Adrenocortical Carcinoma Role of Adjuvant and Neoadjuvant Therapy
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Lisa Kenney, MDª,*, Marybeth Hughes, MDb
KEYWORDS
. Adrenocortical carcinoma . Mitotane . Adjuvant chemotherapy
. Neoadjuvant chemotherapy
KEY POINTS
· Existing evidence is limited for the use of adjuvant and neoadjuvant chemotherapy in the treatment of adrenocortical carcinoma (ACC).
· The single current US Food and Drug Administration-approved medication for ACC in both treatment and palliation is mitotane.
· The use of adjuvant cytotoxic medications for the treatment of ACC is typically reserved for patients with high risk of recurrence or advanced disease (stage III or greater) and cur- rent evidence supports the combination use of etoposide, doxorubicin, cisplatin, and mi- totane for these patients.
· Neoadjuvant chemotherapy is used in the treatment of ACC to facilitate complete resec- tion. Much of the rationale for neoadjuvant approach is derived from existing data on adju- vant therapy.
· Surgery remains the only mechanism to cure ACC and should be carefully considered by experienced surgeons in the context of multidisciplinary care.
INTRODUCTION
Following surgical resection of adrenocortical carcinoma (ACC) greater than 50% of patients develop relapse of their disease within 5 years,1 and a significant number of patients initially present with metastatic disease.2 Thus, medical therapy is an important component of treatment of this cancer. However, given the rarity of ACC, limited evidence exists for specific regimens of treatment, and there are only a few prospective trials available. Complete surgical resection remains the cornerstone and most important factor in patient outcomes. The single current US Food and Drug Administration approved medication for ACC in both treatment and palliation is mitotane, which acts to inhibit steroidogenesis.3 However, existing data on mitotane
a Department of Surgery, Eastern Virginia Medical School, 825 Fairfax Avenue, Suite 610, Norfolk, VA 23507, USA; b Department of Surgery, Division of Surgical Oncology, Eastern Vir- ginia Medical School, 825 Fairfax Avenue, Suite 610, Norfolk, VA 23507, USA
* Corresponding author.
E-mail address: kenneylm@evms.edu
| Table 1 | |
|---|---|
| Chemotherapeutic agents that interact with mitotane | |
| Chemotherapeutic Class | Medications |
| Tyrosine kinase inhibitors | Axitinibª Dasatinib Erlotinib Gefitinib Imatinib Nilotinib Lapatinib Sorafenibª Sunitinibª Vandetanib |
| mTOR inhibitors | Everolimusª |
| Topoisomerase inhibitors | Etoposideª |
| Vinca alkaloids | Vincristineª |
| Taxols | Docetaxel |
| Anthracyclines | Doxorubicinª |
a Drugs currently in use or under investigation for use in the treatment of ACC.
Adapted from Kroiss M, Quinkler M, Lutz WK, Allolio B, Fassnacht M. Drug interactions with mi- totane by induction of CYP3A4 metabolism in the clinical management of adrenocortical carci- noma. Clin Endocrinol (Oxf). 2011;75(5):585-591. doi:10.1111/j.1365-2265.2011.04214.x.
use for ACC is conflicted and primarily based on retrospective studies. Current stan- dard practice recommendations support combination therapy for mitotane with chemotherapy agents such as etoposide, doxorubicin, and cisplatin, though existing evidence on such treatment is limited.2,4,5 Current research efforts in this disease pro- cess involve determining the molecular characteristics of ACC to find specific targets for therapy, and include strategies for immunotherapy, tyrosine kinase inhibitors, and directed therapies. The need for more comprehensive understanding of this disease limits current options for treatment.
