Presentation on theme: "Maintenance Therapy With PLD Following Standard Chemotherapy for MBC Significantly Prolongs TTP in a Multicenter Phase III Randomized Trial: GEICAM 2001-01."— Presentation transcript:
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 death 1 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 1 st -line regimen of anthracycline/paclitaxel 2 Trial stopped early Confounding variables 1 Coates et al. Am Soc Clin Oncol Ed Book. 2003;pp 119-121; 2 Gennari et al. J Clin Oncol. 2006;24:3912-3918.
Randomized Studies of Chemotherapy Duration in MBC StudyTreatment SchedulesN TTP, median (months) Coates (1987)AC/CMF until PD vs AC x 33056* vs 4 Muss (1991)FAC x 6 → CMF x 12 vs FAC x 61459.4* vs 3.2 Ejlertsen (1993)FEC x 18 (+ TAM) vs FEC x 6 (+ TAM)25414* vs 10 Gregory (1997)VAC/VEC x 6 → MMM x 6 vs VAC/VEC/MMM x 610010* vs 7 Falkson (1998)A x 6 → CMFPTH x 8 vs A x 619518.7* vs 7.8 FESG (2000)FEC-75 x 11 vs FEC-100 x 4 → FEC-50 x 8 vs FEC-100 x 439210.3 vs 8.3 vs 6.2 Nooij (2003)CMF until PD vs CMF x 61965.2* vs 3.5 Gennari (2006)AP/EP x 6-8 → P x 8 vs AP/EP x 6-8215 † 8 vs 9 *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 MBC 1 –Significantly less cardiotoxicity –Less nausea/vomiting, alopecia, and myelosuppression 1 O’Brien et al. Ann Oncol. 2004;15:440-449.
GEICAM 2001-01 Background and Aim Regimen choice for this trial based on GEICAM 9903 1 –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 1 st -line treatment of MBC Trial utilizes 1 st -line standard GEICAM regimen and assesses the role of maintenance therapy, utilizing pegylated liposomal anthracycline, or no maintenance therapy as an approach to 1 st -line MBC 1 Alba et al. J Clin Oncol. 2004;22:2587-2593.
GEICAM 2001-01 Study Design *Patients assessed at same time points in both study arms. PLD 40mg/m 2 q 28daysx 6cycles* Observation* CR PR SD R A N D O M I Z A T I O N Design Phase III trial Multicenter Eligibility MBC after 1 st -line induction chemotherapy with A → T
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
Cardiotoxicity PLD (n=78) Observation (n=77) Median LEVF at cycle 661%60% Decrease in LVEF ≥ 10%5 (6%)1 (1%) Drop of LVEF < 50%2* (3%)0 Congestive heart failure00 *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 Emilio Alba – Hospital Virgen de la Victoria Manuel Ruiz Borrego – Hospital Virgen del Rocío Miguel Martín – Hospital Clínico San Carlos Mireia Margeli – Hospital Trias i Pujol Rodríguez Lescure – Hospital General de Elche Mel Lorenzo – Hospital Xeral Calde Amparo Ruíz – Instituto Valenciano de Oncología Pedro Sánchez – Hospital Ciudad de Jaén Ramos Vázquez – Centro Oncológico de Galicia Carlos Jara – Fundación Hospital Alcorcón López Vega – Hospital Marques de Valdecilla Lourdes Calvo – Complejo Hospitalario Juan Canalejo Antonio Antón – Hospital Miguel Servet Ricardo Cubedo – Clínica Puerta de Hierro Isabel Moreno – Hospital de Badalona Enrique Aranda – Hospital Provincial Reina Sofia Antonio Fernandez – Hospital General de Albacete Cesar Mendiola – Hospital Universitario 12 de Octubre GEICAM 2001-01 Investigators