Systemic Treatment of Adrenocortical Carcinoma in Children: Data from the German GPOH-MET 97 Trial

Abstract

Background:

Adrenocortical cancer (ACC) in childhood is a rare disease with poor prognosis. Complete surgical resection, systemic chemotherapy, and mitotane therapy are important curative treatment options for patients with advanced-stage tumors. Since 1997, pediatric ACC patients in Germany have been treated according to the non-randomized, single arm study GPOH-MET-97.

Patients and methods:

Data regarding disease course, treatment, and survival rates of 60 patients (age 0.24–17.8 years) with ACC treated according to the GPOH-MET-97 protocol were collected and analyzed to determine outcome, with a focus on examining the effectiveness of mitotane therapy.

Results:

Among all patients, event-free survival and overall survival were found to be 43.3% and 64.8%, respectively. Chemotherapy with VCR, IFO, ADR, CARBO, and VP16 had been provided to 34 patients (56.6%) in different settings (neoadjuvant, adjuvant, and salvage) and mitotane therapy to 32 patients (53.3%). Duration of mitotane treatment longer than 6 months and mitotane levels greater than 14 mg/l were found to be associated with significantly better survival. Local relapse was found to be associated with a worse prognosis compared to distant metastasis only.

Conclusions:

Systemic chemotherapy and mitotane therapy are important therapeutic options in the treatment of advanced pediatric ACC patients. Neoadjuvant therapy should be considered for patients with primarily incomplete resectable or inoperable tumors, and tumor spillage is an indication for adjuvant chemo- and mitotane therapy. All pediatric ACC patients should be treated in pediatric oncological centers according to a consistent protocol in a highly interdisciplinary setting.

Zusammenfassung

Hintergrund:

Nebennierenrindenkarzinome (ACC) sind bei Kindern seltene Tumoren, die eine hohe Letalität besitzen. Neben der kompletten chirurgischen Resektion des Tumors sind die systemische Chemo- und Mitotanetherapie wichtige Optionen für einen kurativen Ansatz. Seit 1997 werden Kinder mit ACC in Deutschland nach der einarmigen, nicht-randomisierten GPOH-MET-97 Studie behandelt.

Patienten und Methoden:

60 Patienten mit ACC im Alter zwischen 2 Monaten und 18 Jahren wurden nach dem GPOH-MET-97-Protokoll behandelt. Erkrankungsverlauf, Therapie und Ergebnisse wurden unter besonderer Berücksichtigung der Mitotanetherapie analysiert.

Ergebnisse:

Das ereignisfreie Überleben von allen Patienten betrug 43.3%, das Gesamtüberleben 64.8%. Die Chemotherapie bestehend aus VCR, IFO, ADR, CARBO und VP16 erhielten 34 Patienten (56.6%) in unterschiedlichen Settings (neoadjuvant, adjuvent, salvage). Mit Mitotane wurden insgesamt 32 Patienten behandelt (53.3%). Mitotanebehandlung länger als 6 Monate und Mitotanespiegel >14 mg/l waren mit einem signifikant besseren Überleben assoziiert. Patienten mit lokalem Rezidiv hatten eine schlechtere Prognose als Patienten mit Fernmetastasen.

Schlussfolgerung:

Die Behandlung von Patienten mit ACC mit Chemotherapie und Mitotane ist eine wichtige Option bei Kindern mit fortgeschrittenem ACC. Eine neo­adjuvente Therapie sollte bei Patienten mit primär inkomplett rese­zierbar oder inoperablen Tumoren in Be­tracht gezogen werden. Tumor Spillage ist eine Indi­kation für systemische Chemo- und Mito­tanetherapie. Alle Kinder mit ACC sollten in ­pädiatrisch-onkologischen Zentren in enger interdisziplinärer Zusammenarbeit nach einheitlichen Therapieprotokollen betreut werden.

Key words

adrenocortical carcinoma - GPOH-MET-97 protocol - mitotane - neoadjuvant therapy - pediatric oncology

Schlüsselwörter

Nebennierenrindenkarzinom - GPOH-MET-97 Protokoll - Mitotane - neoadjuvante Chemo­therapie - Kinderonkologie

