Carcinomi Surrenalici
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Transcript of Carcinomi Surrenalici
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Aspetti Patogenetici edOpzioni Terapeutiche del
Carcinoma Surrenalico
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Molecular Pathogenesis
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Gene/protein Chromosomal Gene alterations Referenceslocation
IGF2/IGFII 11p15.5 Loss of imprinting; Gicquel et al. 1997frequent dupl. of
paternal allele; high
mRNA overexpression
TP53/p53 17p13.1 Frequent point Ohgaki et al. 1993mutations Reincke et al. 1994
Lin et al. 1995
MC2R/ACTH-R 18p11.2 No point mutations; Latronico et al. 1995frequent deletions; low Reincke et al. 1997
mRNA expression
Genes in ACC
Kjellman et al., World J. Surg. 25, 948-956, 2001
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An inherited p53 mutation that contributes ina tissue-specific manner to pediatric adrenal cortical
carcinoma
35 of 36 patients had an identical germ-line point
mutation of p53 encoding anR337H amino acid
substitution.
No history of increased cancer incidence among
family members. This p53 mutation represents a
low-penetrance p53 allele that contributes in a
tissue-specific manner to the development of
pediatric ACC.
Ribeiro et al., PNAS, 2001, Vol. 98, No. 16
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Gene Expression in AdrenocorticalTumors
Giordano et al., AJP February 2003, Vol. 162, No.2
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De Reynes et al., 2009
The combined expression of BUB1B and PINK1 was the bestpredictor of overall survival and remained significant afteradjusting for MacFarlane staging.
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DIAGNOSIS
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DIAGNOSTIC APPROACHTO AN ADRENAL MASS
Is the mass malignant?
Does the mass have endocrine activity?May prove adrenocortical origin (andexclude pheo!)
May suggest malignancy
May detect residual tumor or tumorrecurrence after surgery
Prevent life-threatening adrenalinsufficiency after surgery
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Glucocorticoid excess(minimum 3 out of 4 tests)
1 mg DST 24 hour UFC basal serum cortisol basal plasma ACTH
Sexual steroids and steroid precursors Serum DHEA-S
Serum 17-OHPSerum androstenedioneSerum testosteroneSerum 17-beta-estradiol (only in menand postmenopausal women)
Mineralocorticoid excess Serum potassiumAldosterone/renin ratio (only in patientswith arterial hypertension and/orhypokalemia)
Exclusion of a pheochromocytoma 24 hour urinary catecholamines orfractionated metanephrines
Plasma meta- and normetanephrines
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How to Detect ACC?
Young, 2007
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Max
Min
75%
25%
Median
MASS SIZE AND HISTOLOGY(380 cases)
0
4
8
12
16
20
24
adenoma
carcinoma
cyst
myelolipoma
metastasis
ganglioneuroma
pheo
other
C T D IA M E T E R ( c
m )
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Radiological assessment ofRadiological assessment ofadrenal massesadrenal masses
Mass size has been previously reported to be the most
reliable way to diagnose malignancy (or nonadenomas), but
more recent studies found attenuation value to be a superior
parameter.
Unenhanced CT is the initial imaging procedure and an
attenuation value of 10 HU is able to differentiate adenomas
from non-adenomas
Delayed contrast-enhanced CT should be used whenbaseline density is > 10 HU. It is the most accurate imaging
test to differentiate adrenal lesions.
PET/CT is useful when CT is inconclusive.
