Factors influencing catheter-related infections in the Dutch multicenter study on high-dose chemotherapy followed by peripheral SCT in high-risk breast cancer patients.

Neutropenia following high-dose chemotherapy leads to a high incidence of infectious complications, of which central venous catheter-related infections predominate. Catheter-related infections and associated risk factors in 392 patients participating in a randomized adjuvant breast cancer trial and assigned to receive high-dose chemotherapy and peripheral stem-cell reinfusion were evaluated. Median catheter dwell time was 25 days (range 1-141). Catheter-related infections were seen in 28.3% of patients (11 infections per 1000 catheter-days). Coagulase-negative staphylococci were found in 104 of 186 positive blood cultures (56%). No systemic fungal infections occurred. Cox regression analysis showed that duration of neutropenia >10 days (P=0.04), using the catheter for both stem-cell apheresis and high-dose chemotherapy (P= <0.01), and use of total parenteral nutrition (TPN, P=0.04) were predictive for catheter-related infections. In conclusion, a high incidence of catheter-related infections after high-dose chemotherapy was seen related to duration of neutropenia, use of the catheter for both stem-cell apheresis and high-dose chemotherapy, and use of TPN. Selective use and choice of catheters could lead to a substantial reduction of catheter-related infectious complications.

[Guideline 'Treatment of breast cancer 2008' (revision)]. / Richtlijn 'Behandeling van het mammacarcinoom 2008' (herziening).

The Dutch evidence-based guideline 'Treatment of breast cancer' has been revised, and integrated with the guideline 'Screening for and diagnosis of breast cancer'. The guideline can be found on www. oncoline.nl and on www.cbo.nl. The Internet programme 'Adjuvant!' (www.adjuvantonline.com) can be used to predict both the prognosis and the efficacy of systemic adjuvant therapy for each patient. The indications for adjuvant chemotherapy and endocrine therapy have been widened. The aim is to reduce the absolute probability of death by at least 4-5% within 10 years. The goal of neoadjuvant chemotherapy in operable breast cancer is to enable breast-conserving therapy for large tumours in relatively small breasts. One could consider transferring responsibility for follow-up after 5 years from the hospital to the screening organisation following mastectomy, to the family doctor following breast-conserving therapy, and to an outpatient clinic for hereditary tumours in carriers of gene mutation. Cessation of follow-up above the age of 75 could also be considered.

Adverse effect on bone marrow protection of prechemotherapy granulocyte colony-stimulating factor support.

BACKGROUND: Increased proliferation of endogenous bone marrow progenitor cells in response to the administration of hematopoietic growth factors, followed by reduced cell cycling or entrance of the cells into a quiescent state upon withdrawal of the growth factors, may have clinically relevant effects on the tolerance of the hematopoietic system to subsequent myelotoxic treatments. PURPOSE: We investigated the ability of granulocyte colony-stimulating factor (G-CSF) to protect progenitor cells in the bone marrow of cancer patients from the toxic effects of subsequent treatments with chemotherapeutic agents. METHODS: Thirty-six patients with histologically documented, locally advanced or metastatic breast cancer were randomly assigned to receive doxorubicin once every 3 weeks at a dose of 75 mg/m2 and cyclophosphamide at a dose of 1000 mg/m2, with G-CSF administered either before and after chemotherapy (18 patients) or after chemotherapy only (18 patients). For prechemotherapy administration of G-CSF, recombinant human methionyl (r-met Hu) G-CSF was administered subcutaneously to patients twice per day for 5 days at a dose of 5 micrograms/kg, with the last dose given 48 hours before the start of chemotherapy. For postchemotherapy administration of G-CSF, r-met Hu G-CSF was administered subcutaneously to patients once per day for 7 days at a dose of 5 micrograms/kg, with the first dose given 24 hours after chemotherapy. RESULTS: The incidence or the duration of grade 4 neutropenia was not reduced in all patients by the use of prechemotherapy G-CSF; the incidence over all cycles of chemotherapy was 74% for patients treated with prechemotherapy and postchemotherapy G-CSF and 66% for patients treated with postchemotherapy G-CSF only (two-sided P, adjusted for dose = .21) and the median duration in both treatment arms was 3 days (two-sided P = .19). Unexpectedly, the incidence of grades 3 and 4 thrombocytopenia was much greater in patients who received prechemotherapy G-CSF compared with those who did not (54% versus 6%, respectively, over all chemotherapy cycles; two-sided P, adjusted for dose < .001). No difference in the decrease in hemoglobin level (adjusted for red blood cell transfusions) between patients in the two treatment arms was observed. CONCLUSIONS AND IMPLICATIONS: No beneficial effects were associated with the administration of G-CSF to cancer patients prior to chemotherapy. The observation of more severe thrombocytopenia in patients treated with prechemotherapy G-CSF led us to conclude that the proliferation of progenitor cells was still increased 48 hours after the last dose of G-CSF and that the administration of chemotherapy at or within this time period actually worsens the toxic effects on bone marrow. This result has important ramifications for the design of clinical cancer treatment protocols, especially those that involve shortened intervals between cycles of chemotherapeutic agent administration.

