Eva-Maria Grischke

Predictive value of serum interleukin‐6 and ‐8 levels in preterm labor or rupture of the membranes

Background. The aim of this prospective study was to examine if serum concentrations of cytokines are of value in the identification of patients at risk for preterm delivery.

Intraperitoneal bispecific antibody (HEA125XOKT3) therapy inhibits malignant ascites production in advanced ovarian carcinoma

Bispecific antibody HEA125xOKT3 was shown to redirect T lymphocytes toward carcinoma cells and to induce tumor cell lysis in vitro. Preclinical studies have demonstrated that tumor‐associated lymphocytes (TAL) derived from malignant ascites can be used as effector cells with a high efficacy and without prior stimulation. These data provided the rationale for a clinical trial to investigate whether bsAb HEA125xOKT3 is also able to induce tumor cell lysis in vivo and can be used for local treatment of malignant ascites arising from ovarian carcinoma. Ten ovarian carcinoma patients presenting with malignant ascites resistant to chemotherapy were enrolled in the study. They received weekly intraperitoneal injections of 1 mg bsAb diluted in 500 ml NaCl solution to allow homogeneous antibody distribution within the peritoneal cavity. All patients responded clinically well to the therapy. Eight patients experienced a complete and 2 patients a partial reduction of ascites production. A decrease or stabilization of tumor marker CA125 was detected in the sera of 8 patients. Only WHO Grade I and II toxicity was observed including mild fever, chills and allergic eczema. Thus, intraperitoneal application of bsAb HEA125xOKT3 appears to be an easy and cost effective palliative treatment for ovarian carcinoma with recurrent ascites that leads to a substantially increased quality of life for the patients. During therapy TNF‐α concentrations raised markedly in the ascites fluid whereas VEGF and sFLT‐1 ascites levels declined. This indicates that not only T cell‐mediated tumor cell lysis but also changes in vascular permeability due to downregulation of VEGF and its receptors might be responsible for the beneficial therapeutic effect.

Clinical relevance of genomic aberrations in homogeneously treated high-risk stage II/III breast cancer patients

Little is known about the prognostic impact of chromosome aberrations in breast cancer. The aim of our study was to determine whether genomic aberrations of prognostic relevance can be identified in the context of a clinical study using molecular cytogenetics. Paraffin‐embedded tumor samples of 44 patients with high‐risk stage II/III breast cancer were analyzed by comparative genomic hybridization. All patients received identical therapy including dose‐escalated chemotherapy followed by peripheral blood stem cell transplantation. The most frequent chromosomal aberrations were gains on chromosome arms 17q (24 cases), 1q (21 cases), 8q (17 cases), 20q (13 cases), 6p (9 cases) as well as losses on chromosome arms 13q (25 cases), 11q (20 cases), 5q (11 cases), 6q (11 cases), 9p (10 cases), 18q (10 cases), 8p (9 cases) and 16q (9 cases). In univariate analysis, the correlation with the clinical outcome revealed a higher risk for patients with tumors exhibiting 13q losses and a reduced risk for tumors exhibiting 16q losses (p = 0.020), 6q losses (p = 0.041) and estrogen‐receptor positivity (0.051). In multivariate analysis using the Cox model, only the loss of 16q exhibited borderline significance (p = 0.065). These data show that comparative genomic hybridization can be performed in the context of a clinical trial. In our subgroup of high‐risk breast cancer patients, chromosomal aberrations were valuable prognostic parameters.

Local and systemic tolerability of magnesium sulphate for tocolysis.

An open-label, randomised, parallel-group, study was conducted in three study centres in women with premature labor and indication for a single agent intravenous tocolysis therapy with magnesium sulphate. The aim of this study was to examine the local and general tolerability and side-effects of magnesium sulphate for tocolysis. Furthermore, we tested the tolerability of a ready-for-use magnesium solution. No measurements of efficacy were performed during this study. Initially, patients received a loading dose of 4.0 g magnesium sulphate administered over 30 min. Thereafter, a continuous intravenous infusion of 1-2 g magnesium sulphate per hour up to 21 days was given. Venous score (Maddox), vital signs, adverse events as well as general tolerability (assessed by investigator and patients) and blood parameters were assessed. We showed good local and systemic tolerability of high dose magnesium sulphate for tocolysis. Only seven patients (15%) were withdrawn from the study prematurely due to minor adverse events. Potential serious complications of MgSO(4) such as respiratory arrest or clinically relevant respiratory depression were not observed. The most frequently reported local adverse events were injection site pain, itching, erythema, swelling, induration and palpable venous cord. The most common systemic adverse events considered to be possibly related to the study drugs involved the nervous system (dizziness) followed by the digestive system (nausea, constipation). Systolic and diastolic blood pressure changed only slightly during the treatment. Respiratory rate and body temperature remained stable also. Toxic magnesium levels (>2.5 mmol/l) were not observed. The assessment of the clinical investigators with regard to tolerability was very good or good in 72.5% of the patients. The introduction of the ready-to-use solution has the advantage of eliminating the need to mix the solution prior to administration. This means a lower risk of overdose and contamination.

