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Clinical management and outcomes associated with etoposide, doxorubicin, and cisplatin plus mitotane treatment in metastatic adrenocortical carcinoma: a single institute experience
Masaki Uchihara1,2 . Maki Tanioka1 (D . Yuki Kojima1 . Tadaaki Nishikawa1 . Kazuki Sudo1 . Tatsunori Shimoi1 . Emi Noguchi1 . Akiko Miyagi Maeshima3 . Kan Yonemori1
Received: 17 July 2021 / Accepted: 23 August 2021 / Published online: 1 September 2021 @ Japan Society of Clinical Oncology 2021
Abstract
Background Adrenocortical carcinoma (ACC) is a rare and aggressive disease that is often diagnosed at an advanced stage. There is no standard treatment for metastatic ACC; EDP-M (etoposide, doxorubicin, and cisplatin plus mitotane) is one treatment option. A randomized controlled trial (FIRM-ACT) evaluating the efficacy of EDP-M showed progression-free survival (PFS) was 5.0 months, overall survival (OS) was 14.8 months, the response rate was 19%, and adrenal insufficiency occurred in 3.4% of patients. However, the efficacy and safety of this regimen in Asia are not fully reported.
Methods We retrospectively analyzed 43 patients diagnosed with metastatic ACC at the National Cancer Center Hospital between 1997 and 2020. We evaluated PFS, OS, and response in 17 patients who received EDP-M as first-line therapy. Results The median age at treatment initiation was 45 years (range 18-74). Eight patients (47%) had autonomous hormone production, including six patients with hypercortisolism. The best response of partial response and stable disease was seen in two (12%) and ten (59%) patients, respectively. The median PFS was 6.2 months [95% confidence interval (CI): 4.3-10.0]. The median OS was 15.4 months (95% CI 11.6-not reached). Three patients received only one cycle due to adverse effects associated with hypercortisolism. Grade 3/4 adverse events associated with adrenal insufficiency occurred in three (17%) cases, resulting in EDP-M discontinuation.
Conclusions The EDP-M regimen had similar PFS to that observed in FIRM-ACT. Adrenal insufficiency was more frequent in the current study, but this could be managed with supportive endocrinological care such as cortisol replacement.
Keywords Adrenocortical carcinoma . EDP . Mitotane . Adrenal insufficiency . Hypercortisolism
Introduction
Adrenocortical carcinoma (ACC) is an extremely rare endo- crine tumor with an estimated annual incidence of 0.7-2.0 per million people [1, 2]. ACC patients are often diagnosed at an advanced stage. Patients with metastatic status have
☒ Maki Tanioka mtanioka@ncc.go.jp
1 Department of Medical Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan
2 Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine, Toyama 1-21-1, Shinjuku-ku City, Tokyo 162-8655, Japan
3 Department of Diagnostic Pathology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan
a poor prognosis; the 5 year survival rate is less than 20% [3]. Therapeutic options for advanced ACC are limited. One standard chemotherapy for advanced ACC is etopo- side, doxorubicin, and cisplatin plus oral mitotane (EDP- M). The FIRM-ACT trial (First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment) revealed the efficacy of the EDP-M regimen; progression-free survival (PFS) was 5.0 months, overall survival (OS) time was 14.8 months, the response rate was 19%, stable disease was achieved in 35% of patients, and adrenal insufficiency occurred in 3.4% of patients [4]. Modern therapies including molecularly targeted therapies or immune checkpoint inhibitors have not shown a clear benefit in the treatment of ACC. Although EDP-M has only limited efficacy, it is the only recommended treatment for metastatic ACC according to current treatment guidelines [3]. In addition, ACC is a very rare cancer that is treated by
clinicians from various hospital departments such as oncol- ogy, endocrinology, and urology, which makes it difficult to collect clinical data. There are few reports in other Asian countries [5], and detailed information on clinical outcomes in Asia is limited. Furthermore, the EDP-M regimen is not covered by insurance in Japan due to limited therapeutic experience, which further limits the available data associ- ated with this therapy. For these reasons, the efficacy of the EDP-M regimen in Asia is unknown. Adrenocortical carcinoma has the unique feature of being a type of can- cer that affects the endocrine system. Some adrenocortical carcinomas are capable of producing steroids, which cause complications such as infections and cardiovascular disease, thus requiring management of hormonal excess [6, 7]. On the other hand, mitotane is used in ACC as a treatment for metastatic recurrence and as a postoperative adjuvant, and may cause adrenal insufficiency due to adrenal destruction [3]. Moreover, some studies revealed that interethnic differ- ences affect both the efficacy and toxicity of chemotherapy [8, 9]. In Asia, EDP-M regimen has been extrapolated based on the results in Western population, but the differences in efficacy and toxicity among these different ethnic groups have not been fully investigated. In this research, we present the outcome of patients with metastatic ACC treated with EDP-M in Japan.