Prognostic value of urokinase-type plasminogen activator in 671 primary breast cancer patients.

Urokinase-type plasminogen activator (uPA) may be responsible for the invasive and metastasizing capacity of tumor cells. Evidence has been presented that primary breast cancer patients with tumors containing high levels of uPA experience a worse prognosis. In the present study we have assessed uPA status in routinely prepared cytosols of 671 primary human breast tumors and have evaluated its association with disease-free and overall survival. Isotonic regression analysis with length of disease-free survival as an end point revealed 1.15 ng/mg protein as the best cutoff point to discriminate between uPA positive (32% of the tumors) and uPA negative. In both Cox univariate and multivariate regression analysis (including also patient's age, menopausal status, lymph node status, and the number of positive lymph nodes, tumor size, and estrogen and progesterone receptor status), uPA positivity was significantly associated with increased rates of relapse and death. Corrected for all relevant factors in multivariate analyses for subgroups of patients, uPA positivity was significantly associated with an increased relapse rate in the subgroups of node-negative (P = 0.002; relative failure rate, 2.33), node-positive (P < 0.0001; relative failure rate, 1.95), postmenopausal (P < 0.0001; relative failure rate, 2.59), and steroid receptor-positive patients (P < 0.0001, relative failure rate, 2.76). We conclude that uPA positivity of human primary breast tumors is an important independent variable for the identification of patients at high risk for recurrence, also in clinically important subgroups of patients.

Corticosteroids significantly delay the onset of docetaxel-induced fluid retention: final results of a randomized study of the European Organization for Research and Treatment of Cancer Investigational Drug Branch for Breast Cancer.

PURPOSE: To confirm the efficacy of docetaxel in patients with breast cancer previously treated with one chemotherapy regimen for advanced or metastatic disease and to compare the incidence of fluid retention (FR) and skin toxicity when docetaxel is administered with and without prophylactic corticosteroids. PATIENTS AND METHODS: Eighty-three patients, pretreated with one chemotherapy regimen for metastatic breast cancer (MBC) with bidimensionally measurable and progressive disease, were eligible for this randomized trial. Docetaxel with prophylactic oral antihistamine was administered at a dose of 50 mg/m2 as a 1-hour infusion on days 1 and 8 every 21 days and patients were randomized to receive methylprednisolone (40 mg days -1, 0, 1, 7, 8, and 9 of each cycle) (arm A) or no methylprednisolone (arm B). RESULTS: Twenty-eight patients (34%, 95% confidence interval [CI], 23% to 45%) achieved on objective response. The median time to disease progression and median overall survival time were 5 and 13.5 months, respectively. In total, 415 cycles of docetaxel were administered (arm A: N = 219, median = six; arm B: N = 196, median = five). The most common toxicity observed was grade 3 or 4 neutropenia, which occurred in 79% of patients. Clinically significant nonhematologic side effects included skin reactions and asthenia. In an intent-to-treat analysis, patients who received methylprednisolone premedication had a delayed onset of FR (median time to onset of FR: arm A, 84 days; arm B, 62 days; P = .01) and received a higher median cumulative dose of docetaxel before the onset of FR (arm A, 333 mg/m2; arm B, 215 mg/m2; P = .001). There was no statistically significant difference in the incidence of skin toxicity between the two arms. CONCLUSION: Docetaxel, at this dose and schedule, has definite antitumor activity in pretreated MBC patients. Moreover, this is the first randomized trial to show that corticosteroids have a favorable impact on docetaxel-induced FR.

