ENDOCRINE SOCIETY
OXFORD
Clinical Research Article
Combination of Mitotane and Locoregional Treatments in Low-Volume Metastatic Adrenocortical Carcinoma
Alice Boilève,1,* Elise Mathy,1* Charles Roux,2 Matthieu Faron,3 Julien Hadoux,1 Lambros Tselikas,2 Abir Al Ghuzlan,4 Segolene Hescot, 5
Sophie Leboulleux,1 Thierry de Baere,2 Livia Lamartina,1 Frédéric Deschamps,2 and Eric Baudin1
1Institut Gustave Roussy, Département d’oncologie endocrinienne, F-94805, Villejuif, France; 2Institut Gustave Roussy, Département de radiologie interventionnelle, F-94805, Villejuif, France; 3Institut Gustave Roussy, Département de chirurgie, F-94805, Villejuif, France; 4Institut Gustave Roussy, Département d’anatomopathologie, F-94805, Villejuif, France; and 5Institut Curie, Département de médecine oncologique, 75005, Paris, France
ORCID numbers: 0000-0003-3708-4909 (A. Boileve); 0000-0003-2331-0792 (M. Faron); 0000-0002-2198-3582 (E. Baudin).
*A.B. and E.M. are co-first authors of this work.
Abbreviations: ACC, adrenocortical carcinoma; CR, complete response; GRAS, grade, R status, age, and symptoms; HR, hazard ratio; IQR, interquartile range; LRT, locoregional treatment; LTB, low tumor burden; mENSAT, modified European Network for the Study of Adrenal Tumors; OS, overall survival; PFS, progression-free survival; TTC, time to chemotherapy.
Received: 8 March 2021; Editorial Decision: 15 June 2021; First Published Online: 18 June 2021; Corrected and Typeset: 30 July 2021.
Abstract
Context: European and French guidelines for ENSAT stage IV low tumor burden or indolent adrenocortical carcinoma (ACC) recommend a combination of mitotane and locoregional treatments (LRT) as first-line treatment. Nevertheless, the benefit of LRT in combination with mitotane has never been evaluated in this selected group of patients. Objective: This work aimed to evaluate the therapeutic strategy of LRT combined with mitotane in patients with low tumor burden stage IVA ACC.
Methods: A retrospective chart review was performed from 2003 to 2018 of patients with stage IV ACC with 2 or fewer tumoral organs who received mitotane in our center. The primary end point was the delay between mitotane initiation and first systemic chemotherapy. Secondary end points were progression-free survival (PFS) and overall survival (OS) from mitotane initiation. Adjusted analyses were performed on the main prognostic factors.
Results: Out of 79 included patients, 48 (61%) patients were female and the median age at stage IVA diagnosis was 49.8 years (interquartile range [IQR], 38.8-60.0 years). Metastatic
sites were mainly lungs (76%) and liver (48%). Fifty-eight (73%) patients received LRT including adrenal bed radiotherapy (14 patients, 18%), surgery (37 patients, 47%), and/ or interventional radiology (35 patients, 44%). Median time between mitotane initiation and first chemotherapy administration was 9 months (IQR, 4-18 months). Median PFS1 (first tumor-progression) was 6.0 months (95% CI, 4.5-8.6). Median OS was 46 months (95% CI, 41-68). PFS1, PFS2, and OS were statistically longer in the mitotane plus LRT group compared to the mitotane-only group (hazard ratio [HR] = 0.39; 95% CI, 0.22-0.68; HR = 0.35; 95% CI, 0.20-0.63; and HR = 0.27; 95% CI, 0.14-0.50, respectively). Ten (13%) patients achieved complete response (CR), all from the mitotane plus LRT group.
Conclusion: Our results endorse European and French guidelines for stage IV ACC with 2 or fewer tumor organs and favor the combination of mitotane and LRT as first-line treatment. For the first time, a significant number of CRs were observed. Prospective studies are expected to confirm these findings.
Key Words: adrenocortical carcinoma, interventional radiology, surgery, mitotane, chemotherapy
Adrenocortical carcinoma (ACC) is a rare and aggressive tumor that originates from the adrenal cortex. Prognosis is poor at advanced stages (1, 2), with a 5-year overall sur- vival (OS) of less than 15% in most studies (1-4).
