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CONTINUING EDUCATION- ENDOCRINE TUMORS
Adjuvant and Neoadjuvant Therapy, Treatment for Advanced Disease, and Genetic Considerations for Adrenocortical Carcinoma: An Update from the SSO Endocrine and Head and Neck Disease Site Working Group
Paxton V. Dickson, MD1, Lawrence Kim, MD2, Tina W. F. Yen, MD, MS3, Anthony Yang, MD4, Elizabeth G. Grubbs, MD, MS5, Dhavel Patel, MD6, and Carmen C. Solórzano, MD7
1Division of Surgical Oncology, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN;
2Division of Surgical Oncology and Endocrine Surgery, University of North Carolina, Chapel Hill, NC; 3Division of Surgical Oncology, Medical College of Wisconsin, Milwaukee, WI; 4Department of Surgery, Division of Surgical Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL; 5University of Texas MD Anderson Cancer Center, Houston, TX; ‘Endocrine Oncology Branch, National Institutes of Health, Bethesda, MD; 7Division of Surgical Oncology and Endocrine Surgery, Vanderbilt University, Nashville, TN
ABSTRACT This is the second of a two-part review on adrenocortical carcinoma (ACC) management. While margin-negative resection provides the only potential cure for ACC, recurrence rates remain high. Furthermore, many patients present with locally advanced, unresectable tumors and/or diffuse metastases. As a result, selecting patients for adjuvant therapy and understanding systemic therapy options for advanced ACC is important. Herein, we detail the current literature supporting the use of adjuvant mito- tane therapy, consideration of adjuvant radiation therapy, and utility of cytotoxic chemotherapy in patients with advanced disease. Ongoing investigation into molecular targeted agents, immunotherapy, and inhibitors of steroidogenesis for the treatment of ACC are also high- lighted. Lastly, the importance of genetic counseling in patients with ACC is addressed as up to 10% of patients will have an identifiable hereditary syndrome.
Patients with adrenocortical carcinoma (ACC) often have locally advanced unresectable tumors or distant metastases at the time of diagnoses. Moreover, following
potentially curative resection, recurrence rates are high. Systemic therapy options for adjuvant use and treatment of metastatic disease are limited by both modest efficacy and significant toxicity. In addition, appreciating the associa- tion of ACC with hereditary conditions is important when evaluating these patients.
ADJUVANT AND NEOADJUVANT THERAPY
Mitotane
While complete resection is the only potentially curative treatment for ACC, high rates of recurrence make adjuvant therapy an important consideration. Despite the lack of randomized prospective data, mitotane represents the most common agent used. This is supported most notably by an interinstitutional study of 177 patients that demonstrated the addition of adjuvant mitotane to surgery for stage I-III ACC was associated with decreased recurrence (49% with mitotane vs. 73% [Italian group] and 91% [German group] without mitotane) and sustained recurrence-free survival at the subsequent 9-year follow-up.2 A review from the University of Michigan found adjuvant mitotane reduced the risk of recurrence (hazard ratio [HR] 0.723, 95% con- fidence interval [CI] 0.533-0.981), but showed no difference in overall survival.3 Other retrospective series have failed to identify a clear benefit for adjuvant mitotane. In a study from MD Anderson Cancer Center, patients who underwent index resection at that institution, the majority
@ Society of Surgical Oncology 2018
First Received: 1 April 2018
P. V. Dickson, MD e-mail: pdickso1@uthsc.edu
of whom did not receive adjuvant mitotane, had a recur- rence rate of 50%, similar to the 49% 5-year recurrence- free survival of patients in a previously cited European trial who had resection plus adjuvant mitotane.4 The authors emphasized the importance of completeness of resection, rather than adjuvant mitotane, in reducing recurrence. A recent multicenter study including 207 patients from 13 US institutions found no improvement in recurrence-free or overall survival between patients receiving or not receiving adjuvant mitotane.5 Each of the aforementioned studies is limited by their retrospective nature, inherent selection bias, use of other therapies in addition to mitotane in some patients, and heterogeneity among patients with regard to stage and other prognostic features. Importantly, the majority of studies evaluating the efficacy of adjuvant mitotane fail to include data on serum mitotane levels and duration of therapy, each important components to its potential efficacy. Despite these limitations, mitotane remains recommended for patients with known or sus- pected residual disease after resection and in those with an RO resection who have high-risk disease (Ki-67 index > 10%). The impact of adjuvant mitotane in completely resected low- to intermediate-risk European Network for the Study of Adrenal Tumors (ENSAT) stage I-III ACC is being investigated in the ADIUVO trial (NCT00777244).
