Carcinomi Surrenalici

7/31/2019 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.


9/70Zsabo et al., 2010


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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


6 g 6 g 6 g 6 g 6 g 6 g 6 g

Week 1


1.0 g 1.0 g 1.5 g 1.5 g 1.5 g 2.0 g 2.0 g

Week 2


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

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Carcinomi Surrenalici