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Maintenance Therapy With PLD
Following Standard Chemotherapy for MBC
Significantly Prolongs TTP in a Multicenter
Phase III Randomized Trial: GEICAM 2001-01 Study
E. Alba (1), M. Ruiz-Borrego (2), M. Martín (3), M. Margelí (4),
Á. Rodríguez-Lescure (5), P. Sánchez-Rovira (6), A. Ruiz (7),
N. Ribelles (1), E. Calvo (2), A. Casado (3)
(1) Hospital U. Virgen de la Victoria, Málaga, Spain; (2) Hospital U. Virgen del Rocío, Sevilla, Spain; (3)
Hospital U. Clínico San Carlos, Madrid, Spain; (4) Hospital Germans Trias i Pujol, Badalona, Spain; (5)
Hospital Gral. U. de Elche, Elche, Spain; (6) Complejo Hospitalario de Jaén, Jaén, Spain; (7) Instituto
Valenciano de Oncología, Valencia, Spain
Role of Maintenance Therapy for MBC
 Randomized trials demonstrate consistent benefit favoring prolonged vs
standard duration of chemotherapy
 Meta-analysis revealed a reduction in hazard of death1
 Maintenance therapy offers a strategy to prolong time to progression, but
must be weighted against side effects
 Optimal duration of treatment a matter of debate
 No benefit in MANTA 1 trial of maintenance paclitaxel after 1st-line regimen
of anthracycline/paclitaxel2
 Trial stopped early
 Confounding variables
1Coates
et al. Am Soc Clin Oncol Ed Book. 2003;pp 119-121; 2Gennari et al. J Clin Oncol. 2006;24:3912-3918.
Randomized Studies of Chemotherapy Duration in MBC
N
TTP, median
(months)
AC/CMF until PD vs AC x 3
305
6* vs 4
Muss (1991)
FAC x 6 → CMF x 12 vs FAC x 6
145
9.4* vs 3.2
Ejlertsen (1993)
FEC x 18 (+ TAM) vs FEC x 6 (+ TAM)
254
14* vs 10
Gregory (1997)
VAC/VEC x 6 → MMM x 6 vs VAC/VEC/MMM x 6
100
10* vs 7
Falkson (1998)
A x 6 → CMFPTH x 8 vs A x 6
195
18.7* vs 7.8
FESG (2000)
FEC-75 x 11 vs FEC-100 x 4 → FEC-50 x 8 vs FEC-100 x 4
392
10.3 vs 8.3 vs 6.2
Nooij (2003)
CMF until PD vs CMF x 6
196
5.2* vs 3.5
Gennari (2006)
AP/EP x 6-8 → P x 8 vs AP/EP x 6-8
215†
8 vs 9
Study
Treatment Schedules
Coates (1987)
*Statistically significant; †assessed in futility analysis.
Pegylated Liposomal Doxorubicin (PLD)
as Maintenance Therapy
 Anthracyclines are cornerstone of treatment for breast cancer
 Conventional anthracyclines limited by cardiac toxicity
 PLD has comparable efficacy and significantly improved safety profile
compared with conventional doxorubicin in MBC1
– Significantly less cardiotoxicity
– Less nausea/vomiting, alopecia, and myelosuppression
1O’Brien
et al. Ann Oncol. 2004;15:440-449.
GEICAM 2001-01
Background and Aim
 Regimen choice for this trial based on GEICAM 99031
– A→T equally effective, less toxic compared with concomitantly administered
AT
– Significantly reduced rate of febrile neutropenia
– Based on these results, considered a regimen of choice for 1st-line
treatment of MBC
 Trial utilizes 1st-line standard GEICAM regimen and assesses the role of
maintenance therapy, utilizing pegylated liposomal anthracycline, or no
maintenance therapy as an approach to 1st-line MBC
1Alba
et al. J Clin Oncol. 2004;22:2587-2593.
GEICAM 2001-01 Study Design
Design
 Phase III trial
 Multicenter
CR
PR
SD
Eligibility
 MBC after 1st-line
induction chemotherapy
with A → T
R
A
N
D
O
M
I
Z
A
T
I
O
N
*Patients assessed at same time points in both study arms.
PLD 40 mg /m2
q 28 days x
6 cycles *
Observation*
Study Endpoints
 Primary
– Time to progression (TTP)
 Secondary
– Toxicity
– Overall survival (OS)
Study Assessments
 Prior to randomization
– Response to induction chemotherapy 6 wks after last dose and within 8 wks
prior to study registration
 After randomization
– All patients followed q 28 days during the first 6 months
– Disease status assessed in all patients (without signs or symptoms of
progression) at 3-mo intervals up to 24 mo
– Patients followed until disease progression documented or until study
completed
 Cardiotoxicity
– LVEF by echocardiography or MUGA at baseline, cycle 3, cycle 6, and
every 6 months thereafter
Statistical Methodology

Sample size:
– Assuming an increase of median TTP of 66% (log-rank test)
– With an alpha error of 0.01 (1-sided) and a power of 80%, 77
patients per arm needed

Statistical analysis:
– ITT population
– Log-rank test for treatment arm comparisons
– Cox regression model to control risk factors
Eligibility

Key Inclusion Criteria
– Women with MBC with response (CR or PR) or SD after first-line induction
therapy
– Age > 18 years
– ECOG PS 0, 1, or 2
– At least one measurable lesion by RECIST
– Normal cardiac function

