Aspetti Patogenetici ed Opzioni Terapeutiche del Carcinoma Surrenalico

Molecular Pathogenesis

Genes in ACC
Gene/protein Chromosomal Gene alterations location
IGF2/IGFII 11p15.5

References

Loss of imprinting; Gicquel et al. 1997 frequent dupl. of paternal allele; high mRNA overexpression Frequent point mutations Ohgaki et al. 1993 Reincke et al. 1994 Lin et al. 1995

TP53/p53

17p13.1

MC2R/ACTH-R

18p11.2

No point mutations; Latronico et al. 1995 frequent deletions; low Reincke et al. 1997 mRNA expression

Kjellman et al., World J. Surg. 25, 948-956, 2001

An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma
Ribeiro et al., PNAS, 2001, Vol. 98, No. 16

35 of 36 patients had an identical germ-line point mutation of p53 encoding an R337H 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.

Gene Expression in Adrenocortical Tumors

Giordano et al., AJP February 2003, Vol. 162, No.2

De Reynes et al., 2009

The combined expression of BUB1B and PINK1 was the best predictor of overall survival and remained significant after adjusting for MacFarlane staging.

Zsabo et al., 2010

DIAGNOSIS

DIAGNOSTIC APPROACH TO AN ADRENAL MASS

Is the mass malignant? Does the mass have endocrine activity?
May prove adrenocortical origin (and exclude pheo!) May suggest malignancy May detect residual tumor or tumor recurrence after surgery Prevent life-threatening adrenal insufficiency after surgery

RECOMMENDED HORMONAL WORK-UP IN PATIENTS WITH SUSPECTED ACC

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-OHP Serum androstenedione Serum testosterone Serum 17-beta-estradiol (only in men and postmenopausal women) Mineralocorticoid excess Serum potassium Aldosterone/renin ratio (only in patients with arterial hypertension and/or hypokalemia) 24 hour urinary catecholamines or fractionated metanephrines Plasma meta- and normetanephrines

Exclusion of a pheochromocytoma

How to Detect ACC?

Young, 2007

MASS SIZE AND HISTOLOGY

CT DIAMETER (cm)
(380 cases) 24 20 16 12 8 4 0

Max Min

adenoma cyst metastasis pheo carcinoma myelolipoma ganglioneuroma

75% 25%

other

Median

Radiological assessment of adrenal 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 when baseline density is > 10 HU. It is the most accurate imaging test to differentiate adrenal lesions. PET/CT is useful when CT is inconclusive.

CLINICAL PRESENTATION

STAGE I STAGE II STAGE III STAGE IV

4% 24%

COCHIN SERIES 202 patients

24% 6%

19%

51%

18%

50%

SAN LUIGI SERIES 187 patients

SAN LUIGI SERIES from 1988 to 2009

187 patients aged 44, 17-85 yrs

42%

58 %

MEDIAN ACC SIZE: 11, 2-25 cm MEDIAN WEISS SCORE: 6, 3-9 MEDIAN Ki67% VALUE: 20, 1-87

COCHIN SERIES, n=202

CUSHING and VIRILIZATION OTHER SECRETIONS VIRILIZATION NON FUNCTIONING CUSHING 16% 48% 24% 7% 5% NON FUNCTIONING OTHER SECRETIONS VIRILIZATION CUSHING and VIRILIZATION 36% 20% 5% 4% 11% 24%

SAN LUIGI SERIES, n=187

CUSHING CUSHING and OTHER STEROIDS

INCIDENTAL ACC

24 22

DIAMETER (cm)

20 18 16 14 12 10 8 6 4 2 0 1 2 3 4

23% of ACC are INCIDENTALOMAS

STAGE

Staging of 82 cases of ACC

Kasperlik Zaluska et al.,

N=139

RECURRENCE FREE SURVIVAL

Completed Censored

Proportion Recurrence Free Surviving

1,0 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0,0 -0,1 0 20 40 60 80 100 120 140 160 180 200 220

