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Alfredo BerrutiUniversità degli Studi
di BresciaAzienda Ospedaliera
Spedali CiviliBrescia
Adrenal Cancers
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Disclosures
Research funding for ACC from Janssen Cilag and
Sanofi
Advisory Board HRA
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ADRENAL GLAND
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Malignant ACC
Malignant
Pheocromocytoma
Adrenal cancer
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Origin of paraganglioma
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Epidemiology
ACC PCC/PGL
Annual incidence: 0.5-2.0 case million/year 2-8 case million/year
Europe: 375-1.500 new cases/year 1.500-6.000 new cases/year
Ratio Male/Female: 1 : 1.5 1:1
Berruti et al ESMO guidelines, Ann Oncol Suppl 7:vii131-8, 2012
Fassnacht et al ESE Guidelines Eur J Endocrinol. 179(4): G1-G46, 2018
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Diagnostic work-up for adrenal cancer ESMO-ENS@T
Hormone assessment is important
Orbassano and Brescia series
Crona J et al Endocr Rev, 38(6):489-515; 2017Do not duplicate or d
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Diagnostic work-up
for adrenal cancer
(ENS@T)
Berruti A et al ESMO guidelines 2012
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PheochromocytomaAdrenocortical Carcinoma
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VHL
RET
NF1
PCC/PGLs susceptibility genes
SDHC
SDHB
PGL 1
PGL 3
PGL 4
von HIPPEL LINDAU
MEN2
NEUROFIBROMATOSIS 1
SDHx
SDHD
PGL 2SDHAF2
TMEM127 PHEOs/PGLs
SDHA sPGL
Castro-Vega et al Nature Comm 2015
Curras Freixes et al J Med Genet 2015
Up to 40% germ line mutations
Germ line and somatic
alterations in 70%Do not duplicate or d
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9 Driver genes
CTNNB1,
ZNRF3
TP53,
RB1
CDKN2A,
MEN1
DAXX,
TERT
MED12
Assié G et al. Nature Genetics 46(6): 607-12; 2014
Juhlin CC et al. J Clin Endocrinol Metabol 100(3):E493-502; 2015
Zheng S et al. Cancer Cell 29(5):723-36; 2016
ACC: genomics and pathophysiology
Wnt/beta catenin pathway
(activating mutations in >30%)
Insulin-like Growth Factor-2 (IGF-2)
pathway (overexpressed in 90%)
p53 pathway
(inactivating mutations in >30%; allelic losses(LOH) in >85% )
3 major pathways
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Surgery is the mainstay of therapy
ACC
Type: Laparotomy (preferred)
Goal: potentially cure
PCC/PGL
Type: laparoscopy
Goal:allow long-term remission, prevent
tumor growth and progression to metastatic
disease
Preparation includes alpha- blockers
followed by the addition beta-blockers
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Characterization of Malignant PCC/PGLs
• 15-17% of PCC/PGLs are malignant
5-20% PCC
15-35% PGL
• Risk of malignancy = size of primary tumor, sympatetic PGL, SDHB mutation
Metastatic spread
– Lymph nodes 80%
– Bone tissue 72%
– Liver 50%
– Lungs 50%
5 yr mortality rate: 37% (95% CI 24-51)Jimenez et al, Curr Oncol Rep, 2013
Plouin et al EJE, 2016
Hamidi et al Clin Endocrinol 2017
Crona et al Endocr Rev 2017
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ACC: prognostic parameters
Stage
Ki67
Fassnacht M et al Cancer. 115(2):243-50; 2009.
Beuschlein F et al J Clin Endocrinol Metab. 100(3):841-9; 2015Do not duplicate or d
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ACC: prognostic parameters
p < 0,001
0
0,2
0,4
0,6
0,8
1
0 1 2 3 4 5 6 7 8 9 10
years
overa
ll s
urv
ival
R0 resect.; n=177
R1 resec.; n=27Radical Surgery (R0)
Cortisol hypersecretion
Berruti A et al. Eur Urol 65(4):832-8; 2014
ACC German Registry
Crucitti F et al Surgery 119(2):161-70; 1996
Icard P et al Surgery. 112(6):972-9; 1992
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Crona J et al Endocr Rev, 38(6):489-515; 2017
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ion from author a
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Clinical Trials
Berruti et al ESMO guidelines, 2012;
Treatment for pheochromocytoma and
paraganglioma
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Eur J Endocrinol. 179(4): G1-G46, 2018
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N Engl J Med 356 (23): 2372-80, 2007
177 ACC patients
radically operated
Adjuvant
Mitotane:
45 italian
patients
Control1:
55 italian
patients
Control2:
75 German
patients
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J Clin Endocrinol Metab 102: 1358–1365, 2017
Additional 10 yr follow-up
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Fassnacht M et al, Eur J Endocrinol. 179(4): G1-G46, 2018
Adjuvant non randomized ACC studies
Progression Free Survival
Overall Survival
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Adjuvant chemotherapy for adrenocortical
carcinoma: a multicenter randomized open label
phase III trial ACACIA trial
Italian Agency of Medicine
Adiuvant Chemotherapy for Adrenocortical CarcInomA
15 italian centers involved
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Eur J Endocrinol. 179(4): G1-G46, 2018
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EDP-M median PFS: 5.0 months
Sz-M median PFS: 2.1 months
EDP-M median OS: 14.8 months
Sz-M median OS: 12.0 months
NEJM 366(23):2189-97; 2012
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Systemic therapy for Adrenocortical carcinoma:
we are still in the Dinos era
Mitotane
Mitotane + chemotherapy
EDP scheme:
Etoposide
Doxorubicin
CisplatinBob Benjamin, MDACCDo not duplica
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Inoperable, recurrent and/or metastatic ACC
Terzolo M et al J Endocrinol Invest 37 (3): 207-17 2014
+ local regional options
G = grade (Weiss score <6 or >6 or Ki67 <20% or >20%
R = resection status of the primary
A = age younger than or older than 50 years
S = hormone-related symptoms at diagnosis
mENSATstage 5-year OS rates
III 50%
IVa 2 tumor organs 15%
IVb 3 tumor organs 14%
IVc >3 tumor organs 2%
Libe R rt al Ann Oncol 26: 2119–2125, 2015
Baudin E Endocrinol Metab Clin N Am 44: 411–434, 2015
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Serum mitotane levels as a target
Hermsen et al. J Clin Endocrinol Metab 96(6):1844-51; 2011
Survival
Haak H et al 1994
Baudin E et al. 2001
Objective response
Cancer. 92(6):1385-92
Br J Cancer. 69(5):947-51.
Major drawback:
the therapeutic range is attained within 2-3 months
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What is the advantage of combining mitotane and chemo?
chemo
effect Mitotane
maintenance Chemotherapy can obtain a
disease control when mitotane
levels is not in the therapeutic
range
Grisanti S. personal presentation
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Clinical Trials
Berruti et al ESMO guidelines, 2012
Treatment for pheochromocytoma and
paraganglioma
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Baudin E, personal presentation
MIBG therapy:published series
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Baudin E, personal presentation
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Baudin E, personal presentation
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Baudin E, personal presentation
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Take home messages
The management of ACC and PCC/PGL is challenging
These patients should be preferentially treated in
experienced centers adopting a multidisciplinary approach
The extreme rarity of these diseases requires multinational
cooperation Do not duplicate or d
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THANK-YOU
Our patients and their familiesDo not duplicate or d
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