other cytotoxic drugs compared with mitotane alone remains unknown. The results of the combination of etoposide and cisplatinum or cyclophosphamide, doxorubicin, cisplatin without mito- tane has been published in 2 studies87,96; PR rates were 11% to 18% (see Table 3). Two phase 2 studies have analyzed the antitumor effect of mitotane combined with 1 single drug chemotherapy: cisplatinum or streptozotocin in 35 and 22 patients, respectively97,98; a PR of 30% has been reported with a 7.9-month median duration97 and a 36% PR rate with a 7-month median duration.98
Five other studies have analyzed the antitumor effect of mitotane combined with cytotoxic polychemotherapy. PR rates between 14% and 55% were re- ported.70,96,99-102 Cisplatinum or doxorubicin was the most frequently used drug. Response rate higher than 20% was reported in all series that used at least mitotane and cisplatinum chemotherapy with a disease control rate for 3 to 9 months. In pa- tients pretreated with streptozotocin- or cisplatinum-based chemotherapy (see Table 4), 2 PRs in 28 patients were reported with the combination of gemcitabine and 5-fluorouracil and a time to progression of 5.3 months, which constitutes the best result reported to date. 103-105
Recently, the first international randomized in locally advanced and metastatic adrenocortical carcinoma phase 3 trial (FIRMACT) performed in patients with ACC, which compared the OS of patients with advanced ACC randomized for either an MEDP or mitotane and streptozotocin (MS) regimen was published.28 A nonstat- istically significant gain in OS of 2.8 months was reported with a statistically significant impact of the MEDP arm on secondary end points like PR rate or progression-free survival (PFS) compared with the MS regimen. These results estab- lished MEDP as the first standard of chemotherapy in patients with advanced ACC.4 The gain in OS (17.1 vs 4.7 months) in the subgroup of 119 patients with ACC who did not receive second-line chemotherapy but were given MEDP as first line also supports the use of MEDP as a standard. The PR rate or median PFS was 30% and 5 months or 11% and 2.1 months in the MEDP or MS arms, respectively. Based on these results, the use of streptozotocin in patients with ACC seems ineffective. Although these trials did not meet the primary end point, this first randomized study on ACC provided robust results to rationalize future phase 2 hypotheses. In parallel, it is well known that combining mitotane with other cytotoxic agents increases the rate of side effects.97 Therefore, there is an urgent need for novel therapies for ACC that are both more effective and better tolerated than the current MEDP stan- dard. With a 10% OR in second or third lines and 5.3-month time to progression, the combination of gemcitabine and 5-fluorouracil is recommended after cisplatinum- based chemotherapy, but no validation has been provided. 104
MOLECULAR TARGETED THERAPIES
Few studies have investigated the use of targeted molecular therapies for ACC mostly in the post-first-line setting and in combination with mitotane (see Tables 2 and 4). Based on insulin growth factor 2 hyperexpression, and cell signaling through insulin growth factor 1 receptor (IGF-1R) and insulin receptor (IR), preclinical and phase 1 studies have investigated the role of IGF-1R inhibitors with PRs in some phase 1 studies106,107 but not in all.108 Recently, the negative results of a placebo-controlled phase 3 study analyzing the antitumor effect of linsitinib, a dual IGF-1R and IR small molecule inhibitor, on OS and PFS analyses were reported.109 However, 4 of 139 pa- tients clearly benefited from the drug, as shown by prolonged tumor responses, with no escape after 23 months or more. These results suggest a benefit of IGF-1R inhibi- tion, as a single agent, in 3% of patients with ACC in whom the molecular background remains to be identified. Using the same approach, IGF-1R antibody cixutumumab combined with mitotane as first-line therapy for 19 cases of ACC, with 1 PR and a PFS of 6 weeks, was considered insufficient to proceed to a phase 2 study.107 By contrast, the combination of cixutumumab with temsirolimus-mammalian target of rapamycin pathway inhibitor yielded interesting results, as shown by a 42% rate of stabilization at 6 months in a series of heavily pretreated ACCs. 110 These results await further confirmation. Prognostic characteristics of patients with ACC and plasma level
mitotane levels were lacking, precluding precise conclusions. In 2 different series, 19 and 10 patients were treated with epidermal growth factor receptor inhibitors in com- bination with gemcitabine in one111,112; no PR was observed. Four patients with ACC received imatinib or everolimus in 2 studies, with no response. 113,114
