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Treatment of Adrenocortical Carcinoma
Anand Vaidya, MD, MMSca,*, Matthew Nehs, MDb,C, Kerry Kilbridge, MDb,c,d
KEYWORDS
· Adrenocortical carcinoma · Adrenal · Mitotane · Adrenal cortex · Cancer
Key points
· Adrenocortical carcinoma (ACC) is a rare cancer that is usually associated with a poor prognosis.
. ACC can often grow rapidly and produce excess adrenal hormones that contribute to morbidity
· Surgery is the cornerstone of therapy and currently the only avenue for a potential cure
· Adjuvant systemic medical therapies, such as mitotane, chemotherapy, and radiation, also are reviewed.
ABSTRACT
A drenocortical carcinoma (ACC) is a rare ma- lignancy with a poor prognosis. ACC is capable of secreting excess adrenocortical hormones, which can compound morbidity and compromise clinical outcomes. By the time most ACCs are diagnosed, there is usually locoregional or metastatic disease. Surgery is the most impor- tant treatment to offer possibility of cure or prolong survival. Several adjuvant therapies are used depending on grade and stage of the tumor and other patient-related factors. This review provides an overview of treatment approaches for ACC, highlighting evidence to support each treatment and acknowledging where more data and research are needed to improve care.
OVERVIEW
Adrenocortical carcinoma (ACC) is a rare malig- nancy, with an estimated incidence of 1 million to
2 million cases per year.1-3 ACC most commonly diagnosed in the fifth to seventh decades of life, but it can arise at any age. Although most ACCs are considered sporadic and without a known cause, a minority of cases are attributable to known hereditary predispositions, including Li-Fraumeni syndrome, Lynch syndrome, multiple endocrine neoplasia type 1, and familial adenomatous polypo- sis. 1,4-6 The prognosis of ACC is usually poor; by the time ACC is diagnosed, a majority of patients have locally or systemically advanced disease, often with hormonal hypersecretion that increases morbidity. The combination of its rarity and gener- ally short survival time has resulted in few prospec- tive or randomized trials, and, therefore, most best practices for ACC therapy are driven by lower grades of evidence and consensus opinion. Surgery is the most important treatment modality and the only avenue to achieve cure. Adjuvant systemic therapies usually are used, depending on the stage and grade of the tumor, to influence progression- free survival and overall survival.
Disclosures: M. Nehs and K. Kilbridge have nothing to disclose. A. Vaidya has been a consultant and/or scien- tific advisory board member for Corcept Therapeutics, Ionis Pharmaceuticals, Selenity Therapeutics, HRA Pharma, and Orphagen Pharmaceuticals.
ª Division of Endocrinology Diabetes, and Hypertension, Department of Medicine, Center for Adrenal Disor- ders, Brigham and Women’s Hospital, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA;
b Brigham and Women’s Hospital, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA; Department of Surgery, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; d Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA
* Corresponding author. Brigham and Women’s Hospital, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115.
E-mail address: anandvaidya@bwh.harvard.edu
https://doi.org/10.1016/j.path.2019.08.010
This article provides a brief overview of the approach to treating ACC. This review is designed specifically to provide an overview for pathologists who wish to better understand how ACC is treated and how pathologic parameters influence treatment decisions. More comprehen- sive guidelines on ACC treatment are available elsewhere.1
CLINICAL PRESENTATION AND EVALUATION
ACC is a unique malignancy in that it can autonomously secrete one, or multiple, adrenal cortical hormones that can substantially com- pound morbidity. ACC is consequently commonly diagnosed either during the evalua- tion of hypercortisolism or Cushing syndrome, hyperandrogenism, or primary aldosteronism or during the evaluation of a concerning adrenal mass that was incidentally discovered on imag- ing.7,8 Imaging characteristics of ACC typically include a heterogeneous and often large adrenal mass that also may exhibit calcifications, hemor- rhage/necrosis, and poor contrast washout char- acteristics on delayed computed tomography.7,8 Less commonly, ACC is diagnosed during the evaluation of nonspecific symptoms that raise concern for a malignancy, such as weight loss, fevers, night sweats, back or flank pain, or abdominal fullness. More than half of ACCs have clinically relevant adrenal hormone excess, although it is likely that most ACCs secrete sub- clinical levels of adrenal cortical hormones or their intermediate metabolites.9 The most effective approach to mitigating the adverse ef- fects of hypercortisolism, hyperandrogenism, and hyperaldosteronism is a complete surgical resection. When this cannot be accomplished, medical therapies directed at inhibiting or blocking cortisol, the use of mineralocorticoid antagonists, and supportive care may be necessary.