N=7 ACC stage I

N=96 ACC stage II

N=36 ACC stage III

Months

N=187

OVERALL SURVIVAL
Completed Censored

1,0

Proportion Surviving

0,8

N=7 ACC stage I

p=0.00019
N=96 ACC stage II

0,6

0,4

0,2

N=48 ACC stage IV

0,0

N=36 ACC stage III

-0,2 0 50 100 150 200 250 300 350 400 450

Months

Disease-specific survival stratified according to the new 2008 ENS@T staging classification for ACC on 416 patients. Fassnacht et al., 2009
3 out of 4 stage I patients who died of ACC suffered tumor spillage during surgery. Excluding such patients, disease specific survival was significantly better than for stage II (p=0.012).

SURGERY

n = 3482

Margin status

Successful primary surgery has a dominant role on disease-specific survival.

German ACC Registry, 2008
0

Bilmoria et al., 2008

overall survival

00 , 00 , 00 , 00 , 0 0 0 0 0 0 0 0 0 0 0 0 0 p < 0000 ,

R0resect.; n=000 R0resec.; n=00

years

63 patients with stage I-II ACC operated between 2002-2008 1 patient treated with LA excluded due to conversion to OA 5 patients treated with OA excluded for non- radical 1 patient treated with LA excluded surgery for non- radical surgery (PSM) (PSM) 56 patients with stage 1-2 ACC radically operated between 20022008 2 patients excluded for concomitant illnesses 11 patients excluded for extensive surgery (OA + nephrectomy)

43 patients included in the study

25 OA 18 LA
Porpiglia et al., 2010

C o m p le te d a t a 1 ,0 0 ,9

C e n s o re d d a ta

Proportion Overall Surviving Overall survival

0 ,8 0 ,7 0 ,6 0 ,5 0 ,4 0 ,3 0 ,2 0 ,1 0 ,0 0 10 20 30 40 50 60 70 80 G ro u p A [O A ] G ro u p B [L A ]

M o n th s

Porpiglia et al., 2010 3 Fig.

SURGERY

Radical resection

Minimal residual tumor

Significant residual tumor

LOCAL RADIOTHERAPY IN ACC

Fassnacht et al., 2006

ADIUVANT MITOTANE

RECURRENCE OF ACC AFTER RADICAL RESECTION

BERTAGNA & ORTH 1981, 32 pts KHORRAM-MANESH 1998, 13 pts LIPSETT 1963 NADER 1983, 18 pts 80% 46%

80%

52% 78% 35% 23%

GONZALES 2007, 174 pts WAJCHEMBERG 1999,

CRUCITTI 1995, 34 pts

POMMIER & BRENNAN 1992, 53 pts MEYER 2004, 20 pts

85% 80%

Outcome of adjuvant mitotane treatment

First author, year Schteingart (1982) Bodie (1989) Venkatesh (1989) Pommier (1992) Vassipoulou-Sellin (1993) Haak (1994) Barzon (1997) Dickstein (1998) Kasperlik-Zaluska (2000) Icard (2001) Baudin (2001) Terzolo (2007) # 4 21 7 7 8 11 7 4 55 83 11 47 Mitotane (g/day) 6 NA NA NA 4-6 4-8 4-8 1.5-2.0 4-5 3-8 6-12 1-5 No effect on survival. Positive effect on survival. No control group. No effect on DFI. Comment Positive effect on survival. No control group.

Negative effect on DFI. MIT was discontinued early in 5 patients for toxicity.

No effect on survival. Six patients had MIT levels >14 mg/L. No effect on survival and DFI. Positive effect on DFI. No control group. Positive effect on survival. No effect on survival. Comparable control group?

No effect on DFI. Eight patients had MIT levels >14 mg/L. No control group.

Positive effect on DFI and survival. Two contemporary control groups of 55 and 75 patients.

