tumorsMalignant tumoursMalignant tumours2224-50572587-6813Rosoncoweb10.18027/2224-5057-2021-11-3-36-44tumors-918Research ArticleОБЗОРЫ И АНАЛИТИКАREVIEWS AND ANALYSISСовременные опции и перспективы системной терапии местнораспространенного и метастатического адренокортикального ракаСurrent options and perspectives of systemic therapy for advanced or metastatic adrenocortical cancerЖуликовЯ. А.ZhulikovYa.  A.

 Ярослав А. Жуликов, врач-онколог онкологического отделения лекарственных методов лечения (химиотерапевтического № 1)

Москва 

 Yaroslav A. Zhulikov, oncologist, Medical Oncology Department (Chemotherapy Department No. 1)

Moscow

yarikzhulikov@gmail.comКоваленкоЕ. И.KovalenkoE.  I.

 Елена И. Коваленко, к. м. н., старший научный сотрудник онкологического отделения лекарственных методов лечения (химиотерапевтического № 1)

Москва 

 Elena I. Kovalenko, MD, PhD, Senior Researcher, Medical Oncology Department (Chemotherapy Department No. 1)

 Moscow

e.i.kovalenko@mail.ruБохянВ. Ю.BokhianV.  Yu.

 Ваган Ю. Бохян, д. м. н., заведующий онкологическим отделением хирургических методов лечения (эндокринной онкологии) № 5,  профессор кафедры онкологии и лучевой терапии 

Москва 

 Vagan Yu. Bohyan, MD, PhD, DSc, Head of Surgical Oncology Department (Endocrine Oncology) No. 5, Professor, Oncology and Radiation Therapy Department

Moscow

b.vagan@mail.ruАртамоноваЕ. В.ArtamonovaE.  V.

 Елена В. Артамонова, д. м. н., заведующий онкологическим отделением лекарственных методов лечения (химиотерапевтическим № 1), профессор кафедры онкологии и лучевой терапии 

Москва 

 Elena V. Artamonova, MD, PhD, DSc, Head of Medical Oncology Department (Chemotherapy Department No. 1), Professor, Oncology and Radiation Therapy Department

 Moscow

artamonovae@mail.ruФГБУ «НМИЦ онкологии им. Н.Н. Блохина» Минздрава РоссииРоссияN. N. Blokhin National Medical Research Center of OncologyRussian FederationФГБУ «НМИЦ онкологии им. Н.Н. Блохина» Минздрава России; ФГАОУ ВО «Российский национальный исследовательский медицинский университет имени Н.И. Пирогова» Минздрава РоссииРоссияN. N. Blokhin National Medical Research Center of Oncology; Pirogov Russian National Research Medical UniversityRussian FederationФГБУ «НМИЦ онкологии им. Н.Н. Блохина» Минздрава России; ФГАОУ ВО «Российский национальный исследовательский медицинский университет имени Н.И. Пирогова» Минздрава РоссииРоссияN. N. Blokhin National Medical Research Center of Oncology; Pirogov Russian National Research Medical UniversityRussian Federation2021040120221133644Copyright © Жуликов Я.А., Коваленко Е.И., Бохян В.Ю., Артамонова Е.В., 20222022Жуликов Я.А., Коваленко Е.И., Бохян В.Ю., Артамонова Е.В.Zhulikov Y.A., Kovalenko E.I., Bokhian V.Y., Artamonova E.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.malignanttumors.org/jour/article/view/918

Адренокортикальный рак относится к орфанным опухолям и характеризуется неблагоприятным прогнозом.

Комбинация химиотерапии по схеме EDP и митотана является стандартом первой линии терапии. Эффективных опций второй и последующих линий терапии не существует. Стандартом второй линии терапии является комбинация гемцитабина, капецитабина и митотана, позволяющая добиться объективного ответа у 4–7% пациентов. Достижение терапевтической концентрации митотана — важнейший предиктивный фактор эффективности второй линии терапии по схеме GemCap +митотан, в связи с чем рекомендовано продолжать терапию митотаном даже при прогрессировании на его фоне. За последние несколько лет опубликовано много исследований, посвященных изучению эффективности таргетной и иммунотерапии адренокортикального рака, однако стандарты третьей и последующей линии терапии не определены.