The clinical evaluation of ACC involves measurements to assess adrenocortical hor- mone excess and cross-sectional imaging. A biopsy is often tempting to make a tissue diagnosis but is strongly discouraged because the heterogeneity of ACC can result in nonmalignant or uninterpretable results that can be falsely reassuring. Additionally, there is a theoretic risk for seeding the needle track.7,8,10 When the imaging appear- ance of an adrenal mass is concerning for ACC, a surgical resection should be strongly considered for diagnosis, prognostication, and treatment.7,8
HISTOPATHOLOGIC EVALUATION AND STAGING
Although a clinical evaluation often strongly sug- gests ACC (ie, a large heterogeneous adrenal mass with Cushing syndrome and hyperandrogen- ism), definitive diagnosis is made by histopatho- logic examination. The most commonly used histopathologic tool to make the distinction be- tween an adrenocortical adenoma and ACC uses Weiss criteria on hematoxylin-eosin-stained slides. 11,12 Three or more of the following Weiss criteria are strongly indicative of ACC: high nuclear grade, more than 5 mitoses per 50 high-power fields, atypical mitotic figures, less than 25% clear cells, diffuse architecture, necrosis, venous inva- sion, sinusoidal invasion, and capsular invasion. To complement the Weiss criteria, several other classification systems exist and can be useful for borderline tumors. 13-17 For more details regarding the histopathologic evaluation of adrenocortical tumors, please see the article by Anjelica Hodgson and colleagues’, “A Diagnostic Approach to Adre- nocortical Tumors,” in this issue.
The prognosis for ACC is poor, with an overall survival of less than 5 years from the time of diag- nosis. The prognosis varies greatly, however, by the stage and grade of disease and the treatment center that is coordinating care.1,2 Widely accepted staging criteria include the American Joint Committee on Cancer and the European Network for the Study of Adrenal Tumors (ENSAT); both criteria are similar. Stage I ACC is defined as T1, NO, MO, where the primary tumor is ≤ 5cm in size. Stage II ACC is defined as T2, N0, M0 where the primary tumor is > 5 cm in size. Stage III ACC is defined as T1-T2, N1, M0 or T3-T4, N0-N1, M0 where a primary tumor of any size has infiltrated surrounding periadrenal tissue or invaded adja- cent organs or there is tumor thrombus in the inferior vena cava or renal vein or there is involve- ment of lymph nodes. Stage IV ACC is defined as T1-T4, N0-N1, M1 where there is evidence of distant metastases regardless of other factors.1 The only cure for ACC is complete surgical resec- tion, whereas nonsurgical therapies (discussed later) are not curative and can have poor efficacy and/or be toxic.
