levoleucovorin and taxane

To define the cyclophosphamide (CTX) maximal tolerated dose when combined with fixed doses of gemcitabine, fluorouracil (5-FU) and folinic acid (leucovorin, LFA) in metastatic breast cancer patients pretreated with anthracyclines and taxanes.. Metastatic breast cancer patients aged < or = 75 years, with ECOG performance status 0-2, were eligible, provided that they had received previous anthracycline- and taxane-based chemotherapy for the advanced disease. Chemotherapy consisted of gemcitabine 1,000 mg/m(2), 5-FU 425 mg/m(2), LFA 100 mg/m(2) and escalating doses of CTX, starting from 500 mg/m(2), on days 1 and 8 every 3 weeks. The dose escalation was stopped if dose-limiting toxicity (DLT) occurred in > 33% of patients of a given cohort. After the definition of DLT, a further escalation with the addition of granulocyte colony-stimulating factor (G-CSF; on days 3-5 and 10-12) was planned.. Since March 1999, 69 patients have entered this trial through seven different cohorts. The dose escalation was stopped at the CTX dose of 600 mg/m(2) since 3/6 patients showed DLT. A further dose escalation was attempted in the presence of G-CSF support. A CTX dose of 800 mg/m(2) proved to be safe and was chosen for the phase II. A total of 33 patients were treated at this dose level. The treatment was fairly well tolerated, grade 3-4 neutropenia and thrombocytopenia occurring in 38 and 16% of patients, respectively. No cases of sepsis or bleeding were registered. Four patients required a packed red blood cell transfusion. Severe nonhematologic toxicity was also uncommon, occurring in 10 patients. Three complete and 24 partial responses were recorded for an overall response rate of 38% (95% CI = 26-50). Two complete and 12 partial responses were recorded in the 33 patients treated in the phase II for an overall response rate (ORR) of 42% (95% CI = 25-61).. The gemcitabine-CTX-5-FU/LFA combination is a well-tolerated treatment for poor-prognosis breast cancer patients with previous exposure to anthracyclines and taxanes. With the addition of G-CSF, a cumulative CTX dose of 1,600 mg/m(2) can be safely delivered every 3 weeks. The evidence of an ORR approaching 40% is very promising and justifies further evaluations in this subset of patients.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cyclophosphamide; Deoxycytidine; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Fluorouracil; Follow-Up Studies; Gemcitabine; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Paclitaxel; Survival Rate; Taxoids

The purpose of this study was to evaluate the activity and tolerance of high-dose leucovorin (LV) and infusional 5-fluorouracil (5-FU) in combination with conventional doses of cyclophosphamide (CPM) as salvage chemotherapy in patients with metastatic breast cancer (MBC) pretreated with anthracyclines and taxanes. 41 patients (median age 59 years) with MBC refractory or resistant to anthracyclines and taxanes were enrolled. The patients' performance status (WHO) was 0 in 10 patients (24%), 1 in 22 (54%), and 2 in 9 (22%). 30 (73%) patients had received 2 or more prior chemotherapy regimens. Cyclophosphamide (600 mg m(-2)) was given i.v. bolus on day 1 and LV (500 mg m(-2) d(-1)) as a 2-h infusion followed by 5-FU (1.5 g m(-2) d(-1)) over a 22 h c.i. for 2 consecutive days. Cyclophosphamide was administered every 28 days while 5-FU/LV every 14 days. In an intention-to-treat analysis, complete response (CR) was achieved in 2 (4.9%) patients and partial response (PR) in 9 (22%) (overall response rate 26.9%; 95% CI: 13.27-40.39%). Stable disease (SD) and progressive disease (PD) were observed in 9 (22%) and 21 (51%) patients, respectively. The overall response rate was 6% and 40% in patients with primary and secondary resistance to anthracyclines/taxanes, respectively (P = 0.047). The median duration of response and the median time to disease progression was 8 and 9.5 months, respectively. The median overall survival was 13 months and the probability for 1-year survival 51%. Grade 3/4 neutropenia occurred in 9 (22%) patients and 4 (9%) patients developed grade 3/4 thrombocytopenia. Non-haematological toxicity was mild. There were no cases of febrile neutropenia, toxic deaths or treatment-related hospital admissions due to toxicity. The combination of high-dose 5-FU/LV with conventional doses of cyclophosphamide is a well tolerated and effective salvage regimen in patients with MBC heavily pretreated with both anthracyclines and taxanes.

