J
ORIGINAL
ONCE * SINCE 1925*
Japanese single-institution analysis of mitotane for patients with adrenocortical carcinoma
Akihiro Ohmoto1), Yasuyuki Shigematsu2),3), Naoki Fukuda1), Xiaofei Wang1), Tetsuya Urasaki1),
Naomi Hayashi1), Yasuyoshi Sato1), Kenji Nakano1), Mayu Yunokawa1), Makiko Ono1), Yoshinobu Komai4), Noboru Numao4), Takeshi Yuasa4), Junji Yonese4), Junichi Tomomatsu1), Kentaro Inamura2),3) and Shunji Takahashi1)
1) Department of Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan
2) Department of Pathology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan
3) Division of Pathology, The Cancer Institute of Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan
4) Department of Genitourinary Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan
Abstract. Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis. While mitotane is the only agent approved for ACC, clinical data are scarce, especially in the Asian population. We reviewed 10 patients with ACC who received mitotane as a single agent or in combination with other agents in our institution. Patient characteristics, clinical outcomes, and toxicities were analyzed. Mitotane was administered to 2 patients as an adjuvant therapy and to 8 patients for systemic control. In the latter 8 patients, 1 patient had locally advanced disease and 1 had metastatic disease at the time of initial diagnosis, whereas the other 6 patients experienced metastatic relapse at mitotane initiation. The administered regimen was mitotane alone in 7 patients, and mitotane plus cytotoxic chemotherapy in 3 patients. The initial daily mitotane dose was 3.0 g in 2 patients, 1.5 g in 7 patients, and 1.0 g in 1 patient. The median duration of treatment was 3.7 (range, 0.7-22.1) months. In 8 systemic cases, the median overall survival from chemotherapy initiation was 7.2 months, and only 1 patient survived over 1 year. The median interval from mitotane termination to death in systemic cases was 2.8 months, and the cause was progressive disease in 4 patients and toxicity (hallucination, mycobacteriosis, or liver injury) in 3 patients. As a second- line regimen, 2 systemic cases and 1 adjuvant case were enrolled in clinical trials. Our analysis exhibited extremely poor prognosis under mitotane-based regimens, and further treatment strategies are warranted to improve outcomes.
Key words: Adrenocortical carcinoma, Chemotherapy, Mitotane, Japanese cohort
ADRENOCORTICAL CARCINOMA (ACC) is a rare malignancy, and the estimated annual incidence is 0.5- 2.0 per million people per year [1, 2]. The peak age of onset is 40-50 years, although patients can develop ACC regardless of age [3]. While most ACC cases occur sporadically, several hereditary syndromes such as Li- Fraumeni syndrome and multiple endocrine neoplasia type 1 are associated with onset in some cases [4, 5]. Conditions leading to excess hormones, including hyper- cortisolism, are observed in more than half of these patients [6]. The prognosis is heterogeneous depending
on the clinical stage. According to a study based on the revised European Network for the Study of Adrenal Tumors (ENSAT) classification, the 5-year disease- specific survival rate was 82% for stage I, 61% for stage II, 50% for stage III, and 13% for stage IV [7]. Clinical behavior in metastatic cases is highly aggressive, and further treatment strategies are strongly warranted.
Mitotane is the only agent approved for inoperable advanced ACC by the Food and Drug Administration (FDA) or the European Medicines Agency (EMA), although there have been no randomized trials on mito- tane alone [8]. In Japan, an application for the manufac- ture and sale of this agent was approved in 1983. Although it has been proposed that this agent can mechanically suppress the adrenal cortex with cellular destruction, the mechanism of action has not been fully elucidated [8]. Mitotane is used not only as a single agent but also in combination with other cytotoxic agents
E-mail: akihiro.omoto@jfcr.or.jp
such as etoposide, doxorubicin, and cisplatin (EDP) [9]. As for advanced cases, clinicians consider various fac- tors such as tumor burden, site of disease, pathological features, clinical symptoms, and patient performance sta- tus, and select mitotane alone or a mitotane combination regimen [10]. This agent is also adopted in adjuvant ther- apy following complete resection, and the application is individually judged depending on the ENSAT stage and pathological features (Ki-67 index) [10].