Stage I and stage II ACC have 5-year survival rates of 60% to 80% respectively because they are most amenable to complete surgical resec- tion; however, detection of ACC at these stages is not common.1,2 ACC is most commonly detected with locoregional disease (stage III) or advanced disease (stage IV), where despite adju- vant therapies the overall survival rates at 5 years
are 30% to 50% and less than 25%, respec- tively.1,2,18 For these reasons and the fact that expertise in ACC care is not widespread, it is strongly recommended that patients with ACC be treated by multidisciplinary teams at highly experienced centers.1,7 A complete surgical resection by an experienced surgical team is crit- ical for optimal outcomes and a multidisciplinary approach to adjuvant systemic and localized ther- apies by an experienced medical team can amplify these gains.
| Key Points ON CLINICAL PRESENTATION AND HISTOPATHOLOGIC EVALUATION AND STAGING | |
| · ACC can autonomously secrete one or multi- ple adrenal cortical hormones that can sub- stantially compound morbidity. | |
| . The prognosis for ACC is poor, with an overall survival of less than 5 years from the time of diagnosis. | |
| · Tumor stage, grade, and Ki-67 proliferative index are the parameters most predictive of the prognosis and survival. | |
SURGERY
A complete surgical resection (R0 resection) is currently the only known pathway to cure in ACC. Incomplete surgical resections are associ- ated with better long-term outcomes and survival than no resection at all2; therefore, it is strongly recommended that highly experienced surgical teams evaluate and assess each case of ACC.
PERIOPERATIVE SURGICAL PLANNING
A contrast-enhanced abdominal CT scan is an essential part of the preoperative work-up to assess for tumor size, necrosis, invasion into sur- rounding organs, lymphadenopathy, and a pa- tient’s body habitus (Fig. 1). Obesity and excess retroperitoneal fat (as are often seen in patients with ACC-related Cushing syndrome) can com- pound the difficulty of exposure and necessitate a larger surgical exposure, such as a thoracoab- dominal incision. These large incisions have increased morbidity and pain in the postoperative recovery period, but they may provide the only exposure that allows for a safe and oncologically sound resection. All patients with Cushing syn- drome or cortisol hypersecretion should be
suspected of having suppression of the contralat- eral adrenal gland and, therefore, may have adre- nal insufficiency postoperatively. This can be effectively addressed with intraoperative and postoperative hydrocortisone supplementation, ideally in conjunction with experienced anesthesi- ology and endocrinology teams.
SURGICAL APPROACH
Radical adrenalectomy should be performed by surgeons with considerable experience with adre- nal or oncologic surgery.1 ACCs often are large invasive masses that are stuck to surrounding tis- sues and organs; therefore, the surgical team should assess the tumor’s characteristics when planning the surgical approach.
There are no large randomized trials comparing open to laparoscopic adrenalectomy for ACC. Early reports of laparoscopic resection of ACC had increased rates of tumor capsule disruption and spillage, and a meta-analysis from 2016 showed a significantly higher rate of peritoneal carcinomatosis with a laparoscopic approach.19 Several retrospective case series, however, have reported no difference in mortality when comparing a laparoscopic approach for tumors less than 10 cm.19,20 If invasion is seen during laparoscopic adrenalectomy, conversion to an open/radical approach is generally undertaken, in line with standard oncologic principles. In the absence of randomized controlled trial data, consensus guidelines recommend open surgery for known or suspected ACC as the gold standard approach.1 This may be particularly important for stage I and stage II tumors, where an R0 resection and cure is still possible.21 Open surgery allows for wide exposure and en bloc resection of the adre- nal mass, perinephric fat, and surrounding organs that may be involved (eg, spleen, pancreas, and kidney). Furthermore, open surgery increases the ability to sample surrounding lymph nodes, which is important for accurate staging.
The surgical approach to the adrenal mass de- pends greatly on the side and size of the tumor. Left-sided ACCs generally are adherent or invasive to the spleen, pancreas, left kidney, splenic flexure of the colon, and/or stomach. The surgical expo- sure and approach should consider that these or- gans may need to be resected at the time of the operation. Often, the tail of the pancreas and spleen need to be excised in order to gain expo- sure to the left adrenal mass (Fig. 2). It is less com- mon for the parenchyma of the left kidney to be invaded by tumor; however, the blood supply to the left kidney (left renal artery and/or vein) often is involved, which necessitates left nephrectomy
A
B
ACC
IVC
ACC
C
D
Aortocaval Lymph Nodes
Aorta
Right Renal Artery
ACC
IVC
0
Aortocaval Lymph Nodes
A
as part of the resection (Fig. 3). Lymph nodes that are commonly involved include the para-aortic, left renal, and splenic nodes; however, ACC can spread to contralateral nodal basins as well.