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CLINICAL PRESENTATIONCLINICAL PRESENTATION
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STAGE I
STAGE II
STAGE III
STAGE IV
SAN LUIGI SERIES
187 patients
COCHIN SERIES202 patients
51%19%
6%24%
18%
24%
4%
50%
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187 patients aged 44, 17-85 yrs
MEDIAN ACC SIZE: 11, 2-25 cmMEDIAN WEISS SCORE: 6, 3-9MEDIAN Ki67% VALUE: 20, 1-87
SAN LUIGI SERIESfrom 1988 to 2009
42% 58 %
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SAN LUIGI SERIES, n=187
NON FUNCTIONING
OTHER SECRETIONS
VIRILIZATION
CUSHING and VIRILIZATION
CUSHING
COCHIN SERIES, n=202
NON FUNCTIONING
OTHER SECRETIONS
VIRILIZATION
CUSHING and VIRILIZATION
CUSHING
CUSHING and OTHER STEROIDS
48%
16%
24%
7% 5%
36%
5%
4% 11% 24%
20%
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23% of ACC are
INCIDENTALOMAS
INCIDENTAL ACC
1 2 3 4
0
2
4
6
8
10
12
14
16
18
20
22
24
STAGE
DIAMETER(cm)
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Staging of 82 cases ofACC
Kasperlik Zaluska et al.,Kasperlik Zaluska et al.,
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Months
Proportio
n
Recurrence
Free
Survivin
g
N=139
0 20 40 60 80 100 120 140 160 180 200 220
-0,1
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0
RECURRENCE FREE SURVIVAL
N=7 ACC stage I
N=96 ACC stage II
N=36 ACC stage III
Completed Censored
VER LL RV V L
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Proportion
Surviving
OVERALL SURVIVALN=187
0 50 100 150 200 250 300 350 400 450
-0,2
0,0
0,2
0,4
0,6
0,8
1,0
Months
Completed Censored
N=7 ACC stage I
N=96 ACC stage II
N=36 ACC stage III
N=48 ACC stage IV
p=0.00019
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Disease-specific survival stratified according to the new2008 ENS@T staging classification for ACC on 416patients. Fassnacht et al., 2009
3 out of 4 stage I patients who died of ACC suffered tumor spillage duringsurgery. Excluding such patients, disease specific survival was significantlybetter than for stage II (p=0.012).
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SURGERYSURGERY
n 3482
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Margin status
n = 3482
p < ,000
0
,00
,00
,00
,00
0
0 0 0 0 0 0 0 0 0 0 00
years
overallsurvival
R resect.; n=0 000
R resec.; n=0 00
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18 LA25 OA
56 patients with stage 1-2 ACCradically operated between 2002-
20082 patients excluded for
concomitant illnesses
11 patients excluded for extensive
surgery (OA + nephrectomy)
43 patients included inthe study
63 patients with stage I-II ACCoperated between 2002-2008
5 patients treatedwith OA excluded
for non- radical
surgery
(PSM)
1 patient treated with LA excludedfor non- radical surgery (PSM)
1 patient treated with LA excluded
due to conversion to OA
Porpiglia et al., 2010
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C o m p l e t e d a t a C e n s o r e d d a t a
0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0
M o n t h s
0 , 0
0 , 1
0 , 2
0 , 3
0 , 4
0 , 5
0 , 6
0 , 7
0 , 8
0 , 9
1 , 0
ProportionOve
rallSurviving
G r o u p A [ O A ]
G r o u p B [ L A ]
Fig. 3
Overalls
urvival
Porpiglia et al., 2010
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SURGERY
Significant residualtumorMinimal residual tumorRadical resection
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LOCAL RADIOTHERAPY IN ACC
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ADIUVANT MITOTANEADIUVANT MITOTANE
RECURRENCE OF ACC AFTER RADICAL RESECTION
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BERTAGNA & ORTH 1981, 32 pts
KHORRAM-MANESH 1998, 13 pts
LIPSETT 1963
WAJCHEMBERG 1999,
CRUCITTI 1995, 34 pts
GONZALES 2007, 174 pts
NADER 1983, 18 pts
POMMIER & BRENNAN 1992, 53 pts
MEYER 2004, 20 pts
85%
80%
23%
35%
78%
52%
80%
80%
46%
RECURRENCE OF ACC AFTER RADICAL RESECTION
O f dj i
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Outcome of adjuvant mitotane treatment
First author, year # Mitotane(g/day)
Comment
Schteingart (1982) 4 6 Positive effect on survival. No control group.
Bodie (1989) 21 NA No effect on survival.
Venkatesh (1989) 7 NA Positive effect on survival. No control group.
Pommier (1992) 7 NA No effect on DFI.
Vassipoulou-Sellin(1993)
8 4-6 Negative effect on DFI. MIT was discontinued early inpatients for toxicity.
Haak (1994) 11 4-8 No effect on survival. Six patients had MIT levels >14mg/L.
Barzon (1997) 7 4-8 No effect on survival and DFI.
Dickstein (1998) 4 1.5-2.0 Positive effect on DFI. No control group.