Mitotane has various unique toxicity profiles such as gastrointestinal symptoms, central nervous system distur- bances, and adrenal insufficiency [11]. Moreover, this agent is metabolized in the liver and functionally en- hances CYP3A4 activity [8]. It should be noted that mitotane itself is not pharmacologically active and it is its metabolites that have an adrenolytic effect. Therefore, drug interactions with other agents often become a prac- tical problem. As there is little data in the Asian popula- tion regarding mitotane, we conducted a Japanese single- institution analysis of clinical efficacy and toxicity along with dose modification and treatment duration. In this study, we aimed to obtain referential information about the use of mitotane in daily practice.
Materials and Methods
We retrospectively reviewed the Cancer Institute Hospital of the Japanese Foundation for Cancer Research database of patients with pathologically proven ACC from 1987 to 2018. This study was reviewed and approved by the Institutional Review Board of the Japanese Foundation for Cancer Research and conducted in accordance with the precepts established by the Helsinki Declaration. Clinically suspected cases without pathological diagnosis were excluded, and only patients who received mitotane as a single agent or combination therapy in our institution proceeded to further analysis. Clinical data reviewed included sex, age at initial diag- nosis, smoking/alcohol history, history of any cancer, family history of any cancer in a first-degree relative (FDR), primary site (right or left adrenal gland), longest tumor diameter, clinical stage (ENSAT stage) at initial diagnosis, disease status at relapse, existence of Cushingoid features, serum levels of cortisol and dehydroepiandrosterone (DHEAS), level of plasma adre- nocorticotropic hormone (ACTH), treatment approach (surgery or chemotherapy), chemotherapy regimen, and toxicity in relation to the agent. To evaluate the patholog- ical features, hematoxylin and eosin-stained 4-um sec- tions of formalin-fixed paraffin-embedded tissue were used. The diagnosis of ACC was made according to the Weiss histopathologic system, which is the most com- monly used method for assessing the likelihood of malig-
nancy [12]. The pathological features of all available cases were reviewed by two experienced pathologists (Y.S. and K.I.). For immunohistochemistry for Ki-67/ Mib-1, sequential 4-um sections were stained with a monoclonal antibody (1:200; clone: MIB-1; DAKO, Glostrup, Denmark). Moreover, we tried to collect information on the initial dose and subsequent dose mod- ification of mitotane. The administration duration was calculated as the interval from mitotane initiation to the last administration date, and in patients who were trans- ferred to another hospital and whose subsequent medical records were unavailable, the transfer day was described as the last day of administration. Overall survival (OS) was calculated as the interval from mitotane initiation to death or the last follow-up, and survival curves were estimated using the Kaplan-Meier method. Univariate analyses of risk factors for OS were performed using a Cox proportional hazards regression model. Effects were considered statistically significant if two-sided p-values were below 0.05. All statistical analyses were performed using EZR version 1.53 (Saitama Medical Center, Jichi Medical University), which is based on R and R commander (http://www.jichi.ac.jp/saitama-sct/ SaitamaHP.files/download.html) [13].
Results
Patient characteristics
Over a 30-year period, 17 patients were pathologically diagnosed with ACC. Among them, 4 patients who did not receive any chemotherapy, 1 who received chemo- therapy without mitotane, and 2 who received a mitotane-based regimen in another hospital were excluded from the analysis. The clinical characteristics of the remaining 10 patients who received a mitotane- based regimen in our institution are summarized in Table 1. Detailed clinical data for each patient are listed in Table 2. The median patient age was 59.5 years (range, 48-71 years), and the percentage of patients aged <50 years was 30%. The left adrenal gland was the primary lesion site in 70% of the cases, and the median tumor diameter was 8.8 cm (range, 3.1-18.0 cm). According to the histological evaluation, 4 cases had a Weiss score of 4 and 5 cases had a score of 6. The Ki-67 index ranged between 10-50% (median 30%). The initial ENSAT stage was stage I in 1 patient, stage II in 5 patients, stage III in 1 patient, and stage IV in 1 patient. While 1 patient had locally advanced disease (ENSAT stage III) and 1 had metastatic disease (ENSAT stage IV) at the time of initial diagnosis, the other 6 patients experienced meta- static relapse during their clinical course. In the 6 patients with a metastatic relapse, the median interval from the initial diagnosis to the metastatic relapse, and
| Variables | Number (%) |
|---|---|
| Age | Median 59.5 (48-71) |
| Sex | |
| Male | 3 (30%) |
| Female | 7 (70%) |
| Primary site | |
| Right adrenal gland | 3 (30%) |
| Left adrenal gland | 7 (70%) |
| Tumor diameter (cm) | Median 8.8 (3.1-18.0) |
| ENSAT stage at initial diagnosis | |
| I | 1 (13%) |
| II | 5 (63%) |
| III | 1 (13%) |
| IV | 1 (13%) |
| Smoking | |
| Yes | 2 (22%) |
| Alcohol | |
| Yes | 5 (56%) |
| History of any cancer | 3 (30%) |
| Family history of any cancer with FDR | 4 (50%) |
ACC, adrenocortical carcinoma; ENSAT, European Network for the Study of Adrenal Tumors; FDR, first-degree relative.