В данном обзоре будет описаны современные представления и перспективы системной терапии местно-распространенного и метастатического адренокортикального рака.

Adrenocortical cancer is an orphan tumor with poor prognosis. The combination of EDP chemotherapy regimen and mitotane is the standard for the first‑line therapy. But there are no effective options for the second and consequent lines of therapy. The standard of second‑line therapy is the combination of gemcitabine, capecitabine and mitotane, which provides an objective response in 4–7 % of patients. Achievement of the therapeutic concentration of mitotane is the most important predictive factor of efficiency of GemCap + mitotane regimen, and, therefore, it is recommended to continue mitotane therapy after progression to mitotane. Recently, many researches regarding the efficiency of targeted and immunotherapy of adrenocortical cancer have been published. However, there are no standards for the third and subsequent lines of treatment. This review outlines the current views and perspectives of systemic therapy for advanced and metastatic adrenocortical cancer.

адренокортикальный ракмитотанхимиотерапияиммунотерапияadrenocortical cancermitotanechemotherapyimmunotherapyReferencesSchteingart DE, Doherty GM, Gauger PG, et al. Management of patients with adrenal cancer: recommendations of an international consensus conference. Endocr Relat Cancer. 2005;12(3):667-680.Schteingart DE, Doherty GM, Gauger PG, et al. Management of patients with adrenal cancer: recommendations of an international consensus conference. Endocr Relat Cancer. 2005;12(3):667-680.Margonis GA, Kim Y, Prescott JD, et al. Adrenocortical Carcinoma: Impact of Surgical Margin Status on Long-Term Outcomes. Ann Surg Oncol. 2016;23(1):134-141.Margonis GA, Kim Y, Prescott JD, et al. Adrenocortical Carcinoma: Impact of Surgical Margin Status on Long-Term Outcomes. Ann Surg Oncol. 2016;23(1):134-141.Fassnacht M, Johanssen S, Quinkler M, et al. Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a Revised TNM Classification. Cancer. 2009;115(2):243-250.Fassnacht M, Johanssen S, Quinkler M, et al. Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a Revised TNM Classification. Cancer. 2009;115(2):243-250.Kerkhofs TM, Verhoeven RH, Van der Zwan JM, et al. Adrenocortical carcinoma: a population-based study on inci-dence and survival in the Netherlands since 1993. Eur J Cancer. 2013;49(11):2579-2586.Kerkhofs TM, Verhoeven RH, Van der Zwan JM, et al. Adrenocortical carcinoma: a population-based study on inci-dence and survival in the Netherlands since 1993. Eur J Cancer. 2013;49(11):2579-2586.Icard P, Goudet P, Charpenay C, et al. Adrenocortical carcinomas: surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons study group. World J Surg. 2001;25(7):891-897.Icard P, Goudet P, Charpenay C, et al. Adrenocortical carcinomas: surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons study group. World J Surg. 2001;25(7):891-897.Lughezzani G, Sun M, Perrotte P, et al. The European Network for the Study of Adrenal Tumors staging system is prognostically superior to the international union against cancer-staging system: a North American validation. Eur J Cancer. 2010;46(4):713-719.Lughezzani G, Sun M, Perrotte P, et al. The European Network for the Study of Adrenal Tumors staging system is prognostically superior to the international union against cancer-staging system: a North American validation. Eur J Cancer. 2010;46(4):713-719.Megerle F, Herrmann W, Schloetelburg W, et al. Mitotane Monotherapy in Patients With Advanced Adrenocortical Carcinoma. J Clin Endocrinol Metab. 