Multicenter, randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer.

PURPOSE AND METHODS: The objective of this multicenter study was to compare the therapeutic index of two different doses of paclitaxel given as a 3-hour infusion in patients with metastatic breast cancer (MBC), who had failed to respond to previous chemotherapy. A total of 471 patients with MBC were randomized to receive intravenous paclitaxel at a dose of 175 or 135 mg/m2 every 3 weeks. RESULTS: Better treatment results were achieved with high-dose (HD) versus low-dose (LD) paclitaxel: overall response rate, 29% versus 22% (P = .108); complete response (CR) rate, 5% versus 2% (P = .088); median time to disease progression, 4.2 versus 3.0 months (P = .027); and median survival time, 11.7 versus 10.5 months (P = .321). Patients previously exposed or resistant to anthracyclines were as likely to respond as those without such prior exposure. Treatment was well tolerated, as documented by the number of administered treatment courses (median, six v five; range, one 17 v one to 18), the low frequency of dose reductions (14% v 7%, P = .024), and the small number of patients (n = 9 or 4% vn = 5 or 2%) who required treatment discontinuation for adverse reactions. The incidence and severity of neutropenia and peripheral neuropathy were dose-related. After quality-of-life-adjusted time-to-progression analysis, the HD arm (175 mg/m2) retained its advantage over the LD arm (135 mg/m2). CONCLUSION: The results of this trial substantiate the activity of paclitaxel in the treatment of MBC. The observed superior efficacy with a dose of 175 mg/m2 over 135 mg/m2 suggests a dose-effect relationship. The clinical activity in anthracycline-resistant patients is particularly noteworthy. Paclitaxel in breast cancer needs further evaluation in large trials that use combination chemotherapy and involve earlier disease stages.

Value of estrogenic recruitment before chemotherapy: first randomized trial in primary breast cancer.

PURPOSE: Several preclinical studies showed that short-term pretreatment of breast cancer cells with estrogens can increase the antitumor efficacy of different cytotoxic drugs. Some early clinical studies in patients with advanced breast cancer did seem to support these findings. Therefore, the efficacy of estrogenic recruitment followed by chemotherapy was compared with that of chemotherapy alone in a randomized phase III study in women with lymph node-positive primary breast cancer. PATIENTS AND METHODS: Three hundred twenty-eight patients with stage II/IIIA breast cancer who were younger than 66 years of age were randomly allocated to chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide (FAC) or FAC plus pretreatment with ethinyl estradiol (EE(2)). FAC (500, 50, and 500 mg/m(2), respectively) was administered intravenously once every 4 weeks for four cycles. EE(2) (0.5 mg) was administered orally, both 24 hours and immediately preceding FAC chemotherapy. RESULTS: Patient and tumor characteristics and chemotherapy dosages were comparable in both treatment groups. Of 318 assessable patients, with a median follow-up of 6.8 years, 177 patients had a relapse and 127 died. No significant differences were observed between the two treatment groups with respect to relapse-free, local recurrence-free, and overall survival according to univariate and multivariate analyses adjusted for age, menopausal status, tumor size, grade, number of positive nodes, and steroid-receptor status. The power for the detection of an increase of 50% in the median relapse-free survival was 80%. CONCLUSION: Estrogenic recruitment of breast cancer cells before FAC chemotherapy did not influence the efficacy of adjuvant chemotherapy in stage II/IIIA breast cancer patients after a follow-up of 6.8 years.