Right-sided ACCs can invade the right kidney, liver, and inferior vena cava (IVC). Aortocaval lymph node metastases are a common location of lymphadenopathy for right-sided ACC (see Fig. 1C, D). If the ACC invades the IVC (often along the right adrenal vein), a portion of the IVC along with tumor thrombus needs to be excised. This can require complete isolation of the retrohepatic IVC and/or cardiopulmonary bypass. Invasion of the liver may require an en bloc resection of the adrenal tumor with the right lobe of the liver.
COMPLICATIONS
The risks and complications of adrenalectomy greatly depend on which adrenal gland is involved. The risks of left-sided multivisceral resections include renal failure/insufficiency, pancreatic fis- tula, postsplenectomy sepsis, and/or delayed gastric emptying. The main risk of resection of a right-sided ACC is massive life-threatening bleeding from injury to the IVC. Para-aortic lymph node dissection also can include the risk of chyle leak from damage to the cisterna chyli and
retroperitoneal lymphatics. Complications that are common to both left and right open adrenal re- sections include wound infection, hernia, bleeding, and adrenal insufficiency in addition to periopera- tive cardiovascular morbidity, such as myocardial infarction and deep venous thrombosis or venous thromboembolism.
Key Points FOR SURGERY
· Complete surgical resection is the only known avenue for a potential cure of ACC.
· Open radical adrenalectomy performed by surgeons with considerable experience with adrenal or oncologic surgery is the preferred approach.
· ACC can be adherent and invasive to local sur- roundings, thereby increasing the complica- tion rates.
ADJUVANT MITOTANE THERAPY
Mitotane is a derivative of the insecticide dichloro- diphenyltrichloroethane (DDT).22 For decades it
Distal Pancreas
Spleen
Tumor
had been considered to have adrenolytic proper- ties; however, newer data and clinical observa- tions suggest that it may be adrenostatic, at least in some instances.23 Adjuvant mitotane therapy is recommended for patients after complete surgi- cal resection who have either stage III or stage IV disease and/or high-grade disease of any stage (Ki67 index >10%). Although pathologists gener- ally grade ACC according to the mitotic count, treatment algorithms often rely on Ki-67
proliferative index, with a Ki-67 proliferative index less than or equal to 10% considered low grade and a Ki-67 proliferative index greater than 10% considered high grade. Therefore, it is important for pathologists to include a Ki-67 proliferative index in the pathology report. Newer evidence suggests that mitotane monotherapy, or in combi- nation with chemotherapy, may continue to pro- vide benefit for patients with recurrent metastatic disease. 18,24,25 For patients with stage I or stage
INTERPRETATION
Tumor
Tumor
Cardinal Health
Left Renal Vein Left Renal Artery
Left Kidney
Il disease that is low grade (Ki67 ≤10%), after an R0 resection, there is no evidence-based recom- mendation on whether adjuvant mitotane may be beneficial. In these instances, case-by-case deci- sions to initiate adjuvant mitotane are made after weighing a multitude of patient-specific factors and balancing them with potential adverse effects (discussed later). There currently is an ongoing prospective randomized trial that is evaluating the efficacy of adjuvant mitotane compared with no mitotane in low-risk ACC (stages I-III and Ki67 <10% after R0 resection; ADIUVO trial).
