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La doxorubicina liposomiale non pegilata nel MBC:
dati della letteratura in vari profili di pazienti
(naive, pretrattata, anziana)
Dottor Liberato Di Lullo
Direttore U.O.C. DI ONCOLOGIA
P.O. “F. Veneziale” Isernia e P.O. “A. Cardarelli” CB
Chieti, 11 Dicembre 2012
RISK FACTORS FOR THE DEVELOPMENT OF CHRONIC
ANTHRACYCLINE CARDIOTOXICITY (1)
A number of risk factors for the development of chronic anthracycline
cardiotoxicity have been identified. The strongest predictor is
cumulative dose
 Cumulative
dose:
The
development
of
anthracycline-related
cardiotoxicity is strongly correlated to cumulative dose. Based upon
these observations, it has been generally recommended that cumulative
doxorubicin doses be limited to 450 to 500 mg/m2 in adults. However,
there is variable sensitivity to anthracyclines among patients, with some
tolerating doses as high as 1000 mg/m2, and others experiencing
cardiotoxicity at doses lower that 300 mg/m2. Early data suggest that
inherited polymorphisms in one of the carbonyl reductase genes that
catalyze the metabolism of anthracyclines to cardiotoxic metabolites
may be involved.
 Age: age extremes predispose to cardiotoxicity at lower cumulative
anthracycline dose. In older patients, preexisting heart disease
(including hypertension) is a risk factor for anthracycline cardiotoxicity.
However, it is not clear whether pre-existing heart disease increases
susceptibility to anthracycline-induced damage, or whether there is less
functional reserve to tolerate additional myocardial damage
 Radiation therapy: prior mediastinal irradiation may increase the
susceptibility to anthracycline cardiotoxicity by inducing endothelial cell
damage and compromising coronary artery blood flow. This risk of
cardiotoxicity is particularly important in women who have received prior
chest wall irradiation for left-sided breast cancer. Concurrent
irradiation also increases risk
 Longer duration of survival: is also a risk factor for cardiac toxicity,
emphasizing the importance of monitoring for long-term effects in the
growing population of cancer survivors
 Concomitant chemotherapy: the administration of nonanthracycline
agents that also cause cardiotoxicity may result in synergistic toxicity
when anthracyclines are given concurrently. The most important agents
in this regard are the taxanes (paclitaxel, docetaxel) and trastuzumab
 Hematopoietic
cell
transplantation:
The
combination
of
cyclophosfamide and total body radiation prior to bone marrow
transplantation is itself capable of causing myocardial damage. Thus, in
patients with prior anthracycline treatment or mediastinal radiation, the
risks of developing cardiotoxicity at the time of bone marrow
transplantation are even greater N Engl J Med. 1998;339(13):900; Am J Med. 1977;62(2):200
Ann Intern Med. 1979;91(5):710; J Clin Oncol. 2008;26(19):3159
J Clin Oncol. 2007;25(25):3991; Ann Intern Med. 1996;125(1):47
Cancer. 2003;97(11):2869; J Clin Oncol. 1998;16(11):3493
J Clin Oncol. 2008;26(34):5537
Annals of Oncology 22: 257-267, 2011
NPLD: Phase II Trials in MBC
1) monochemotherapy 60mg/m2
well tolerated
2) monochemotherapy 75mg/m2
well tolerated
3) 60mg/m2 + 5FU + CF
well tolerated
4) monochemioterapia 135 mg/m2
severe neutropenia
LOWER CARDIAC TOXICITY
RR
PFS
TTF
= doxorubicin
Dose for phase III trials:
75 mg/m2 in monotherapy, 60 mg /m2 in combination
1) Batist et al, 1992 - 2) Ervin data on file - 3) Valero et al, 1999 - 4) Shapiro et al, 1999
adapted
NPLD: Phase III Trials in MBC
adapted
Vs doxorubicin – naïve and pre-treated patients
Study
Batist et al. JCO
2001
Harris et al.
Cancer 2002
Chemotherapy
(dose mg/m2)
N.
RR
(%)
OS
(months)
Cardiac toxicity
(%)
Cases
of CHF
M 60 + CTX 600
vs
Doxo 60+ CTX 600
142
43
19
6
0
155
43
16
ns
21
p= 0,0001
5
p= 0,02
Myocet 75
vs
Doxo 75
108
26
16
13
2
116
26
20
ns
29
p= 0,0001
9
p= 0,0001
Vs epirubicin – naïve patients
Study
Chan et al.
