Dose-dense nonpegylated liposomal Doxorubicin and docetaxel combination in breast cancer: dose-finding study.

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%. CONCLUSION: 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.

Modulation of GemOx chemotherapy according to CIRS in elderly patients with advanced pancreatic cancer.

The present study evaluated activity and toxicity of modulated doses of gemcitabine associated to oxaliplatin in patients with secondary CIRS and with locally advanced pancreatic adenocarcinoma (LAPC) and metastatic pancreatic adenocarcinoma (MPC). Since January 2006, untreated LAPC and MPC patients have been assessed with ADL, IADL, CIRS to modulate chemotherapy dosages according to co-morbidity stage. Patiens aged<75 years, co-morbidity stage primary/intermediate, or ≥75 years and co-morbidity stage primary, received gemcitabine 1,000 mg/m² as a 10 mg/m²/min infusion on day 1 and oxaliplatin 70 mg/m² as a 2-h infusion on day 2 every 2 weeks. Patiens aged<75 years, co-morbidity stage secondary or ≥75 years and co-morbidity stage intermediate/secondary patients received gemcitabine 800 mg/m². Primary endpoint was the overall response rate (ORR). Secondary endpoints were disease control rate (DCR), PFS, OS and toxicity. Thirty-one patients were recruited: 26% (8/31) LAPC and 74% (23/31) MPC; median age 69 years. Co-morbidity stage primary/intermediate, 19; secondary, 12. Twenty-seven valuable patients: ORR 30% (CI±0.14); disease control rate 85% (CI±0.18). Median follow-up 13 months: median PFS and OS were 6 and 15 months, respectively. Valuable cycles 140. Grade 3/4 toxicity per patient: leukopenia, 18.5%; neutropenia, 55,5%; thrombocytopenia, 7.4%; SGOT/SGPT, 7.4%; gamma-GT, 7.4%; fever without neutropenia, 3.7%. Median received dose intensity: gemcitabine 400 mg/m2/w; oxaliplatin 35 mg/m2/w. Modulation of GemOx chemotherapy according, to CIRS stage in advanced pancreatic cancer confirms reported efficacy and tolerability.