Randomised phase II trial of gemcitabine plus vinorelbine vs gemcitabine plus cisplatin vs gemcitabine plus capecitabine in patients with pretreated metastatic breast cancer.

BACKGROUND: An increasing proportion of patients are exposed to anthracyclines and/or taxanes in the adjuvant or neoadjuvant setting. Re-exposure in the metastatic stage is limited by drug resistance, thus evaluation of non-cross-resistant regimens is mandatory. METHODS: Anthracycline-pretreated patients were randomly assigned to three gemcitabine-based regimens. Chemotherapy consisted of gemcitabine 1.000 mg m(-2) plus vinorelbin 25 mg m(-2) on days 1+8 (GemVin), or plus cisplatin 30 mg m(-2) on days 1+8 (GemCis), or plus capecitabine 650 mg m(-2) b.i.d. orally days 1-14 (GemCap), q3w. The primary end point was response rate. RESULTS: A total of 141 patients were recruited on the trial. The overall response rates were 39.0% (GemVin), 47.7% (GemCis) and 34.7% (GemCap). Median progression-free survival was estimated with 5.7, 6.9 and 8.3 months, respectively. Corresponding median survival times were 17.5 (GemVin), 13.0 (GemCis) and 19.4 months (GemCap). Neutropenia ≥grade 3 occurred in 16.7% (Gem/Vin), 4.4% (GemCis) and 0% (Gem/Cap), whereas non-haematological toxicities were rarely severe except grade 3 hand-foot syndrome in 2.0% of the GemCap patients (per patient analysis). CONCLUSIONS: This randomised phase II trial has revealed comparable results for three gemcitabine-based regimens regarding treatment efficacy and toxicity. Gemcitabine-based chemotherapy appears to be a worthwhile treatment option for pretreated patients with metastatic breast cancer.

Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel.

Bisphosphonates (BP) prevent, reduce, and delay cancer-related skeletal complications in patients, and have substantially decreased the prevalence of such events since their introduction. Today, a broad range of BP with differences in potency, efficacy, dosing, and administration as well as approved indications is available. In addition, results of clinical trials investigating the efficacy of BP in cancer treatment-induced bone loss (CTIBL) have been recently published. The purpose of this paper is to review the current evidence on the use of BP in solid tumours and provide clinical recommendations. An interdisciplinary expert panel of clinical oncologists and of specialists in metabolic bone diseases assessed the widespread evidence and information on the efficacy of BP in the metastatic and nonmetastatic setting, as well as ongoing research on the adjuvant use of BP. Based on available evidence, the panel recommends amino-bisphosphonates for patients with metastatic bone disease from breast cancer and zoledronic acid for patients with other solid tumours as primary disease. Dosing of BP should follow approved indications with adjustments if necessary. While i.v. administration is most often preferable, oral administration (clodronate, IBA) may be considered for breast cancer patients who cannot or do not need to attend regular hospital care. Early-stage cancer patients at risk of developing CTIBL should be considered for preventative BP treatment. The strongest evidence in this setting is now available for ZOL. Overall, BP are well-tolerated, and most common adverse events are influenza-like syndrome, arthralgia, and when used orally, gastrointestinal symptoms. The dose of BP may need to be adapted to renal function and initial creatinine clearance calculation is mandatory according to the panel for use of any BP. Subsequent monitoring is recommended for ZOL and PAM, as described by the regulatory authority guidelines. Patients scheduled to receive BP (mainly every 3-4 weeks i.v.) should have a dental examination and be advised on appropriate measures for reducing the risk of jaw osteonecrosis. BP are well established as supportive therapy to reduce the frequency and severity of skeletal complications in patients with bone metastases from different cancers.

Survival analyses from the ZEBRA study. goserelin (Zoladex) versus CMF in premenopausal women with node-positive breast cancer.

The Zoladex Early Breast Cancer Research Association (ZEBRA) trial compared the efficacy and tolerability of goserelin (Zoladex) with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) chemotherapy in pre-/perimenopausal women with node-positive early breast cancer. The results of disease-free survival (DFS) analyses have already been published. Here we present an update including data on overall survival (OS) from the ZEBRA trial at a median follow-up of 7.3 years. In patients with oestrogen receptor (ER)-positive tumours, non-inferiority of goserelin versus CMF for OS was shown; goserelin was again shown to be equivalent to CMF for DFS. This updated analysis has demonstrated that the two treatments are also equivalent for distant disease-free survival (DDFS). In patients with ER-negative disease, goserelin was inferior to CMF for DFS, DDFS and OS. This follow-up analysis confirms the previously reported outcomes from the ZEBRA trial and demonstrates that goserelin offers an effective alternative to CMF chemotherapy for adjuvant therapy of premenopausal patients with ER-positive, node-positive early breast cancer.

Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: The Zoladex Early Breast Cancer Research Association Study.

PURPOSE: Current adjuvant therapies have improved survival for premenopausal patients with breast cancer but may have short-term toxic effects and long-term effects associated with premature menopause. PATIENTS AND METHODS: The Zoladex Early Breast Cancer Research Association study assessed the efficacy and tolerability of goserelin (3.6 mg every 28 days for 2 years; n = 817) versus cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy (six 28-day cycles; n = 823) for adjuvant treatment in premenopausal patients with node-positive breast cancer. RESULTS: Analysis was performed when 684 events had been achieved, and the median follow-up was 6 years. A significant interaction between treatment and estrogen receptor (ER) status was found (P =.0016). In ER-positive patients (approximately 74%), goserelin was equivalent to CMF for disease-free survival (DFS) (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.84 to 1.20). In ER-negative patients, goserelin was inferior to CMF for DFS (HR, 1.76; 95% CI, 1.27 to 2.44). Amenorrhea occurred in more than 95% of goserelin patients by 6 months versus 58.6% of CMF patients. Menses returned in most goserelin patients after therapy stopped, whereas amenorrhea was generally permanent in CMF patients (22.6% v 76.9% amenorrheic at 3 years). Chemotherapy-related side effects such as nausea/vomiting, alopecia, and infection were higher with CMF than with goserelin during CMF treatment. Side effects related to estrogen suppression were initially higher with goserelin, but when goserelin treatment stopped, reduced to a level below that observed in the CMF group. CONCLUSION: Goserelin offers an effective, well-tolerated alternative to CMF in premenopausal patients with ER-positive and node-positive early breast cancer.

