Capecitabine and mitomycin C is an effective combination for anthracycline- and taxane-resistant metastatic breast cancer.

Capecitabine is converted to 5-fluorouracil by thymidine phosphorylase, and mitomycin C is capable of upregulating the expression of thymidine phosphorylase suggesting a synergistic effect. Fifty-three patients (median age 62 years) with anthracycline- and taxane-resistant, metastatic breast cancer received mitomycin C 6 mg/m(2) on day 1, and capecitabine (Xeloda) 2,000 mg/m(2)/day from day 1 to day 14 with cycles repeated every 4 weeks. Overall, 77.4% had visceral metastases and 33 were pretreated with >/=3 chemotherapy lines. A median of 6 cycles were given (range 1-19) with a complete response observed in 2 patients (3.9%), partial response in 17 (33.3%) and stable disease in 19 (37.2%). Overall response rate was 37.2% (95% CI, 24.0-50.5%), with a median duration of 10.4 months. Median time to progression was 8.1 months and median survival was 17.4 months (1- and 2-year survival rates of 60 and 28%, respectively). Toxicity was mild. The most frequent grade 3/4 events were neutropenia (5.7% of patients), diarrhea (3.8%), and deep venous thrombosis (3.8%). Capecitabine plus mitomycin C may represent an effective and manageable treatment option for advanced breast cancer patients resistant to anthracyclines and taxanes. This approach provides an alternative for pretreated patients with advanced breast cancer.

Paclitaxel and epirubicin followed by cyclophosphamide, methotrexate and 5-fluorouracil for patients with stage IIIC breast cancer with ten or more involved axillary lymph nodes.

OBJECTIVE: The aim of this study was to evaluate the feasibility of a combination of epirubicin and paclitaxel followed by intravenous (iv) cyclophosphamide, methotrexate, and 5-fluorouracile (CMF) as adjuvant treatment of breast cancer patients with 10 or more metastatic axillary lymph nodes. METHODS: Forty-four patients entered this multicenter study and received 4 cycles of epirubicin (E 120 mg/m2 day 1, q3 weeks) and paclitaxel (T 135 mg/m2 day 1, q3 weeks), followed by 4 cycles of iv CMF (days 1 and 8, q4 weeks). Patients with positive hormonal receptors received sequentially tamoxifen associated with LH-RH analogue if premenopausal. The endpoints were the evaluation of the feasibility of this schedule and disease free survival (DFS). RESULTS: Median age of patients was 55; median number of positive axillary nodes was 14 (range, 10-47). Hormonal receptor status was positive in 57% of patients. The combination of epirubicin and paclitaxel was well tolerated; NCI grade 3/4 events were: leucopenia in 27% of patients, neutropenic fever in 5 patients, anemia in 7%, thrombocytopenia in 7%, nausea in 18%, vomiting in 14%, and neurotoxicity in 4%. CMF regimen caused a few cases of grade 3/4 hematologic toxicity. No cardiac toxicity was recorded. With a median follow-up of 59 months, 18 (41%) patients relapsed. Sites of relapse were mainly bone, skin/soft tissues, liver, and lung. Median DFS was 78 months, with a 5-year rate of 60%. CONCLUSIONS: The combination of paclitaxel at low dose and epirubicin followed by CMF is a feasible regimen, which seems to be effective in high-risk node positive breast cancer patients and requires further investigations.

Uridine diphosphate glucuronosyl transferase 1A1 promoter polymorphism predicts the risk of gastrointestinal toxicity and fatigue induced by irinotecan-based chemotherapy.