It is important to recognize that there are currently no prospective studies or randomized tri- als evaluating the efficacy of mitotane. The land- mark evidence to support its use comes from retrospective cohort studies that showed that adju- vant mitotane therapy was associated with signifi- cantly prolonged recurrence-free survival, and possibly greater overall survival compared with no adjuvant therapy among patients with locore- gional/stage III ACC.26,27 These data have resulted in the recommendation to use adjuvant mitotane monotherapy for high-grade disease and stage III or greater disease and combination mitotane plus chemotherapy in advanced and recurrent ACC (discussed later).18,26 Adjuvant mitotane therapy generally is continued for approximately 2 years un- less limited by severe or intolerable adverse events and/or substantial recurrences in disease despite optimal mitotane dosing; however, anecdotal re- ports suggest that long-term continuation of mito- tane therapy may reduce or maintain the burden of disease in select subgroups.24,25 Patients with metastatic ACC may continue mitotane indefinitely if it is tolerated and there seems to be clinical benefit associated with its use.
Among the most common adverse effects are nausea, vomiting, diarrhea, and generalized fa- tigue.1 Neurologic complications can arise, particu- larly when mitotane doses and levels are high, including ataxia, memory loss, lethargy, and depres- sion. Liver toxicity can occur at any level or dose of mitotane and can range from a mild transaminitis to overt hepatic dysfunction and liver failure. Mito- tane can cause substantial hypercholesterolemia, pancytopenia, and drug-induced skin rash.
Several endocrinopathies are known to be induced by mitotane. Adrenal insufficiency is induced due to inhibition of steroidogenesis by mitotane and possibly also an adrenolytic effect on the remaining contralateral gland. For this reason, patients on mitotane should be treated with glucocorticoids and, at times, mineralocorticoids. Hypothyroidism may occur, although the pattern of laboratories can indicate either primary or second- ary hypothyroidism. For this reason, many patients
on mitotane need supplemental thyroid hormone. Mitotane can induce a primary or secondary hypo- gonadism in men with or without gynecomastia, and it has been observed to cause endometrial hy- pertrophy. Both of these reproductive abnormalities require careful monitoring and have unclear ramifications. Insufficient treatment of these endo- crinopathies can cause fatigue, hypotension, depression, and other symptoms that may limit the intensity of therapy or be misattributed to other fac- tors. To further compound these endocrine alterations, mitotane increases hepatic globulin syn- thesis and secretion, including that of cortisol- binding globulin, thyroid hormone-binding globulin, and sex-hormone binding globulin. Further, mito- tane increases cytochrome P450 3A4 (CYP3A4) ac- tivity, which is responsible for the metabolism of supplemental hormone therapy and many other routine medications. For all these reasons, when hormone replacement therapy is indicated for adre- nal insufficiency, hypothyroidism, and hypogonad- ism, the doses needed to recapitulate physiologic homeostasis can be much higher than traditional replacement doses.
Patients on mitotane require routine monitoring for adverse effects. This includes laboratory evalua- tions for liver injury, blood counts, thyroid and adrenal hormone status, cholesterol, and periodi- cally testosterone deficiency. In addition, patients should be seen every 3 months for history and examination and imaging surveillance of the abdomen and chest to assess for recurrence or pro- gression. In the absence of recurrence or progres- sion, mitotane therapy and monitoring should be continued for approximately 2 years. When recur- rence is confirmed, intensification of therapy with alternative modalities (discussed later) should be considered.
Key Points FOR MITOTANE THERAPY
. Mitotane is a derivative of the insecticide DDT and is the most common adjuvant therapy.
· Adjuvant mitotane therapy is recommended for patients after complete surgical resection who have either stage III or stage IV disease and/or high-grade disease of any stage (Ki67 index >10%).
. Mitotane can induce a variety of gastrointes- tinal, hepatic, hematological, and neurologic complications in addition to multiple endo- crinopathies.
