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Exp Clin Endocrinol Diabetes 2019; 127(02/03): 109-116
DOI: 10.1055/a-0715-1946
Review
© Georg Thieme Verlag KG Stuttgart · New York

Advanced Adrenocortical Carcinoma – What to do when First-Line Therapy Fails?

Felix Megerle
1   Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital Würzburg, University of Würzburg, Germany
,
Matthias Kroiss
2   Comprehensive Cancer Center Mainfranken, University of Würzburg, Germany
,
Stefanie Hahner
1   Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital Würzburg, University of Würzburg, Germany
,
Martin Fassnacht
1   Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital Würzburg, University of Würzburg, Germany
2   Comprehensive Cancer Center Mainfranken, University of Würzburg, Germany
› Author Affiliations
Further Information

Publication History

received 09 July 2018
revised 20 August 2018

accepted 23 August 2018

Publication Date:
23 November 2018 (online)

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Abstract

Adrenocortical carcinoma is a rare endocrine malignant disease with a generally unfavorable but heterogeneous prognosis. Although even in advanced stages a subset of patients experiences long-term disease stabilisation, effective systemic treatment options are limited. Mitotane is the only approved drug and the combination of etoposide, doxorubicin and cisplatin (plus mitotane) is currently considered as treatment standard for advanced adrenocortical carcinoma based on the results of a large randomized phase III trial. However, progression-free survival is often limited and further treatment options are frequently needed. Here we summarize the current knowledge about second and third-line therapeutic modalities (local and systemic) in advanced disease. Following the recent ESE-ENSAT guidelines local therapies play an important role for these patients. Regarding systemic therapies the best data are available for gemcitabine+capecitabine or streptozotocin (both with or without mitotane). Furthermore, we introduce our own approach to patients with advanced adrenocortical carcinoma based on our experience as a large multidisciplinary clinic dedicated to the care of patients with this orphan disease.