2018;103(4):1686-1695Megerle F, Herrmann W, Schloetelburg W, et al. Mitotane Monotherapy in Patients With Advanced Adrenocortical Carcinoma. J Clin Endocrinol Metab. 2018;103(4):1686-1695Hermsen IG, Fassnacht M, Terzolo M, et al. Plasma concentrations of o,p’DDD, o,p’DDA, and o,p’DDE as predictors of tumor response to mitotane in adrenocortical carcinoma: results of a retrospective ENS@T multicenter study. J Clin Endocrinol Metab. 2011;96(6):1844-1851.Hermsen IG, Fassnacht M, Terzolo M, et al. Plasma concentrations of o,p’DDD, o,p’DDA, and o,p’DDE as predictors of tumor response to mitotane in adrenocortical carcinoma: results of a retrospective ENS@T multicenter study. J Clin Endocrinol Metab. 2011;96(6):1844-1851.Zhulikov Ya.A., Kovalenko E.I., Bohyan V.Yu. et al. Efficacy of EDP ± mitotane chemotherapy in the treatment of met-astatic adrenocortical carcinoma. Predictive and prognostic factors of efficacy. Malignant tumours. 2021;11(1):37-46. (In Russ.) https://doi.org/10.18027/2224-5057-2021-11-1-37-46Zhulikov Ya.A., Kovalenko E.I., Bohyan V.Yu. et al. Efficacy of EDP ± mitotane chemotherapy in the treatment of met-astatic adrenocortical carcinoma. Predictive and prognostic factors of efficacy. Malignant tumours. 2021;11(1):37-46. (In Russ.) https://doi.org/10.18027/2224-5057-2021-11-1-37-46Fassnacht M, Terzolo M, Allolio B, et al. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med. 2012;366(23):2189-2197. PMID: 22551107. DOI: 10.1056/NEJMoa1200966.Fassnacht M, Terzolo M, Allolio B, et al. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med. 2012;366(23):2189-2197. PMID: 22551107. DOI: 10.1056/NEJMoa1200966.Sperone P, Ferrero A, Daffara F, et al. Gemcitabine plus metronomic 5-fluorouracil or capecitabine as a second-/third-line chemotherapy in advanced adrenocortical carcinoma: a multicenter phase II study. Endocr Relat Cancer. 2010;17(2):445-453.Sperone P, Ferrero A, Daffara F, et al. Gemcitabine plus metronomic 5-fluorouracil or capecitabine as a second-/third-line chemotherapy in advanced adrenocortical carcinoma: a multicenter phase II study. Endocr Relat Cancer. 2010;17(2):445-453.Henning JEK, Deutschbein T, Altieri B, et al. Gemcitabine-Based Chemotherapy in Adrenocortical Carcinoma: A Multicenter Study of Efficacy and Predictive Factors. J Clin Endocrinol Metab. 2017;102(11):4323-4332.Henning JEK, Deutschbein T, Altieri B, et al. Gemcitabine-Based Chemotherapy in Adrenocortical Carcinoma: A Multicenter Study of Efficacy and Predictive Factors. J Clin Endocrinol Metab. 2017;102(11):4323-4332.Ardolino L, Hansen A, Ackland S, Joshua A. Advanced Adrenocortical Carcinoma (ACC): a Review with Focus on Second-Line Therapies. Horm Cancer. 2020.Ardolino L, Hansen A, Ackland S, Joshua A. Advanced Adrenocortical Carcinoma (ACC): a Review with Focus on Second-Line Therapies. Horm Cancer. 2020.ZGonzalez RJ, Tamm EP, Ng C, et al. Response to mitotane predicts outcome in patients with recurrent adrenal cor-tical carcinoma. Surgery. 2007;142(6):867-875; discussion 867-875. PMID: 18063070. DOI: 10.1016/j.surg.2007.09.006.ZGonzalez RJ, Tamm EP, Ng C, et al. Response to mitotane predicts outcome in patients with recurrent adrenal cor-tical carcinoma. Surgery. 2007;142(6):867-875; discussion 867-875. PMID: 18063070. DOI: 10.1016/j.surg.2007.09.006.Terzolo M, Baudin AE, Ardito A, et al. Mitotane levels predict the outcome of patients with adrenocortical carcinoma treated adjuvantly following radical resection. Eur J Endocrinol. 