Mitotane, a derivative of the pesticide dichlorodiphenyl- trichloroethane (DDT) has nuances with its administration that require dosing and management be handled by clinicians with experience in treating patients with this drug. Because mitotane has adrenolytic activity that affects both tumor and normal adrenal tissue, patients require glucorticoid supple- mentation to avoid adrenal insufficiency. In addition, patients must be monitored for potential hepatotoxicity, hypothyroidism, and hypercholesterolemia, and have careful review of medications that may have altered metabolism while taking mitotane. In general, mitotane is started at low doses, with a goal of titrating up to 6 g/day over a period of 4-12 weeks as tolerated. Ultimately, serum mitotane levels of 14-20 µg/L are targeted to achieve a therapeutic effect.6,7 The appropriate duration of adjuvant mitotane is unknown, however at least 2 years has been suggested.8 Given the time taken for mitotane to reach therapeutic levels, patients suf- fering from severe symptoms of Cushing’s syndrome should receive rapid-acting steroidogenesis inhibitors such as metyrapone or ketoconazole.9,10
Tumor Bed External Beam Radiation
Radiation therapy (XRT) is another potential adjuvant treatment, particularly in patients at high risk of local recurrence (e.g. close/positive margin, tumor capsule rup- ture/tumor spillage, tumor size > 8 cm with vascular invasion, Ki-67 > 10%)0.11 However, given the rarity of
ACC, data regarding XRT use are limited to small retro- spective analyses. An evaluation of patients from the German ACC registry found local recurrence occurred in only 2 of 14 patients who received postoperative XRT, compared with 11 of 14 patients who were matched for stage, tumor size, margin status, and receipt of adjuvant mitotane.12 Similarly, in a study of 40 patients with resectable ACC treated at the University of Michigan, local recurrence was observed in 1/20 (5%) patients treated with XRT, compared with 12/20 in the non-XRT treated group (HR 12.59, 95% CI 1.62-97.88)0.13 Although these data demonstrate a benefit with regard to decreased rates of local recurrence, the addition of XRT has not been found to offer disease-free or overall survival benefit secondary to high rates of distant relapse among these patients. Further studies are needed to determine if there is a group of patients in whom achievement of local control with XRT may confer improvement in overall survival.14
Neoadjuvant Cytotoxic Chemotherapy
While adjuvant therapy for ACC has been discussed for several decades, the concept of neoadjuvant therapy is a more recent consideration. A small retrospective study evaluated the use of neoadjuvant chemotherapy for patients with borderline resectable ACC (BRACC), defined as disease in which imaging suggests a need for en bloc multiorgan/vascular resection; imaging suggesting poten- tially resectable oligometastases; and/or patients possessing marginal performance status/comorbidities precluding immediate surgery.15 Median disease-free survival for resected BRACC patients who underwent neoadjuvant therapy was 28.0 months (95% CI 2.9-not attained) versus 13 months (95% CI 5.8-46.9; p = 0.40) for patients who underwent surgery as initial treatment for resectable dis- ease, despite the BRACC group having more advanced disease. Five-year overall survival was similar for resected neoadjuvantly treated BRACC (N = 13) versus upfront surgery patients (N = 38) [65% vs. 50%, p = 0.72]. How- ever, it is important to appreciate that 2 of 15 patients in this study initiated on ‘neoadjuvant therapy’ did not pro- ceed to resection because of disease progression or poor performance status, demonstrating the immortal time bias in this type of approach and analysis. Arguments in favor of neoadjuvant therapy for patients presenting with BRACC include initiating systemic therapy for presumed or documented metastatic disease at the earliest possible time, downsizing tumor size to increase the probability of R0 resection and minimize the magnitude of operation required, administering nephrotoxic systemic therapy prior to possible ipsilateral nephrectomy, biologic selection of patients for radical surgery to include those who have responded to induction therapy, and in vivo assessment of
the effectiveness of systemic therapy.15 Prospective ran- domized trials are required to determine which patients would most benefit from this neoadjuvant approach.