Ann Oncol 2004
Chemotherapy
(dose mg/m2)
N.
RR
(%)
Duration of
response
TTF
TTP
Cardiac
toxicity (%)
Cases
of CHF
M 75 + CTX 600
vs
Epi 75+ CTX 600
80
46
10
5,7
7,7
12
0
80
39
ns
7,7
0,005
4,4
0,007
5,6
0,02
10
ns
0
Vs doxorubicin – only pre-treated
Study
Batist G et al.
Anticancer Drug s 2006
Chemotherapy
(dose mg/m2)
N.
RR
(%)
OS
(months)
TTF
TTP
Cardiac
toxicity (%)
Cases
of CHF
NPDL q3wk
vs
Doxorubicin q3wk
32
31
16
4,2
4,5
22
1
36
11
0,04
15
0,71
2,1
0,01
3,4
0,06
39
0,001
3
FIRST LINE IN MBC HER2 -
Author
Pts
Drugs
%RR
mOS (m)
-------------------------------------------------------------------------
My+DTX
50
Curtit
34
My+DTX
79
Del Barco 53
My+GEM
51
Livi
34 My+DTX/CYC
71
Rosati
56 wMy+DTX/TAX
73
Valero
51 My+CYC+FU
73
Schmid
51
25
28.2
25.4
-23
19.4
M. S. Rosati et al
Endpoint I:
CB e toxicity
Endpoint II:
TTP e OS
Combined weekly administration of taxane and NPLD is well tolerated and
CB data encourage phase III study design
E. Curtit et al
L’associazione di antracicline e trastuzumab mostra
attività clinica significativa…
Pivotal phase III combination trial (H0648g), IHC 3+
H = Herceptin; AC = anthracycline/cyclophosphamide
Slamon D, et al. N Engl J Med 2001; 344: 783 – 92
Smith I. Anticancer Drugs 2001; 12:S3 - 10
. . . ma anche un tasso elevato di cardiotossicità
30
25
20
15
10
5
0
Modified from Seidman A et al
J Clin Oncol 20(5):1215-1221, 2001
FIRST LINE IN MBC HER2 +
Author
Pts
Drugs
%RR
< LVEF
---------------------------------------------------------------Theodoulou 40
My+T
50
13%
Venturini
31
My+DTX+T 65
9.7%
Amadori
52
My+DTX+T 55
8%
Cortes
37
My+TAX+T 96
17%
RECHALLENGE WITH ANTHRACYCLINE
 rechallenge with anthracyclines remains an option for metastatic
breast cancer patients, provided relapse-free survival is >1 year after
the end of adjuvant anthracycline-containing chemotherapy
 may be appropriate in symptomatic patients, requiring a rapid
response
 published data indicating that re-treatement with anthracyclines in
the metastatic setting is active also in anthracycline-pretreated
patients, but discouraged by the risk of cardiotoxicity associated with
high cumulative doses
 NPLD is associated with a significantly reduced risk of cardiotoxicity
compared with conventional doxorubicin, even in patients with prior
anthracycline exposure
Airoldi el al, Tumori 2011; 97 (6): 690-692
CLINICAL RECOMMENDATIONS
 NPLD can be safely administered up to high cumulative doses and
may represent an attractive drug for patients requiring anthracycline
rechallenge
 NPLD may be used in HER2-negative patients in combination with
taxanes, as this is a viable option in clinical practice
 NPLD in combination with cyclophosphamide may be used as a firstline metastatic option due to the low cardiotoxic potential, which allows
higher cumulative anthracycline dosages
 NPLD can be also considered in anthracycline-pretreated patients in
subsequent lines of treatment if sequential monochemotherapy is the
preferred choice
Airoldi el al, Tumori 2011; 97 (6): 690-692
CONCLUSIONS
 NPLD is a viable option in breast cancer
 NPLD use should be preferred to conventional anthracyclines,
especially in those patients at risk of developing cardiotoxicity
 Patients candidate to rechallenge with anthracyclines after
adjuvant administration could be suitable for NPLD due to the
possibility of a more prolonged treatment, not limited by
cumulative dosages
Airoldi el al, Tumori 2011; 97 (6): 690-692
GRAZIE PER L’ATTENZIONE….