Kasperlik-Zaluska
(2000)
55 4-5 Positive effect on survival.
Icard (2001) 83 3-8 No effect on survival. Comparable control group?
Baudin (2001) 11 6-12 No effect on DFI. Eight patients had MIT levels >14mg/L. No control group.
Terzolo (2007) 47 1-5 Positive effect on DFI and survival. Two contemporar
control groups of 55 and 75 patients.
Li it f th il bl lit tLimits of the available literature
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Limits of the available literatureLimits of the available literature
Retrospective nature of the studies
Small number of patients
Variable duration and dosing of treatment
Absence of matched control group
No standard criteria to assess tumor response
No monitoring of plasma mitotane concentrations
The rarity of ACC precluded the organization of prospectiverandomized trials
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Terzolo et al., 2007
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Terzolo et al., 2007
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feel the recently reported study suffers from problemon to many retrospective studies and doesnt suppcommendation of adjuvant mitotane for all patients.
ever, we agree it should be considered in selected
ients with completely resected ACC and poorgnostic features.
J Clin Endocrinol Metab. 2008, 93: 373032
Mitotane treatment is
complex owing to itstoxicity, the need to
monitor levels, and theneed for corticosteroidreplacement.
J Clin Endocrinol Metab. 2009, 94: 1879-80
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EFFICACY OF ADJUVANT MITOTANE
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EFFICACY OF ADJUVANT MITOTANETREATMENT IN PROLONGING RECURRENCE-
FREE SURVIVAL IN PATIENTS WITH
ADRENOCORTICAL CARCINOMA AT LOW-INTERMEDIATE RISK OF RECURRENCESUBMITTED TO RADICAL RESECTION
Coordinating CenterDipartimento di Scienze Cliniche e Biologiche Universit di Torino
Medicina Interna I, ASO San Luigi, Orbassano (TO)
Massimo Terzolo, MD Tel. ++39011 9026292; Fax ++39011 9026992;
email: [email protected]
Oncologia Medica,ASO San Luigi, Orbassano (TO)
Alfredo Berruti, MD Tel. ++39011 9026512; Fax ++39011 9026992;
email: [email protected]
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Low risk patients
Stage I-IIIR0 resectionKi67
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Bertherat et al., 2007
High-dose regimen
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Week 1
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7
1.5 g 3 g 4.5 g 6 g 6 g 6 g 6 g
Week 2
Day 8 Day 9 Day 10 Day 11 Day 12 Day 13 Day 14
6 g 6 g 6 g 6 g 6 g 6 g 6 g
Week 1
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7
1.0 g 1.0 g 1.5 g 1.5 g 1.5 g 2.0 g 2.0 g
Week 2
Day 8 Day 9 Day 10 Day 11 Day 12 Day 13 Day 14
2.0 g 2.5 g 2.5 g 2.5 g 3.0 g 3.0 g 3.0 g
Low-dose regimen
High dose regimen
RESULTS OF MITOTANE MONITORING
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RESULTS OF MITOTANE MONITORING
All patients reachedmitotane concentrationsgreater than 14 mg/lafter 3-9 months.
+3 MONTHS + 6 MONTHS +9 MONTHS
53% 30%
17%
23 %
77 %77% of patients maintainedmitotane concentrationsgreater than 14 mg/l after 1year.
Median
25%-75%
0 3 6 9 12
Months
0
4
8
12
16
20
24
Mitotane (mg/l)
M it t DDD
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Mean mitotane DDD
concentrationsLOW DOSE
GROUP
0
5
10
15
20
25
5 12 19 26 33 40 47 54 61 68 75 82
Days
CMinssD
DDg/ml
MEAN(g/ml) (+I.C.) (-I.C.)
HIGH DOSEGROUP
0
5
10
15
20
25
5 12 19 26 33 40 47 54 61 68 75 82
Days
CMinssD
DDg/ml
MEAN(g/ml) (+I.C.) (-I.C.)