THERAPY FOR ADVANCED DISEASE
Treatment options for advanced unresectable and metastatic ACC are limited. Most regimens have included mitotane in combination with other chemotherapeutic agents. In an early phase II study of 72 patients with advanced ACC, the combination of cisplatin, etoposide, doxorubicin, and mitotane (EDP-mitotane) resulted in a complete hormonal response rate in 38% of patients with functional tumors, and an overall response rate of 49%0.16 Subsequently, the phase III FIRM-ACT study group coordinated the largest trial assessing combination chemotherapy in advanced ACC (stage III or higher).17 Patients were randomized to EDP-mitotane (n = 151) versus streptozocin plus mitotane (n = 153). The primary
endpoint was overall survival, with the ability for patients with progressive disease to cross over. Patients receiving EDP-mitotane as first-line therapy had a 23.2% response rate compared with a 9.2% response rate for those patients receiving streptozocin-mitotane (p < 0.001). Furthermore, median progression-free survival was 5.0 months for patients receiving EDP-mitotane compared with 2.1 months for the streptozocin-mitotane group (HR 0.55, 95% CI 0.43-0.69; p < 0.001). Patients receiving EDP- mitotane as second-line therapy after crossing over showed a similar increase in median progression-free survival (5.6 months vs. 2.2 months). Overall survival was not significantly different between the two regimens. Although quality of life was similar between the two treatment arms, both regimens had a high rate of serious adverse events (58% with EDP-mitotane and 42% with streptozocin-mi- totane). Another important caveat to this study was the low rate of patients in both arms who achieved therapeutic levels of mitotane (≥ 14 mg/L); therefore, the study may
| Therapy | Molecular target | Study phase | Patients enrolled | Best response (%) | Median PFS | Median OS |
|---|---|---|---|---|---|---|
| Sunitinib38 | VEGFR, PDFGR | II | 35 | SD 14.3 | 2.8 months | 5.4 months |
| PD 85.7ª | ||||||
| Axitinib44 | VEGFR | II | 13 | SD 61.5 | 5.48 months | 13.7 months |
| PD 30.8 | ||||||
| Sorafenib + paclitaxel45 | VEGFR, PDFGR, RAF-1 | II | 10 | PD 90.0 | 2 monthsb | NR |
| Bevacizumab + capecitabine4 | VEGF-A | II | 10 | PD 100.0 | 2 months | 4.1 months |
| Erlotinib + gemcitabine | EGFR | II | 10 | SD 10.0℃ | 3 months | 5.5 months |
| PD 80.0 | ||||||
| Cixutumumab + temsirolimus4 | IGF-1R + mTOR | I | 26 | SD 42.0 | 9 monthsd | NR |
| PD 57.7 | ||||||
| Cixutumumab + mitotane49 | IGF-1R | II | 20 | PR 5.0 | 6 weeks | NR |
| SD 35.0 | ||||||
| PD 60.0 | ||||||
| Linsitinib18 | IGF-1R, insulin | III | 139 (90 linsitinib, | PR 3.0e | 44 days linsitinib vs. | 323 days linsitinib vs. |
| receptor | 49 placebo) | SD 32.2 | 46 days placebo | 356 days placebo | ||
| PD 64.4 |
VEGFR vascular endothelial growth factor receptor, PDGFR platelet-derived growth factor receptor, VEGF-A vascular endothelial growth factor A, EGFR epidermal growth factor receptor, mTOR mammalian target of rapamycin, IGF-1R insulin-like growth factor 1 receptor, SD stable disease, PD progressive disease, PR partial response, NR not reported, PFS progression-free survival, OS overall survival
aSix patients died prior to evaluation and therefore had PD
“One patient interrupted treatment at 2 weeks. All nine evaluable patients progressed at the first evaluation performed after 8 weeks
“One patient had treatment stopped after the administration of the first cycle of gemcitabine due to cerebral seizures
dTime to progression reported
“Best response is shown for the linsitinib arm. There were no patients with PR in the placebo arm. SD and PD rates for the placebo arm were not different compared with the SD and PD rates for the linsitinib arm