Key words

adrenal cancer - ACC - second line therapy
 

  • References

  • 1 Berruti A, Baudin E, Gelderblom H. et al. Adrenal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012; 23 (Suppl. 07) vii131-vii138
    CrossrefPubMedGoogle Scholar
  • 2 Else T, Kim AC, Sabolch A. et al. Adrenocortical carcinoma. Endocr Rev 2014; 35: 282-326
    CrossrefPubMedGoogle Scholar
  • 3 Fassnacht M, Dekkers OM, Else T. et al. Management of adrenocortical carcinoma in adult patients - A European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol 2018; 2018 Jul 24. pii: EJE-18-0608. DOI: 10.1530/EJE-18-0608.
    CrossrefPubMedGoogle Scholar
  • 4 Abiven G, Coste J, Groussin L. et al. Clinical and biological features in the prognosis of adrenocortical cancer: poor outcome of cortisol-secreting tumors in a series of 202 consecutive patients. J Clin Endocrinol Metab 2006; 91: 2650-2655
    CrossrefPubMedGoogle Scholar
  • 5 Assie G, Antoni G, Tissier F. et al. Prognostic parameters of metastatic adrenocortical carcinoma. J Clin Endocrinol Metab 2007; 92: 148-154
    CrossrefPubMedGoogle Scholar
  • 6 Fassnacht M, Allolio B. Clinical management of adrenocortical carcinoma. Best Pract Res Clin Endocrinol Metab 2009; 23: 273-289
    CrossrefPubMedGoogle Scholar
  • 7 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: 891-897
    CrossrefPubMedGoogle Scholar
  • 8 Libe R. Adrenocortical carcinoma (ACC): Diagnosis, prognosis, and treatment. Front Cell Dev Biol 2015; 3: 45
    CrossrefPubMedGoogle Scholar
  • 9 Hermsen IG, Gelderblom H, Kievit J. et al. Extremely long survival in six patients despite recurrent and metastatic adrenal carcinoma. Eur J Endocrinol 2008; 158: 911-919
    CrossrefPubMedGoogle Scholar
  • 10 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: 667-680
    CrossrefPubMedGoogle Scholar
  • 11 Terzolo M, Angeli A, Fassnacht M. et al. Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med 2007; 356: 2372-2380
    CrossrefPubMedGoogle Scholar
  • 12 Megerle F, Herrmann W, Schloetelburg W. et al. Mitotane monotherapy in patients with advanced adrenocortical carcinoma. J Clin Endocrinol Metab 2018; DOI: 10.1210/jc.2017-02591.
    CrossrefPubMedGoogle Scholar
  • 13 Baudin E, Pellegriti G, Bonnay M. et al. Impact of monitoring plasma 1,1-dichlorodiphenildichloroethane (o,p'DDD) levels on the treatment of patients with adrenocortical carcinoma. Cancer 2001; 92: 1385-1392
    CrossrefPubMedGoogle Scholar
  • 14 Haak HR, Hermans J, van de Velde CJ. et al. Optimal treatment of adrenocortical carcinoma with mitotane: results in a consecutive series of 96 patients. Br J Cancer 1994; 69: 947-951
    CrossrefPubMedGoogle Scholar
  • 15 van Slooten H, Moolenaar AJ, van Seters AP. et al. The treatment of adrenocortical carcinoma with o,p'-DDD: Prognostic implications of serum level monitoring. Eur J Cancer Clin Oncol 1984; 20: 47-53
    CrossrefPubMedGoogle Scholar
  • 16 Fassnacht M, Terzolo M, Allolio B. et al. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med 2012; 366: 2189-2197
    CrossrefPubMedGoogle Scholar
  • 17 Wood BJ, Abraham J, Hvizda JL. et al. Radiofrequency ablation of adrenal tumors and adrenocortical carcinoma metastases. Cancer 2003; 97: 554-560
    CrossrefPubMedGoogle Scholar
  • 18 Cazejust J, De Baere T, Auperin A. et al. Transcatheter arterial chemoembolization for liver metastases in patients with adrenocortical carcinoma. J Vasc Interv Radiol 2010; 21: 1527-1532
    CrossrefPubMedGoogle Scholar
  • 19 Wong E, Jacques S, Bennett M. et al. Complete response in a patient with stage IV adrenocortical carcinoma treated with adjuvant trans-catheter arterial chemo-embolization (TACE). Asia Pac J Clin Oncol 2017; DOI: 10.1111/ajco.12759.
    CrossrefPubMedGoogle Scholar
  • 20 Li SH, Huang CH, Ko SF. et al. Extended survival in a patient with recurrent and metastatic adrenal cortical carcinoma by aggressive transarterial embolization–a case report. J Surg Oncol 2005; 90: 101-105
