Maria Vincenza Mancini

Poker association of weekly alternating 5-fluorouracil, irinotecan, bevacizumab and oxaliplatin (FIr-B/FOx) in first line treatment of metastatic colorectal cancer: a phase II study

BackgroundThis phase II study investigated efficacy and safety of weekly alternating Bevacizumab (BEV)/Irinotecan (CPT-11) or Oxaliplatin (OHP) associated to weekly 5-Fluorouracil (5-FU) in first line treatment of metastatic colorectal carcinoma (MCRC).MethodsSimon two-step design: delta 20% (p0 50%, p1 70%), power 80%, α 5%, β 20%. Projected objective responses (ORR): I step, 8/15 patients (pts); II step 26/43 pts. Schedule: weekly 12 h-timed-flat-infusion/5-FU 900 mg/m2, days 1-2, 8-9, 15-16, 22-23; CPT-11 160 mg/m2 plus BEV 5 mg/kg, days 1,15; OHP at three dose-levels, 60-70-80 mg/m2, days 8, 22; every 4 weeks.ResultsFifty consecutive, unselected pts < 75 years were enrolled: median age 63; young-elderly (yE) 24 (48%); liver metastases (LM) 33 pts, 66% Achieved OHP recommended dose, 80 mg/m2. ORR 82% intent-to-treat and 84% as-treated analysis. Median progression-free survival 12 months. Equivalent efficacy was obtained in yE pts. Liver metastasectomies were performed in 26% of all pts and in 39% of pts with LM. After a median follow-up of 21 months, median overall survival was 28 months. Cumulative G3-4 toxicities per patient: diarrhea 28%, mucositis 6%, neutropenia 10%, hypertension 2%. They were equivalent in yE pts. Limiting toxicity syndromes (LTS), consisting of the dose-limiting toxicity, associated or not to G2 or limiting toxicities: 44% overall, 46% in yE. Multiple versus single site LTS, respectively: overall, 24% versus 20%; yE pts, 37.5% versus 8%.ConclusionPoker combination shows high activity and efficacy in first line treatment of MCRC. It increases liver metastasectomies rate and can be safely administered.Trial registrationOsservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali (OsSC) Agenzia Italiana del Farmaco (AIFA) Numero EudraCT 2007-004946-34

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.

Timed-flat infusion of 5-fluorouracil associated with docetaxel as first-line treatment of patients with metastatic breast cancer.

To the Editor: The combination of 5-fluorouracil (5-FU) and docetaxel (dTX) has demonstrated significant antitumor activity in anthracycline-pretreated patients with metastatic breast cancer (MBC) (1). In a previous study (2), we determined the optimal doses of dTX in combination with a 12-hour (10:00 p.m.–10:00 a.m.) timed-flat infusion of 5-FU (TFI ⁄ 5-FU) in MBC. TFI ⁄ 5-FU may reduce the frequency of mucositis (stomatitis and diarrhea) that appeared to be the dose-limiting toxicity of the 5-FU-dTX regimen. Thus, TFI ⁄ 5FU associated with docetaxel (dTX) was evaluated in a phase II study as a first-line treatment of patients with metastatic breast cancer (MBC). Patients were recruited at the Unit of Medical Oncology (University of L’Aquila, Italy) between December 1999 and July 2004. The study was approved by the Local Ethics Committee and all patients provided written informed consent. Treatment was administered on an outpatient basis as follows: dTX (Taxotere ; Aventis Farma, Dagenaham, UK) was given over 1-hour infusion at 85 mg ⁄ m on day 1 associated with a 12-hour TFI ⁄ 5-FU (fluorouracil TEVA ; Pharmachemic B.V., Haarlem, the Netherlands) at 800 mg ⁄ m ⁄ day, over 5 days. Cycles were repeated every 3 weeks. An implanted venous access device was required for 5-FU administration by means of a portable pump (CADD Plus, SEVIT ; Deltec, Inc., St. Paul, MN, USA), programmed to infuse 5-FU at a constant rate over a period of 12 hours, starting at 10:00 p.m. Tumor response was assessed according to WHO response criteria (3) for every three cycles of treatment. Patients were considered assessable for response to therapy if they received at least 3 treatment cycles. For the evaluation of activity, data from the 14 patients enrolled in the previous dose-finding study (2) were considered together with data of the 18 patients enrolled in the present study and treated at the recommended dose, as the average dose intensity (rDI) received by the two groups were quite similar (5-FU 1321 mg ⁄ m ⁄ week and dTX 27.7 mg ⁄ m ⁄ week versus 5-FU 1333 mg ⁄ m ⁄ week and dTX 28.3 mg ⁄ m ⁄ week). Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria. Granulocyte colony stimulating factor (G-CSF) was administered at the first occurrence of grade (G) 4 neutropenia and prophylactically given from then onwards. Among 31 evaluable patients out of 32 recruited, 4 complete responses (13%) and 14 partial responses (45%) were observed for an overall response rate (ORR) of 58% (a 0.05, CI ± 18%). Among the 19 patients pretreated with adjuvant anthracyclines, the ORR was of 47% (a 0.05, CI ± 23%), whereas, the ORR was of 75% (a 0.05, CI ± 23%) among the 12 patients non-receiving adjuvant anthracyclines. The median time to progression was 10 months (range 4– 28 months) and the median overall survival 25 months (range 4–46+ months). In the 18 patients enrolled in the present study at the recommended dose, a total of 141 cycles were administered with a median of 6 cycles per patient (range 3–12 cycles). The main non-hematologic toxicity was G3–4 stomatitis occurring in 22% of the patients and 2% of cycles. No G3–4 diarrhea was recorded. In the previous study using the same drugs with 5-FU administered in 24 hour-continuous infusion G3–4 stomatitis was equivalent and G3 diarrhea occurred in 7% of patients. It points out that TFI ⁄ 5-FU may reduce the incidence of gastrointestinal mucositis. G4 neutropenia, occurring in 72% of patients and requiring prophylactic G-CSF support, represented the main toxic event of the present regimen, but febrile neutropenia rarely occurred (one patient). The most common G1-2 non-hematologic toxicities were nausea (46% of patients and 13% of cycles), diarrhea (33% of patients and 4% of cycles), and stomatitis (33% of patients and 10% of cycles). Address correspondence and reprint requests to: Enrico Ricevuto, MD, Unit of Medical Oncology, S. Salvatore Hospital, University of L’Aquila, Via Vetoio, Coppito, 67100 L’Aquila, Italy, or e-mail: enrico.ricevuto@univaq.it