| Syndrome | Gene (locus) | Syndrome-associated tumors | Association with ACC | Genetic testing and surveillance recommendations |
|---|---|---|---|---|
| LFS | TP53 (17p13) | Breast, brain, lung cancers, sarcoma, leukemia | Accounts for 50-80% of children with ACC | Genetic testing TP53 germline testing should be considered in all ACC patients (children and adults), regardless of family history. |
| Accounts for 4-8% of patients with adult-onset ACC ACC accounts for 10-14% of cancers in patients with LFS | Surveillance Perform annual whole-body MRI (or equivalent), preferably in the context of a longitudinal study. Provide education regarding signs and symptoms of cancer, particularly signs and symptoms of abnormal growth, virilization, precocious puberty, and Cushing syndrome in children | |||
| Overall, 6-10% of all patients with LFS have ACC | ||||
| LS | MLH1 (3p22.2) MSH2 (2p21) MSH6 (2p16.3) PMS2 (7p22.1) | Colorectal, endometrial, pancreatic and ovarian cancer, and sebaceous neoplasms | Accounts for 3% of ACC cases | Genetic testing Routine immunohistochemical screening of the four MMR proteins in ACC tumors, regardless of family history, followed by germline testing in the absence of one or more MMR proteins Surveillance No adrenal imaging or biochemical screening guidelines exist. Provide education about the increased risk of ACC and the need to evaluate any adrenal mass and signs and symptoms of adrenal hormone excess |
| MEN1 | Menin (11q13) | Primary hyperparathyroidism, Pancreatic/foregut neuroendocrine tumors, pituitary tumors | Accounts for 1-2% of ACC cases | Genetic testing Most meet the criteria for clinical or molecular diagnosis of MEN1 prior to ACC diagnosis. |
| 1% of patients with MEN1 have ACC | Surveillance No regular monitoring for ACC, but routine imaging to detect pancreatic neuroendocrine tumors typically includes the adrenal glands. | |||
| 13.8% of patients with MEN1 and adrenal tumors > 1 cm have ACC | Because of the risk of malignant transformation of pre-existing adrenal lesions, any adrenal lesion should be closely monitored with at least annual imaging, endocrine evaluation, and consideration for surgical removal, particularly if the lesion is > 4 cm, increases in size, or develops radiologically suspicious features | |||
| NF1 | NF1ª (17q11.2) | Neurofibromas, malignant peripheral nerve sheath tumors, sarcomas, breast, lung and gastrointestinal cancers | < 1% of patients with NF1 have ACC (6 case reports) | No recommendations for gene mutation screening in patients with ACC Surveillance No adrenal imaging or biochemical screening guidelines exist. Provide education about the increased risk of ACC and the need to evaluate |
| FAP | APCª (5q12- 22) | Colon cancer, duodenal cancer, desmoid tumors | < 1% of patients with FAP have ACC | any adrenal mass and signs and symptoms of adrenal hormone excess For BWS, regular screening for Wilms tumor and hepatoblastoma may |
| CNC | PRKAR1Aª (17q22.24, 2p16) | Cardiac and skin myxomas, spotty skin pigmentation and endocrine overactivity | Rare (2 case reports of ACC in patients with CNC) | visualize the adrenal gland |
| BWS | IGF-2, CDKN1C, KCNQ10T1, H19 (11p15.5) | Wilms tumor, hepatoblastoma, rhabdomyosarcoma, neuroblastoma | < 1% of children with BWS develop ACC | |
| ACCs comprise up to 10% of cancers in children with BWS |
LFS Li-Fraumeni syndrome, LS Lynch syndrome, MEN 1 multiple endocrine neoplasia 1, ACC adrenocortical carcinoma, MRI magnetic resonance imaging, MMR mismatch repair, NF1 neurofibromatosis 1, FAP familial adenomatous polyposis, CNC Carney complex, BWS Beckwith-Widemann syndrome ªOncosuppressor genes
have underestimated the efficacy of both regimens. Cur- rently, this trial provides the basis for recommending patients with advanced unresectable or metastatic ACC to receive EDP-mitotane as first-line therapy.