    CrossrefPubMedGoogle Scholar
  • 21 Luton JP, Cerdas S, Billaud L. et al. Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. N Engl J Med 1990; 322: 1195-1201
    CrossrefPubMedGoogle Scholar
  • 22 Pommier RF, Brennan MF. An eleven-year experience with adrenocortical carcinoma. Surgery 1992; 112: 963-970 discussion 970-961
    PubMedGoogle Scholar
  • 23 Fassnacht M, Hahner S, Polat B. et al. Efficacy of adjuvant radiotherapy of the tumor bed on local recurrence of adrenocortical carcinoma. J Clin Endocrinol Metab 2006; 91: 4501-4504
    CrossrefPubMedGoogle Scholar
  • 24 Ho J, Turkbey B, Edgerly M. et al. Role of radiotherapy in adrenocortical carcinoma. Cancer J 2013; 19: 288-294
    CrossrefPubMedGoogle Scholar
  • 25 Polat B, Fassnacht M, Pfreundner L. et al. Radiotherapy in adrenocortical carcinoma. Cancer 2009; 115: 2816-2823
    CrossrefPubMedGoogle Scholar
  • 26 Sabolch A, Feng M, Griffith K. et al. Adjuvant and definitive radiotherapy for adrenocortical carcinoma. Int J Radiat Oncol Biol Phys 2011; 80: 1477-1484
    CrossrefPubMedGoogle Scholar
  • 27 Pin Y, Paix A, Le Fevre C. et al. A systematic review of palliative bone radiotherapy based on pain relief and retreatment rates. Crit Rev Oncol Hematol 2018; 123: 132-137
    CrossrefPubMedGoogle Scholar
  • 28 Li X, Fan W, Zhang L. et al. CT-guided percutaneous microwave ablation of adrenal malignant carcinoma: Preliminary results. Cancer 2011; 117: 5182-5188
    CrossrefPubMedGoogle Scholar
  • 29 Eriksson B, Oberg K, Curstedt T. et al. Treatment of hormone-producing adrenocortical cancer with o,p'DDD and streptozocin. Cancer 1987; 59: 1398-1403
    CrossrefPubMedGoogle Scholar
  • 30 Khan TS, Imam H, Juhlin C. et al. Streptozocin and o,p'DDD in the treatment of adrenocortical cancer patients: Long-term survival in its adjuvant use. Ann Oncol 2000; 11: 1281-1287
    CrossrefPubMedGoogle Scholar
  • 31 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: 445-453
    CrossrefPubMedGoogle Scholar
  • 32 Henning JEK, Deutschbein T, Altieri B et al. Gemcitabine-based chemotherapy in adrenocortical carcinoma: a multicentric study on efficacy and predictive factors. J Clin Endocrinol Metab 2017. jc.2017-01624-jc.02017-01624
    PubMed
  • 33 Hahner S, Kreissl MC, Fassnacht M. et al. [131I]iodometomidate for targeted radionuclide therapy of advanced adrenocortical carcinoma. J Clin Endocrinol Metab 2012; 97: 914-922
    CrossrefPubMedGoogle Scholar
  • 34 Hahner S, Sundin A. Metomidate-based imaging of adrenal masses. Horm Cancer 2011; 2: 348-353
    CrossrefPubMedGoogle Scholar
  • 35 Kreissl MC, Schirbel A, Fassnacht M. et al. [(1)(2)(3)I]Iodometomidate imaging in adrenocortical carcinoma. J Clin Endocrinol Metab 2013; 98: 2755-2764
    CrossrefPubMedGoogle Scholar
  • 36 Kroiss M, Deutschbein T, Schlotelburg W. et al. Salvage treatment of adrenocortical carcinoma with trofosfamide. Horm Cancer 2016; 7: 211-218
    CrossrefPubMedGoogle Scholar
  • 37 Chacon R, Tossen G, Loria FS. et al. CASE 2. Response in a patient with metastatic adrenal cortical carcinoma with thalidomide. J Clin Oncol 2005; 23: 1579-1580
    CrossrefPubMedGoogle Scholar
  • 38 Lu G, Middleton RE, Sun H. et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 2014; 343: 305-309
    CrossrefPubMedGoogle Scholar
  • 39 Zhu YX, Braggio E, Shi CX. et al. Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood 2011; 118: 4771-4779
    CrossrefPubMedGoogle Scholar
  • 40 Kroiss M, Deutschbein T, Schloetelburg W. Treatment of refractory adrenocortical carcinoma with thalidomide: Analysis of 27 patients from the European Network for the Study of Adrenal Tumours Registry. Exp Clin Endocrinol Diabetes 2018; DOI: 10.1055/a-0747-5571.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 41 de Reynies A, Assie 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: 1108-1115