PK ancillary study to FIRM-ACT Preliminary data
Courtesy of R. Chadarevian, HRA PHARMA
Impact of mitotane levels in 39 patients treated
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0 2 0 40 60 80 100 120 140 160
-0,1
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0
MonthsProportionRecurrence
Fre
e
Surviving
Plasma mitotane > 14 mg/l in in 6 months; n= 10
Plasma mitotane > 14 mg/l in 3 months; n= 22
P=NS
Median follow up 36 months (9-145)
Plasma mitotane > 14 mg/l in >9 months; n= 7
Impact of mitotane levels in 39 patients treatedprospectively with adjuvant mitotane
Impact of mitotane levels in 39 patients treated
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0 20 40 60 80 100 120 140 160
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0
MonthsProportion
RecurrenceF
ree
Surviving
Impact of mitotane levels in 39 patients treatedprospectively with adjuvant mitotane
Median follow up 36 months (9-145)
Plasma mitotane > 14 mg/l; n= 30
Plasma mitotane < 14 mg/l; n= 9
P= 0.07
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Therapeutic impact of o,pDDD concentrations
Objective tumor response:
o,pDDD level
> 14 mg/L < 14 mg/L
Haak et al. 1994 (n=62) 55% 0%
Baudin et al. 2001 (n=24) 31% 0%
Median interval > 3 months to achieve highest o,pDDD
o,pDDD level > 20 mg/L is associated with neurological toxicity
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GI symptoms occur early in the
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y p ycourse of treatment and areassociated with dose increments.Patients develop tolerance.Inadequate cortisol replacement
may contribute to toxicity.GGT increases in all patients butdoesnt need mitotane discontinuationunless very high levels are observed.Important liver toxicity is rare.
Moderate CNS toxicity may befrequent (memory impairment,attention deficit, etc). Severetoxicity is dose-related.
All patients become hypoadrenal butmineralocorticoid supplementation is notalways necessary.In men, hypogonadism may develop aftersome time. Gynecomastia occurs earlier
due to the estrogenic action ofmitotane.
Daffara et al., 2008
20
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Median
25%-75%
0 3 6 9 12
Months
0
4
8
12
16
Median
25%-75%
0 3 6 9 12
Months
0
40
80
120
160
200
Cortisol ( g/dl)
CBG (ng/ml)
1,2
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Median
Min-Max
0 3 6 9 12
Months
0,0
0,3
0,6
0,9
Median
25%-75%
0 3 6 9 12
Months
0
1
2
3
4
5
FT4 ng/dl
TSH mU/l
16
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Median
25%-75%
0 3 6 9 12
Months
0
4
8
12 Testosterone (ng/ml)
Median
25%-75%
0 3 6 9 12
Months
0
5
10
15
20
25
30
35
Freetestosterone (pg/ml)
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17 pts radically resected for ACC were prospectively treated withmitotane in an adjuvant setting from 1999-2006 with a medianduration of treatment of 22 months (range, 12-84)
Chronic mitotane treatment in anadjuvant setting is feasible butspecific expertise is needed.
Side effects are frequent but well-informed and motivated patientsare able to cope with them withoutdiscontinuing permanentlymitotane, proven that a carefultailoring of the mitotane schedule
is done.
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TUMOR RECURRENCE
SURVIVAL AFTER TUMOR
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0 50 100 150 200 250 300 350 400
Tempo
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0
Proportion
ofSurviving
Months
GROUP 1, n=32
GROUP 2, n=13
P
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ADVANCED DISEASEADVANCED DISEASE
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Time to progression
Overall survival
P
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Metastatic Adrenocortical Carcinoma Treatment
F I R M A C T t r i a l
Study-Design:
randomized prospective controlled open-label multi-center
international parallel-group study
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Ronchi et al., 2009
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NOVEL THERAPIES
POTENTIAL TARGETS IN ADRENOCORTICAL
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POTENTIAL TARGETS IN ADRENOCORTICAL
CANCER
EGFR Kamio et al 1990Sasano et al 1994
Edgren et al 1997
IGF2 Gicquel et al 1997
FGR1 de Fraipont et al 2005
K-ras Lin S-R et al 2000
VEGF Kolomecki et al 2001
Benini et al 2002
Zaharieva S et al 2004
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Fassnacht et al. 2009
Clinical Management of ACCClinical Management of ACC
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C ca a age e t o CCg
Surgery whenever possible
primary
repeat (following recurrence or chemo)
Adjuvant mitotane treatment
higher dose
longer duration
Mitotane or EDP + mitotane in advanceddisease
Gemcitabine + capecitabine as salvage
Organization of prospective trials withnovel drugs is urgently needed