DISCUSSION Mitotane Therapy
The first clinical application of mitotane, or 2,4’-(dichlorodiphenyl)-2,2-dichloroethane (o,p’-DDD), was discovered in 1949 by Nelson and Woodard when it was observed that the drug caused atrophy of the adrenal cortex in canine models.6 Initially derived from the pesticide dichlorodiphenyltrichloroethane, this medication has remained a staple of adjuvant therapy for ACC since its application in human patients in 1960,7 although the full mechanism of action is still being investigated. Although the effect of mitotane varies between species, it is recognized that high levels damage the zona fasciculata and reticularis of the adrenal gland in humans, whereas the zona glo- merulosa is spared. On a cellular level, it acts on the mitochondria to affect mem- branes of the respiratory chain.8 Studies investigating the effects of mitotane on steroidogenesis show inhibitory effects on the synthesis of 11ß-hydroxylase, 3ß-hydroxysteroid dehydrogenase, and 18-hydroxylase.9,10 As an inducer of cyto- chrome CYP34A, mitotane affects the metabolism of several medications, including other chemotherapeutic agents in use for ACC.11 Table 1 lists known therapies for ACC affected by mitotane. Patients who are on mitotane often experience significant side effects including alterations to thyroid and testosterone metabolism, especially at
the targeted therapeutic level of 14 to 20 mcg/mL. Patients on mitotane therapy will also typically need long-term glucocorticoid replacement therapy.12,13
The 2018 European Society of Endocrinology (ESE) Clinical Practice Guidelines recommend the use of mitotane for patients with ACC, particularly in patients who have at least one feature: (1) stage III disease, (2) R1-surgical resection, or (3) Ki67 greater than 10%. Those without such characteristics should be evaluated on an indi- vidual basis for mitotane therapy.14 Thus, mitotane is supported in patients who are deemed high risk for recurrence. However, questions remained on the appropriate use of mitotane in those deemed low risk.
The first randomized trial on adjuvant mitotane in ACC patients, known as the Adjuvo study, sought to fill the recommendation gap from the ESE Clinical Practice Guidelines on the use of mitotane in ACC patients with low or intermediate risk of recurrence. The inclusion criteria were (1) stage I to III disease, R0 surgery, and Ki- 67 less than 10%. They were randomized to mitotane therapy or observation after resection. A total of 91 patients were enrolled with 45 in the mitotane arm and 46 in the observational arm. The results of the study found no difference recurrence free survival (RFS) in this subset of patients, with the hazard ratio (HR) for recurrence was 1.321 (95% CI, 0.55-3.32, P = . 54) and HR for death 2.171 (95% CI, 0.52- 12.12, P = . 29). Thus, mitotane was not recommended for low to intermediate recur- rence risk ACC patients after resection. 15
A recent meta-analysis on prognostic benefits of adjuvant mitotane after resection of ACC in patients without distant metastasis was performed by Tang and colleagues at Sichuan University in Chengdu, China, and included 5 studies (which were all retro- spective) reporting on 1249 patients. The meta-analysis found significantly longer RFS (HR = 0.62; 95% CI, 0.42-0.94; P < . 05) and prolonged overall survival (OS; HR = 0.69; 95% CI, 0.55-0.88, P < . 05), supporting the use of adjuvant mitotane in ACC. The au- thors specifically excluded studies, which involved patients with metastatic disease, no prior resection of the tumor, neoadjuvant therapy before surgery, or other chemo- therapeutic agents in addition to mitotane. However, adjuvant radiotherapy was allowed as part of the meta-analysis. The patients were not stratified based on stage of disease, resection margins, or Ki67 percentage.16 Thus, the authors suggest that monotherapy with mitotane is beneficial in the adjuvant setting for patients who show no signs of metastasis.
Adjuvant Chemotherapy, Immunotherapy, and Targeted Therapies
The use of adjuvant cytotoxic medications for the treatment of ACC is still debated and is typically reserved for patients with high risk of recurrence or advanced disease (stage III or greater), as most existing studies have small enrollment sizes and the benefit is not clear. The introduction and use of immunotherapies and targeted thera- pies, such as use of monoclonal antibodies, checkpoint inhibitors, and tyrosine kinase inhibitors in cancer treatment has been an area of recent interest in the treatment of ACC.17 Such therapies can be devised by understanding the mechanisms by which cancer cells escape surveillance of the immune system. Thus, several trials involving monoclonal antibodies such as anticytotoxic T cell antigen 4 (anti-CTLA-4), antiprog- rammed cell death protein 1 (anti-PD-1), and antiprogrammed cell death protein ligand 1 (anti-PD-L1) against various types of cancer are being studied (Refer to Table 2). However, no significant breakthrough for ACC has been discovered thus far for these novel types of treatments.