Surgery remains the only curative treatment for ACC, but most patients relapse or exhibit distant metastases in 21% to 46% of cases at diagnosis (4-10). Half of distant metastases are synchronous (11). Most frequent metastatic sites are the lungs and liver, less frequently bone and the peritoneum (3, 9, 11, 12). In case of advanced/metastatic disease, first-line systemic therapy based on mitotane or mitotane plus chemotherapy is recommended in patients with low tumor burden (LTB) or indolent tumor (1, 13, 14).
Recently, modified European Network for the Study of Adrenal Tumors (mENSAT) stage and grade, R status, age, and symptoms (GRAS) parameters were identified as independent prognostic factors in patients with advanced ACC (9). GRAS parameters include (i) tumor grade (Weiss score > 6 and/or Ki67 ≥ 20%), (ii) resection status of the primary tumor, (iii) age (≥ 50 years), and (iv) tumor-related or hormone-related symptoms (9). Regarding best tumor staging, the number of tumor sites, including primary tumor or local recurrence but also lymph nodes, was iden- tified as a major prognostic factor triggering a proposal for new mENSAT categorization of advanced ACC patients (3). ENSAT stage IVA ACC was defined as metastatic disease with no more than 2 tumor sites (4). According to this new classification (9), 31% of advanced ACC patients were clas- sified as stage IVA experiencing 5-year OS of 15% (95% CI, 8%-22%) and a median OS of 21.2 months (95% CI, 15.7-25.9).
Recent European Society for Medical Oncology and European Society of Endocrinology guidelines pro- pose locoregional treatments (LRT) including surgery,
interventional radiology, and radiation therapy, in addition to systemic therapy in selected LTB patients such as stage IVA ACC (1, 13). The goals of LRT are to control tumor growth and hypersecretion-related symptoms, to allow op- timization of mitotane prescription, and to improve sur- vival. Nevertheless, the benefit of the combination of LRT with systemic therapy has never been evaluated at the time of diagnosis in this selected group of patients.
In this retrospective study, we aimed to evaluate the therapeutic strategy of LRT combined to mitotane in pa- tients with low tumor burden stage IVA ACC (LTB stage IVA ACC).
Materials and Methods
This retrospective study was approved by the institutional review board of our institution (No. GR2021-14) and is compliant with the Declaration of Helsinki.
Patients with ACC were identified through the electronic files of our center from 2003 to 2018. Inclusion criteria were as follow: mENSAT LTB stage IVA disease either syn- chronous or metachronous, defined by the presence of a maximum of 2 tumor sites if the primary tumor had been removed, or one metastatic site if the primary tumor had not been removed. Exclusion criteria were other mENSAT stages (stages I, II, III, IVB, or IVC), missing data or lost to follow-up, and patients younger than 18 years.
Clinical characteristics and treatment-related outcomes were retrospectively collected by hospital chart review. Patients were followed by thoracic and abdomen-pelvic com- puter tomography scans plus or minus fluorodeoxyglucose positron emission tomography scans every 3 months. For patients experiencing recurrence during adjuvant mitotane, whenever possible, mitotane was continued and optimized
and LRT was considered if metastases were accessible to a locoregional therapy.
End Points and Evaluation
The primary end point was the time to chemotherapy (TTC) defined as the time between the initiation of mitotane and the introduction of first systemic cytotoxic chemotherapy, to consider the delay to achieve plasma mitotane therapeutic plasma level but also to finalize the LRT procedures. Overall, TTC can be considered as the time to strategy failure. Mitotane initiation was defined as the time of initiation of mitotane in synchronous meta- static patients, or as the time of LTB stage IVA diagnosis in case of metachronous metastatic patients already under mitotane for adjuvant treatment. Progression-free survival (PFS) and OS were considered as secondary end points. For these reasons, 2 PFS categories were also defined:
- PFS1 was defined as the time between mitotane initiation and first disease progression or death, or the date of last follow-up in patients alive without progression.
- PFS2 was defined as the time between mitotane initiation and second disease progression (with or without combination of systemic chemotherapy) or death after one progression, or the date of last follow-up in patients alive without second progression.
Disease progression was defined using the RECIST 1.1 cri- teria, on targets that had been and had not been treated by LRT. All computed tomography scans were independently and blindly reviewed by a radiologist (C.R.). OS was de- fined as the time between mitotane initiation and death, or the date of last follow-up in patients. Comparison of survival between the mitotane-only and mitotane plus LRT groups during the same period of time was performed.