An immunomagnetic epithelial tumor cell enrichment model for minimal residual disease detection of cytokeratin 8+ malignancies.

Immunocytochemical detection of isolated tumor cells in peripheral blood and bone marrow is currently the most established method for monitoring early dissemination in epithelial cancer. In this study we used an immunomagnetic selection technique to develop an enrichment model for disseminated tumor cells in blood. Buffy coat cells spiked with varying numbers of BT-474 carcinoma cells were permeabilized and fixed, following which carcinoma cells were magnetically labelled with an anti-cytokeratin 8 mAb. Labelled cells were enriched by the use of magnetic columns. The eluted cytokeratin 8+ tumor cells were detected by flow cytometry and immunocytochemistry. Spiked samples were split and processed freshly in the immunomagnetic enrichment assay, as well as cryopreserved and processed in the assay after thawing. Enumeration of BT-474 cells demonstrated a detection limit of one BT-474 cell in 1.0 x 10(7) leukocytes in both fresh and cryopreserved-thawed samples. The pair wise comparison showed a significantly higher recovery of spiked BT-474 cells from freshly processed samples than from cryopreserved and thawed samples (57% vs 21%). Viability tests suggested that this outcome might be due to a greater susceptibility of BT-474 cells than buffy coat cells to the used cryopreservation and thawing technique. Altogether our findings show that the performance of the immunomagnetic enrichment assay on fresh samples is satisfactory with a recovery rate of almost 60% and a sensitivity of 10(-7). However, performance of the assay on cryopreserved and thawed cells needs to be improved.

Clinical experience with venlafaxine in the treatment of hot flushes in women with a history of breast cancer.

OBJECTIVE: To obtain practical experience with venlafaxine for hot flushes in breast cancer patients and incorporate this in a treatment protocol. METHOD: Twenty-two women with a history of breast cancer (mean age 49.2 years, range 35-65) were referred for consideration of treatment with venlafaxine for hot flushes. Patients received extensive information on treatment with venlafaxine and were advised to self-monitor the frequency of their hot flushes. RESULTS: Eight women did not start venlafaxine because they had no postmenopausal complaints, were lost to follow-up, had too low a frequency of hot flushes, or refused treatment. Eventually 14 women started venlafaxine. Two of them did not tolerate venlafaxine, four reported some effect but stopped because of side effects, two women had no effect whatsoever. Six women observed a clear ( > 50%) reduction in their hot flush frequency that was maintained at a median follow-up of 13 months. CONCLUSION: The group of patients referred for treatment was more heterogeneous and more patients dropped out because of side effects than expected. Extensive patient education, patient selection and evaluation of the treatment effect (by self-monitoring of hot flush frequency) are mandatory to avoid useless (continuation of) treatment and to prepare patients for side effects. Under these conditions, a substantial minority of patients benefit from venlafaxine.

Cell biological factors associated with the response of breast cancer to systemic treatment.

A large number of cell biological parameters are currently available to predict the prognosis of patients with breast cancer, but it is still difficulty accurately to predict the response to treatment. A valuable prognostic factor can be a poor predictive factor for response, and vice versa. High tumor levels of ER, PgR, AR and pS2 predict a relatively good response to endocrine therapy, while EGF-R positively, HER2/neu positivity, aneuploidy, high proliferation indices and possibly high uPA levels indicate a high chance of poor response to endocrine therapy in metastatic breast cancer. With respect to chemotherapy, a high proliferation rate and HER2/neu amplification predict a good response to therapy in metastatic disease, while MDR gene expression and possibly c-myc amplification are related to a worse response. In conclusion, the newer cell biological parameters can be used to select high and low-risk patients, type of systemic treatment, and as targets for new treatment modalities.