    CrossrefPubMedGoogle Scholar
  • 42 Gicquel C, Bertagna X, Gaston V. et al. Molecular markers and long-term recurrences in a large cohort of patients with sporadic adrenocortical tumors. Cancer Res 2001; 61: 6762-6767
    PubMedGoogle Scholar
  • 43 Gicquel C, Bertagna X, Schneid H. et al. Rearrangements at the 11p15 locus and overexpression of insulin-like growth factor-II gene in sporadic adrenocortical tumors. J Clin Endocrinol Metab 1994; 78: 1444-1453
    PubMedGoogle Scholar
  • 44 Gicquel C, Raffin-Sanson ML, Gaston V. et al. Structural and functional abnormalities at 11p15 are associated with the malignant phenotype in sporadic adrenocortical tumors: study on a series of 82 tumors. J Clin Endocrinol Metab 1997; 82: 2559-2565
    PubMedGoogle Scholar
  • 45 Barlaskar FM, Spalding AC, Heaton JH. et al. Preclinical targeting of the type I insulin-like growth factor receptor in adrenocortical carcinoma. J Clin Endocrinol Metab 2009; 94: 204-212
    CrossrefPubMedGoogle Scholar
  • 46 Haluska P, Worden F, Olmos D. et al. Safety, tolerability, and pharmacokinetics of the anti-IGF-1R monoclonal antibody figitumumab in patients with refractory adrenocortical carcinoma. Cancer Chemother Pharmacol 2010; 65: 765-773
    CrossrefPubMedGoogle Scholar
  • 47 Lerario AM, Worden FP, Ramm CA. et al. The combination of insulin-like growth factor receptor 1 (IGF1R) antibody cixutumumab and mitotane as a first-line therapy for patients with recurrent/metastatic adrenocortical carcinoma: a multi-institutional NCI-sponsored trial. Horm Cancer 2014; 5: 232-239
    CrossrefPubMedGoogle Scholar
  • 48 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: 426-435
    CrossrefPubMedGoogle Scholar
  • 49 Naing A, Lorusso P, Fu S. et al. Insulin growth factor receptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with metastatic adrenocortical carcinoma. Br J Cancer 2013; 108: 826-830
    CrossrefPubMedGoogle Scholar
  • 50 Ganesan P, Piha-Paul S, Naing A. et al. Phase I clinical trial of lenalidomide in combination with temsirolimus in patients with advanced cancer. Invest New Drugs 2013; 31: 1505-1513
    CrossrefPubMedGoogle Scholar
  • 51 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: 451-458
    CrossrefPubMedGoogle Scholar
  • 52 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: 1291-1297
    CrossrefPubMedGoogle Scholar
  • 53 Quinkler M, Hahner S, Wortmann S. et al. Treatment of advanced adrenocortical carcinoma with erlotinib plus gemcitabine. J Clin Endocrinol Metab 2008; 93: 2057-2062
    CrossrefPubMedGoogle Scholar
  • 54 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: 3495-3503
    CrossrefPubMedGoogle Scholar
  • 55 van Erp NP, Guchelaar HJ, Ploeger BA. et al. Mitotane has a strong and a durable inducing effect on CYP3A4 activity. Eur J Endocrinol 2011; 164: 621-626
    CrossrefPubMedGoogle Scholar
  • 56 Chortis V, Taylor AE, Schneider P. et al. Mitotane therapy in adrenocortical cancer induces CYP3A4 and inhibits 5alpha-reductase, explaining the need for personalized glucocorticoid and androgen replacement. J Clin Endocrinol Metab 2013; 98: 161-171
    CrossrefPubMedGoogle Scholar
  • 57 Kroiss M, Quinkler M, Lutz WK. et al. Drug interactions with mitotane by induction of CYP3A4 metabolism in the clinical management of adrenocortical carcinoma. Clin Endocrinol 2011; 75: 585-591
    CrossrefPubMedGoogle Scholar
  • 58 Theile D, Haefeli WE, Weiss J. Effects of adrenolytic mitotane on drug elimination pathways assessed in vitro. Endocrine 2015; 49: 842-853
    CrossrefPubMedGoogle Scholar
  • 59 Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: A common denominator approach to cancer therapy. Cancer Cell 2015; 27: 450-461
    CrossrefPubMedGoogle Scholar
  • 60 Le Tourneau C, Hoimes CJ, Zarwan C. et al. Avelumab (MSB0010718C; anti-PD-L1) in patients with advanced adrenocortical carcinoma from the JAVELIN solid tumor phase Ib trial: Safety and clinical activity. J Clin Oncol 2016; 34