2013;169(3):263-270. PMID: 23704714. DOI: 10.1530/EJE-13-0242Terzolo M, Baudin AE, Ardito A, et al. Mitotane levels predict the outcome of patients with adrenocortical carcinoma treated adjuvantly following radical resection. Eur J Endocrinol. 2013;169(3):263-270. PMID: 23704714. DOI: 10.1530/EJE-13-0242van Slooten H, Moolenaar AJ, van Seters AP, Smeenk D. The treatment of adrenocortical carcinoma with o,p’-DDD: prognostic implications of serum level monitoring. Eur J Cancer Clin Oncol. 1984;20(1):47-53.van Slooten H, Moolenaar AJ, van Seters AP, Smeenk D. The treatment of adrenocortical carcinoma with o,p’-DDD: prognostic implications of serum level monitoring. Eur J Cancer Clin Oncol. 1984;20(1):47-53.Fassnacht M, Dekkers OM, Else T, et al. European Society of Endocrinology Clinical Practice Guidelines on the man-agement of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2018;179(4):G1-G46.Fassnacht M, Dekkers OM, Else T, et al. European Society of Endocrinology Clinical Practice Guidelines on the man-agement of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2018;179(4):G1-G46.Postlewait LM, Ethun CG, Tran TB, et al. Outcomes of Adjuvant Mitotane after Resection of Adrenocortical Carci-noma: A 13-Institution Study by the US Adrenocortical Carcinoma Group. J Am Coll Surg. 2016;222(4):480-490.Postlewait LM, Ethun CG, Tran TB, et al. Outcomes of Adjuvant Mitotane after Resection of Adrenocortical Carci-noma: A 13-Institution Study by the US Adrenocortical Carcinoma Group. J Am Coll Surg. 2016;222(4):480-490.Terzolo M, Baudin AE, Ardito A, et al. Mitotane levels predict the outcome of patients with adrenocortical carcinoma treated adjuvantly following radical resection. Eur J Endocrinol. 2013;169(3):263-270.Terzolo M, Baudin AE, Ardito A, et al. Mitotane levels predict the outcome of patients with adrenocortical carcinoma treated adjuvantly following radical resection. Eur J Endocrinol. 2013;169(3):263-270.Kerkhofs TM, Baudin E, Terzolo M, et al. Comparison of two mitotane starting dose regimens in patients with ad-vanced adrenocortical carcinoma. J Clin Endocrinol Metab. 2013;98(12):4759-4767.Kerkhofs TM, Baudin E, Terzolo M, et al. Comparison of two mitotane starting dose regimens in patients with ad-vanced adrenocortical carcinoma. J Clin Endocrinol Metab. 2013;98(12):4759-4767.Berruti A, Terzolo M, Pia A, Angeli A, Dogliotti L. Mitotane associated with etoposide, doxorubicin, and cisplatin in the treatment of advanced adrenocortical carcinoma. Italian Group for the Study of Adrenal Cancer. Cancer. 1998;83(10):2194-2200.Berruti A, Terzolo M, Pia A, Angeli A, Dogliotti L. Mitotane associated with etoposide, doxorubicin, and cisplatin in the treatment of advanced adrenocortical carcinoma. Italian Group for the Study of Adrenal Cancer. Cancer. 1998;83(10):2194-2200.Matthew T. Campbell, Emily Lemke, Khaled M. Elsayes et al. A retrospective analysis of carboplatin plus etoposide in patients with adrenal cortical carcinoma. Journal of Clinical Oncology 2018 36:15_suppl, e16591-e16591. DOI: 10.1200/JCO.2018.36.15_suppl.e16591Matthew T. Campbell, Emily Lemke, Khaled M. Elsayes et al. A retrospective analysis of carboplatin plus etoposide in patients with adrenal cortical carcinoma. Journal of Clinical Oncology 2018 36:15_suppl, e16591-e16591. DOI: 10.1200/JCO.2018.36.15_suppl.e16591Urup, T., Pawlak, W. Z., Petersen, P. M. et al. Treatment with docetaxel and cisplatin in advanced adrenocortical carcinoma, a phase II study. British journal of cancer, 108(10), 1994–1997. https://doi.org/10.1038/bjc.2013.229Urup, T., Pawlak, W. Z., Petersen, P. M. et al. Treatment with docetaxel and cisplatin in advanced adrenocortical carcinoma, a phase II study. British journal of cancer, 108(10), 1994–1997. https://doi.org/10.1038/bjc.2013.229Laganа M, Grisanti S, Cosentini D, et al. Efficacy of the EDP-M Scheme Plus Adjunctive Surgery in the Management of Patients with Advanced Adrenocortical Carcinoma: The Brescia Experience. Cancers (Basel). 