Patients and methods
We retrospectively analyzed 43 patients diagnosed with met- astatic ACC at the National Cancer Center Hospital between April 1997 and January 2020. The diagnosis of ACC was based on pathological findings. We conducted a retrospec- tive evaluation of 17 patients with metastatic ACC who received EDP-M as first-line therapy. Other patients who received other systemic chemotherapy (4), mitotane mon- otherapy (15), and palliative care (7) were excluded from our analysis. Patients had not been treated with cytotoxic drugs, except mitotane, prior to starting EDP-M therapy. No patients were under the age of 18 or had a history of other neoplasms.
EDP-M chemotherapy was administered to patients who had an Eastern Cooperative Oncology Group (ECOG) per- formance status of 0-2, and adequate hematological and biochemical function. The EDP-M regimen consisted of etoposide at a dose of 100 mg/m2 on days 2-4, 40 mg/m2 doxorubicin on day 1, and 40 mg/m2 cisplatin on days 3 and 4. This cycle was repeated every 4 weeks. Treatment was discontinued early when unacceptable toxicity was observed, when patients refused to continue treatment, or when dis- ease progression occurred. Dose adjustments of EDP were made according to organ dysfunction such as renal func- tion. Oral mitotane was initiated at low starting dose usually
1500 mg/day, and progressive dose increments were given up to 4000 mg/day or the maximum-tolerated dose. Mito- tane was administered concurrently with chemotherapy, dur- ing the withdrawal period between successive cycles, and thereafter until disease progression or the onset of severe toxicity. Measurements of blood concentrations of mitotane were not performed in most patients due to a lack of insur- ance coverage in our country. Patients were evaluated at the beginning of each treatment cycle for a physical examina- tion and routine chemistry tests (including blood cell counts, electrolytes, renal, and liver function tests). Tumor response, measured according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 [10], was assessed every two to three cycles of EDP by computed tomography or magnetic reso- nance imaging of the chest and abdomen. We defined PFS as the time from the beginning of EDP treatment until the date of disease progression, and we defined OS as the time from the beginning of EDP treatment until the date of death or the last date of follow-up. Functional ACC was defined as the presence of clinical manifestations caused by hormo- nal hypersecretion and/or elevated serum hormone levels at diagnosis or prior to treatment. Common Terminology Criteria for Adverse Effects (CTCAE) version 4.0 was used to determine the grade of the adverse effects.
We analyzed PFS, OS, and tumor response in 17 patients who received EDP-M as first-line therapy. OS and PFS data were analyzed using the Kaplan-Meier method. Statistical analyses were conducted using R software version 4.1.0 (R foundation for Statistical Computing, Vienna, Austria).
The study protocol was approved by the Institutional Review Board of the National Cancer Center Hospital, Tokyo, Japan (approval numbers: 2012-335).
Results
Seventeen patients were included in the analysis (Table 1). The median age before initiation of EDP-M was 45 years (range 18-74 years). At clinical presentation, six patents had symptoms commonly associated with hormonal excess. Four patients had abdominal or back pain, and four patients had adrenal incidentaloma. Eight patients (47%) had autonomous hormone production including six patients with hypercor- tisolism. The location of metastatic lesions was liver (12 patients), lung (11 patients), peritoneum (seven patients), lymph nodes (four patients), and bone (two patients). Ten patients underwent adrenalectomy after diagnosis and relapsed thereafter. The remaining seven patients had unre- sectable metastatic lesions at the time of the initial diagnosis.