Due to the lack of highly effective therapies, molecular targeted agents have been investigated as treatment options. Several phase I and II studies targeting epidermal growth factor receptor (EGFR), mammalian target of rapamycin (mTOR), insulin-like growth factor 1 receptor (IGF-1R), fibroblast growth factor receptor (FGFR), and vascular endothelial growth factor (VEGF) have been conducted. Unfortunately, most have demonstrated limited efficacy (Table 1). Inhibition of the insulin-like growth factor (IGF) system was a potentially promising target given the high rates of overexpression of IGF-2 and the IGF-1R in patients with ACC. A double-blind, randomized, phase III trial enrolled 139 patients with advanced or metastatic ACC to placebo (n = 49) or linsitinib (n = 90), a potent, oral small molecular inhibitor of both IGF-1R and the insulin receptor. Unfortunately, linsitinib failed to improve progression-free or overall survival.18
Recent progress with immune checkpoint inhibitors for other relatively chemoresistant tumors such as melanoma and non-small cell lung cancer19,20 has prompted interest in exploring this line of therapy in ACC. There are currently three phase II trials listed on ClinicalTrials.gov evaluating pembrolizumab (NCT0267333), nivolumab (NCT02720 484), and combination nivolumab and ipilimumab (NC T02834013) for patients with ACC.
Another potential therapeutic target for advanced ACC is inhibition of steroid synthesis. Acetyl-CoA acetyltrans- ferase 1 (ACAT1) catalyzes the esterification of intracellular free cholesterol to acyl-CoA and is important in steroidogenesis. ACAT1 inhibition was initially evalu- ated as a treatment for atherosclerosis. Notably, the treatment resulted in significant adrenocortical toxicity in preclinical models.21 ATR-101, a selective inhibitor of ACAT1, is currently under investigation in a phase I trial (NCT101898715) for advanced ACC.
Like many malignancies, ACC can have heterogeneous patterns of behavior, and efforts should be made to tailor therapies to the best extent possible. Recent advances have been made in understanding the molecular underpinnings in the development of ACC, as well as detecting mutational profiles with prognostic implications.22-25 Furthermore, given the limited efficacy of current therapies available for advanced ACC, tumor mutational profiling performed through either institutional or commercially available testing may be used to evaluate potentially actionable tar- gets for patients progressing through standard therapy.22,23 With this accumulation of data and continued development of high-throughput molecular profiling, future efforts
should be made toward personalized management of ACC patients,9 and trials designed to account for molecular heterogeneity of this disease.
GENETIC COUNSELING
Approximately 10% of patients with ACC have an identifiable hereditary syndrome.26-28 All of the syndromes listed in Table 2 are inherited in an autosomal dominant fashion. The most commonly associated genetic syndromes are Li-Fraumeni syndrome (LFS), Lynch syndrome (LS), and multiple endocrine neoplasia 1 (MEN1).