from the metastatic relapse to mitotane initiation, was 29.3 months (range, 6.5-114.5 months) and 8.5 months (range, 0.3-60.2 months), respectively. Three of the 6 patients with a metastatic or locally advanced relapse had previously undergone surgical resection of the relapsed lesion, with intervals of 26.2, 18.3, and 10.9 months between the surgery and the subsequent recurrence. The most common metastatic organs were the lung in 3 patients and the liver in 2. Elevated levels of cortisol, ACTH, and DHEAS at the time of mitotane initiation were detected in 40% (4/10), 20% (2/10), and 13% (1/8) of patients, respectively. According to the available data, 3 patients exhibited some Cushingoid feature including 2 patients with striking cortisol or DHEAS levels (ID-7, ID-8). The percentages of smokers and drinkers were 22% and 56%, respectively. Three (30%) patients had a history of any cancer, and four (50%) patients had a family history of cancer in an FDR. Patient ID-10 with a history of breast cancer and a family history of lung and uterine cancer harbored a mutation in BRCA1, which is a homologous recombination repair gene. As part of the screening test in a clinical trial, genomic analysis in patient ID-10 was conducted using resected tumor speci- mens but not in blood samples, and it was unknown
whether this patient was categorized as hereditary breast and ovarian cancer syndrome (HBOC).
Detailed information about mitotane-based chemotherapy
Eight (80%) patients received mitotane for systemic control (7 for metastatic disease and 1 for locally advanced disease), and two received the agent as adju- vant therapy without residual lesion. Regimen selection was based on the clinician’s choice, and mitotane combi- nation regimens were used primarily for treating clini- cally aggressive cases. Mitotane was administered as a single agent in 7 patients, and in combination with EDP in 2 patients or carboplatin/paclitaxel in 1 patient (Table 3). The initial mitotane daily dose was 3.0 g in 1 patient, 1.5 g in 8 patients, and 1.0 g in 1 patient, and the maxi- mum daily dose was 6.0 g in 1 patient, 4.5 g in 2 patients, and 1.5 g in 7 patients. The median initial dose and median maximum dose was 1.5 g, and dose modifi- cation from the initial dose was conducted in 5 cases (50%). The median treatment interval in the entire cohort was 3.7 months (range, 0.2-12.3 months), with a median interval of 3.7 months for systemic therapy and 5.0 months for adjuvant therapy. Mitotane was discontinued because of progressive disease (PD) in 4 patients and adverse events (hallucination, mycobacteriosis, or liver injury [elevated y-GTP with grade 4, elevated alanine aminotransferase with grade 3, and elevated aspartate aminotransferase with grade 2]) in 3 patients.
Clinical outcomes
In the 8 systemic cases, the median OS from mitotane initiation was 7.2 months, and only 1 patient survived over 1 year (1-year OS rate: 12.5%) (Fig. 1). There was no significant difference in OS between cases with a Ki-67 index ≥40% and those with a Ki-67 index <40% (p = 0.31), or between cases with a Weiss score of 6 and those with a Weiss score of 4 (p = 0.45). When calculated from initial diagnosis, the median OS was 37.5 months. None of the patients achieved a shrinkage of the tumor volume on radiology (Table 3). The median interval from mitotane termination to death in systemic cases was 2.8 months. However, 2 adjuvant cases sur- vived for approximately 3 years or more. Following con- firmed PD, two systemic cases (ID-3, ID-5) and one adjuvant case (ID-10) were enrolled in clinical trials as second-line regimens. After mitotane termination, the two patients with systemic disease (ID-3 and ID-5) developed hypertension, and multiple classes of antihy- pertensive agents (calcium channel blockers, alpha- blockers and angiotensin II receptor blockers for ID-3; calcium channel blockers and thiazide diuretics for ID-5) were required to control the hypertension.