Key Exclusion Criteria
– Previous grade II or higher cardiac dysfunction as assessed by NYHA
criteria or congestive cardiac failure
– Hypersensitivity to anthracyclines or Cremophor®
– Radiation therapy in previous 4 weeks
– Symptomatic brain metastases
Patient Registration and Randomization
288 Patients Registered
133 (46.2%)
Not randomized
155 Randomized
Progression/death: 63
Toxicity: 14
Patient refusal: 25
Logistics/scheduling: 9
Unknown/other: 22
PLD: 78
Observation: 77
Patient and Disease Characteristics
PLD
(n=78)
Observation
(n=77)
P-value
Age, median
58
55
.624
ECOG PS
0
1
2
Unknown
45 (58%)
20 (26%)
5 (6%)
8 (10%)
43 (56%)
28 (36%)
2 (3%)
4 (5%)
.209
Characteristic
Hormonal status
ER+ and/or PR+
ER- and/or PRUnknown
Dominant site of disease
Visceral
Non-visceral
Unknown
.654
53 (68%)
17 (22%)
8 (10%)
56 (73%)
15 (19%)
6 (8%)
.839
46 (59%)
31 (40%)
1 (1%)
43 (56%)
31 (40%)
3 (4%)
Patient and Disease Characteristics
Characteristic
PLD
(n=78)
Observation
(n=77)
P-value
Response status at randomization
Complete response
Partial response
Stable disease
.055
3 (4%)
38 (49%)
37 (47%)
7 (9%)
47 (61%)
23 (30%)
Prior adjuvant/neo-adjuvant therapy
Chemotherapy
Hormonal therapy
48 (62%)
33 (42%)
44 (57%)
32 (42%)
.575
.945
Prior adjuvant anthracycline
23 (30%)
27 (35%)
.186
Maintenance Treatment Description
Characteristic
Cycles
Mean
Median (range)
PLD
(n=78)
4.9
6 (0-6)
Patients completing all planned cycles
39 (50%)
Discontinuation reason
PD or death
Toxicity
Other
21 (54%)
8 (20%)
10 (26%)
Time to Progression – From Randomization
1.0
% Progression–Free Survival
0.9
0.8
P-value (log-rank test) = .0006
0.7
HR = 0.54 (95% CI, 0.38-0.77)
0.6
0.5
0.4
0.3
PLD maintenance median:
8.38 months
0.2
Observation median:
5.06 months
0.1
0.0
0
PLD
Observation
6
12
Months
18
24
0–6m
6 -12 m
12 -18 m
18 – 24 m
28
48
20
16
8
1
2
1
Time to Progression – From Initial Induction Treatment
% Progression–Free Survival
1.0
0.9
P-value (log-rank test) = .0005
0.8
HR = 0.53 (95% CI, 0.37-0.76)
0.7
0.6
0.5
0.4
PLD maintenance median:
13.22 months
0.3
Observation
median:
10.16 months
0.2
0.1
0.0
0
10
20
Months
30
Maintenance Treatment:
Hematologic Toxicity (NCI-CTC.2)
% of Patients
PLD
(n=78)
Toxicity
Neutropenia
Anemia
Observation
(n=77)
Grade 1 / 2
Grade 3 / 4
Grade 1 / 2
Grade 3 / 4
32
35
12
0
9
12
0
0
 Febrile neutropenia occurred in only 2.6% of PLD patients
Maintenance Treatment:
Non-Hematologic Toxicity (NCI-CTC.2)
% of Patients
PLD
(n=78)
Observation
(n=77)
Grade 1 / 2
Grade 3 / 4
Grade 1 / 2
Grade 3 / 4
Nausea/vomiting
21
0
4
0
Fatigue
32
3
8
0
Alopecia
Infusion reaction
29
1
0
1
4
0
0
0
Mucositis
PPE
32
29
5
4*
0
0
0
0
Toxicity
*Grade 3 only
Cardiotoxicity
PLD
(n=78)
Observation
(n=77)
Median LEVF at cycle 6
61%
60%
Decrease in LVEF ≥ 10%
5 (6%)
1 (1%)
Drop of LVEF < 50%
2* (3%)
0
0
0
Congestive heart failure
*LVEF value at cycle 6 → 47% and 44%
Conclusions
 Maintenance therapy with PLD significantly prolongs TTP (3.33 months)
 Most progressions are avoided while the patients are on treatment with
PLD
 Toxicity is infrequent and manageable, especially subjective toxicity (eg,
nausea/vomiting and alopecia)
 Cardiotoxicity incidence has not been relevant
 Maintenance therapy with PLD is a therapeutic option in non-progressing
patients with MBC after first-line chemotherapy
 Based on these results, adding PLD to responding MBC patients, will be
the standard arm on future GEICAM studies
Acknowledgements
 All the women who participated in this trial
 GEICAM personnel
 Investigators and their support staff who enrolled patients onto the trial
GEICAM 2001-01
Investigators
Emilio Alba – Hospital Virgen de la Victoria
Carlos Jara – Fundación Hospital Alcorcón
Manuel Ruiz Borrego – Hospital Virgen del Rocío
López Vega – Hospital Marques de Valdecilla
Miguel Martín – Hospital Clínico San Carlos
Lourdes Calvo – Complejo Hospitalario Juan Canalejo
Mireia Margeli – Hospital Trias i Pujol
Antonio Antón – Hospital Miguel Servet
Rodríguez Lescure – Hospital General de Elche
Ricardo Cubedo – Clínica Puerta de Hierro
Mel Lorenzo – Hospital Xeral Calde
Isabel Moreno – Hospital de Badalona
Amparo Ruíz – Instituto Valenciano de Oncología
Enrique Aranda – Hospital Provincial Reina Sofia
Pedro Sánchez – Hospital Ciudad de Jaén
Antonio Fernandez – Hospital General de Albacete
Ramos Vázquez – Centro Oncológico de Galicia
Cesar Mendiola – Hospital Universitario 12 de Octubre
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