2020;12(4).Laganа M, Grisanti S, Cosentini D, et al. Efficacy of the EDP-M Scheme Plus Adjunctive Surgery in the Management of Patients with Advanced Adrenocortical Carcinoma: The Brescia Experience. Cancers (Basel). 2020;12(4).Creemers SG, van Koetsveld PM, van den Dungen ES, et al. Inhibition of Human Adrenocortical Cancer Cell Growth by Temozolomide in Vitro and the Role of the MGMT Gene. J Clin Endocrinol Metab. 2016;101(12):4574-4584.Creemers SG, van Koetsveld PM, van den Dungen ES, et al. Inhibition of Human Adrenocortical Cancer Cell Growth by Temozolomide in Vitro and the Role of the MGMT Gene. J Clin Endocrinol Metab. 2016;101(12):4574-4584.Cosentini D, Badalamenti G, Grisanti S, et al. Activity and safety of temozolomide in advanced adrenocortical car-cinoma patients. Eur J Endocrinol. 2019;181(6):681-689.Cosentini D, Badalamenti G, Grisanti S, et al. Activity and safety of temozolomide in advanced adrenocortical car-cinoma patients. Eur J Endocrinol. 2019;181(6):681-689.Cosentini D., Turla A., Carminati O. et al. Case Report: Exceptional Response to Second Line Temozolomide Therapy in a Patient With Metastatic Adrenocortical Carcinoma. Frontiers in Endocrinology 2021; 12: 407 10.3389/fendo.2021.674039Cosentini D., Turla A., Carminati O. et al. Case Report: Exceptional Response to Second Line Temozolomide Therapy in a Patient With Metastatic Adrenocortical Carcinoma. Frontiers in Endocrinology 2021; 12: 407 10.3389/fendo.2021.674039Ferrero A., Sperone P, Ardito A. et al. Metronomic chemotherapy may be active in heavily pre-treated patients with metastatic adreno-cortical carcinoma. J Endocrinol Invest. 2013 Mar;36(3):148-52. doi: 10.3275/8334. Epub 2012 Apr 5. PMID: 22522572.Ferrero A., Sperone P, Ardito A. et al. Metronomic chemotherapy may be active in heavily pre-treated patients with metastatic adreno-cortical carcinoma. J Endocrinol Invest. 2013 Mar;36(3):148-52. doi: 10.3275/8334. Epub 2012 Apr 5. PMID: 22522572.de Reynius A, Assiu G, Rickman DS, et al. Gene expression profiling reveals a new classification of adrenocortical tumors and identifies molecular predictors of malignancy and survival. J Clin Oncol. 2009;27(7):1108-1115.de Reynius A, Assiu G, Rickman DS, et al. Gene expression profiling reveals a new classification of adrenocortical tumors and identifies molecular predictors of malignancy and survival. J Clin Oncol. 2009;27(7):1108-1115.de Fraipont F, El Atifi M, Cherradi N, et al. Gene expression profiling of human adrenocortical tumors using com-plementary deoxyribonucleic Acid microarrays identifies several candidate genes as markers of malignancy. J Clin Endocrinol Metab. 2005;90(3):1819-1829.de Fraipont F, El Atifi M, Cherradi N, et al. Gene expression profiling of human adrenocortical tumors using com-plementary deoxyribonucleic Acid microarrays identifies several candidate genes as markers of malignancy. J Clin Endocrinol Metab. 2005;90(3):1819-1829.Fassnacht M, Berruti A, Baudin E, et al. Linsitinib (OSI-906) versus placebo for patients with locally advanced or metastatic adrenocortical carcinoma: a double-blind, randomised, phase 3 study. Lancet Oncol. 