    PubMedGoogle Scholar
  • 61 Vezzosi D, Do Cao C, Hescot S. et al. Time until partial response in metastatic adrenocortical carcinoma long-term survivors. Horm Cancer 2017; DOI: 10.1007/s12672-017-0313-6.
    CrossrefPubMedGoogle Scholar
  • 62 Lippert J, Appenzeller S, Liang R. et al. Targeted molecular analysis in adrenocortical carcinomas: A strategy towards improved personalized prognostication. J Clin Endocrinol Metab 2018; DOI: 10.1210/jc.2018-01348.
    CrossrefPubMedGoogle Scholar
  • 63 Venkatesh S, Hickey RC, Sellin RV. et al. Adrenal cortical carcinoma. Cancer 1989; 64: 765-769
    CrossrefPubMedGoogle Scholar
  • 64 Henley DJ, van Heerden JA, Grant CS. et al. Adrenal cortical carcinoma–A continuing challenge. Surgery 1983; 94: 926-931
    PubMedGoogle Scholar
  • 65 King DR, Lack EE. Adrenal cortical carcinoma: A clinical and pathologic study of 49 cases. Cancer 1979; 44: 239-244
    CrossrefPubMedGoogle Scholar
  • 66 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: 1844-1851
    CrossrefPubMedGoogle Scholar
  • 67 Berruti A, Terzolo M, Sperone P. et al. Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: A large prospective phase II trial. Endocr Relat Cancer 2005; 12: 657-666
    CrossrefPubMedGoogle Scholar
  • 68 Gonzalez RJ, Tamm EP, Ng C. et al. Response to mitotane predicts outcome in patients with recurrent adrenal cortical carcinoma. Surgery 2007; 142: 867-875. discussion 867-875
    CrossrefPubMedGoogle Scholar
  • 69 Williamson SK, Lew D, Miller GJ. et al. Phase II evaluation of cisplatin and etoposide followed by mitotane at disease progression in patients with locally advanced or metastatic adrenocortical carcinoma: A Southwest Oncology Group Study. Cancer 2000; 88: 1159-1165
    CrossrefPubMedGoogle Scholar
  • 70 Bukowski RM, Wolfe M, Levine HS. et al. Phase II trial of mitotane and cisplatin in patients with adrenal carcinoma: A Southwest Oncology Group study. J Clin Oncol 1993; 11: 161-165
    CrossrefPubMedGoogle Scholar
  • 71 Abraham J, Bakke S, Rutt A. et al. A phase II trial of combination chemotherapy and surgical resection for the treatment of metastatic adrenocortical carcinoma: continuous infusion doxorubicin, vincristine, and etoposide with daily mitotane as a P-glycoprotein antagonist. Cancer 2002; 94: 2333-2343
    CrossrefPubMedGoogle Scholar
  • 72 Decker RA, Elson P, Hogan TF. et al. Eastern Cooperative Oncology Group study 1879: Mitotane and adriamycin in patients with advanced adrenocortical carcinoma. Surgery 1991; 110: 1006-1013
    PubMedGoogle Scholar
  • 73 Bonacci R, Gigliotti A, Baudin E. et al. Cytotoxic therapy with etoposide and cisplatin in advanced adrenocortical carcinoma. Br J Cancer 1998; 78: 546-549
    CrossrefPubMedGoogle Scholar
  • 74 Urup T, Pawlak WZ, Petersen PM. et al. Treatment with docetaxel and cisplatin in advanced adrenocortical carcinoma, a phase II study. Br J Cancer 2013; 108: 1994-1997
    CrossrefPubMedGoogle Scholar
  • 75 Baudin E, Docao C, Gicquel C. et al. Use of a topoisomerase I inhibitor (irinotecan, CPT-11) in metastatic adrenocortical carcinoma. Ann Oncol 2002; 13: 1806-1809
    CrossrefPubMedGoogle Scholar
  • 76 Schlumberger M, Brugieres L, Gicquel C. et al. 5-Fluorouracil, doxorubicin, and cisplatin as treatment for adrenal cortical carcinoma. Cancer 1991; 67: 2997-3000
    CrossrefPubMedGoogle Scholar
  • 77 Khan TS, Sundin A, Juhlin C. et al. Vincristine, cisplatin, teniposide, and cyclophosphamide combination in the treatment of recurrent or metastatic adrenocortical cancer. Med Oncol 2004; 21: 167-177
    CrossrefPubMedGoogle Scholar
  • 78 Wortmann S, Quinkler M, Ritter C. et al. Bevacizumab plus capecitabine as a salvage therapy in advanced adrenocortical carcinoma. Eur J Endocrinol 2010; 162: 349-356
    CrossrefPubMedGoogle Scholar