Statistics
Study end points were TTC, PFS1, PFS2, and OS. All vari- ables were summarized as median (range or interquartile range [IQR]) or number and percentages. Quantitative variables were compared using a Mann-Whitney U test. Qualitative variables were compared using a Fisher exact test. Comparisons between delays of TTC were per- formed with a Wilcoxon rank sum test. The Kaplan-Meier method was used for survival analyses. A Cox model was used for adjusted analyses of potential prognostic factors. Correlation between survival end points was calculated by the iterative multiple imputation method (15). A P value of less than .05 was considered statistically significant. All
statistical analyses were performed using R, version 4.0.2 (The R Core Team).
Results
Clinical Characteristics
Out of 358 identified ACC patients, 79 (22%) were en- rolled (Fig. 1). Overall, 48 (61%) patients were female and the median age at ACC diagnosis was 47.5 years (range, 18-77 years). Median age at LTB stage IVA diagnosis was 49.8 years (range, 18.5-79 years) (Table 1).
Only 13 (16%) patients had synchronous LTB stage IVA ACC at the time of diagnosis. Seventy-eight patients (99%) underwent surgery of the primary tumor, mainly by lapar- otomy/open surgery (see Table 1).
Regarding GRAS factors (9), 52 (66%) patients ex- hibited hormonal secretion, Ki67 percentage was 20% or greater in 25 (32%) patients, Weiss score was 6 or greater in 54 (68%) patients, primary resection R1 or R2 resection in 11 (14%) patients, and 37 (47%) were 50 years or older (see Table 1).
Only one patient had the primary tumor not removed, 26 (33%) patients had only one metastatic site, and 53 patients (67%) had 2 metastatic sites. The most common metastatic sites were the lungs (n = 60, 76%) and liver (n = 38, 48%). Local relapse was observed in 26 (33%) pa- tients (see Table 1).
Clinical characteristics between the mitotane-only group and the mitotane plus LRT group were similar with regard to the number, the type of tumor sites, and GRAS param- eters, but the Weiss score was significantly more elevated in the mitotane-only group (P = . 0007) (Table 1). Patients in the mitotane-only group did not receive LRT for the fol- lowing reasons (nonexclusive): inadequate volume (too big, 3 patients) or location of the metastases (inadequate ana- tomical location for LRT targeting, 7 patients), inclusion in an ongoing chemotherapy protocol (6 patients), too small tumor burden (eg, pulmonary micronodules, 3 patients), progressive disease at time of first LRT (they were then rejected from LRT and considered for cytotoxic chemo- therapy, 3 patients), treatments received in a period when LRT was not available for all locations (n = 2, 11%), safety issue (n = 1, 5%), and patient refusal (n = 1, 5%).
Treatment Characteristics
All patients received mitotane in a median delay from LTB stage IVA diagnosis of 0 months (IQR, 0-1.6 months) and 46 (58%) patients achieved at least one plasma mitotane level of 14 mg/L or greater (therapeutic rate), with no
ACC followed at GR 2003-2018 N=358
Other stages (I, II, III, IVB, IVC) n=204
Missing data (unclear initial stage) or loss to follow-up (patients from other centers) n=73
<18 years n=2
Stage IV A ACC N=79
difference between the 2 groups. Mitotanemia peak was obtained in 8.6 months (SD 14.0 months). The median time to reach target mitotane concentration (from stage IVA diagnosis) was 4.2 months (IQR, 0.0-13.2 months) in the whole population. In the mitotane-only group, time to reach target mitotane concentration was 0.5 months (IQR, 0.0-5.7 months) and 10.8 months (IQR, 0.7-31.5 months) in the mitotane plus LRT group. Plasma mitotane levels of greater than 20 mg/L were observed in 26 (33%) patients with no difference between groups. Mitotane was with- drawn in 34 (43%) patients, including permanent discon- tinuation in 7 (21%) patients. The most common adverse events of mitotane were digestive disorders (n = 27, 34%), neurological symptoms (n = 23, 29%), and dyslipidemia (n = 16, 20%). No information was available regarding ad- verse events in 8 (10%) patients.
Overall, 58 (73%) patients received LRT for local and or metastatic recurrences. LRT consisted of adrenal bed radiotherapy in 14 (18%) patients, surgery in 37 (47%) patients, and interventional radiology in 35 (44%) patients. Regarding surgery, resected sites were locoregional relapse (n = 23, 29%), hepatic (n =6, 8%), pulmonary (n = 8, 10%), or, rarely, bone or nodes metastatic sites (n = 3). Interventional radiology treatments included transcatheter arterial chemoembolization (n = 20, 25%), radiofrequency ablation (n = 18, 23%), cryoablation (n =7, 9%), and microwave ablation (n = 5, 6%). Treated sites were liver (n = 22, 28%), lung (n = 15, 19%), bone (n = 2, 3%), and other (n = 2, 3%) (see Table 1).
