title: Dose-dense nonpegylated liposomal Doxorubicin and docetaxel combination in breast cancer: dose-finding study.
abstract: BACKGROUND
  Anthracyclines and taxanes are effective drugs in breast cancer (BC), but their toxicity profiles limit their use in combination. A dose-finding study was performed to determine maximum tolerated doses (MTDs) of nonpegylated liposomal doxorubicin (TLC-D99) and docetaxel (DTX) as a dose-dense schedule, to maintain dose intensity, and to limit toxicity, particularly cardiac.
  
  
  METHODS
  Twenty-four patients were enrolled, 12 with metastatic BC, 5 with locally advanced BC, and 7 with early BC. An intra- and interpatient approach was planned in two sequential steps. In the first step, TLC-D99 was administered at dose levels of 40, 45, and 50 mg/m(2) plus DTX at a fixed dose of 50 mg/m(2). In the second step, TLC-D99 was administered at the dose established in the first step plus DTX at dose levels of 55, 60, and 65 mg/m(2). Every treatment cycle was delivered on day 1 every 14 days. Pegylated granulocyte colony-stimulating factor was scheduled on day 2. Dose-limiting toxicities (DLTs) were defined as G4 hematological; G3 nonhematological; ≥10% or ≥20% left ventricular ejection fraction (LVEF) reduction if the final value was <50% or ≥50%, respectively; severe arrhythmia; and symptomatic heart failure. LVEF was evaluated by echocardiography every two cycles, and precursor brain natriuretic peptide (pBNP) and cardiac troponin I (cTnI) were monitored on days 1 and 2.
  
  
  RESULTS
  Five DLTs occurred (20.8%). No cardiac event of congestive heart failure was reported; 2 events of grade 3 cardiac dysfunction (8.3%), including a ≥20% LVEF reduction in 1 patient and symptomatic arrhythmia in another; 2 incidences of G4 neutropenia (8.3%); and 1 occurrence of G3 asthenia (4.2%) were reported. MTDs were not reached. The recommended doses were established as TLC-D99 50 mg/m(2) and DTX 65 mg/m(2). Cumulatively, mild (G1-G2) cardiac dysfunction was observed in 58.4% of patients: G1 cardiac arrhythmia was noted in 50%, G1-G2 general cardiac toxicity occurred in 25%, and concomitant toxicity was present in 17%. cTnI never increased. pBNP was increased in 25% and was associated with limiting arrhythmia in 4% and cardiac dysfunction in 16%.
  
  
  CONCLUSIONS
  Dose-dense TLC-D99 50 mg/m(2) and DTX 65 mg/m(2) can be safely administered in combination every 2 weeks for breast cancer, with the highest projected dose intensity for each drug at 25 and 32.5 mg/m(2) per week, respectively.
authors.affiliation: Medical Oncology, enrico.ricevuto@univaq.it.
authors.forename: Enrico
authors.initials: E
authors.lastname: Ricevuto
authors.affiliation: Medical Oncology.
authors.forename: Valentina
authors.initials: V
authors.lastname: Cocciolone
authors.affiliation: Medical Oncology.
authors.forename: Maria
authors.initials: M
authors.lastname: Mancini
authors.affiliation: Medical Oncology.
authors.forename: Katia
authors.initials: K
authors.lastname: Cannita
authors.affiliation: Cardiology, Department of Internal Medicine and Public Health.
authors.forename: Silvio
authors.initials: S
authors.lastname: Romano
authors.affiliation: Medical Oncology.
authors.forename: Gemma
authors.initials: G
authors.lastname: Bruera
authors.affiliation: Medical Oncology.
authors.forename: Michela
authors.initials: M
authors.lastname: Pelliccione
authors.affiliation: Medical Oncology.
authors.forename: Maria Ilaria
authors.initials: MI
authors.lastname: Adinolfi
authors.affiliation: Radiology, and.
authors.forename: Antonietta
authors.initials: A
authors.lastname: Ciccozzi
authors.affiliation: Breast Unit, S. Salvatore Hospital, University of L'Aquila, L'Aquila, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bafile
authors.affiliation: Cardiology, Department of Internal Medicine and Public Health.
authors.forename: Maria
authors.initials: M
authors.lastname: Penco
authors.affiliation: Medical Oncology.
authors.forename: Corrado
authors.initials: C
authors.lastname: Ficorella
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000473:pathology; D005260:Female; D006801:Humans; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects; D043823:Taxoids / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D043823:Taxoids; C506643:liposomal doxorubicin; D000077143:Docetaxel; D011092:Polyethylene Glycols; D004317:Doxorubicin