Outcome data are included in Table 2. The best response of either partial response (PR), stable disease (SD), or pro- gressive disease (PD) was observed in two (12%), ten (59%), and two (12%) patients, respectively. The response could not
| Baseline characteristics | n (%) |
|---|---|
| Sex, female | 10 |
| Age, median | 45 years (18-74) |
| Clinical presentation | |
| Suspicion of hormonal hypersecretion | 6 (35%) |
| Abdominal/back pain | 4 (24%) |
| Adrenal incidentaloma | 4 (24%) |
| Other | 2 (12%) |
| Unknown | 1 (6%) |
| Functional status | |
| Cortisol | 5 (29%) |
| Cortisol plus androgen | 1 (6%) |
| Androgen | 1 (6%) |
| Aldosterone plus estrogen | 1 (6%) |
| Non-functional | 9 (53%) |
| Left adrenal/right adrenal | 10/7 |
| Site of metastasesª | |
| Liver | 12 (71%) |
| Lung | 11 (65%) |
| Peritoneum | 7 (41%) |
| Lymph nodes | 4 (24%) |
| Bone | 2 (12%) |
| Prior surgery | |
| Adrenalectomy isolated | 8 (47%) |
| Adrenalectomy multi-organ | 2 (12%) |
| Prior systemic therapy | |
| Adjuvant mitotane | 4 (24%) |
| Palliative local treatment of metastatic lesions | |
| Surgical treatment | 6 (35%) |
| Radiotherapy | 4 (24%) |
| Trans arterial embolization | 1 (6%) |
| Post other chemotherapies | 2 (12%) |
aMultiple metastases in a single patient were counted separately
be evaluated in three patients who received only one treat- ment cycle due to an adverse effect or infections suspected to be associated with hypercortisolism. The median PFS was 6.2 months [95% confidence interval (CI) 4.3-10.0]. The median OS was 15.4 months (95% CI 11.6-not reached). The median follow-up duration was 15.6 months (95%CI 11.3-26.4). The median number of treatment cycles was 4 (range 1-16).
The correspondence between the efficacy of EDP-M, hormonal status, and reason for discontinuing EDP-M are shown in Table 3. There were no treatment-related deaths. Grade 3 adrenal insufficiency occurred in three (18%) cases, which led to the discontinuation of chemotherapy. Adrenal insufficiency while on mitotane and hydrocortisone was clinically diagnosed based on fatigue, anorexia, nausea, diar- rhea, hypotension, hyponatremia, hypoglycemia, elevated
ACTH, and good response to hydrocortisone dose increases. We describe one typical clinical course of adrenal insuf- ficiency in Fig. 1. We also highlight an early intervention case, where increased dosing of hydrocortisone enabled the patient to continue chemotherapy (Fig. 2). Due to symptoms that were attributed to hypercortisolism including infection and perforation of the bowel, three patients discontinued chemotherapy (cases 13, 14, and 16 in Table 3). Grade 3 or higher side effects of bone marrow toxicity, febrile neutro- penia, adrenal insufficiency, infection, fatigue, and neuro- logic toxicity were recorded in 5, 3, 3, 1, 1, and 1 patients, respectively. In case of organ damage such as decreased renal function or blood cell loss, the dose of chemotherapy was reduced to an appropriate level.
Discussion
In this report, we describe the outcomes of EDP-M in 17 patients with metastatic ACC. The effectiveness of EDP-M in our study was in agreement with the results of FIRM- ACT, which found that PFS was 5.0 months and OS was 14.8 months. Our findings in Asian patients are compara- ble to results from previous studies conducted in Western countries.