Limits 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 prospective randomized trials

131 patients with ACC

4 patients with concomitant other cancers, 3 with heart failure 21 patients underwent incomplete, or wedge, or segmental resection 4 patients underwent other concomitant adjuvant therapies 102 patients radically resected 75 german patients left untreated after radical resection

47 patients treated with adjuvant mitotane

55 patients left untreated

OUTCOME RESULTS

Terzolo et al., 2007

OUTCOME RESULTS

Terzolo et al., 2007

Mitotanereported study suffers from problem treatment is e feel the recently mmon to many retrospective studies and doesnt suppo complex owing to its ecommendation of adjuvant mitotane for all patients. toxicity, the need to wever, we agree it should be considered in selected monitor levels, ACCand the tients with completely resected and poor ognostic features.for need corticosteroid replacement.

J Clin Endocrinol Metab. 2008, 93: 373032

J Clin Endocrinol Metab. 2009, 94: 1879-80

Doubts with adjunctive treatment Efficacy Patient selection Complexity of treatment Toxicity Timing and duration of treatment

EFFICACY OF ADJUVANT MITOTANE TREATMENT IN PROLONGING RECURRENCEFREE SURVIVAL IN PATIENTS WITH ADRENOCORTICAL CARCINOMA AT LOWINTERMEDIATE RISK OF RECURRENCE SUBMITTED TO RADICAL RESECTION
Coordinating Center Dipartimento 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: terzolo@usa.net Oncologia Medica, ASO San Luigi, Orbassano (TO) Alfredo Berruti, MD Tel. ++39011 9026512; Fax ++39011 9026992; email: alfredo.berruti@gmail.com

ADIUVO STUDY
www.adiuvo-trial.org
Low risk patients Stage I-III R0 resection Ki67 <10% # patients 200 Observation

R A N D O M

Adjuvant mitotane

Primary endpoint: Recurrence Free Survival

Bertherat et al., 2007

Week 1 Day 1 1.5 g Day 2 3g Day 3 4.5 g Day 4 6g Week 2 Day 8 6g Day 9 6g Day 10 6g Day 11 6g Day 12 6g

High-dose regimen
Day 5 6g Day 6 6g Day 7 6g

Day 13 6g

Day 14 6g

Low-dose regimen
Week 1 Day 1 1.0 g Day 8 2.0 g Day 2 1.0 g Day 9 2.5 g Day 3 1.5 g Day 10 2.5 g Day 4 1.5 g Week 2 Day 11 2.5 g Day 12 3.0 g Day 13 3.0 g Day 14 3.0 g Day 5 1.5 g Day 6 2.0 g Day 7 2.0 g

RESULTS OF MITOTANE MONITORING

Mitotane (mg/l)

24 20
53%

16 12 8

30%

All patients reached mitotane concentrations greater than 14 mg/l after 3-9 months.
17%

+3 MONTHS

+ 6 MONTHS

+9 MONTHS

77% of patients maintained 0 mitotane concentrations 0 3 greater than 14 mg/l after 1 year.

6 Months

77 % 12

Median 25%-75%

23 %

Mean mitotane DDD concentrations

25 20 15 10 5 0 5 12 19 26 33 40 47 54 61 68 75 82 Days MEAN(g/ml) (+I.C.) (-I.C.) MEAN(g/ml)

LOW DOSE GROUP

CMinss DDD g/ml

25 20 15 10 5 0 5 12 19 26

HIGH DOSE GROUP

CMinss DDD g/ml

33

40

47

54

61

68

75

82

Days (+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 prospectively with adjuvant mitotane

1,0

Proportion Recurrence Free Surviving

0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0,0 -0,1 0 20 40

Plasma mitotane > 14 mg/l in 3 months; n= 22

P=NS Plasma mitotane > 14 mg/l in in 6 months; n= 10

Plasma mitotane > 14 mg/l in >9 months; n= 7

60 80 100 120 140 160

Months
Median follow up 36 months (9-145)