Preliminary experiences from several other endocrine cancers show prolonged tumor control with antiangiogenic therapy, but the benefit of this strategy has not yet been confirmed in patients with ACC. Two phase 2 trials analyzed the antitumor response to sunitinib or axitinib and reported no PR and median PFS of 83 days or 5 months in 35 or 13 pretreated patients with ACC, respectively.90,115 In 2 additional phase 2 trials, combination of antiangiogenic agents with chemotherapy was investigated. In 1 study, bevacizumab plus capecitabine in 10 pretreated patients with ACC produced no PR and median PFS was 59 days.116 In a second study, tu- mor progression was observed in all 9 patients at 2 months treated with the combi- nation of sorafenib and taxol.117 One recent phase 1 trial with the combination of imatinib with dacarbazine and capecitabine in 7 pretreated patients with ACC produced 1 PR.118 These results show no role of antiangiogenic agents in patients with ACC, but the absence of pharmacokinetic analysis of these agents at the time of investigation makes the potential interaction of mitotane a possible explanation.90
PREDICTORS AND SURROGATE MARKERS OF RESPONSE
The elucidation of predictors of response to mitotane therapy or the MEDP regimen is a key step to select patients with ACC who are the most likely to respond and to encourage likely nonresponders to undergo first-line protocols with alternative agents. Studies of predictors and surrogate markers of response in patients with ACC in the recently published FIRMACT trials are ongoing.
PREDICTORS OF RESPONSE
Mitotane plasma level monitoring is recommended in ACC management with the objective of reaching 14 to 20 mg/L,3,4 but this level is achieved in only up to 50% of patients with ACC.3,4,18,85,88 Higher PR rates85,88,119 and improved OS or recurrence-free survival have been reported71,85,95,119,120 in retrospective studies when plasma mitotane levels higher than 14 mg/L were reached. One recent retro- spective study confirmed the 14-mg/L mitotane plasma level as the best compro- mise to predict tumor response but also found a better sensitivity of 89% or specificity of 90% when the 10-mg/L or 20-mg/L cutoffs were used.119 These results suggest a revision of the 14-mg/L to 20-mg/L standard plasma mitotane window to a standard of 10 to 30 mg/L.119 Recent studies have shown that a high-dose strategy may increase the chance of obtaining earlier therapeutic plasma mitotane levels, but no statistical difference was observed.121,122 Based on these recent results, we now use a maximum tolerated dose approach, as described in Fig. 3, based on the search for the highest tolerated dose maintained during at least 2 RECIST evalua- tions 2 to 3 months apart and a range of plasma mitotane levels between 10 and 30 mg/L. Other predictors of response to mitotane therapy have been proposed, including DNA repair gene excision repair complementation group 1,71,123 high ribo- nucleotide reductase large subunit, 124 CYP2W1125 and cortisol secretion, 14 but these have not been confirmed. In addition, 1 recent study119 failed to show any additional value of mitotane metabolite measurements, especially 1,1-(o,p’-dichlorodiphenyl) acetic acid.
Mitotane 4-6 g/d at initiation RECIST evaluation every 2-3 months
Clinical tolerance Mitotane plasma level RECIST evaluation
RECIST response from the date of second highest tolerated dose
MAINTAIN-ADJUST in case of NO PROGRESSION, good tolerance and plasma level<30mg/L
STOP in case of PROGRESSION or absence of plasma level>8- 10 mg/L for 1 year
Rechallenge highest tolerated dose in case of RECIST partial response
SURROGATES OF RESPONSE
Four retrospective studies have reported a relationship between complete response or PR and improved survival19,70,71,101 but this was not confirmed in 1 study.97 Pro- longed median survival of responders more than 34 months was reported. These results suggest that responders should be reconsidered for proper personalized management, including locoregional options such as surgery. One preliminary study did not disclose any role for FDG-PET as an early surrogate of response.34 Circu- lating tumor cells may also be a tool to consider in the future. 126
FUTURE STRATEGIES FOR DEVELOPING TREATMENTS AGAINST ADRENOCORTICAL CARCINOMA
Looking for actionable targets in each patient with ACC is a major goal of personalized therapy. Major breakthroughs have been achieved in the identification of relevant mo- lecular alterations in ACC but no simple actionable target has emerged. Among these molecular abnormalities, the overexpression of IGFII is the most frequent but its role as a target for therapy for ACC has been invalidated by a recent phase 3 clinical trial that failed to show any significant antitumor efficacy.109,127,128 B-Catenin signaling and p53/Rb pathways as well as chromatin remodeling constitute the most frequent molecular alterations in ACC of various TNM stages.35-39 CTNNB1 and TP53 muta- tions are present in 20% to 70% and 16% to 31% of patients with ACC, respec- tively,35-39,53,128-130 but no simple targeting of such molecular abnormalities is available.