2015;16(4):426-435.Fassnacht M, Berruti A, Baudin E, et al. Linsitinib (OSI-906) versus placebo for patients with locally advanced or metastatic adrenocortical carcinoma: a double-blind, randomised, phase 3 study. Lancet Oncol. 2015;16(4):426-435.Berruti A, Sperone P, Ferrero A, et al. Phase II study of weekly paclitaxel and sorafenib as second/third-line therapy in patients with adrenocortical carcinoma. Eur J Endocrinol. 2012;166(3):451-458.Berruti A, Sperone P, Ferrero A, et al. Phase II study of weekly paclitaxel and sorafenib as second/third-line therapy in patients with adrenocortical carcinoma. Eur J Endocrinol. 2012;166(3):451-458.O’Sullivan C, Edgerly M, Velarde M, et al. The VEGF inhibitor axitinib has limited effectiveness as a therapy for adrenocortical cancer. J Clin Endocrinol Metab. 2014;99(4):1291-1297.O’Sullivan C, Edgerly M, Velarde M, et al. The VEGF inhibitor axitinib has limited effectiveness as a therapy for adrenocortical cancer. J Clin Endocrinol Metab. 2014;99(4):1291-1297.Quinkler M, Hahner S, Wortmann S, et al. Treatment of advanced adrenocortical carcinoma with erlotinib plus gemcitabine. J Clin Endocrinol Metab. 2008;93(6):2057-2062.Quinkler M, Hahner S, Wortmann S, et al. Treatment of advanced adrenocortical carcinoma with erlotinib plus gemcitabine. J Clin Endocrinol Metab. 2008;93(6):2057-2062.Kroiss M, Quinkler M, Johanssen S, et al. Sunitinib in refractory adrenocortical carcinoma: a phase II, single-arm, open-label trial. J Clin Endocrinol Metab. 2012;97(10):3495-3503.Kroiss M, Quinkler M, Johanssen S, et al. Sunitinib in refractory adrenocortical carcinoma: a phase II, single-arm, open-label trial. J Clin Endocrinol Metab. 2012;97(10):3495-3503.van Erp NP, Guchelaar HJ, Ploeger BA, Romijn JA, Hartigh J, Gelderblom H. Mitotane has a strong and a durable inducing effect on CYP3A4 activity. Eur J Endocrinol. 2011;164(4):621-626.van Erp NP, Guchelaar HJ, Ploeger BA, Romijn JA, Hartigh J, Gelderblom H. Mitotane has a strong and a durable inducing effect on CYP3A4 activity. Eur J Endocrinol. 2011;164(4):621-626.Kroiss M, Megerle F, Kurlbaum M, et al. Objective Response and Prolonged Disease Control of Advanced Adrenocor-tical Carcinoma with Cabozantinib. J Clin Endocrinol Metab. 2020;105(5).Kroiss M, Megerle F, Kurlbaum M, et al. Objective Response and Prolonged Disease Control of Advanced Adrenocor-tical Carcinoma with Cabozantinib. J Clin Endocrinol Metab. 2020;105(5).Nguyen L, Holland J, Miles D, et al. Pharmacokinetic (PK) drug interaction studies of cabozantinib: Effect of CYP3A inducer rifampin and inhibitor ketoconazole on cabozantinib plasma PK and effect of cabozantinib on CYP2C8 probe substrate rosiglitazone plasma PK. J Clin Pharmacol. 2015;55(9):1012-1023.Nguyen L, Holland J, Miles D, et al. Pharmacokinetic (PK) drug interaction studies of cabozantinib: Effect of CYP3A inducer rifampin and inhibitor ketoconazole on cabozantinib plasma PK and effect of cabozantinib on CYP2C8 probe substrate rosiglitazone plasma PK. J Clin Pharmacol. 2015;55(9):1012-1023.Maqsood MH, Tameez Ud Din A, Khan AH. Neuroendocrine Tumor Therapy with Lutetium-177: A Literature Review. Cureus. 2019 Jan 30;11(1):e3986. doi: 10.7759/cureus.3986. PMID: 30972265; PMCID: PMC6443107.Maqsood MH, Tameez Ud Din A, Khan AH. Neuroendocrine Tumor Therapy with Lutetium-177: A Literature Review. Cureus. 