• References

• 1 Allolio B, Hahner S, Weismann D et al. Management of adrenocortical carcinoma. Clin Endocrinol (Oxf) 2004; 60: 273-287
• 2 Berruti A, Ferrero A, Sperone P et al. Emerging drugs for adrenocortical carcinoma. Expert Opin Emerg Drugs 2008; 13: 497-509
• 3 Berruti A, Terzolo M, Pia A et al. 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: 2194-2200
• 4 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
• 5 Bucsky P. Interdisziplinäre multizentrische Therapieoptimierungs­studie: Maligne endokrine Tumoren im Kindes- und Jugendalter GPOH-MET 97. Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) 1997;
• 6 Ciftci AO, Senocak ME, Tanyel FC et al. Adrenocortical tumors in children. J Pediatr Surg 2001; 36: 549-554
• 7 Daffara F, De FS, Reimondo G et al. Prospective evaluation of mitotane toxicity in adrenocortical cancer patients treated adjuvantly. Endocr Relat Cancer 2008; 15: 1043-1053
• 8 Dehner LP, Hill DA. Adrenal cortical neoplasms in children. Why so many carcinomas and yet so many survivors?. Pediatr Dev Pathol 2009; 12: 284-291
• 9 Fassnacht M, Allolio B. Clinical management of adrenocortical carcinoma. Best Pract Res Clin Endocrinol Metab 2009; 23: 273-289
• 10 Fassnacht M, Johanssen S, Fenske W et al. Improved survival in patients with stage II adrenocortical carcinoma followed up prospectively by specialized centers. J Clin Endocrinol Metab 2010; 95: 4925-4932
• 11 Fassnacht M, Terzolo M, Allolio B et al. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med 2012; 366: 2189-2197
• 12 Göbel U, Gortner L. Disease management programs for adults with often diseases and competence networks for children and adolescents with rare diseases. Klin Padiatr 2011; 223: 1-3
• 13 Golden SH, Robinson KA, Saldanha I et al. Clinical review: prevalence and incidence of endocrine and metabolic disorders in the United States: a comprehensive review. J Clin Endocrinol Metab 2009; 94: 1853-1878
• 14 Grubbs EG, Callender GG, Xing Y et al. Recurrence of adrenal cortical carcinoma following resection: surgery alone can achieve results equal to surgery plus mitotane. Ann Surg Oncol 2010; 17: 263-270
• 15 Hanna AM, Pham TH, Skegard-Giesmann JR et al. Outcome of adrenocortical tumors in children. J Pediatr Surg 2008; 43: 843-849
• 16 Huang H, Fojo T. Adjuvant mitotane for adrenocortical cancer – a ­recurring controversy. J Clin Endocrinol Metab 2008; 93: 3730-3732
• 17 Hubertus J, Boxberger N, Redlich A et al. Surgical aspects in the treatment of adrenocortical carcinomas in children: data from the GPOH-MET 97 Trial. Klin Padiatr 2012; 224: 143-147
• 18 Johanssen S, Hahner S, Saeger W et al. Deficits in the management of patients with adrenocortical carcinoma in Germany. Dtsch Arztebl Int 2010; 107: 885-891
• 19 Lacroix A. Approach to the patient with adrenocortical carcinoma. J Clin Endocrinol Metab 2010; 95: 4812-4822
• 20 Loncarevic IF, Hering A, Posorski N et al. Number of imbalances correlates with the overall survival for adrenocortical cancer in childhood. Pediatr Blood Cancer 2008; 51: 356-362
• 21 Michalkiewicz E, Sandrini R, Figueiredo B et al. Clinical and outcome characteristics of children with adrenocortical tumors: a report from the International Pediatric Adrenocortical Tumor Registry. J Clin Oncol 2004; 22: 838-845
• 22 Parlowsky T, Bucsky P, Hof M et al. Malignant endocrine tumours in childhood and adolescence – results of a retrospective analysis. Klin Padiatr 1996; 208: 205-209
• 23 Parlowsky T, Dralle H, Farahati J et al. Maligne endokrine Tumoren im Kindesalter. Eine interdisziplinäre multizentrische Therapieoptimierungsstudie. Deutsches Ärzteblatt 2001; 98: A764-A767
• 24 Polat B, Fassnacht M, Pfreundner L et al. Radiotherapy in adrenocortical carcinoma. Cancer 2009; 115: 2816-2823
• 25 Ribeiro RC, Figueiredo B. Childhood adrenocortical tumours. Eur J Cancer 2004; 40: 1117-1126
• 26 Rodriguez-Galindo C, Figueiredo BC, Zambetti GP et al. Biology, clinical characteristics, and management of adrenocortical tumors in children. Pediatr Blood Cancer 2005; 45: 265-273
• 27 Sandrini R, Ribeiro RC, DeLacerda L. Childhood adrenocortical tumors. J Clin Endocrinol Metab 1997; 82: 2027-2031
• 28 Schneider DT, Brecht IB. Care for rare cancers: improved care requires improved communication. Klin Padiatr 2010; 222: 124-126
• 29 Terzolo M, Fassnacht M, Ciccone G et al. Adjuvant mitotane for adrenocortical cancer—working through uncertainty. J Clin Endocrinol Metab 2009; 94: 1879-1880
• 30 Wieneke JA, Thompson LD, Heffess CS. Adrenal cortical neoplasms in the pediatric population: a clinicopathologic and immunophenotypic analysis of 83 patients. Am J Surg Pathol 2003; 27: 867-881