| Patient ID | Sex | Age at initial diagnosis (years) | Primary site | Lesions at mitotane initiation | Tumor diameter (cm) | Weiss score | Ki-67 index | ENSAT stage at initial diagnosis | Cushingoid feature | Serum cortisol level before treatment (µg/dL) | Plasma ACTH level before treatment (pg/mL) | Serum DHEAS level before treatment (µg/dL) | Smoking (BI) | Alcohol | History of any cancer | Family history of any cancer with FDR |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | F | 48 | Left adrenal | Pericardium, pleural effusion | 12.6 | 6 | 20% | 2 | None | 22.9 | 88.5 | NA | 0 | NO | None | NA |
| 2 | F | 48 | Right adrenal | Mediastinum | NA | 4 | 40% | NA | None | 20.1 | 5.0> | NA | 560 | NO | None | Uterine cancer (mother) |
| 3 | M | 48 | Left adrenal | Lung, pleural, hilar LN | 7.2 | 4 | 30% | 2 | None | 9.7 | 16.7 | 113 | 300 | YES | None | None |
| 4 | F | 54 | Left adrenal | Lung | 7.0 | 6 | 40% | 2 | None | 11.2 | 38.5 | 52 | 0 | YES | Liver cancer, breast cancer | Colorectal cancer (mother 70 years) |
| 5 | F | 58 | Left adrenal | Paraaortic LN, subclavian LN | 8.6 | 6 | 50% | 3 | HT | 10.9 | 110 | 214 | 0 | NO | None | None |
| 6 | M | 61 | Left adrenal | Liver | 12.0 | 6 | 50% | 4 | None | 13.7 | 21.1 | 745 | 0 | YES | None | None |
| 7 | M | 62 | Right adrenal | Lung | 3.1 | 4 | 10% | 1 | HT, palpitation, lower limb edema, moon face | 67.6 | 7.1 | 360 | 0 | YES | Kidney cancer, colorectal cancer | Esophageal cancer (mother 62 years), breast cancer (sister 62 years) |
| 8 | F | 71 | Left adrenal | Liver | NA | NA | NA | NA | HT, night sweat | 27.7 | 10 | 3,200 | 0 | NO | None | None |
| 9 | F | 69 | Right adrenal | None | 9.0 | 6 | 20% | 2 | None | 11.4 | 47.3 | 3 | NA | NA | None | NA |
| 10 | F | 69 | Left adrenal | None | 18.0 | 4 | 10% | 2 | None | 14.1 | 22.1 | 75 | 0 | YES | Breast cancer | Lung cancer (brother 60 years), uterine cancer (sister 47 years) |
ENSAT, European Network for the Study of Adrenal Tumors; BI, Brinkman Index; FDR, first-degree relative; F, female; M, male; NA, not available; LN, lymph nodes; HT, hypertension. Reference ranges : 4.0-18.3 µg/dL for cortisol, 9-52 pg/mL for ACTH, and 50-1,000 µg/dL for dehydroepiandrosterone sulfate
| Patient ID | Regimen | Purpose of treatment | Mitotane dose at initiation | Maximum mitotane dose | Mitotane dose at termination | Best radiological response | Treatment duration | Cause of termination | Second- line regimen | OS from treatment initiation | OS status |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Oral CY followed by mitotane | Systemic | 1.5 g | 4.5 g | 1.0 g | NA | 3.2 months | NA (hospital transfer) | None | 3.9 months | Dead |
| 2 | Mitotane | Systemic | 3.0 g | 6.0 g | 3.0 g | PD | 5.7 months | NA (hospital transfer) | None | 7.5 months | Dead |
| 3 | EDP- mitotane | Systemic | 1.5 g | 1.5 g | 1.5 g | PD | 4.6 months | PD | Novel agent | 8.2 months | Dead |
| 4 | Mitotane | Systemic | 1.5 g | 4.5 g | 3.0 g | SD | 12.3 months | PD | None | 34.4 months | Dead |
| 5 | EDP- mitotane | Systemic | 1.5 g | 1.5 g | 1.5 g | PD | 1.4 months | PD | Novel agent | 8.5 months | Dead |
| 6 | Mitotane | Systemic | 1.5 g | 1.5 g | 1.5 g | NA | 0.4 months | NA (hospital transfer) | None | 1.7 months | Dead |
| 7 | Mitotane | Systemic | 1.5 g | 1.5 g | 1.5 g | NA | 0.2 months | Hallucination | None | 3.6 months | Dead |
| 8 | CBDCA/ PTX- Mitotane | Systemic | 1.0 g | 1.5 g | 1.5 g | PD | 4.6 months | PD | None | 6.9 months | Dead |
| 9 | Mitotane | Adjuvant | 1.5 g | 1.5 g | 1.0 g | Excluded | 7.9 months | Mycobacteriosis | None | 35.9 months | Alive |
| 10 | Mitotane | Adjuvant | 1.5 g | 1.5 g | 1.5 g | Excluded | 2.1 months | Liver injury | Novel agent | 119.1 months | Alive |
OS, overall survival; CY, cyclophosphamide; EDP, etoposide, doxorubicin and cisplatin; CBDCA, carboplatin; PTX, paclitaxel; NA, not available; PD, progressive disease; SD, stable disease.
