Can we predict chemo-induced hematotoxicity in elderly patients treated with pegylated liposomal doxorubicin? Results of a population-based model derived from the DOGMES phase II trial of the GINECO.
BACKGROUND
Use of anthracyclines is often limited in older patients due to cardiac and hematologic toxicities. Thanks to its reduced toxicity profile, Pegylated Liposomal Doxorubicin (PLD) allows an extended use of doxorubicin to this population. We aimed at modeling PLD-induced hematotoxicity in patients with metastatic breast cancer ≥70 years old and at finding predictive factors of neutrophil nadir value.


METHODS
Sixty patients, enrolled in the DOGMES prospective multicentric phase II trial, were treated with PLD at 40mg/m(2) every 28days during six cycles. Trial design included geriatric covariates assessment at inclusion and monitoring of cells count every week for three cycles. A population model was developed to describe hematopoiesis and hematopoietic reserve in these patients. The effect of co-administered G-CSF (granulocyte colony-stimulating factor) was also examined.


RESULTS
A pharmacodynamic model was built using data from 53 patients not receiving G-CSF. This model assumed an instantaneous effect of PLD on the system. Based on this model, exact neutrophil nadir value was computed and ranged between 0.069K/mm(3) and 2.63K/mm(3) confirming the weak hematotoxicity of PLD. The same model was then applied to the 7 patients receiving G-CSF and showed that basal neutrophil count was higher for these patients. No other difference was found between both cohorts. Among the covariates collected, three were predictive of neutrophil nadir value: diabetes, frailty syndrome and assistance at home.


CONCLUSIONS
This developed model allowed the identification of predictive factors of nadir ANC and the identification of patients that are more likely to develop hematotoxicity that should be monitored with attention.
EMR3738, ciblage Thérapeutique en Oncologie, Faculté de Médecine et de Maïeutique Lyon-Sud, Charles Mérieux, Université Claude Bernard-Lyon 1, 69921 Oullins, France. Electronic address: alexandre.sostelly@gmail.com.
Alexandre
A
Sostelly
Emilie
E
Henin
Laure
L
Chauvenet
Anne-Claire
AC
Hardy-Bessard
Véronique
V
Jestin-Le Tallec
Sylvie
S
Kirsher
Cécile
C
Leyronnas
Catherine
C
Ligeza-Poisson
Soraya
S
Ramdane
Jacques
J
Salavt
Sylvie
S
Van-Hult
Jean-Michel
JM
Vannetzel
Gilles
G
Freyer
Michel
M
Tod
Claire
C
Falandry
D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy*; D004317:Doxorubicin / Q000009:adverse effects / Q000031:analogs & derivatives*; D005260:Female; D016330:Frail Elderly; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006397:Hematinics / Q000008:administration & dosage; D006801:Humans; D008954:Models, Biological; D009503:Neutropenia / Q000139:chemically induced*; D011092:Polyethylene Glycols / Q000009:adverse effects; D011446:Prospective Studies
D000903:Antibiotics, Antineoplastic; D006397:Hematinics; C506643:liposomal doxorubicin; D016179:Granulocyte Colony-Stimulating Factor; D011092:Polyethylene Glycols; D004317:Doxorubicin