In our analytical analysis, grade 3 adrenal insufficiency occurred in three cases (17%), which was more frequent than in FIRM-ACT (3.4%) [4]. Since mitotane increases steroid clearance and increases levels of cortisol-binding globulin [11], glucocorticoid replacement is recommended for all patients treated with mitotane (except those with a cortisol- producing tumor) and usually requires at least twice the standard replacement dose [3]. There are no reliable labora- tory indicators to determine the optimal dose of hydrocor- tisone [11, 12], and so dosing should be adjusted according to clinical judgment, similar to the situation that occurs in the management of patients with non-ACC adrenal insuf- ficiency. Therefore, if adrenal insufficiency is suspected in the presence of anorexia, hyponatremia, and elevated ACTH levels, the hydrocortisone dose should be increased by two- to threefold [3].
Three patients experienced adverse events that were associated with hypercortisolism. Two patients had an infection and one patient suffered a perforated bowel. Hypercortisolism results in various systemic complica- tions such as infection, cardiovascular disease, and diabe- tes [6, 7]. Hypercortisolism can cause thinning of the col- lagen layer that forms part of the colonic lamina propria, which can lead to intestinal perforation [13]. Metyrapone is recommended for the management of hypercortisolism [14]. Endocrinological interventions such as cortisol sup- pression therapy with metyrapone could have improved the prognosis of the patients that had adverse events that
| Outcomes | n (%) |
|---|---|
| Cycle of EDP, median (range) | 4 (1-16) |
| Best response | |
| PR | 2 (12%) |
| SD | 10 (59%) |
| PD | 2 (12%) |
| Could not be evaluated for response ª | 3 (18%) |
| Progression-free survival, median (95% CI) | 6.2 months (4.3-10.0) |
| Overall survival, median (95% CI) | 15.4 months (11.6-not reached) |
| Reason for discontinuation | |
| Adverse eventsb | 8 (47%) |
| Progressive disease | 4 (24%) |
| Symptoms due to hypercortisolismc | 3 (18%) |
| Withdrawal of consent (stable disease) | 2 (12%) |
EDP etoposide, doxorubicin, and cisplatin, PR partial response, SD Stable disease, PD progressive disease, CI confidence interval
aThree patients received only one cycle
bGrade 3/4 adverse events occurred in three (17%) cases of adrenal insufficiency and three (17%) cases of febrile neutropenia
“Septic shock, infection, and perforation of the bowel each occurred in one patient
| Case no | Cycles of EDP | PFS (months) | Functional status | Reason for discontinuation |
|---|---|---|---|---|
| 1 | 16 | 19.6 | Silent | PD |
| 2 | 6 | 16.0 | Silent | Withdrawal of consent |
| 3 | 10 | 14.0 | Androgen | FN |
| 4 | 7 | 11.7 | Silent | Loss of memoryª |
| 5 | 7 | 9.6 | Cortisol | Withdrawal of consent |
| 6 | 7 | 8.0 | Cortisol plus androgen | Anemia |
| 7 | 6 | 7.1 | Silent | FN |
| 8 | 5 | 6.8 | Silent | Adrenal insufficiency |
| 9 | 3 | 6.2 | Silent | PD |
| 10 | 4 | 5.5 | Silent | Adrenal insufficiency |
| 11 | 3 | 4.8 | Aldosterone plus estrogen | PD |
| 12 | 2 | 4.3 | Silent | Adrenal insufficiency, FN |
| 13 | 3 | 3.2 | Cortisol | Septic shock |
| 14 | 2 | 1.6 | Cortisol | PD |
| 15 | 1 | 1.6 | Cortisol | Perforation of the bowel |
| 16 | 1 | 1.1 | Cortisol | Infection |
| 17 | 1 | 0.4 | Silent | Fatigue |
EDP etoposide, doxorubicin, and cisplatin, PFS progression-free survival, PD progressive disease, FN febrile neutropenia
aLoss of memory was suspected to be associated with the use of mitotane
were associated with hypercortisolism. Together, these findings suggest that endocrinological supportive care is necessary for patients to continue EDP-M chemotherapy. Hypercortisolism is also associated with high mortality and poor prognosis [15-17]. However, it is not known if this association occurs because of a negative effect of
cortisol action or a more aggressive ACC subtype, and further research is required.