1.0
0.8
Probability
0.6
0.4
0.2
0.0
0
2
4
6
8
10
12
months from mitotane initiation
Number at risk 8 7
5
5
3
1
1
Discussion
This study showed remarkable features in Japanese patients with ACC. First, 6 out of 8 cases with systemic mitotane experienced metastatic relapse after surgical resection. Ayala-Ramirez et al. reviewed 330 ACC cases at the University of Texas MD Anderson Cancer Center and showed that distant metastasis was observed in 66% of the cases during follow-up [14]. Clinicians should carefully monitor the possibility of subsequent relapse even after surgery. Second, our cases had a relatively high proportion of a history of any cancer (30%) and family history with an FDR of any cancer (50%). According to the aforementioned study, the proportion of patients with any cancer history was 12%, and 2% and 0.3% of the patients were diagnosed with Li-Fraumeni syndrome and multiple endocrine neoplasia type 1, respectively [14]. Third, 3 patients with metastatic or locally advanced relapse initially received surgery but not chemotherapy and experienced a considerable relapse-free period. Widespread metastases are not ame- nable to salvage resection. Conversely, cases with an interval of more than 12 months between the primary resection and the clinical relapse, and a single metastatic
site, may be suitable for surgery [8].
Patients with ACC who received a mitotane-based regimen had an extremely poor prognosis. The median OS of 8 patients who received mitotane for systemic control was only approximately 7 months. Similarly, 2 larger-scaled studies including 85 and 330 metastatic cases in the United States exhibited a short OS (median OS: 10.8 months and 9.1 months, respectively) with mitotane [14, 15]. Because of the rarity of ACC, clinical data from Japan are extremely limited. Nishida et al. conducted a retrospective analysis of 14 ACC cases over 34 years [16]. In their study, mitotane was administered to 7 patients and mitotane plus EDP to 3 patients for dis- ease recurrence and metastasis, respectively. The average OS from surgery was 108 months in patients with stage II-III and only 2 months in those with stage IV cancer. In terms of actual dose and period, the median daily mito- tane dose was 3.0 g (range, 0.5-12.0 g), and the median duration was 11 months. The Ki-67 index is regarded as a useful tool to estimate subsequent clinical behaviors. Regarding resected cases, Beuschlein et al. reported that patients with a Ki-67 index <10%, 10-19%, and >20% all significantly differed in terms of OS [17]. The ESMO guidelines recommend adjuvant mitotane after complete resection for patients with a Ki-67 index >10% [10]. However, its impact on advanced cases has not been determined [18]. In our analysis, 6 of 7 patients with advanced disease had a Ki-67 index ≥20%, which might be related to their poor prognosis. The Weiss score was 4 or 6 in all available cases, which fulfills the diagnosis of adrenocortical malignancy [12].