The first phase 3 clinical trial involving systemic therapy for ACC was published in 2012. Known as the First International Randomized Trial in Locally Advanced and Met- astatic Adrenocortical Carcinoma Treatment (FIRM-ACT), it compared the treatment
Kenney & Hughes
| Table 2 Relevant clinical trials investigating the use of adjuvant chemotherapy, immunotherapy, and targeted therapies in the treatment of ACC, 2012-2022 | |||
|---|---|---|---|
| Reference | Chemotherapy | Number of Patients | Results |
| Fassnacht et al, 18 2012 | Mitotane plus etoposide, doxorubicin, and cisplatin vs mitotane plus streptozocin | 304 with advanced ACC | Higher response rate (23.2% vs 9.2%, P <. 001) and longer median PFS (5.0 vs 2.1 mo, HR 0.55; 95% CI, 0.43- 0.69; P < . 001) in mitotane plus etoposide, doxorubicin, and cisplatin group. No significant difference in OS |
| Berruti et al,20 2012 | Sorafenib (kinase inhibitor) plus metronomic paclitaxel | 25 with metastatic ACC | No benefit |
| Kroiss et al,21 2012 | Sunitinib (kinase inhibitor) | 38 patients with refractory ACC (after treatment with mitotane and cytotoxic chemotherapy) | 5 patients experienced stable disease, 24 had progressive disease, and 6 patients died from ACC before the first evaluation; also had some evidence of drug interaction with mitotane |
| Urup et al,22 2013 | Cisplatin plus docetaxel | 19 with advanced ACC | The response rate was 21% (95% CI: 3%-39%). No patients obtained a complete response, 32% had stable disease, and 37% progressed while on treatment. The median PFS was 3 mo (95% CI: 0.7-5.3 mo) |
| Naing et al,23 2013 | Cixutumumab (monoclonal antibody against IGF-1R) plus temsirolimus | 20 with metastatic ACC | Stable disease >6 mo (range 6-21 mo) in 42% of participants |
| O'Sullivan et al,24 2014 | Axitinib (tyrosine kinase inhibitor) | 13 with metastatic ACC (previously treated with at least 1 chemotherapy regimen with or without mitotane) | No benefit |
| Fassnacht et al,25 2015 | Linsitinib (inhibitor of IGF-1R) | 139 locally advanced or metastatic ACC | No benefit |
|---|---|---|---|
| Le Tourneau et al,26 2018 | Avelumab (monoclonal antibody against PD-L1) | 50 with metastatic ACC (previously treated) | The response rate was 6% (95% CI: 1.3%-16.5%). 42% had stable disease. Median PFS was 2.6 mo (95% CI: 1.4-4.0) |
| Habra et al,27 2019 | Pembrolizumab (monoclonal antibody against PD-1 receptor) | 16 with ACC (prior treatment failure in last 6 mo), 2 lost to follow-up | The response rate was 14% (95% CI: 2%-43%). At 27 wk, 2 had a partial response, 7 had stable disease, and 5 had progressive disease |
| Carneiro et al,28 2019 | Nivolumab (monoclonal antibody against PD-1 receptor) | 10 with metastatic ACC (previously treated with platinum-based chemotherapy or mitotane) | Median PFS was 1.8 mo (95% CI, 0.1- 4.3). 2 of the 10 participants showed stable disease for 48 and 11 wk |
| Raj et al,29 2020 | Pembrolizumab (monoclonal antibody against PD-1 receptor) | 39 with advanced ACC | Objective response rate was 23% (95% CI: 11%-39%). Median PFS was 2.1 mo (95% CI: 2.0-10.7) |
Adapted from Paragliola RM, Corsello A, Locantore P, Papi G, Pontecorvi A, Corsello SM. Medical Approaches in Adrenocortical Carcinoma. Biomedicines. 2020;8(12):551. Published 2020 Nov 29. https://doi.org/10.3390/biomedicines8120551.
of metastatic ACC with etoposide, doxorubicin, cisplatin, and mitotane (EDP-mitotane group) versus treatment with streptozotocin and mitotane (streptozocin-mitotane group). This was a randomized controlled trial that was conducted in 12 countries at 40 specialized centers and thus had a higher participant enrollment than all prior phase 2 trials combined at the time, with 304 total enrolled patients. The patients in the EDP-mitotane group had a significantly higher response rate than those in the streptozocin-mitotane group (23.2% vs 9.2%, P < . 001) and longer progression-free survival (PFS; 5.0 vs 2.1 months; HR 0.55 95% CI, 0.43-0.69; P < . 001). There was no significant between-group difference in OS (OS; 14.8 and 12.0 months, 95% CI, 0.61-1.02; P = . 07).18 A retrospective study in Tokyo, Japan, involving 43 patients with metastatic ACC at the National Cancer Center Hospital between 1997 and 2020 showed similar outcomes to the FIRM-ACT trial, with a median PFS of 6.2 months (95% CI: 4.3-10.0) and OS of 15.4 months (95% CI 11.6-not reached). 19 Table 2 ref- erences the relevant clinical trials (2012-2022) involving systemic chemotherapy and immunotherapy in the treatment of ACC.