The safety of dose-dense liposomal-encapsulated doxorubicin in association with docetaxel (MyTax) in breast cancer.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #2157 Background: Liposomal-Encapsulated Doxorubicin (LED) shows equivalent efficacy, better cardiac tolerability at higher cumulative dose than conventional anthracyclines in breast cancer treatment. Methods: Sixteen pts were enrolled in a dose-finding study of LED (TLC-D99 Myocet ®) associated to Docetaxel (TXT). Twelve pts were treated with a fixed TXT dose (50 mg/m2) and TLC-D99 at three dose levels, 40-45-50 mg/m2, days 1 and 15 every 2 weeks using an intra- and inter-patient approach; four pts wrere treated at the TLC-D99 recommended dose (50 mg/m2). Cardiac monitoring of LVEF was performed every two cycles; Precursor Brain Natriuretic Peptide (proBNP) and cardiac Troponin (c-TnI) before and after 24 h chemotherapy was evaluated. Results : Breast cancer (BC) disease extension: metastatic (MBC), 8; locally advanced BC, 5; T2-T3 BC, 3. Previous chemotherapy: untreated, 11 pts; adjuvant, 5 pts. Enrolled pts for each dose-level: I, 7; II, 9; III, 14. Newly treated pts: I dose-level, 7; II dose-level, 3; III dose-level, 6. Valuable cycles for each dose-level in a total 77 cycles: I, 14; II, 21; III, 42. DLTs were observed in 3 pts, 21%, and 3 cycles, 4%: 2 cardiac, characterized by a 19% LVEF decrease and a symptomatic arrhythmia; one G4 hematologic resistant to G-CSF. DLTs for each dose-level by pts and cycles, respectively: I, 14% (1/7 pts) and 7% (1/14 cycles); II, no DLT in 9 pts and 21 cycles; III, 14% (2/14 pts) and 5% (2/42 cycles). Cumulative G3-4 toxicities by pts and cycles, respectively: cardiac arrhythmia 6% and 1,3%, cardiac general (symptomatic LVEF decrease), 6% and 1,3%; alopecia 81% and 65%; neutropenia resistant to G-CSF, 6% and 1,3%. Cardiac DLTs were observed in 2 elderly pts (>65 y). The 2 cardiac DLTs were observed in 2 out of 3 pts with pre-existing diastolic dysfunction. No pathologic increase of c-TnI levels was detected. Seven pts showed increased pro-BNP after chemotherapy; 1 of these with increased pro-BNP after chemotherapy, persistent the day 1 of each subsequent chemotherapy showed a DLT; G2 toxicities by patients and cycles, respectively: asthenia 37% and 18%, stomatitis/mucositis 12% and 5%, nausea 31% and 12%. Median rDI of TLC-D99 was 25 mg/m2/w and TXT 25 mg/m2/w for pts, respectively. Preliminary efficacy in 16 assessable pts: LA-BC and MBC, 1 CR (pCR) 7 PR (OR 62%), 4 SD and 1 PD; T2-T3 BC, 2 PR and 1 SD. Conclusion: dose-dense TLC-D99/Docetaxel association can be safely recommended at the dose of 50 mg/m2 for each drug. Docetaxel intensification is ongoing. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2157.