Although there is no standard administration dose or schedule of mitotane, dose modification targeting blood levels between 14 µg/mL and 20 µg/mL is generally rec- ommended [8]. Fay et al. proposed an initial daily dose of 0.5 g and an increased dose of 0.5 g per week [8]. Pre- vious studies showed that cases with a mitotane serum level ≥14 mg/L harbored a better OS than those with a lower level [14, 19]. Owing to the lack of insurance approval, monitoring is not currently pervasive in Japan, and there is no information about whether mitotane blood concentration in our series has reached the effec- tive range. According to the medical package insert of mitotane, the recommended initial dose is 2-6 g in the United States, 2-3 g in Europe, and 1.5-3 g in Japan [20-22]. Most of our cases started the treatment at a daily dose of 1.5 g, and subsequent dose modification was not conducted. While 1.5 g is within the recommended dose in Japan, it is below the recommended dose in the United States or Europe. From the perspective of different liver metabolisms between ethnic groups, trial data with phar- macokinetics for the Asian population are warranted. Another essential topic is the suitable time for treatment
discontinuation. In our analysis, 3 cases and 4 cases ter- minated mitotane because of adverse events and disease progression, respectively. Of note, the duration from mitotane termination to death was less than 3 months, which would reflect the practical use in a palliative set- ting. In fact, 3 patients who were transferred to receive terminal care continued taking mitotane orally. The European Society of Endocrinology Guidelines present no definite recommendation about mitotane termination time [23]. This is because several experts consider mito- tane termination when PD is confirmed under the appro- priate blood level, whereas other experts often consider an indefinite treatment continuation. Treatment tolerabi- lity is another important factor in treatment continuation. According to a Finnish single-center analysis including 34 patients with adjuvant mitotane, 91% of patients had some side effects, where gastrointestinal symptoms (e.g., nausea, diarrhea, or appetite loss) and neurocognitive symptoms were observed in 62% and 21% of the cases, respectively [24]. Treatment was terminated in 32% of the patients, and the major causes were increased liver enzymes (9%), nausea/neurocognitive symptoms (9%), and diarrhea (6%). Liver injury and hallucination as a type of neurocognitive symptom, both found in our cases, are possible toxicities of mitotane. Another explanation for hallucination in patient ID-7 is the influ- ence of hormone hypersecretion. Despite the lack of visi- ble tumor shrinkage following mitotane administration, two patients who received mitotane-EDP developed hypertension after mitotane termination. This suggests that mitotane-based regimens might contribute to reliev- ing hormonal symptoms, including hypertension, even in aggressive cases.
After mitotane failure, few treatment options are saved, and participation in clinical trials is recommended for tolerable patients [23]. Here, personal genomic infor- mation is useful in searching for promising agents. According to a comprehensive genomic analysis of ACC, gene alterations in relation to the p53/Rb (e.g., TP53 and CDKN2A) and Wnt/beta-catenin pathways (e.g., ZNRF3 and CTNNB1) were characteristically detected [25]. Whole genomic and transcriptomic analy- ses of 6 metastatic ACC cases had alterations in DNA damage repair genes (BRCA2, ARID1B, FANCA, ATM, RAD52) as well as cell-cycle regulating genes [26]. In our study, patient ID-10 harboring a BRCA1 mutation was successfully enrolled in a clinical trial using olaparib.
Several limitations of this study should be clarified. First, this was a retrospective, non-randomized study without placebo, and the sample size was small. There- fore, we cannot ignore selection bias, and further analy- sis is required to assess the clinical benefit more rigidly. Second, owing to the retrospective nature, detailed
information about hormone hypersecretion symptoms or any side effect was unavailable, and the time of image evaluation, such as computed tomography and blood hormonal level monitoring, was heterogeneous in the respective cases. Third, the mitotane administration interval was too short to assess radiological response in many cases. Finally, comprehensive genomic analysis was not conducted in this study, and elucidating patho- physiological associations with hereditary syndromes or identifying all druggable targets was impossible.
In conclusion, our analysis exhibited unsatisfactory prognosis under a mitotane-based regimen. The out- comes might partly reflect the clinical practice in which mitotane administration is not stopped even in terminal care. Further treatment strategies including novel agents
are warranted in the future. Our clinical data in the Asian cohort potentially contribute to future meta-analyses.
Acknowledgments
We wish to thank all of the patients who contributed to this study, and Mr. Motoyoshi Iwakoshi and Ms. Tomoyo Kakita for their kind assistance in sample preparation. We would also like to thank Editage (www.editage.com) for English language editing.
Disclosure
None of the authors have any potential conflicts of interest associated with this research.
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