Next-generation sequencing allows for the analysis of a large set of genes in a time span compatible with clinical needs. In a recently published study, we screened new potentially targetable molecular abnormalities in a large cohort of advanced ACCs.130 No simple actionable alteration of genes, including EGFR, BRAF, KIT, PIK3CA, RET, or PDGFR-A, that are targetable by available drugs was found. Based on the most common gene abnormalities detected (TP53
Box 2 Recommendations for future studies in ACC
· Patients with ACC who undergo any kind of therapeutic intervention should be subject to clear definition and to a thorough clinical and molecular standardized characterization of their disease
· Studies on prognostic stratification should still be implemented to achieve the most precise characterization of ACC outcomes within each TNM and GRAS subgroup
· Recommended therapeutic strategies used for patients with ACC should be prospectively recorded, once patient permission is granted, in dedicated registries to minimize missing data and to achieve progresses with historical therapies
. Mitotane plasma levels should be recorded at the time of new therapeutic evaluation as well as best response under mitotane therapy. Scenarios on the best modality of evaluation of new drug therapy in patients treated with mitotane should be clarified in near future
· Predictors of response to mitotane therapy and markers of resistance as well as surrogates of OS should be elucidated
· Researchers should develop parallel single-arm phase 2 clinical trials with similar primary end points in which PR or PFS is a major end point. In all cases, precise molecular characterization should be implemented at the time of enrollment and progression
· Efforts should be made to enroll patients with ACC within phase 1
· Phase 3 should remain the last step of drug validation, keeping in mind that a gain in 2 months of OS requires 300 patients per arm to provide statistically significant results. Stratification for mitotane therapy and prognostic parameters should be implemented
(15%), ATM (12.5%), and CTNNB1 (10%) mutations, CDK4 (cyclin-dependent kinase-4) amplification (17.9%) and CDKN2A (14.3%) and CDKN2B (10.7%) deletion genes, which are all directly or indirectly involved in controlling G1-S phase cell cycle progression, are the most commonly altered. We recently suggested that drugs targeting the cell cycle could be the most relevant new therapeutic approach.130 Based on frequent gains of fibroblast growth factor receptors (FGFR) 1 to 4, we also suggested that the FGFR pathway could be a potential target for treatment in patients with ACC. Conversely, HER2 (ERBB2) amplifi- cation was not present in ACC, in accordance with previous reports. Recently, a similar approach was conducted and similar conclusions were reached, with most frequent genomic abnormalities occurring on TP53, CDKN21, CTNNB1, and ATM and NF1 and MEN1 in more than 10% of cases. 131
Making therapeutic advances against ACC, a rare cancer, is a formidable chal- lenge facing patients and clinicians. The rarity of ACC makes phase 3 clinical trials as the basis of proof of concept a challengeable practice when urgent improvements are expected. However, recommendations such as those described in Box 2 may help in the development of new treatments for ACC. These strategies are supported by multiple expert groups on different continents and international networking initia- tives such as ENSAT.
ACKNOWLEDGMENTS
The members of the Endocrine Tumor Board of Gustave Roussy (Department of Endocrine Oncology and Nuclear Medicine), who served as co-authors for this article,
are: Segolene Hescot, MD; Amandine Berdelou, MD; Isabelle Borget, PharmD; Caroline Caramella, MD; Frederic Dumont, MD; Desirée Deandreis, MD; Frederic Deschamps, MD; Eric Deutsch, MD, PhD; Abir Al Ghuzlan, MD; Marc Lombes, MD, PhD; Rossella Libe, MD; Angelo Paci, PharmD; Jean-Yves Scoazec, MD, PhD; Jacques Young, MD, PhD; Sophie Leboulleux, MD, PhD; Martin Schlumberger, MD, PhD.
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