In our study, only a limited number of patients discon- tinued chemotherapy due to PD; the majority of cases dis- continued therapy because of complications such as adrenal insufficiency or hypercortisolism. Accordingly, ACC is a
a
0
1
2
4
7
11
14
(months)
Surgery
Mitotane
EDP-M 2 cycles
Palliative care
Diagnosis Recurrence (Lung, Liver, Bone)
PD
Discontinuation
Death
Adrenal insufficiency
b
d
c
e
f
Diarrhea
Fatigue/Anorexia/Nausea
Plasma ACTH (pg/ml)
1500
1000
500
0
0
30
60
90
120
150
180 (days)
EDP
Mitotane (mg)
#1
#2
6000
7500
Hydrocortisone (mg)
10
30
150
300
difficult disease to manage, requiring both endocrinological management and control of the local lesions of the tumor. In addition, adequate attention should be paid to endocrinologi- cal management to enable the patient to cope with the side effects of chemotherapy.
There are some limitations of our research. Because of the retrospective study, information on adverse effects could not be comprehensively recorded. Also, the methods
of endocrinological interventions such as hydrocortisone coverage are not perfectly standardized. Therefore, we do not know the reason why adrenal insufficiency was more frequent in our research than in FIRM-ACT, whether it was due to ethnic differences or differences in endocrinological management. In addition, mitotane is known to be effec- tive when within an appropriate concentration range in the blood. Some small studies suggest that blood drug levels of
a
0
1
4.5
5.5
11
12
17
(Months)
Surgery for primary tumor
EDP-M 6 cycles
Onset
Recurrence (Right adrenal grands, Peritoneal nodules)
Discontinuation
PD
Adrenal insufficiency
b
C
d
Plasma ACTH (pg/ml)
Fatigue / Anorexia
500
400
300
200
100
0
0
30
60
90
120
150
(days)
EDP
#1
#2
#3
#4
#5
#6
Mitotane (mg)
1500
3000
4000
Hydrocortisone (mg)
20
30
60
90
Intervention of Endocrinologist
mitotane above 14 mg/L increase the antitumor activity of mitotane monotherapy [18, 19]. We were unable to measure the concentration of mitotane regularly since this test is not covered by insurance in our country. Mitotane concentra- tions was measured only when side effects suspected to be due to mitotane use were observed.
Recent molecular biology findings have revealed genetic mutations that can be targeted for ACC therapy [20]. There- fore, molecularly targeted agents may be one day useful for patients who are refractory to EDP-M. However, molecu- larly targeted agents such as linsitinib (a small molecule inhibitor of both IGF1R and the insulin receptor) [21], vascular endothelial growth factor receptor inhibitors [22], and multityrosine kinase inhibitors [23] showed limited efficacy in clinical trials. Regarding immunotherapy, the effect of avelumab on metastatic ACC that did not respond to platinum-based chemotherapy was disappointing, with a median PFS survival of 2.6 months [24]. Possible reasons for the modest results of immunotherapy trials for ACC include immunosuppressive effects of locally secreted
glucocorticoids and impaired immune cell infiltration due to disruption of Wnt/ß-catenin signaling [25]. Biomark- ers such as topoisomerase 2-alpha (TOP2A) and excision repair cross-complementing group 1 (ERCC1) are needed to predict the treatment response to EDP-M because of its therapeutic intensity. However, no useful markers have been identified in previous studies [26-29]. Since the EDP-M reg- imen was associated with a low response rate and signifi- cant toxicities, including leukopenia and neurological side effects, the discovery of biomarkers to predict therapeutic efficacy is urgently required.
In conclusion, our retrospective analytical analysis indi- cated that the EDP-M regimen has similar PFS and OS to that observed in FIRM-ACT. Adrenal insufficiency was more frequent in our study than in FIRM-ACT, but it is pos- sible to manage this side effect with appropriate supportive care from an endocrinologist.
Acknowledgements We wish to thank all of the patients and medical staff who participated in this study.
Funding No funding was used for the completion of this paper.
Declarations
Conflict of interest The authors have nothing to disclose.
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