[Nonhormonal prevention of breast cancer]. / Nichthormonale Prävention des Brustkrebses.

BACKGROUND: Despite the use of currently available drug therapies, the life expectancy of patients with metastasized breast cancer can still only be extended by about 14 to 16 months in comparison to a completely untreated patient population. In light of these figures, and the associated economic costs, all possible means to reduce the incidence of the disease are of great potential importance and must be examined seriously. PREVENTION: Increased consumption of alcohol is a risk factor for breast cancer. Increased intake of phytoestrogens, dietary fiber, and beta-carotene as well as regular physical activity and normal body weight lower the risk of breast cancer. The increased risk of breast cancer associated with alcohol consumption can be reduced by adequate intake of folate. The significance of retinoids is at present ambiguous. CONCLUSION: Effective preventive measures, along with adequate early detection schemes, are the best means of reducing mortality due to breast cancer. Both folate and retinoids deserve to be subjected to further studies. It would also be desirable to supplement currently ongoing adjuvant therapy trials with studies examining the use of folate versus placebo.

Adjuvant randomized trials of doxorubicin/cyclophosphamide versus doxorubicin/cyclophosphamide/tamoxifen and CMF chemotherapy versus tamoxifen in women with node-positive breast cancer.

PURPOSE: We report two randomized trials of adjuvant systemic therapy in 747 patients < or = 65 years of age with histologically proven node-positive breast cancer. PATIENTS AND METHODS: Patients were selected for the two trials on the basis of lymph node and hormone receptor status. The only stratification was based on the treating institution. In patients with a lower probability of recurrence (n = 276), a comparison between endocrine therapy (tamoxifen [Tam] 30 mg/d for 2 years) and chemotherapy (cyclophosphamide, methotrexate, and fluorouracil [CMF] intravenously [IV], six cycles every 4 weeks) was performed. In patients with a higher risk of recurrence (n = 471), a comparison between chemotherapy alone (doxorubicin plus cyclophosphamide [AC] i.v., eight cycles every 3 weeks) and the same chemotherapy plus Tam was made. RESULTS: Overall, we found that CMF and Tam are equally effective in a subgroup of patients with a relatively good prognosis (low-risk patients). However, in the subset of women < or = 49 years old, a significantly greater disease-free survival (DFS) rate (P = .01) and overall survival (OS) rate (P = .002) was observed following therapy with CMF compared with Tam. In patients > or = 50 years old, the opposite was found, and Tam appeared to be superior to CMF (DFS, P = .003; OSm P = .5). These results must be interpreted cautiously, since a post-hoc stratification of patients by age (< or = 49, > or = 50) was performed, and significantly more younger, low-risk patients were randomized to receive chemotherapy alone and more older patients to receive Tam alone. Among patients with a relatively poor prognosis (high-risk patients), a combination of AC plus Tam was equivalent to AC and, when women were analyzed by age, this was found to be true of patients < or = 49 years as well. However, the addition of Tam to AC in women age > or 50 years resulted in a statistically significantly higher DFS (P = .01) and a trend toward better OS compared with women who received AC alone. CONCLUSION: Further trials are required to analyze the role of combined simultaneous or sequential chemoendocrine adjuvant treatment or each single therapy alone in defined risk-adapted subsets of node-negative and node-positive patients.

LHRH analogues in early breast cancer.

A steering group has devised a protocol to compare relapse-free survival rates between women under 50 with stage II cancer, given CMF or Zoladex as adjuvant therapy. The design of the trial is discussed.

[Drug sensitivity testing of gynecologic tumors using Volm's test and stem cell assay]. / Chemosensibilitätstestung gynäkologischer Tumoren mittels Volm-Test und Stammzell-Assay.

A variety of test systems have been developed for predicting the efficacy of cytotoxic drugs in the treatment of individual malignant human tumors. The present paper reports on the author's experience with Volm's short-term chemosensitivity test and Hamburger and Salmon's stem-cell assay. In the Volm test the influence of adriamycin on the incorporation of radioactively labelled uridine in an individual tumor cell suspension was investigated. Comparison with a cytostatic-free control permitted conclusions to be drawn with regard to the proliferation-related chemosensitivity. The stem-cell assay is based on the capacity of certain tumor cells, the so-called stem cells, to form colonies in a bilaminar soft agar system. The growth of the colony of pre-incubated cytostatics was evaluated in relation to that of untreated tumor cells. The Volm test was successful in 63 (95%) out of a total of 66 tests conducted. Twelve tumors were chemosensitive in the test and 51 chemoresistant. In the stem-cell assay, growth of a colony which permitted chemosensitivity to be tested was only found in 27 out of 183 tests. The criterion of chemosensitivity with a reduction of at least 50% in the number of cells in the colony by at least one cytostatic was satisfied by 14 (29%) of the 49 stem-cell assays which could be evaluated, there being no differences between breast and ovarian carcinomas. The two test systems indicated the chemosensitivity correctly in less than 50% of 49 retrospectively evaluated courses of disease. In contrast, resistance was predicted correctly in 90%.(ABSTRACT TRUNCATED AT 250 WORDS)