Overall, 53 (67%) patients underwent chemotherapy, initiated less than 6 months after mitotane initiation in 17 (22%) patients and within 3 months for rapid progressive disease for 4 (5%) patients.
Outcome
Median follow-up duration was 108 months (IQR, 83-165 months). The primary end point defined as TTC was 9 months (IQR, 4-18 months), significantly shorter in the mitotane-only group (6 months; IQR, 2-10 months) than in the mitotane plus LRT group (11 months; IQR, 4-30 months) (P = . 02) (Table 2, Fig. 2 and Supplementary Fig. 1A [16]). Patients in the mitotane-only group had re- ceived more often chemotherapy (P < . 004) and more often chemotherapy within 6 months (P <. 0004) (see Table 2, Fig. 2 and Supplementary Fig. 1B [16]).
Median PFS1 (first progression) was of 6.0 months (95% CI, 4.5-8.6) and was higher in the mitotane plus LRT group (6.8 months; 95% CI, 5.0-13) than in the mitotane- only group (3.3 months; 95% CI, 2.2-8.0) (hazard ratio [HR] = 0.39; 95% CI, 0.22-0.68), P = . 001) (Fig. 3A and Supplementary Fig. 2A [17]). Median PFS2 (second pro- gression) was 19 months (95% CI, 15-23) and was higher in the mitotane plus LRT group (21 months; 95% CI, 18-37) than in the mitotane-only group (10 months; 95% CI, 6.8-22) (HR = 0.35; 95% CI, 0.20-0.63) (P <. 001) (Figs 3B and Supplementary Fig. 2B [17]).
Median OS was 46 months (95% CI, 41-68) (Supplementary Fig. 2C [17]). There was a significant dif- ference regarding median OS between the mitotane-only group (22 months; 95% CI, 14-41) and the mitotane plus LRT group (68 months; 95% CI, 46-153) with HR = 0.27; 95% CI, 0.14-0.50) (P <. 001) (Fig. 3C). One-year, 2-year, and 5-year survival probabilities were 90% (95% CI, 83%- 97%), 72% (95% CI, 62%-83%), and 38% (95% CI, 28%-53%) respectively. Our data suggest that the later chemotherapy is introduced, the better the OS, with an HR of 0.95 (95% CI, 0.93-0-97, P <. 001). PFS1 and PFS2 were also positively correlated with OS with a correlation co- efficient of 0.55 (95% CI, 0.32-0.72) and 0.69 (95% CI, 0.54-0.80), respectively, as well as TTC with a correlation coefficient of 0.81 (95% CI, 0.68-0.89).
Ten patients (13%) achieved a complete response (CR) with a median number of 2.8 curative procedures (surgery (n =7), radiotherapy (n = 1,) or interventional radiology (n = 7)). Among these patients, 7 reached a serum mitotane therapeutic rate, and only 2 received chemotherapy. For these last 2 patients, chemotherapy was started after 136 months and 101.5 months, respectively (11.3 years and 8.5 years). The main clinical characteristics and treat- ments characteristics of these patients are given in Table 3.