Topics: Adolescent; Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cyclophosphamide; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Salvage Therapy; Survival Rate; Taxoids; Treatment Outcome

Gastric cancer (GC) is the fifth most frequent malignancy and the fourth leading cause of worldwide cancer-related death. Despite the usage of multimodal perioperative chemotherapy (pCT), GC progressively gains chemoresistance, thereby, the identification of suitable targets to overcome drug resistance is fundamental. Amongst the potential biomarkers, carbonic anhydrase IX (CAIX) - associated with a poor prognosis of several solid cancers - has gained the most attention. In a cohort of GC patients who received perioperative FLOT (i.e., Leucovorin, 5-Fluouracil, Docetaxel, and Oxaliplatin) or FOLFOX (i.e., Leucovorin, 5-Fluouracil, and Oxaliplatin), non-responder patients showed an increased expression of tumor CAIX compared to responder group. Moreover, GC cell lines induced to be resistant to 5-Fluouracil, Paclitaxel, Cisplatin, or the combination of 5-Fluorouracil, Oxaliplatin, and Docetaxel, overexpressed CAIX compared to the control. Accordingly, CAIX-high-expressing GC cells showed increased therapy resistance compared to low-expressing cells. Notably, SLC0111 significantly improved the therapy response of both wild-type and resistant GC cells. Overall, these data suggest a correlation between CAIX and GC drug resistance highlighting the potential of SLC-0111 in re-sensitizing GC cells to pCT.

Topics: Antigens, Neoplasm; Antineoplastic Agents; Carbonic Anhydrase Inhibitors; Carbonic Anhydrase IX; Cell Line; Cell Line, Tumor; Docetaxel; Fluorouracil; Humans; Leucovorin; Oxaliplatin; Stomach Neoplasms; Taxoids

The aim of this study was to evaluate the activity and safety of the combination chemotherapy of 5-fluorouracil (5-FU), leucovorin, and irinotecan (FOLFIRI regimen) after failure of fluoropyrimidine, platinum, and taxane in gastric cancer (GC) and to evaluate the prognostic factors for survival.. Patients received biweekly FOLFIRI chemotherapy as third-line treatment. The FOLFIRI-1 consisted of irinotecan (180 mg/m(2) in a 2-h infusion) on day 1, and then leucovorin (200 mg/m(2) in a 2-h infusion) and 5-FU (a 400 mg/m(2) bolus, followed by 600 mg/m(2) in a 22-h continuous infusion) on days 1 and 2. FOLFIRI-2 consisted of irinotecan (180 mg/m(2) in a 2-h infusion) on day 1, and then leucovorin (400 mg/m(2) in a 2-h infusion) and 5-FU (a 400 mg/m(2) bolus, followed by 2400 mg/m(2) in a 46-h continuous infusion) on day 1.. A total of 158 patients were included. The overall response rate was 9.6 % in patients with measurable lesions. The median progression-free survival (PFS) and overall survival (OS) were 2.1 months [95 % confidence interval (CI), 1.7-2.5] and 5.6 months (95 % CI, 4.7-6.5), respectively. The major grade 3/4 toxicity was myelosuppression (36.7 %). Good performance status (PS), fewer metastatic sites, and longer duration from the first-line to third-line chemotherapy were independent prognostic factors affecting both PFS and OS.. The FOLFIRI regimen showed antitumor activity and tolerable toxicity profiles against advanced GC in the third-line setting. Patients with good PS, fewer metastatic sites and longer previous treatment duration might have the maximal benefit from third-line chemotherapy.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Camptothecin; Carcinoma, Signet Ring Cell; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Platinum; Retrospective Studies; Salvage Therapy; Stomach Neoplasms; Survival Rate; Taxoids; Treatment Outcome