Lhermitte's sign following chemotherapy with docetaxel.

Specific causes for Lhermitte's sign (LS) in cancer patients are spinal cord compression, radiation therapy to the spinal cord, and cisplatin chemotherapy. We observed a transient LS in five of 87 patients treated with more than two cycles of 100 mg/m2 docetaxel (Taxotere). LS developed either concurrently or after the onset of docetaxel-induced sensory neuropathy, and disappeared after the discontinuation or dose reduction of chemotherapy.

Combination chemotherapy of the taxanes and antimetabolites: its use and limitations.

In an effort to improve response rates of chemotherapy, taxanes have been combined with other cytotoxic agents such as antimetabolites. However, the use of some of these combinations in patients has been restricted by severe toxicity. The significance of the sequence of drug administration in combining methotrexate (MTX) and taxanes was recognised in in vitro studies, showing synergistic effects for the sequence of MTX followed by paclitaxel, and antagonism for exposure in the reverse order. A possible explanation might be an MTX-induced synchronisation of cells in the S phase of the cell cycle, after which cells are more susceptible for the cytotoxic action of taxanes. Clinical studies using this sequence were hampered by severe neutropenia and mucositis at relatively low doses of both drugs. As no pharmacokinetic interactions were observed, the excess of toxicity may have been due to sequence-dependent synergistic actions on bone marrow and mucosa. In contrast, and confusingly, in vitro studies on 5-fluorouracil (5-FU) and taxanes indicate that 5-FU preceeding or simultaneously given to paclitaxel impairs cytotoxicity as compared with paclitaxel monotherapy, while the reverse sequence results in additive or synergistic cytotoxicity. While almost all clinical studies have used the sequence of a taxane followed by 5-FU, various schedules appeared feasible and effective. The combination of a 5-FU analogue, capecitabine and taxanes was supported by in vitro data. A large phase III trial confirmed the feasibility and superior efficacy of this combination in breast cancer patients relapsing after an anthracycline. Conflicting results exist on the benefit of combining gemcitabine and taxanes in tumour cell lines. Although the accumulation of gemcitabine triphosphate (dFdCTP) in mononuclear cells was significantly higher with an increasing dose of paclitaxel, no pharmacokinetic interactions for both agents were noticed. A pharmacokinetic analysis of the gemcitabine-docetaxel combination therapy has not been published in detail. Despite numerous trials, so far no optimum schedule has been established. Regarding data on actually delivered dose intensities, a 2- or 3-weekly cycle seems favourable and feasible. However, possible severe pulmonary toxicity warrants cautious monitoring of patients treated with this combination. Different outcomes of preclinical and clinical studies reveal that combining two chemotherapeutic agents is not simply a matter of putting antitumour activities together. Drug interaction may result in synergism, not only of efficacy but also of toxic side-effects. Adding two drugs may also implicate antagonism in drug efficacy due to unwanted interference in cytotoxicity or pharmacokinetics. For agents acting at a specific phase of the cell cycle, the sequence of administration may determine the efficacy and toxicity of a combination therapy. Because of an observed discrepancy between in vitro data and clinical studies, we would like to emphasise the need for adequate dose-finding clinical trials together with pharmacokinetic data analysis before examining any new combination chemotherapy in more detail in phase II studies.

Altered clearance of unbound paclitaxel in elderly patients with metastatic breast cancer.