2019 Jan 30;11(1):e3986. doi: 10.7759/cureus.3986. PMID: 30972265; PMCID: PMC6443107.Roslyakova A, Selivanova L, Tarasova A et al. Somatostatin receptors 2A and 5 expression in adrenocortical cancer. Endocrine Abstracts (2020) 70 AEP41 | DOI: 10.1530/endoabs.70.AEP41Roslyakova A, Selivanova L, Tarasova A et al. Somatostatin receptors 2A and 5 expression in adrenocortical cancer. Endocrine Abstracts (2020) 70 AEP41 | DOI: 10.1530/endoabs.70.AEP41Kolomeytseva A.A., Delektorskaya V.V., Orel N.F. et al. Somatostatin receptors as potentialtherapeutic targets in the treatment of advanced adrenocortical cancer. A case report. Siberian journal of oncology 2018;17(2):111-117. (In Russ.) https://doi.org/10.21294/1814-4861-2018-17-2-111-117Kolomeytseva A.A., Delektorskaya V.V., Orel N.F. et al. Somatostatin receptors as potentialtherapeutic targets in the treatment of advanced adrenocortical cancer. A case report. Siberian journal of oncology 2018;17(2):111-117. (In Russ.) https://doi.org/10.21294/1814-4861-2018-17-2-111-117Mariniello B, Finco I, Sartorato P et al. Somatostatin receptor expression in adrenocortical tumors and effect of a new somatostatin analog SOM230 on hormone secretion in vitro and in ex vivo adrenal cells. J Endocrinol Invest. 2011 Jun;34(6):e131-8. doi: 10.1007/BF03346721. Epub 2010 Oct 27. PMID: 21042045.Mariniello B, Finco I, Sartorato P et al. Somatostatin receptor expression in adrenocortical tumors and effect of a new somatostatin analog SOM230 on hormone secretion in vitro and in ex vivo adrenal cells. J Endocrinol Invest. 2011 Jun;34(6):e131-8. doi: 10.1007/BF03346721. Epub 2010 Oct 27. PMID: 21042045.Wang X, Zhou N, Xiao Y et al. Metastatic Adrenal Cortical Carcinoma Responding to Octreotide: A Case Report. Oncologist. 2019 Aug;24(8):e793-e797. doi: 10.1634/theoncologist.2018-0855. Epub 2019 May 9. PMID: 31073023; PM-CID: PMC6693704.Wang X, Zhou N, Xiao Y et al. Metastatic Adrenal Cortical Carcinoma Responding to Octreotide: A Case Report. Oncologist. 2019 Aug;24(8):e793-e797. doi: 10.1634/theoncologist.2018-0855. Epub 2019 May 9. PMID: 31073023; PM-CID: PMC6693704.Grisanti, S., Filice, A., Basile, V. et al. Treatment With 90Y/177Lu-DOTATOC in Patients With Metastatic Adrenocor-tical Carcinoma Expressing Somatostatin Receptors. J Clin Endocrinol Metab. 2020 Mar 1;105(3):dgz091. doi: 10.1210/clinem/dgz091. PMID: 31633759.Grisanti, S., Filice, A., Basile, V. et al. Treatment With 90Y/177Lu-DOTATOC in Patients With Metastatic Adrenocor-tical Carcinoma Expressing Somatostatin Receptors. J Clin Endocrinol Metab. 2020 Mar 1;105(3):dgz091. doi: 10.1210/clinem/dgz091. PMID: 31633759.Lippert J, Appenzeller S, Liang R, et al. Targeted Molecular Analysis in Adrenocortical Carcinomas: A Strategy To-ward Improved Personalized Prognostication. J Clin Endocrinol Metab. 2018;103(12):4511-4523.Lippert J, Appenzeller S, Liang R, et al. Targeted Molecular Analysis in Adrenocortical Carcinomas: A Strategy To-ward Improved Personalized Prognostication. J Clin Endocrinol Metab. 2018;103(12):4511-4523.Raymond VM, Everett JN, Furtado LV, et al. Adrenocortical carcinoma is a lynch syndrome-associated cancer. J Clin Oncol. 2013;31(24):3012-3018.Raymond VM, Everett JN, Furtado LV, et al. Adrenocortical carcinoma is a lynch syndrome-associated cancer. J Clin Oncol. 2013;31(24):3012-3018.Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015;372(26):2509-2520.Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015;372(26):2509-2520.Morse MA, Overman MJ, Hartman L, et al. Safety of Nivolumab plus Low-Dose Ipilimumab in Previously Treated Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer. Oncologist. 2019;24(11):1453-1461.Morse MA, Overman MJ, Hartman L, et al. Safety of Nivolumab plus Low-Dose Ipilimumab in Previously Treated Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer. Oncologist. 