Adjusted Analysis on Potential Prognostic Factors Adjusted analysis was performed on the main relevant prognostic factors (Table 4). Model 1 included GRAS fac- tors (grade according to Weiss score and Ki67 percentage,
| Variables (n,%) | All patients (n = 79) | Mitotane only (n = 19) | LRT + mitotane (n = 60) | |||
|---|---|---|---|---|---|---|
| Age at ACC diagnosis (IQR), y | 47.5 | 37.6-59.0 | 50.7 | 39.5-59.3 | 46.0 | 35.5-58.8 |
| Age at stage IVA diagnosis (IQR), y | 49.8 | 30.0-68.8 | 51.9 | 40.0-60.0 | 48.1 | 38.3-59.8 |
| Median time between ACC diagnosis and stage IVA diagnosis (IQR), mo | 10.0 | 5.5-19.0 | 8.0 | 1.6-17.0 | 9.3 | 0.8-22.0 |
| Sex | ||||||
| Female | 48 | 61% | 14 | 74% | 34 | 57% |
| Male | 31 | 39% | 5 | 26% | 26 | 43% |
| Tumor ENSAT stage at initial ACC diagnosis | ||||||
| II | 37 | 47% | 5 | 26% | 32 | 53% |
| III | 29 | 37% | 8 | 42% | 21 | 35% |
| IVA | 13 | 16% | 6 | 32% | 7 | 12% |
| Hormonal secretions | 53 | 67% | 13 | 68% | 40 | 67% |
| With clinical hypercortisolism | 36 | 68% | 9 | 47% | 27 | 68% |
| Initial primary surgery | 78 | 99% | 18 | 95% | 60 | 100% |
| Laparotomy | 45 | 57% | 13 | 72% | 32 | 53% |
| Celioscopy | 10 | 13% | 0 | 0% | 10 | 17% |
| Unknown | 23 | 29% | 5 | 28% | 18 | 30% |
| Initial resection status (n = 78) | ||||||
| R0 | 30 | 38% | 8 | 44% | 22 | 37% |
| R1 | 10 | 12% | 3 | 17% | 7 | 12% |
| R2 | 1 | 1% | 1 | 6% | 0 | 0% |
| RX | 38 | 49% | 6 | 33% | 31 | 52% |
| Weiss score (n = 78) | ||||||
| < 6 | 23 | 29% | 3 | 17%ª | 60 | 33%ª |
| ≥ 6 | 54 | 68% | 15 | 83%ª | 39 | 65%ª |
| Unknown | 2 | 3% | 0 | 0% | 1 | 2% |
| Ki67 % (n = 78) | ||||||
| < 20% | 21 | 27% | 3 | 17% | 18 | 30% |
| ≥ 20% | 25 | 32% | 7 | 39% | 18 | 30% |
| Unknown | 33 | 42% | 8 | 44% | 24 | 40% |
| Adjuvant mitotane treatment | 45 | 57% | 9 | 47% | 34 | 57% |
| Time from stage IVA diagnosis to mitotane initiation (median, IQR), mo | 0.0 | (0-1.5) | 0.1 | (0.0-1.3) | 0.0 | (0.0-1.9) |
| Period of stage IVA diagnosis | ||||||
| 2003-2010 | 44 | 56% | 11 | 58% | 33 | 55% |
| 2011-2015 | 29 | 37% | 6 | 32% | 23 | 38% |
| 2016-2018 | 6 | 8% | 2 | 11% | 4 | 7% |
| No. of metastatic sites | ||||||
| 1 | 26 | 33% | 7 | 37% | 19 | 32% |
| 2 | 53 | 67% | 12 | 63% | 41 | 68% |
| Metastatic sites | ||||||
| Lung | 60 | 76% | 11 | 58% | 36 | 60% |
| Liver | 38 | 48% | 10 | 53% | 28 | 47% |
| Nodes | 12 | 15% | 4 | 21% | 8 | 13% |
| Peritoneum | 7 | 9% | 0 | 0% | 7 | 12% |
| Bone | 5 | 6% | 1 | 5% | 4 | 7% |
| Local relapse | 26 | 33% | 5 | 26% | 21 | 35% |
| No. of metastases | ||||||
| < 5 | 40 | 51% | 4 | 21%ª | 36 | 60%ª |
| ≥ 5 | 39 | 49% | 15 | 79%ª | 24 | 40%ª |
| Type of treatment | ||||||
| Mitotane only | 19 | 24% | 19 | 100% | – | |
| Mitotane + LRT | 60 | 76% | – | 60 | 100% | |
| Lodge radiotherapy | 14 | 18% | – | 14 | 23% | |
| Second surgery | 34 | 43% | – | 34 | 57% | |
| Locoregional | 25 | 32% | – | 25 | 42% | |
| Hepatic | 9 | 11% | – | 9 | 15% | |
| Pulmonary | 8 | 10% | – | 8 | 13% | |
| Other | 3 | 4% | – | 3 | 5% | |
| Variables (n,%) | All patients (n = 79) | Mitotane only (n = 19) | LRT + mitotane (n = 60) | ||
|---|---|---|---|---|---|
| Interventional radiology | 35 | 44% | – | 35 | 58% |
| Cryotherapy | 7 | 9% | – | 7 | 12% |
| Chemoembolization | 20 | 25% | – | 20 | 33% |
| Radiofrequency | 18 | 23% | – | 18 | 30% |
| Microwaves | 5 | 6% | – | 5 | 8% |
Abbreviations: ACC, adrenocortical carcinoma; ENSAT, European Network for the Study of Adrenal Tumors; IQR, interquartile range; LRT, locoregional treatment.