The pharmacokinetic behaviour of anticancer drugs may be altered with aging due to (for example) differences in body composition and decreased hepatic and renal function. To address this issue for paclitaxel, we studied the pharmacokinetics of the drug in eight elderly women (>or=70 years) with metastatic breast cancer (median age (range), 77 years (70-84 years)) and a control group of 15 patients aged <70 years (median age (range), 54 years (22-69 years)). Paclitaxel was administered as a 1-h intravenous (i.v.) infusion at a dose of 80 (elderly) or 100 mg/m(2) (<70 years), and serial blood samples were obtained at baseline, and up to 24 h after the end of infusion. Paclitaxel concentration-time profiles were fitted to a linear three-compartment model without any demonstration of saturable behaviour. The clearance of unbound paclitaxel was 124+/-35.0 (elderly) versus 247+/-55.4 l/h/m(2) (<70 years) (P=0.002), and was inversely related to the patient's age (R(2)=0.857; P<0.00001). Total plasma clearance of the formulation vehicle Cremophor EL (CrEL) was 150+/-60.7 (elderly) versus 115+/-39.2 ml/h/m(2) (<70 years) (P=0.04). These data indicate an approximately 50% change in total body clearance of unbound paclitaxel and a concomitant significant increase in systemic exposure with age, most likely as a result of altered CrEL disposition. The clinical relevance of these observations with respect to toxicity profiles and antitumour efficacy requires further evaluation.

Paclitaxel (Taxol) induces cumulative mild neurotoxicity.

Paclitaxel (Taxol), a new antineoplastic drug, has been reported to be neurotoxic at doses above 200 mg/m2 per course. It is uncertain whether neurotoxicity is related to cumulative amounts of paclitaxel. Neuropathy was prospectively assessed in 18 patients with breast cancer, receiving between two and eight courses of 135 or 175 mg/m2 of paclitaxel. Vibratory perception thresholds (VPT) and tendon reflex scores were proportionally related to the corresponding cumulative amounts of paclitaxel (P = 0.002; P = 0.0003). The amounts of paclitaxel administered between the first and last assessments (175-1225 mg/m2) were related to concomitant changes in VPT (P = 0.034). Paclitaxel had no clear neurotoxic threshold; if present, it lies below 540 mg/m2. Rather, VPT appeared to increase 0.1 micron per 400 mg/m2 over the entire range of 175-1225 mg/m2 of paclitaxel. Clinical neuropathy prevailed in 0/8 patients at screening and in 5/10 patients at the final assessment (P = 0.029). Neuropathy never exceeded grade 1. Thus, although neurotoxicity of paclitaxel is frequent and cumulative, it remains mild or subclinical up to at least 1400 mg/m2 administered over eight cycles.

Weekly paclitaxel as first-line chemotherapy for elderly patients with metastatic breast cancer. A multicentre phase II trial.

Paclitaxel is a cytotoxic agent with proven antitumour activity in metastatic breast cancer. Weekly administration of paclitaxel has demonstrated sustained efficacy together with a more favourable toxicity profile (e.g. less myelotoxicity) than the 3-weekly administration. This study evaluates the activity and toxicity of weekly paclitaxel (Taxol(R)) as first-line chemotherapy in elderly patients (>70 years of age) with hormone-refractory metastatic breast cancer. Patients with metastatic breast cancer received 80 mg/m(2) paclitaxel administered weekly on days 1, 8 and 15 of a 28-day cycle. Additional cycles were given until disease progression, or unacceptable toxicity. A dose increase to 90 mg/m(2) was allowed in the absence of toxicity. 26 Patients received a total of 101 cycles (median 4, range 1-11). 22 patients completed at least two cycles (six administrations). In 23 patients who were evaluable for response, there were 10 partial responses (38%), 9 patients with stable disease (35%), while 4 patients had disease progression (15%). The median duration of response was 194 days (>6 months). Overall treatment was relatively well tolerated, but 8 patients (32%) had to prematurely discontinue treatment because of fatigue. Neuropathy >grade 1 was noted only after five or more cycles in 4 patients. Weekly paclitaxel at this dose and schedule is an effective treatment regimen in the elderly patient with metastatic breast cancer, and is feasible, but yields relevant fatigue in a subset of patients.