Neoadjuvant Chemotherapy
Although adjuvant therapy for the treatment of ACC has been a topic of research for decades, the concept of neoadjuvant therapy is a more recent consideration. The cur- rent consensus for use of systemic neoadjuvant chemotherapy in ACC is to reduce the burden of disease to facilitate complete resection.3º Most experts do not recommend neoadjuvant treatment when R0 surgical resection is possible upfront (Fig. 1 below, treatment algorithm for ACC). Much of the rationale for neoadjuvant approach is derived from existing data on adjuvant therapy. Currently, there is a single retrospec- tive study from MD Anderson Cancer Center evaluating the use of neoadjuvant chemotherapy for patients with borderline resectable ACC (BRACC), defined as tumor or patient characteristics at presentation that argue against immediate surgery because of an unacceptable risk of morbidity/mortality, incomplete resection, or
Adrenocortical carcinoma
Resectable (RO)
Borderline resectable (R1)
Metastatic disease
Neoadjuvant mitotane +/- chemotherapy
Resectable disease?
Surgical Resection
High risk of recurrence?
No
Yes
No
Yes
Adjuvant mitotane +/- chemotherapy
Mitotane +/- chemotherapy consider clinical trial
+/- metastasectomy with experienced surgeon
+/- mitotane
Surgical resection
recurrence. The study included 53 patients with ACC, 15 (28.3%) of which were considered BRACC and underwent neoadjuvant therapy. Of these 15 patients, 12 (80%) received mitotane and etoposide/cisplatin-based chemotherapy, 2 (13%) received mitotane alone, and 1 (7%) received chemotherapy alone. Median disease-free survival for resected BRACC patients who underwent neoadjuvant ther- apy was higher than the patients who underwent surgery for initial treatment, at 28.0 months (95% CI 2.9-not attained) versus 13 months (95% CI 5.8-46.9; P = . 40). Five-year OS was similar between the groups as well (65% vs 50%, P = . 72).31,32 Neoadjuvant therapy in the setting of borderline resectable disease is appropriate for the facilitation of R0 resection, and prospective randomized trials would further determine the benefit of neoadjuvant chemotherapy for these patients.
Surgery remains the only mechanism to cure ACC and should be carefully consid- ered by experienced surgeons in the context of multidisciplinary care.
SUMMARY
Current evidence regarding the use of adjuvant and neoadjuvant chemotherapy in the treatment of ACC is limited by mostly retrospective studies. The use of mitotane has been long used in the treatment of ACC but consensus only supports its use for adju- vant therapy in cases of high risk of recurrence because it has questionable benefit and has many known side effects and drug interactions. Evidence regarding the use of systemic chemotherapy is limited by small sample sizes, and treatment is reserved for patients with high risk of recurrence or advanced disease (stage III or greater). The FIRM-ACT trial was the first phase 3 trial involving systemic chemotherapy and is the basis for use of etoposide, doxorubicin, cisplatin, and mitotane as combination ther- apy. Although the use of targeted therapies and immunotherapy for ACC is promising, breakthroughs have not yet been made. Neoadjuvant therapy in ACC is typically not recommended unless R0 resection is not possible upfront, and limited studies show some benefit of neoadjuvant therapy to facilitate complete surgical removal of tumor. Surgical excision is the definitive treatment of ACC.
CLINICS CARE POINTS
· Surgical excision is the cornerstone of ACC treatment.
· Adjuvant mitotane therapy is generally recommended for ACC in the context of high risk of recurrence or for palliation of symptoms.
· Systemic chemotherapy is used for patients with high risk of recurrence or advanced disease (stage III or greater). Current evidence supports the combination use of etoposide, doxorubicin, cisplatin, and mitotane as combination therapy.
. Neoadjuvant chemotherapy is considered to facilitate RO resection, and no current guidelines exist for specific neoadjuvant therapies.
DISCLOSURE
The authors have nothing to disclose.
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