ªP value less than .05.
| Variable | All patients (n = 79) | Mitotane only (n = 19) | LRT + mitotane (n = 60) | |||
|---|---|---|---|---|---|---|
| Mitotanemia > 14 mg/L | 46 | 58% | 10 | 53% | 36 | 60% |
| Chemotherapy | 53 | 67% | 18 | 95%ª | 35 | 68%ª |
| < 3 mo after stage IVA diagnosis | 4 | 5% | 2 | 11% | 2 | 3% |
| < 6 mo after stage IVA diagnosis | 18 | 23% | 10 | 53%ª | 7 | 12%ª |
| Complete remission | 10 | 13% | 0 | 0% | 10 | 17% |
| Death | 49 | 62% | 17 | 89%ª | 32 | 53%ª |
| Median follow-up, mo | 108 | 83-165 | 83 | 83-NR | 108 | 82-172 |
Abbreviations: LRT, locoregional treatment; NR, not reached. ªP value less than .05.
R status at primary resection, age, and secreting tumor) and the number of metastatic sites at time of stage IVA diag- nosis (< 5 or ≥ 5) (18). Model 2 included GRAS factors and the number of metastatic organs. OS was better in the mitotane plus LRT group after adjusted analysis for these prognostic factors (see Table 4) with an HR = 0.18 (model 1, 95% CI, 0.08-0.43, P <. 001) or 0.18 (model 2,95% CI, 0.08-0.40, P < . 001), as well as PFS1 (model 1: HR = 0.31, 95% CI, 0.16-0.60, P < . 001; model 2: HR = 0.32, 95% CI, 0.16-0.61, P <. 001), PFS2 (model 1: HR =0.24, 95% CI, 0.12-0.50, P <. 001; model 2: HR = 0.23, 95% CI, 0.11- 0.48, P <. 001) and TTC (model 1: HR =0.25, 95% CI, 0.12-0.51, P <. 001; model 2: HR = 0.24, 95% CI, 0.12- 0.49, P <. 001).
In addition, we also performed 2 different models of GRAS factor analysis only (Supplementary Table 1 [19]): model 3, with the GRAS factors as described earlier, and model 4, with time between ACC diagnosis and stage IVA diagnosis instead of tumor grade (reflecting tumor aggres- siveness), and hypercortisolism, as defined by increased cortisol secretion regardless of the clinical status, instead of secreting tumor status. A clinically significant benefit for OS (see Supplementary Table 1 [19]), PFS1, PFS2 and TTC (results not shown) was maintained after adjustment with both models.
Discussion
The optimization of ACC treatment strategies is a critical need because effective treatment options are limited (1, 9, 13). Evidence to support the antitumor role of different local options is very limited, mainly based on LRT per- formed in selected patients rather than a systematic strategy at the time of advanced ACC diagnosis. To the best of our knowledge, this is the first study exploring the therapeutic strategy of the association of mitotane with locoregional procedures including surgery for LTB stage IVA ACC sub- group at the time of diagnosis as proposed by European and French guidelines (1, 13, 14). To reach this goal, PFS was used but also new surrogate end points TTC or PFS2. These pragmatic end points were selected to consider the delayed antitumor action of mitotane therapy and the time to perform LRT treatments whose antitumor efficacy may not be properly captured by the first median PFS.
In our study, median OS was 46 months (95% CI, 41-68), with a 5-year OS of 38%, higher than what is re- ported in the literature for stage IVA ACC (9), supporting the potential role of LRT in this increased survival. In pa- tients treated with mitotane plus LRT, the median TTC was 11 months and PFS2 was longer than 1 year, suggesting the efficacy of this combination strategy. Indeed, TTC, PFS1, and PFS2 were positively correlated with OS. None of
Time to chemotherapy
Chemotherapy-free probability
1.00
+ Mitotane only + LRT + Mitotane
0.75
0.50
0.25
p < 0.0001
0.00
0
6
12
18
24
30
36
Delay since mitotane initiation (months)
Number at risk
Mitotane
TLR + mitotane
19
60
10
48
4
39
1
34
1
30
1
27
0
24
0
6
12
18
24
30
36
these end points has been previously explored in the ACC literature. In a more conventional way, median PFS1 was 6 months, twice than previously reported (20, 21). To the best of our knowledge, PFS1 was correlated with OS in our study for the first time in advanced ACC. However, because of the delayed action of mitotane and delayed time to achieve LRT, we also believe that new end points de- serve attention. The striking finding of a median PFS2 of 21 months, roughly 3.5 times the PFS1, suggests that the mitotane plus LRT strategy should not be abandoned at first progression as previously reported if tumor burden re- mains acceptable. Therefore, PFS1 may not be sufficient to validate the antitumor role of such a strategy. However, the correlation of TTC and PFS2 with OS suggests that this approach is well tailored to this particular subgroup of pa- tients and potentially affects “hard” outcomes. Moreover, the importance of maintaining serum mitotane in the therapeutic range has been previously reported, suggesting that the ACC trend of response evaluated at several time points should be considered rather than a one-point evalu- ation (22, 23). Optimizing mitotane treatment is another goal of this strategy by avoiding digestive intolerance both of mitotane and platin-based chemotherapy with a delay in therapeutic plasma mitotane rate achievement. However, the rate of patients achieving a therapeutic rate in our co- hort (58%) is consistent with that reported in the litera- ture, but not improved (20, 21). The longer time to reach target mitotane concentration in the mitotane plus LRT group suggests that this parameter should not be consid- ering as a confounding factor but also that the time needed to achieve the therapeutic level deserves increased vigilance in this subgroup of patients.