Impact of mitotane levels in 39 patients treated prospectively with adjuvant mitotane

Proportion Recurrence Free Surviving

1,0 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0 20 40 60 80 100 120 140 160

P= 0.07
Plasma mitotane > 14 mg/l; n= 30

Plasma mitotane < 14 mg/l; n= 9 Months

Median follow up 36 months (9-145)

Therapeutic impact of o,pDDD concentrations

Objective tumor response: o,pDDD level > 14 mg/L < 14 mg/L
Haak et al. 1994 (n=62) Baudin et al. 2001 (n=24) 55% 31% 0% 0%

Median interval > 3 months to achieve highest o,pDDD o,pDDD level > 20 mg/L is associated with neurological toxicity

Insufficient duration of treatment (median, 29 mos) may have limited the effect on overall survival. The predominant activity of mitotane is to delay cancer growth, then indefinite therapy may help to increase survival.

GI symptoms occur early in the course of treatment and are associated with dose increments. Patients develop tolerance. Inadequate cortisol replacement GGT increases in all patients but may contribute to toxicity. doesnt need mitotane discontinuation unless very high levels are observed. Moderate CNS toxicity may be Important (memory impairment, frequent liver toxicity is rare. attention deficit, etc). Severe toxicity is dose-related.

All patients become hypoadrenal but mineralocorticoid supplementation is not always necessary. In men, hypogonadism may develop after some time. Gynecomastia occurs earlier due to the estrogenic action of mitotane.

Daffara et al., 2008

20

16

Cortisol (g/dl)
200

12

160
0 0 3 6 Months 9 12
Median 25%-75%

120

80

CBG (ng/ml)

40

6 Months

12

Median 25%-75%

1,2

0,9

FT4 ng/dl

0,6

0,3

0,0

6 Months

12
3

Median Min-Max

TSH mU/l

6 Months

12

Median 25%-75%

16

12

Testosterone (ng/ml)

4
35

30

6 Months

12
25 20 15

Median 25%-75%

Free testosterone (pg/ml)

10 5 0

6 Months

12

Median 25%-75%

Chronic mitotane treatment in an 17 pts radically resected for ACC were prospectively treated with adjuvant setting is feasible but mitotane in an adjuvant setting from 1999-2006 with a median duration of treatment of 22 months (range, 12-84) specific expertise is needed. Side effects are frequent but wellinformed and motivated patients are able to cope with them without discontinuing permanently mitotane, proven that a careful tailoring of the mitotane schedule is done.

TUMOR RECURRENCE

SURVIVAL AFTER TUMOR RECURRENCE

1,0

Proportion of Surviving

0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0,0 0 50 100 150 200 Tempo Months 250 300 350 400

P<0.0001

GROUP 1, n=32

GROUP 2, n=13 GROUP 3, n=26

ADVANCED DISEASE

Time to progression

P<0.03

Overall survival

First International Randomized trial in locally advanced and Metastatic Adrenocortical Carcinoma Treatment

FIRMACT trial
Study-Design:
randomized prospective controlled open-label multi-center international parallel-group study

Ronchi et al., 2009

NOVEL THERAPIES

POTENTIAL TARGETS IN ADRENOCORTICAL CANCER

EGFR Kamio et al 1990 Sasano et al 1994 Edgren et al 1997 Gicquel et al 1997 de Fraipont et al 2005 Lin S-R et al 2000 Kolomecki et al 2001 Benini et al 2002 Zaharieva S et al 2004

IGF2 FGR1 K-ras VEGF

Fassnacht et al. 2009

Clinical Management of ACC

Surgery whenever possible

Organization of prospective trials with primary novel drugs is urgently needed repeat (following recurrence or chemo)
Adjuvant mitotane treatment higher dose longer duration Mitotane or EDP + mitotane in advanced disease Gemcitabine + capecitabine as salvage treatment