ADJUVANT RADIATION THERAPY AND OTHER LOCAL THERAPEUTIC MEASURES
Because adrenal cortical carcinoma is a rare neoplasm, there are scant data on the use of adju- vant radiation therapy after surgical resection of the primary tumor. There are no randomized and controlled data to guide treatment recommenda- tions. Data from retrospective cohort studies pro- vide the highest level of evidence available. The largest of these series characterized outcomes for 20 patients compared with controls matched for stage, tumor grade, surgical margin status, and adjuvant mitotane use. Study results suggest a benefit among patients in local recurrence rate but no improvement in recurrence-free survival or over- all survival.28 Other smaller studies did not show benefit in clinical outcomes, but these studies were limited by the inclusion of patients with gross resid- ual tumor (R2 resections) for whom therapy would not have been truly adjuvant, and patients who did not receive adjuvant mitotane.29,30 The decision to proceed with adjuvant radiation must weigh the morbidity of treatment against the probability of tu- mor recurrence for a malignancy that is not likely to be cured if tumor recurs. Adjuvant radiation with mitotane, therefore, should be considered for pa- tients with stage III R0 resection and on a case-by- case basis, for patients with any stage tumor with R1 or Rx resection or other high-risk features, including a high-grade, Ki67 greater than 10%, or intraoperative capsular rupture.
Because surgery is the only curative approach for primary adrenal cortical carcinoma, sequential surgi- cal resections have an established role in the man- agement of recurrent and metastatic tumor. For many patients, however, surgery may not be a ther- apeutic option due to comorbid disease or tumor location. Under these circumstances, local therapy with percutaneous ablation may play a role in dis- ease control. Retrospective series provide the best evidence for using this approach, although available studies included very small sample sizes and many investigations include adrenal metastases from other primary tumor sites in addition to other primary adrenal tumors, such as pheochromocytoma. A va- riety of approaches have been published, including radiofrequency ablation, cryoablation, microwave ablation, and chemoembolization. 31-36 In aggregate, the data suggest that percutaneous ablation and chemoembolization can be performed safely and may provide a measure of local control for a subset of patients. Data from Wood and colleagues36 showed that outcomes were better for tumors less than 5 cm. Although Ripley and colleagues34 found 7 of 8 patients were free of disease at the site of their
radiofrequency ablation of liver metastases, 5 of these patients developed extrahepatic metastases attesting to the need for systemic treatment.
Key Points FOR RADIATION THERAPY AND OTHER LOCAL THERAPEUTIC MEASURES
· Adjuvant radiation therapy should be consid- ered for patients with stage III R0 resection and on a case-by-case basis, for patients with any stage tumor with R1 or Rx resection or other high-risk features, including a high- grade, Ki67 greater than 10%, or intraopera- tive capsular rupture.
. Local therapy with percutaneous ablation and chemoembolization can be performed safely and can be considered on a case-by- case basis as an alternative to surgical therapy and/or systemic chemotherapy
CHEMOTHERAPY AND OTHER SYSTEMIC THERAPIES
First-line therapy for de novo metastatic or recurrent adrenal cortical carcinoma depends on a patient’s performance status and tumor characteristics. Pa- tients with more indolent tumors may be managed with mitotane alone. For those patients who can tolerate systemic chemotherapy who have aggres- sive tumor characteristics, the evidence dictating standard of care stems from the phase III randomized study FIRM-ACT trial (N = 304) that showed the su- periority of the 4-drug regimen, etoposide, doxoru- bicin, and cisplatin with mitotane (EDP-M), over the alternative regimen, streptozocin-mitotane. 18 Fassnacht and colleagues18 demonstrated a statisti- cally significant improvement in progression-free survival for EDP-M compared with streptozocin- mitotane (5.3 months vs 2.0 months). Although there was a suggestion of an overall survival advantage for EDP-M, with a median survival 14.8 months versus 12 months, respectively, and the survival curves did not come together, the difference did not reach sta- tistical significance. Patients were allowed to cross over to the alternative treatment at the time of pro- gression; therefore, it is possible that the efficacy of EDP-M may have been underestimated. Another important realization is that despite the superiority of EDP-M, the mean survival was still dismal, highlighting the limitations of even the gold standard systemic treatment and underscoring the impor- tance of using other treatment options when possible, such as targeted ablations, sequential sur- gical resections, and radiation. Patients with renal dysfunction or baseline neuropathy may not tolerate