It is worth noting that the long PFS found here is ex- plained by a combination of favorable prognostic features of the study population, predictive factors of response to
A
1.00
Survival Probability
0.75
First progression-free survival
0.50
0.25
0.00
0
6
12
18
24
30
36
Number at risk
Time (months)
79
38
22
15
10
9
9
0
6
12
18
24
30
36
B
1.00
Survival Probability
0.75
Second progression-free survival
0.50
0.25
0.00
0
6
12
18
24
30
36
Number at risk
Time (months)
79
68
51
39
26
19
18
0
6
12
18
24
30
36
C
1.00
Survival Probability
Overall survival
0.75
0.50
0.25
0.00
0
12
24
36
48
60
72
84
96
108
120
Number at risk
Time (months)
79
68
50
40
27
21
18
16
12
10
9
0
12
24
36
48
60
72
84
96
108
120
LRT, and therapeutic interventions. Altogether, these data suggest that the combination of mitotane and LRT is asso- ciated with improved outcome in these patients even after adjustment for other negative prognostic factors including GRAS and tumor burden.
Remarkably, 13% CRs were observed. Such a high rate of CRs has to date never been reported in the literature of advanced ACC. All CRs were observed in the Mitotane plus LRT group. Regarding LRT, most patients were treated with surgery and/or transcatheter arterial chemoembolization or radiofrequency targeting mainly the liver or the lung.
Data on LRT in ACC patients are scarce and performed in patients selected mainly based on the course and volume
| Variable | ||
| Age at stage IVA diagnosis (median, range), y | 39.4 | 22.2-68.7 |
| Tumor ENSAT stage at initial ACC diagnosis (n,%) | ||
| II | 6 | 60% |
| III | 3 | 30% |
| IV | 1 | 10% |
| Hormonal secretions (n, %) | 8 | 80% |
| Weiss ≥ 6 (n, %) | 4 | 40% |
| Age ≥ 50 (n, %), y | 2 | 20% |
| No. of metastatic sites (n, %) | ||
| 1 | 6 | 60% |
| 2 | 4 | 40% |
| Metastatic sites (n, %) | ||
| Liver | 8 | 80% |
| Lung | 3 | 30% |
| Local relapse | 3 | 30% |
| Nodes | 1 | 10% |
| Type of LRT (n = 10) | ||
| Lodge radiotherapy | 1 | 10% |
| Interventional radiology | 7 | 70% |
| Cryotherapy | 1 | 10% |
| Chemoembolization | 6 | 60% |
| Radiofrequency | 4 | 40% |
| Microwaves | 2 | 20% |
| Second surgery | 7 | 70% |
| Locoregional | 4 | 40% |
| Hepatic | 3 | 30% |
| Pulmonary | 2 | 20% |
| Other | 1 | 10% |
| No. of locoregional gestures (mean, range) | 2.8 | 1-9 |
| Mitotanemia > 14 mg/dL | 7 | 70% |
| Chemotherapy | 2 | 20% |
| < 6 mo after stage IVA diagnosis | 0 | 0% |
Abbreviations: ACC, adrenocortical carcinoma; ENSAT, European Network for the Study of Adrenal Tumors; IQR, interquartile range; LRT, locoregional treatment.
