TITAN: phase III study of doxorubicin/cyclophosphamide followed by ixabepilone or paclitaxel in early-stage triple-negative breast cancer.

PURPOSE: Ixabepilone is a microtubule stabilizer with activity in taxane-refractory metastatic breast cancer and low susceptibility to taxane-resistance mechanisms including multidrug-resistant phenotypes and high ß-III tubulin expression. Since these resistance mechanisms are common in triple-negative breast cancer (TNBC), ixabepilone may have particular advantages in this patient population. This study evaluated the substitution of ixabepilone for paclitaxel following doxorubicin/cyclophosphamide (AC) in the adjuvant treatment of early-stage TNBC. METHODS: Patients with operable TNBC were eligible following definitive breast surgery. Patients were randomized (1:1) to receive four cycles of AC followed by either four cycles (12 weeks) of ixabepilone or 12 weekly doses of paclitaxel. RESULTS: 614 patients were randomized: 306 to AC/ixabepilone and 308 to AC/paclitaxel. At a median follow-up of 48 months, 59 patients had relapsed (AC/ixabepilone, 29; AC/paclitaxel, 30). The median time from diagnosis to relapse was 20.8 months. The 5-year disease-free survival (DFS) rates of the two groups were similar [HR 0.92; ixabepilone 87.1% (95% CI 82.6-90.5) vs. paclitaxel 84.7% (95% CI 79.7-88.6)]. The estimated 5-year overall survival (OS) rates were also similar [HR 1.1; ixabepilone 89.7% (95% CI 85.5-92.7) vs. paclitaxel 89.6% (95% CI 85.0-92.9)]. Peripheral neuropathy was the most common grade 3/4 event. Dose reductions and treatment discontinuations occurred more frequently during paclitaxel treatment. CONCLUSIONS: Treatment with AC/ixabepilone provided similar DFS and OS in patients with operable TNBC when compared to treatment with AC/paclitaxel. The two regimens had similar toxicity, although treatment discontinuation, dose modifications, and overall peripheral neuropathy were more frequent with AC/paclitaxel. TRIAL REGISTRATION: Clinical Trials.gov Identifier, NCT00789581.

Randomized phase III trial of amrubicin versus topotecan as second-line treatment for patients with small-cell lung cancer.

PURPOSE: Amrubicin, a third-generation anthracycline and potent topoisomerase II inhibitor, showed promising activity in small-cell lung cancer (SCLC) in phase II trials. This phase III trial compared the safety and efficacy of amrubicin versus topotecan as second-line treatment for SCLC. PATIENTS AND METHODS: A total of 637 patients with refractory or sensitive SCLC were randomly assigned at a ratio of 2:1 to 21-day cycles of amrubicin 40 mg/m(2) intravenously (IV) on days 1 to 3 or topotecan 1.5 mg/m(2) IV on days 1 to 5. Primary end point was overall survival (OS); secondary end points included overall response rate (ORR), progression-free survival (PFS), and safety. RESULTS: Median OS was 7.5 months with amrubicin versus 7.8 months with topotecan (hazard ratio [HR], 0.880; P = .170); in refractory patients, median OS was 6.2 and 5.7 months, respectively (HR, 0.77; P = .047). Median PFS was 4.1 months with amrubicin and 3.5 months with topotecan (HR, 0.802; P = .018). ORR was 31.1% with amrubicin and 16.9% with topotecan (odds ratio, 2.223; P < .001). Grade ≥ 3 treatment-emergent adverse events in the amrubicin and topotecan arms were: neutropenia (41% v 54%; P = .004), thrombocytopenia (21% v 54%; P < .001), anemia (16% v 31%; P < .001), infections (16% v 10%; P = .043), febrile neutropenia (10% v 3%; P = .003), and cardiac disorders (5% v 5%; P = .759); transfusion rates were 32% and 53% (P < .001), respectively. NQO1 polymorphisms did not influence safety outcomes. CONCLUSION: Amrubicin did not improve survival when compared with topotecan in the second-line treatment of patients with SCLC. OS did not differ significantly between treatment groups, although an improvement in OS was noted in patients with refractory disease treated with amrubicin.

A prospective multicenter study of paroxysmal nocturnal hemoglobinuria cells in patients with bone marrow failure.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH), a rare clonal hematopoietic stem cell disorder, is characterized by chronic, uncontrolled complement activation leading to intravascular hemolysis and an inflammatory prothrombotic state. The EXPLORE study aimed to determine the prevalence of undiagnosed PNH in patients with aplastic anemia (AA), myelodysplastic syndrome (MDS), and/or other bone marrow failure (BMF) syndromes and the effect of PNH clone size on hemolysis. METHODS: Patients, selected from medical office chart reviews, had blood samples collected for hematologic panel testing and for flow cytometry detection of PNH clones. RESULTS: Granulocyte PNH clones ≥ 1% were detected in 199 of all 5,398 patients (3.7%), 93 of 503 AA patients (18.5%), 50 of 4,401 MDS patients (1.1%), and 3 of 130 other BMF patients (2.3%). Higher-sensitivity analyses detected PNH clones ≥ 0.01% in 167 of 1,746 patients from all groups (9.6%) and in 22 of 1,225 MDS patients (1.8%), 116 of 294 AA patients (39.5%), and four of 54 other BMF patients (7.8%). Among patients with PNH clones ≥ 1%, median clone size was smaller in patients with AA (5.1%) than in those with MDS (17.6%) or other BMF (24.4%), and the percentage of patients with lactate dehydrogenase levels (a marker for intravascular hemolysis) ≥ 1.5 × upper limit of normal was smaller in patients with AA (18.3%) than in those with MDS (42.0%). CONCLUSIONS: These results confirm the presence of PNH clones in high-risk patient groups and suggest that screening of such patients may facilitate patient management and care.