cisplatin, and doxorubicin is contraindicated in pa- tients with poor cardiac function. Alternative first- line options include etoposide and cisplatin (or car- boplatin for patients with renal dysfunction), but this combination has only phase II data to support its use. 37,38
Well-studied second-line therapies after progres- sion on EDP-M or etoposide, cisplatin with mitotane (EP-M) include streptozocin-mitotane and gemcitabine + capecitabine, with or without mito- tane. 18,39,40 The response rates to second-line treat- ment are poor (<10%) although occasional complete responses have been documented. Tyrosine kinase inhibitors are among the other agents that have been tested, but response rates have not shown great potential; however, in at least 1 trial it was found that sunitinib levels may have been profoundly decreased due to mitotane-induced CYP3A4 activa- tion, which may have influenced the results.41 Immu- notherapies offer an appealing treatment possibility based on the tumor agnostic responses that have been observed in other solid tumor malignancies. Initial results, however, from the JAVELIN study, a phase I open-label dose escalation study of avelu- mab (an anti-PD-L1 antibody) found a disappointing overall response rate of only 6%, with a median progression-free survival of less than 3 months. 42 Several clinical trials are currently under way using combined immune checkpoint blockade with anti- CTLA4 and anti-PD-L1 agents in addition to other novel combinations. Several approaches to target the receptors for insulinlike growth factor 1, vascular endothelial growth factor, and epidermal growth fac- tor, as well as mammalian target of rapamycin (mTOR) inhibitors, have been tested without clear ev- idence of benefit.43-49
The quest for targeted and personalized thera- pies in ACC is ongoing. Molecular and genomic studies of ACC by the ENSAT and The Cancer Genome Atlas have revealed several molecular in- sights into ACC with the potential to improve risk stratification of ACC patients and basis for ratio- nale targeted treatment strategies.50-52 These in- sights, however, have not yet been translated to novel treatments or changes in clinical practice.
Key Points FOR CHEMOTHERAPY AND OTHER SYSTEMIC THERAPIES
. EDP with mitotane is the first-line regimen for systemic chemotherapy.
· Multiple clinical studies evaluating immuno- therapies and other targeted therapies for ACC are in process.
SUMMARY
The treatment of ACC continues to be challenging. The mainstay of therapy remains surgery; a com- plete surgical resection of the primary tumor is desired for optimal survival and to reduce the burden of adrenal hormone excess. Whether sub- sequent surgical debulking, radiation, or targeted cytoreduction using ablations has long-term benefit is not yet known but is a common practice that is used on a case-by-case basis. There are only a limited number of systemic medical options used for ACC and they generally are comprised of older and established agents. Adjuvant mitotane is recommended particularly in high-grade and locoregional or metastatic disease. Platinum- based chemotherapy has been shown to be the most effective regimen for advanced ACC, espe- cially when combined with mitotane. Many tar- geted therapeutics have failed to show benefit in ACC treatment; however, there are several ongoing studies, including many immunotherapy- based protocols, the results of which are with highly anticipated. Given the complexity and het- erogeneity in ACC care, highly experienced and multidisciplinary teams are likely to provide the optimal care for such patients until more standard- ized and evidence-based approaches that can be easily disseminated are available. The future advancement of ACC research will similarly require large networks and collaborative research teams to maximize potential, such as the Euro- pean Network for the Study of Adrenal Tumors (ENS@T) (http://www.ensat.org/) and the Amer- ican Australian Asian Adrenal Alliance (https:// adrenal-a5.org/).
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