Randomised trial of paclitaxel versus doxorubicin as first-line chemotherapy for advanced breast cancer: quality of life evaluation using the EORTC QLQ-C30 and the Rotterdam symptom checklist.

The aim of the study was to compare the quality of life (QL) of patients treated with single-agent paclitaxel versus doxorubicin as first-line chemotherapy for advanced breast cancer. 331 patients with advanced breast cancer were randomised, with 294 eligible for analysis. Patients completed both the EORTC QLQ-C30 questionnaire and the Rotterdam Symptom Checklist (RSCL) with six additional items, at baseline and after the third, fifth and seventh cycles of chemotherapy. A significant difference in progression-free survival in favour of doxorubicin caused a bias in the data with differences in expected completion rates of questionnaires beyond cycle three. Therefore, statistical comparisons were performed only for the first three cycles. Baseline compliance was 64% and 61% for the QLQ-C30 and RSCL questionnaires, respectively. Doxorubicin was associated with significantly more nausea/vomiting (P=0.001), loss of appetite (P=0.010) and a greater burden of disease and treatment (P=0.044), but with less bone pain (P=0.042) and rash (P=0.045) than paclitaxel. Both treatments were associated with improved emotional function and reduction in psychological distress at cycle 3. Longitudinal data suggested that doxorubicin was associated with less pain, specifically bone pain. Doxorubicin was more active but may have had more side-effects during the first three cycles. Long-term QL outcomes could not be assessed.

Capecitabine in breast cancer: current status.

Anthracyclines, together with taxanes, are at present the most active agents in metastatic breast cancer, while single-agent, bolus 5-fluorouracil (5-FU) is not very active in this setting. In view of encouraging results and tolerable toxicity of continuous infusion of 5-FU in gastrointestinal cancer, innovative oral 5-FU agents such as capecitabine have been developed. Capecitabine is a prodrug that is converted into the active compound 5-FU preferentially at the tumor site. An intermittent dosing schedule of capecitabine twice daily at a dose of 2510 mg/m2/day on days 1-14 in a 3-week cycle appeared to be feasible and resulted in a high dose intensity. A large phase II study investigating capecitabine in 135 advanced breast cancer patients, pretreated with anthracyclines and taxanes, observed three complete and 24 partial responses (response rate, 20%), with a mean duration of 8.0 months. Preliminary results of a study comparing capecitabine with paclitaxel in 42 breast cancer patients failing anthracyclines indicate that the efficacy of capecitabine is comparable to that of paclitaxel, with response rates of 36% and 21%, respectively. Another study reported a response rate of 25% for capecitabine as first-line therapy for advanced breast cancer in women aged > or = 55 years, which tended to be better than combination chemotherapy with cyclophosphamide/methotrexate/5-FU. In all studies, capecitabine side effects were mainly mild, and treatment-related grade 3/4 toxicity consisted of diarrhea (8%-11%), nausea (4%-11%), hand-foot syndrome (10%-18%), neutropenia (3%-20%), and bilirubin elevation (6%). Capecitabine is clearly an active agent for the treatment of breast cancer. It is currently registered in various countries for use in third-line treatment of metastatic disease. Its further role will have to be defined from data of randomized phase III studies.

Clinical breast cancer, new developments in selection and endocrine treatment of patients.