LFS is a cancer predisposition syndrome caused by germline mutations in the TP53 gene.29 The prevalence of TP53 mutations in children with ACC is 50-80%, but only 4-8% in patients with adult-onset ACC.3º ACC accounts for 10-14% of adult cancers in patients with LFS.31 Compared with ACCs without TP53 mutations, ACCs with TP53 mutations are typically larger, with a more aggressive phenotype.32 Chompret genetic testing criteria recommend that every patient with ACC should be offered germline testing for TP53 mutations or deletions/duplications, regardless of age or family history.33
LS is a disorder due to germline mutations in genes (MLH1, MSH2, MSH6, PMS2) important for DNA mis- match repair (MMR)0.34 Recent studies have demonstrated a prevalence of LS in ACC patients of 3%, which is comparable to the prevalence of LS in colorectal (2-4%) and endometrial (1-5%) cancer.34,35 Because ACC may be the presenting malignancy in patients with LS, all ACCs should be routinely screened for microsatellite instability and immunohistochemistry for MMR proteins, followed by germline genetic testing in the absence of one or more MMR proteins. 28,36
MEN1 is a tumor syndrome caused by defects in the menin gene. Adrenal involvement (hyperplasia, nodularity, neoplasia) has been reported in up to 73% of cases, with bilateral adrenal hyperplasia being present in up to 40% of cases.37 Although ACC is rare (1%), the incidence increases to 13.8% among patients with MEN1 and adrenal tumors > 1 cm.38
The prevalence of ACC in the remaining four inherited syndromes shown in Table 2 (neurofibromatosis type 1, familial adenomatous polyposis, Beckwith-Wiedemann syndrome, and Carney complex) is extremely low (< 1%). For these reasons, there are no recommendations for rou- tine mutational screening in patients with ACC for these specific syndromes.
All patients with ACC should undergo a thorough his- tory and physical examination to evaluate for potential hereditary syndromes, and be offered genetic counseling and evaluation. They should also be offered TP53 germline
testing to assess for LFS, and all ACC tumors should be evaluated for the DNA MMR proteins to assess for LS. All other genetic testing should depend on clinical suspicion based on personal and family history.
Surveillance for Adrenocortical Carcinoma in Patients with Inherited Syndromes
ACC is not part of any screening surveillance recom- mendations for any of the predisposing hereditary conditions listed in Table 239 however, some of the recommended screening studies for other tumors may identify ACC. For LFS patients, several surveillance research protocols are ongoing and recent studies suggest the feasibility of screening for ACC, particularly in early childhood where most are hormone-secreting.40 42 The Toronto surveillance protocol suggests that physical examination, and biochemi- cal and imaging studies to evaluate for ACC, breast cancer, brain tumors, soft tissue and bone sarcoma, colorectal can- cer, melanoma, leukemia or lymphoma are feasible and that early tumor detection through surveillance is associated with improved survival.41 For ACC surveillance, the protocol recommends abdomen/pelvic ultrasound, along with 17-OH-progesterone, total testosterone, dehydroepiandros- terone sulfate and androstenedione, and 24-h urine cortisol (if possible), every 3-4 months. For children, general assessment and parent education for signs and symptoms of abnormal growth, virilization, precocious puberty, and Cushing’s syndrome should be performed. Based on these studies, current National Comprehensive Cancer Network (NCCN) guidelines recommend (category 2B) whole-body MRI (or equivalent) annually, preferably in the context of a longitudinal study (NCCN website-Genetic/Familial High- Risk Assessment: Breast and Ovarian).
For MEN1 patients, NCCN guidelines recommend patients undergo abdominal/pelvic CT or MRI imaging every 1-3 years to detect pancreatic neuroendocrine tumors, which typically includes the adrenal glands (NCCN web- site-Neuroendocrine Tumors). However, no regular monitoring for ACC is recommended because of the risk of malignant transformation of pre-existing adrenal lesions in MEN1 patients; any adrenal lesion should be closely moni- tored with annual imaging, undergo an endocrine evaluation, and be considered for surgical removal, particularly if the lesion is > 4 cm, increases in size, or develops radiologi- cally suspicious features over time. 28,38,43
CONCLUSIONS
ACC remains a difficult-to-treat cancer. Adjuvant treatment with mitotane for resected high-risk ACC con- tinues to be standard of care. Neoadjuvant chemotherapy
regimens, as well as novel targeted and immunotherapies, are actively being pursued and enrollment of these rare patients into clinical trials is of critical importance. Genetic counseling and evaluation should be considered in patients with ACC because of the association with well-defined hereditary syndromes.
DISCLOSURES None of the authors has any financial disclosures related to this work.
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