A Prospective Multicenter Study of Paroxysmal Nocturnal Hemoglobinuria Cells in Patients with Bone Marrow Failure.

Background: Paroxysmal nocturnal hemoglobinuria (PNH), a rare clonal hematopoietic stem cell disorder, is characterized by chronic, uncontrolled complement activation leading to intravascular hemolysis and an inflammatory prothrombotic state. The EXPLORE study aimed to determine the prevalence of undiagnosed PNH in patients with aplastic anemia (AA), myelodysplastic syndrome (MDS), and/or other bone marrow failure (BMF) syndromes and the effect of PNH clone size on hemolysis. Methods: Patients, selected from medical office chart reviews, had blood samples collected for hematologic panel testing and for flow cytometry detection of PNH clones. Results: Granulocyte PNH clones ≥ 1% were detected in 199 of all 5398 patients (3.7%), 93 of 503 AA patients (18.5%), 50 of 4401 MDS patients (1.1%), and 3 of 130 other BMF patients (2.3%). Higher-sensitivity analyses detected PNH clones ≥ 0.01% in 167 of 1746 patients from all groups (9.6%) and in 22 of 1225 MDS patients (1.8%), 116 of 294 AA patients (39.5%), and 4 of 54 other BMF patients (7.8%). Among patients with PNH clones ≥ 1%, median clone size was smaller in patients with AA (5.1%) than in those with MDS (17.6%) or other BMF (24.4%), and the percentage of patients with lactate dehydrogenase levels (a marker for intravascular hemolysis) ≥ 1.5 × upper limit of normal was smaller in patients with AA (18.3%) than in those with MDS (42.0%). Conclusions: These results confirm the presence of PNH clones in high-risk patient groups and suggest that screening of such patients may facilitate patient management and care. © 2013 Clinical Cytometry Society.

Trimodality therapy for stage II-III carcinoma of the esophagus: a dose-ranging study of concurrent capecitabine, docetaxel, and thoracic radiotherapy.

PURPOSE: This dose-escalation study was performed to determine the recommended phase II dose of oral capecitabine to be delivered concurrently with thoracic radiation therapy and weekly docetaxel in patients with locally advanced esophageal carcinoma. METHODS: Patients with operable stage II or III esophageal carcinoma were staged by endoscopic ultrasonography and computed tomography. Two cycles of docetaxel (80 mg/m) and carboplatin (target area under the concentration-time curve: 6 mg/ml × min) were delivered over 6 weeks. This was followed by concurrent weekly docetaxel (15 mg/m), thoracic radiotherapy (50.4 Gy in 28 fractions), and increasing doses of capecitabine (500-3500 mg) given before each fraction of radiotherapy. After restaging, responding patients continued to esophagectomy within 4 to 8 weeks of completing chemoradiotherapy. RESULTS: Forty-four patients were enrolled, and 40 were assessable for the dose-ranging component of concurrent chemoradiotherapy. Endoscopic ultrasonography stages at enrollment were T3N1 (29 patients), T3N0 (4 patients), T2N1 (6 patients), and T4N0 (one patient). The maximum tolerated dose of capecitabine was 3500 mg. Thirty-six patients had surgery; 83% had R0 resection, and 17% had pathological complete response. Median overall survival was 23.5 months, with 34 and 27% alive at 3 and 5 years. CONCLUSION: The recommended phase II dose of capecitabine is 3500 mg when given concurrently with 50.4 Gy of thoracic radiotherapy in 28 fractions and weekly docetaxel. This trimodality therapy for operable locally advanced esophageal carcinoma was very well tolerated and remarkably active. This regimen holds promise for the treatment of esophageal carcinoma and warrants further investigation.

Docetaxel in the treatment of esophageal cancer.

Esophageal cancer is the ninth most common malignancy in the world and the seventh leading cause of death in American men. Because symptoms are often intermittent and vague, patients typically present at an advanced stage, with limited survival. In operable patients, standard care includes surgery with or without adjuvant chemotherapy and radiotherapy; chemotherapy and radiotherapy is the standard care for inoperable disease. Docetaxel, a taxane that promotes polymerization of tubules and inhibits depolymerization of microtubules, has shown in vitro and in vivo antitumor effects on human gastric cell lines and gastric cancer xenografts. These antitumor effects have led to the evaluation of docetaxel as a single agent and in combination with other agents and modalities in patients with esophageal cancer. Results of relevant trials are reviewed herein.