BACKGROUND: In the current Phase II study, the authors evaluated the association between genomic polymorphic variants in uridine diphosphate glucuronosyl transferase (UGT1A1), methylenetetrahydrofolate reductase (MTHFR), and thymidylate synthase (TS) genes, and the incidence of the adverse effects of irinotecan and raltitrexed in previously heavily treated patients with metastatic colorectal carcinoma. METHODS: Fifty-six patients received irinotecan (at a dose of 80 mg/m(2) on Days 1, 8, 15, and 22 every 5 wks), combined with raltitrexed (at a dose of 3 mg/m(2) every 3 wks). Genotyping for the MTHFR C677T polymorphism, the TATA box region in the UGT1A1 promoter, and tandem repeats in the TS promoter was performed on genomic DNA extracted from blood. Nineteen variables related to patient, disease, and treatment characteristics, together with genotypes, were analyzed using a binary logistic regression model with stepwise selection to evaluate their correlation with adverse reactions. RESULTS: Toxicities (determined according to the National Cancer Institute Common Toxicity Criteria) were evaluated in 169 cycles. Grade 3/4 neutropenia was reported to occur in 2% of cycles, Grade 2-4 nausea was reported to occur in 19% of cycles, Grade 2-4 emesis was reported to occur in 9% of cycles, Grade 2-4 diarrhea was reported to occur in 20% of cycles, Grade 2/3 fatigue was reported to occur in 11% of cycles, and Grade 3/4 hepatic toxicity was reported to occur in 7% of cycles. Homozygosis for six TA repeats in the promoter region of the UGT1A1 gene was found to be the main predictive factor for diarrhea (P < 0.00005), emesis (P = 0.0001), and fatigue (P = 0.007). Homozygosis for two tandem repeats in the TS promoter was found to be predictive of a reduced incidence of fatigue (P = 0.044). MTHFR C677T polymorphism was not found to be associated with any adverse reaction. CONCLUSIONS: In the current study, UGT1A1 promoter polymorphism was found to be predictive of the risk of diarrhea, emesis, and fatigue caused by chemotherapy with irinotecan and raltitrexed. Screening for UGT1A1 promoter polymorphism may be clinically useful for identifying patients at a higher risk of developing a severe or potentially life-threatening toxicity after irinotecan-based chemotherapy.

Raltitrexed plus weekly oxaliplatin as first-line chemotherapy in metastatic colorectal cancer: a multicenter non-randomized phase ii study.

AIM: The primary aims of this study were activity and toxicity evaluation of a new raltitrexed and oxaliplatin-based regimen, as a first-line chemotherapy, in patients with metastatic colorectal cancer (MCC). Survival evaluation was considered a secondary endpoint. PATIENTS AND METHODS: Forty-four patients were enrolled into this phase II trial. Treatment consisted of raltitrexed 3 mg/m2 iv on d 1 and oxaliplatin 70 mg/m2 iv on d 1 and d 8 every 3 wk. RESULTS: Twenty patients (45.5%) achieved a response [95% confidence interval (CI): 30.1% to 54.1%], 18 (40.9%) had stable disease, and only 6 (13.6%) developed progressive disease. After a median follow-up time of 14.7 mo (range 6.3-18.6 mo), the median time to disease progression was 6 mo (range 2.0-16.7) (95% CI: 4.4-7.6) and the overall survival was 14.8 mo (range 3-23) (95% CI: 11.2-18.4). Neutropenia was the most common hematological side effect, while transient AST/ALT increase, neurotoxicity, asthenia, and diarrhea were the most common nonhematological side effects. CONCLUSIONS: Our data confirmed that oxaliplatin administered weekly plus raltitrexed is an active combination in newly diagnosed patients with advanced colorectal carcinoma that merits further investigation versus the classic schedule in a randomized, phase III trial.

Randomized, multicenter, phase II study of gemcitabine plus cisplatin versus gemcitabine plus carboplatin in patients with advanced non-small cell lung cancer.

BACKGROUND: We conducted a phase II randomized study to assess the efficacy, with response as the primary endpoint, and the toxicity of gemcitabine/cisplatin (GP) and gemcitabine/carboplatin (GC) in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Patients were randomized to GP (gemcitabine 1200 mg/m(2), days 1 and 8 plus cisplatin 80 mg/m(2) day 2) or GC (gemcitabine 1200 mg/m(2), days 1 and 8 plus carboplatin AUC=5 day 2). Cycles were repeated every 3 weeks. RESULTS: Sixty-two patients were randomized to GP and 58 to GC. A total of 533 cycles were delivered (264 GP, 269 GC), with a median of four cycles/patient. The objective response rate was 41.9% (95% C.I., 29.6-54.2%) for GP and 31.0% (95% C.I., 18.2-42.8%) for GC (P=0.29). No significant differences between arms were observed in median survival (10.4 months GP, 10.8 months GC) and median time to progression (5.4 months GP, 5.1 months GC). Both regimens were very well tolerated with no statistical differences between arms in grade 3/4 toxicities. When all toxicity grades were combined, emesis, neuropathy and renal toxicity occurred more frequently on the GP arm (P<0.005). CONCLUSIONS: GC arm did not provide a significant difference in response rate compared with GP arm, with better overall tolerability. Carboplatin could be a valid alternative to cisplatin in the palliative setting.