2019;24(11):1453-1461.Le Tourneau C, Hoimes C, Zarwan C, et al. Avelumab in patients with previously treated metastatic adrenocortical carcinoma: phase 1b results from the JAVELIN solid tumor trial. J Immunother Cancer. 2018;6(1):111.Le Tourneau C, Hoimes C, Zarwan C, et al. Avelumab in patients with previously treated metastatic adrenocortical carcinoma: phase 1b results from the JAVELIN solid tumor trial. J Immunother Cancer. 2018;6(1):111.Benedito AC, Bhavana K, Rubens BC et al. Nivolumab in Metastatic Adrenocortical Carcinoma: Results of a Phase 2 Trial, The Journal of Clinical Endocrinology & Metabolism, Volume 104, Issue 12, December 2019, Pages 6193–6200, https://doi.org/10.1210/jc.2019-00600Benedito AC, Bhavana K, Rubens BC et al. Nivolumab in Metastatic Adrenocortical Carcinoma: Results of a Phase 2 Trial, The Journal of Clinical Endocrinology & Metabolism, Volume 104, Issue 12, December 2019, Pages 6193–6200, https://doi.org/10.1210/jc.2019-00600Klein O, Senko C, Carlino MS et al. Combination immunotherapy with ipilimumab and nivolumab in patients with advanced adrenocortical carcinoma: a subgroup analysis of CA209-538. OncoImmunology 2021; 10(1).Klein O, Senko C, Carlino MS et al. Combination immunotherapy with ipilimumab and nivolumab in patients with advanced adrenocortical carcinoma: a subgroup analysis of CA209-538. OncoImmunology 2021; 10(1).Raj N, Zheng Y, Kelly V, et al. PD-1 Blockade in Advanced Adrenocortical Carcinoma. J Clin Oncol. 2020;38(1):71-80.Raj N, Zheng Y, Kelly V, et al. PD-1 Blockade in Advanced Adrenocortical Carcinoma. J Clin Oncol. 2020;38(1):71-80.Stah MH, Goldner WS, Benson AI B et al. NCCN Guidelines in Oncology Neuroendocrine and Adrenal Tumors Version 3.2021.Stah MH, Goldner WS, Benson AI B et al. NCCN Guidelines in Oncology Neuroendocrine and Adrenal Tumors Version 3.2021.Chung-Han Lee, Amishi Yogesh Shah, James J Hsieh et al. Phase II trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) for disease progression after PD-1/PD-L1 immune checkpoint inhibitor (ICI) in metastatic clear cell renal cell carcinoma (mccRCC). Journal of Clinical Oncology 2020 38:15_suppl, 5008-5008. DOI: 10.1200/JCO.2020.38.15_suppl.5008Chung-Han Lee, Amishi Yogesh Shah, James J Hsieh et al. Phase II trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) for disease progression after PD-1/PD-L1 immune checkpoint inhibitor (ICI) in metastatic clear cell renal cell carcinoma (mccRCC). Journal of Clinical Oncology 2020 38:15_suppl, 5008-5008. DOI: 10.1200/JCO.2020.38.15_suppl.5008Makker V, Taylor MH, Aghajanian C et al. Lenvatinib Plus Pembrolizumab in Patients With Advanced Endometrial Cancer. Journal of Clinical Oncology 2020 38:26, 2981-2992Makker V, Taylor MH, Aghajanian C et al. Lenvatinib Plus Pembrolizumab in Patients With Advanced Endometrial Cancer. Journal of Clinical Oncology 2020 38:26, 2981-2992Arance Fernandez AM, O’Day SJ, de la Cruz Merino L, et al: Lenvatinib plus pembrolizumab for advanced melanoma that progressed on a PD-1 or PD-L1 inhibitor: Initial results of LEAP-004. ESMO Virtual Congress 2020: Abstract LBA44.Arance Fernandez AM, O’Day SJ, de la Cruz Merino L, et al: Lenvatinib plus pembrolizumab for advanced melanoma that progressed on a PD-1 or PD-L1 inhibitor: Initial results of LEAP-004. ESMO Virtual Congress 2020: Abstract LBA44.Combined lenvatinib and pembrolizumab as salvage therapy in advanced adrenal cortical carcinoma. doi: 10.1136/jitc-2020-001009.Combined lenvatinib and pembrolizumab as salvage therapy in advanced adrenal cortical carcinoma. doi: 10.1136/jitc-2020-001009.

The authors declare that there are no conflicts of interest present.