Breast cancer is the most common malignant tumor among women, comprising an estimated 24% of all cancer cases and 18% of all cancer deaths. At least half of the patients with primary breast cancer will ultimately die by metastatic disease. The tumor characteristics, the natural course of the disease and the response to therapy vary strongly. A number of recently detected cell biological parameters such as oncogenes/suppressor genes, growth factors and secretory proteins are more or less important prognostic factors, because they influence the characteristics and behavior of a tumor with respect to metastatic pattern, extent of cellular differentiation, growth rate and response to treatment. However, there is no clear consensus how best to identify patients at high or low risk. In our experience c-myc amplification and pS2 protein are strong prognosticators for relapse rate, while in advanced disease (apart from a negative estrogen/progesterone receptor/pS2 status) amplification of HER2/neu is a good prognosticator for failure to endocrine therapy. In the diagnosis of breast cancer, in vivo imaging of tumors by labeled hormones or other factors also forms a new development which might have implications for treatment too. With respect to treatment both endocrine and chemotherapy can cure a minority of patients with micrometastases, but in patients with advanced disease only a prolongation of (progression-free) survival can be reached. Response rates decrease with increasing tumor load. In the past decade a number of interesting new endocrine agents has been developed such as new (pure) (anti)steroidal agents, vitamins, aromatase inhibitors, analogs of peptide hormones, prolactin inhibitors and growth factor antagonists. However, less is known on the (potential) interaction between hormones, chemotherapeutic agents, retinoids, cytokins, growth factor antagonists and irradiation. Rapid detection of new powerful combination therapies are needed to improve treatment results during the nineties.

Manipulation of cell cycle kinetics: influence on the cytotoxicity of doxorubicin in human breast cancer cells.

In vitro exposure of estrogen receptor-negative (ER-) EVSA-T human breast cancer cells to insulin and/or estradiol had no effect on cell cycle distribution, in contrast to a 3-5-fold increase in the percentages of cells in the S-phase of the cell cycle in the ER+ MCF-7 cell line. Estrogen pretreatment of MCF-7 cells followed by incubation with doxorubicin resulted in an augmented inhibition of cell growth compared to unstimulated controls. This delay in growth was accompanied by a decrease in the percentages of cells actively synthesizing DNA, and by an augmented percentage of cells exhibiting a G2M-amount of DNA at the end of a 6-9 day period of culture in complete growth medium.

Growth factor-receptor pathway interfering treatment by somatostatin analogs and suramin: preclinical and clinical studies.

UNLABELLED: Interference in growth factor mediated pathways is a new strategy in the treatment of cancer. Somatostatin analogs can inhibit hormone and growth factor secretion, while suramin can block the binding of several growth factors to their receptors. In addition, somatostatin analogs can cause direct growth inhibitory effects after binding to tumoral somatostatin receptors. We tested the efficacy and endocrine effects of chronic treatment with three somatostatin analogs (Sandostatin, R RC-160 and CGP 15-425) or suramin in several tumor models and in patients with various types of cancer. Treatment with somatostatin analogs caused growth inhibition of breast cancer cells (MCF-7) in vitro, and of rat transplantable pancreatic (50-70% inhibition) and prostatic Dunning tumors (12% inhibition). No tumor growth inhibition was observed with respect to DMBA-induced rat mammary tumors, a transplantable colon tumor and a rhabdomyosarcoma in rats. In 34 patients with metastatic pancreatic or gastrointestinal adenocarcinomas chronic Sandostatin treatment caused stable disease in 27% of the patients, but no objective remissions. Somatostatin receptors were found in the responding MCF-7 mammary tumor cells, rat pancreatic tumors and in 20-45% of human breast cancer specimens [J. Steroid Biochem. Molec. Biol. 37 (1990) 1073-1077], but not in rat DMBA-mammary tumors or in 10 human pancreatic adenocarcinomas. Suramin caused significant dose-dependent growth inhibition of human breast cancer cells in vitro and of rat pancreatic tumors in vivo in the presence of plasma levels up to 150 micrograms/ml. In a preliminary clinical study concerning 11 patients with various tumor types we observed significant hematological, biochemical, endocrine and clinical side effects, but no objective remissions in spite of relevant peak plasma suramin concentrations of 270-330 micrograms/ml. IN CONCLUSION: somatostatin analogs and suramin can cause growth inhibition of various experimental tumors in vitro and in vivo, but the clinical value has to be established for several types of cancer, especially with respect to suramin and suramin-like compounds.