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Crown for the 303 Study GroupPurpose: This phase III study compared docetaxel and doxorubicin in patients with metastatic breast cancer who had received previous alkylating agent-containing chemotherapy.Patients and Methods: Patients were randomized to receive an intravenous infusion of docetaxel 100 mg/m 2 or doxorubicin 75 mg/m 2 every 3 weeks for a maximum of seven treatment cycles.Results: A total of 326 patients were randomized, 165 to receive doxorubicin and 161 to receive docetaxel. Overall, docetaxel produced a significantly higher rate of objective response than did doxorubicin (47.8% v 33.3%; P ‫؍‬ .008). Docetaxel was also significantly more active than doxorubicin in patients with negative prognostic factors, such as visceral metastases (objective response, 46% v 29%) and resistance to prior chemotherapy (47% v 25%). Median time to progression was longer in the docetaxel group (26 weeks v 21 weeks; difference not significant). Median overall survival was similar in the two groups (docetaxel, 15 months; doxorubicin, 14 months). There was one death due to infection in each group, and an additional four deaths due to cardiotoxicity in the doxorubicin group. Although neutropenia was similar in both groups, febrile neutropenia and severe infection occurred more frequently in the doxorubicin group. For severe nonhematologic toxicity, the incidences of cardiac toxicity, nausea, vomiting, and stomatitis were higher among patients receiving doxorubicin, whereas diarrhea, neuropathy, fluid retention, and skin and nail changes were higher among patients receiving docetaxel.Conclusion: The observed differences in activity and toxicity profiles provide a basis for therapy choice and confirms the rationale for combination studies in early breast cancer.

BACKGROUND Secretory GTPases like Rab27B control vesicle exocytosis and deliver critical proinvasive growth regulators into the tumor microenvironment. The expression and role of Rab27B in breast cancer were unknown. METHODS Expression of green fluorescent protein (GFP) fused with wild-type Rab3D, Rab27A, or Rab27B, or Rab27B point mutants defective in GTP/GDP binding or geranylgeranylation, or transient silencing RNA to the same proteins was used to study Rab27B in estrogen receptor (ER)-positive human breast cancer cell lines (MCF-7, T47D, and ZR75.1). Cell cycle progression was evaluated by flow cytometry, western blotting, and measurement of cell proliferation rates, and invasion was assessed using Matrigel and native type I collagen substrates. Orthotopic tumor growth, local invasion, and metastasis were analyzed in mouse xenograft models. Mass spectrometry identified proinvasive growth regulators that were secreted in the presence of Rab27B. Rab27B protein levels were evaluated by immunohistochemistry in 59 clinical breast cancer specimens, and Rab3D, Rab27A, and Rab27B mRNA levels were analyzed by quantitative real-time polymerase chain reaction in 20 specimens. Statistical tests were two-sided. RESULTS Increased expression of Rab27B promoted G(1) to S phase cell cycle transition, proliferation and invasiveness of cells in culture, and invasive tumor growth and hemorrhagic ascites production in a xenograft mouse model (n = 10; at 10 weeks, survival of MCF-7 GFP- vs GFP-Rab27B-injected mice was 100% vs 62.5%, hazard ratio = 0.26, 95% confidence interval = 0.08 to 0.88, P = .03). Mass spectrometric analysis of purified Rab27B-secretory vesicles identified heat-shock protein 90alpha as key proinvasive growth regulator. Heat-shock protein 90alpha secretion was Rab27B-dependent and was required for matrix metalloproteinase-2 activation. All Rab27B-mediated functional responses were GTP- and geranylgeranyl-dependent. Presence of endogenous Rab27B mRNA and protein, but not of Rab3D or Rab27A mRNA, was associated with lymph node metastasis (P < .001) and differentiation grade (P = .001) in ER-positive human breast tumors. CONCLUSIONS Rab27B regulates invasive growth and metastasis in ER-positive breast cancer cell lines, and increased expression is associated with poor prognosis in humans.

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The objective was to validate the use of the proposed International Statistical Classification of Diseases and Related Health Problems (10th revision) (ICD-10) criteria for fatigue (P-ICD10) through comparison with the Functional Assessment of Cancer Therapy Fatigue (FACT-F) subscale and three visual analogue scale (VAS) qualities in cancer patients thought to be fatigued. Fatigue was assessed in 834 cancer patients at three clinical centres in Belgium, using P-ICD10, FACT-F, and VAS to assess: level of energy (VAS1), quality of life (VAS2), and ability to perform daily activities (VAS3). Of the 834 interviewed cancer patients, 54% were classified as fatigued by the P-ICD10 criteria. Internal consistency of P-ICD10 was very good (alpha coefficient 0.82). The principal component analysis corroborated good internal consistency with all variables included in the first component; a second component was used to identify psychological fatigue (concentration and short-term memory disabilities). An abridged set of screening tools based on the first three general symptoms of the P-ICD10 is proposed with 100% specificity and 86% specificity, respectively. There was a marked decrease in FACT-F and VAS1 scores in patients diagnosed as fatigued by the P-ICD10 (mean+/-SD, FACT-F 20+/-9 vs 39+/-8, VAS1 34+/-21 vs 61+/-21). A logistic regression model between P-ICD10 criteria diagnosis and FACT-F (VAS1) identified a score of 34 (61) on the FACT-F scale as a proposed cut-off point for the diagnosis of fatigue. The ICD-10 criteria can be recommended as a diagnostic tool, whereas the FACT-F scale and the level of energy 100-mm VAS assess the intensity of fatigue, and are more suitable for follow-up of cancer-related fatigue.

Topotecan in a daily-times-five schedule is an effective regimen as second-line treatment in ovarian cancer. Further investigations of topotecan in ovarian cancer, including first-line use and combination with other active agents, are indicated.

Cancer-related anemia is a cytokine-mediated disorder resulting from complex interactions between tumor cells and the immune system. Overexpression of certain inflammatory cytokines results in shortened survival of red blood cells, suppression of erythroid progenitor cells, impaired iron utilization, and inadequate erythropoietin production. Numerous other factors may also contribute to the development of anemia in cancer patients. The European Cancer Anaemia Survey (ECAS) has provided the most current, comprehensive, prospectively collected data on the incidence and prevalence of anemia among cancer patients, as well as important perspectives on anemia treatment and relationship of hemoglobin and performance status. ECAS enrolled over 15,000 treated and untreated patients with various malignancies from cancer centers in 24 European countries and followed them for up to 6 months. The initial analysis of the ECAS data revealed that 39% of the total cancer patient population was anemic (hemoglobin <12.0 g/dl) at enrollment, although the rate varied according to tumor type, disease status, and cancer treatment status. Of the patients who were not anemic at enrollment and started cancer treatment during the survey, those undergoing chemotherapy – either alone or in combination with radiotherapy – had the highest incidence of anemia (63 and 42%, respectively). Low hemoglobin levels correlated with poor performance status and only 40% of patients who were anemic at some time during the survey received treatment for their anemia. These findings are noteworthy, since a growing body of clinical evidence indicates that the treatment of anemia can significantly improve patients’ quality of life and may also improve the clinical outcome.