of disease. One study focusing on radiofrequency in ACC demonstrated an objective response in 8 of 15 lesions after percutaneous ablation (24). A recent study based on 32 ACC metastases (28 liver and 4 lung) achieved complete ablation in 97% of lesions (25). Radiofrequency is particularly suitable when the number of liver lesions to treat is limited (eg, ≤ 3) with a diameter of 3 cm or less. Regarding transcatheter ar- terial chemoembolization, our previous series of 29 patients demonstrated a tumor size decrease in 22% of 103 treated lesions (26). Moreover, 65% were stable after 3 months. Other studies are mainly case reports with long PFS and OS in selected patients (27, 28). Other limited data are available for radiation therapy in the adjuvant and palliative setting (29-35), and microwave ablation therapy targeting tumors of 5 cm or less in diameter (36). Finally, one study reported prolonged survival of ACC patients when treated by surgery in case of delayed metastatic recurrence (37).
There are several limits to our study. First, this is a monocentric and retrospective study. However, we address the question of mitotane combined with LTR in the largest cohort reported to date and have adjusted our analysis for all known prognostic factors. Second, pa- tients were heterogeneous regarding clinical characteris- tics, and there were fewer patients in the mitotane-only group. Importantly, patients selected for the mitotane- only strategy could be less fit and/or have larger lesions. However, we selected well-characterized LTB stage IVA pa- tients, allowing a clear definition of the population under study. Third, the prognostic value of mitotane concentra- tions in the whole series was not assessed but no signal of higher concentration or more rapid delay to achieve therapeutic rates was observed in the mitotane plus LRT subgroup. On the contrary, the target mitotane concen- tration in the mitotane-only group of only 0.5 months
| Variables | Categories | Multivariate HR (95 CI%) | Multivariate P |
|---|---|---|---|
| Model 1 | |||
| Group | Mitotane (ref) Mitotane + LRT | 0.18 (0.08-0.43) | <. 001 |
| Tumor grade | Weiss ≤ 6 and Ki67% <20 (ref) Weiss > 6 and/or Ki67 % ≥20 | 2.0 (0.91-4.41) | .085 |
| Resection status | R0 (ref) R1, R2, Rx | 0.86 (0.46-1.49) | .6 |
| Age, y | < 50 (ref) ≥ 50 | 0.6 (0.32-1.12) | .11 |
| Secreting tumor | No (ref) Yes | 0.38 (0.39-0.77) | .007 |
| No. of metastases | <5 (ref) ≥5 | 1.12 (0.57-2.21) | .8 |
| Model 2 | |||
| Group | Mitotane (ref) Mitotane + LRT | 0.18 (0.08-0.40) | <. 001 |
| Tumor grade | Weiss ≤ 6 and Ki67 % <20 (ref) Weiss > 6 and/or Ki67 % ≥20 | 2.02 (0.90-4.52) | .089 |
| Resection status | R0 (ref) R1, R2, Rx | 0.85 (0.46-1.56) | .6 |
| Age, y | < 50 (ref) ≥ 50 | 0.59 (0.31-1.10) | .1 |
| Secreting tumor | No (ref) Yes | 0.39 (0.19-0.78) | .008 |
| No. of metastatic organs | 1 (ref) 2 | 1.08 (0.55-2.11) | .8 |
Abbreviations: HR, hazard ratio; LRT, locoregional treatments; ref, category of reference.
suggests that these patients already had a good level of mitotane at the time of diagnosis of stage IVA.
Finally, there were few patients who had bone metas- tases since most of these locations occur in very advanced metastatic ACC patients. A randomized trial if feasible or a prospective cohort of ACC patients treated in centers with or without access to a comprehensive panel of LRT options may provide the best achievable answer to this question.
Conclusion
Our study supports the use of the mitotane plus locoregional strategy in a well-defined population of ACC with LTB stage IVA. A favorable impact on TTC, PFS1, and PFS2 and OS was observed. For the first time, in a subgroup of metastatic ACC patients, 13% of CRs are re- ported. Further prospective studies are advocated to con- firm these findings.
Acknowledgments
Financial Support: The authors received no financial support for the research, authorship, and/or publication of this article.
Additional Information
Correspondence: Matthieu Faron, MD, Département de chirurgie, Institut Gustave Roussy, 114 rue Edouard Vaillant, 94800 Villejuif, France. Email: matthieu.faron@gustaveroussy.fr.
Disclosures: A.B., E.M., C.R., F.D., L.T., M.F., S.H., L.L., J.H. have nothing to disclose. E.B. has received an honorarium for board par- ticipation and grants from HRA.
Data Availability: Data sets generated during and/or analyzed during the present study are publicly available (see “References”).
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