Tandem High-Dose Chemotherapy in High-Risk Primary Breast Cancer: A Multivariate Analysis and a Matched-Pair Comparison With Standard-Dose Chemotherapy

Stem cell-supported high-dose chemotherapy (HDCT) is currently being evaluated in patients with high-risk primary breast cancer (HRPBC), as defined by extensive axillary lymph node involvement. Conclusive results from randomized studies with sufficient patient numbers and follow-up are pending. We retrospectively analyzed 144 HRPBC patients enrolled in a single-arm trial of tandem HDCT at the University of Heidelberg to evaluate the prognostic value of nodal ratio, HER2/neu status, and cytokeratin-positive bone marrow cells and to compare the outcomes of these patients with those of a conventionally treated control group of 91 patients matched by nodal ratio, tumor size, combined hormone-receptor status, and HER2/neu status. The tandem HDCT regimen consisted of 2 cycles of induction chemotherapy followed by 2 cycles of blood stem cell-supported high-dose ifosfamide, 12 g/m2; carboplatin, 900 mg/M2; and epirubicin, 180 mg/m2. Conventionally treated patients received a regimen containing anthracycline without taxanes (52 patients) or CMF (cyclophosphamide, methotrexate, and 5-flurouracil; 39 patients). With a median follow-up of 3.8 years, disease-free, distant disease-free, and overall survival rates were 62%, 65%, and 84%, respectively. In univariate analysis, besides the hormone receptor status (P = .007), HER2/neu overexpression was the strongest predictor of earlier death (P = .017). In multivariate analysis, a nodal ratio of > or =0.8 was found to be the only independent predictor of relapse (relative risk [RR] = 2.09; 95% confidence interval [CI], 1.21-3.60; P = .008) and only the absence of hormone receptors was associated with earlier death (RR = 3.59; 95% CI, 1.45-8.86; P = .006). Despite a trend toward later distant relapse after HDCT compared with standard-dose chemotherapy with a median follow-up of 3 years (P = .059), thus far, matched-pair analysis has not demonstrated significantly better survival rates after HDCT in all matched patients (P = .786) or in the subgroups of anthracycline-treated patients and patients with and without overexpression of HER2/neu. So far, the follow-up time has been too short to draw definite conclusions; however, patients with a nodal ratio of > or =0.8, receptor-negative tumors, or HER2/neu overexpression are at high risk for relapse and death, irrespective of the kind of adjuvant chemotherapy.

Comparison of Double and Triple High‐Dose Chemotherapy with Autologous Blood Stem Cell Transplantation in Patients with Metastatic Breast Cancer

In patients with metastatic breast cancer (MBC), early dose intensification with multiple cycles of peripheral blood stem cell‐supported high‐dose chemotherapy (HDCT) seems superior to a late dose‐intensification strategy. We compared the progression‐free survival (PFS) and overall survival (OS) of 20 patients treated with a double (D)‐HDCT regimen to 20 patients who received a triple (T)‐HDCT, matched by age, estrogen receptor (ER) status, adjuvant chemotherapy, initial disease‐free interval, predominant metastatic site, and number of metastatic sites. At a median follow‐up of 41.5 months (range, 14‐88 months) an intent‐to‐treat analysis showed no difference in PFS (p = 0.72) and OS (p = 0.93) between the matched patients. For all 76 patients treated within the D‐ or T‐HDCT trial, median PFS and OS was 13 months (range, 2‐78 months) and 24.5 months (range, 7‐78 months), respectively. In multivariate analysis independent predictors of shorter OS included negative ER (relative risk [RR] = 3.0 [95% confidence interval (CI) 1.5‐5.9]; p = 0.002), more than two metastatic sites (RR = 2.4 [95% CI 1.0‐5.7]; p = 0.049) and failure to achieve complete remission/no evidence of disease (CR/NED) after HDCT (RR = 4.5 [95% CI 2.0‐10.1]; p < 0.0001). These data show that early dose intensification with T‐HDCT is not superior to a D‐HDCT regimen in patients with MBC. ER‐negative tumors, more than two metastatic sites and no CR/NED after HDCT, are associated with inferior outcome.

Trastuzumab single-drug therapy after failure of cytotoxic treatment for metastatic breast cancer.

Background: Trastuzumab is an established component of breast cancer combination regimens, but data on the safety and efficacy of single-agent therapy is sparse. Patients and Methods: 70 patients with HER2-overexpressing breast cancer after failure of at least one chemotherapy regimen for metastatic disease were recruited from 28 institutions. HER2 overexpression was 3+ in 96% and 2+/FISH+ in 4%. Treatment consisted of a loading dose of 4 mg/kg trastuzumab in the first week and 2 mg/kg per week thereafter, continued until progression. Results: Trastuzumab treatment duration ranged from 1 to 66 weeks (median: 12). Objective responses (complete response (CR)/partial response (PR)) were seen in 12/62 fully evaluable patients (19%; 2 CR) while another 29% showed stabilization of the disease. Half of the patients had experienced progression after 13 weeks while median duration of response reached 44 weeks. Median survival was 68 weeks with nearly one-third of the patients still alive after more than 3 years. The most frequent adverse reaction was infusion-related syndrome arising during the first administration. Significant cardiovascular problems were detected in 3 cases, all with anthracycline pretreatment. Conclusions: Patients with metastatic breast cancer overexpressing HER2 may benefit from trastuzumab single-drug treatment, predominantly due to its favourable safety profile.

Ifosfamide combination chemotherapy in advanced breast cancer

SummaryThe objective of our clinical studies was to develop an effective combination chemotherapy regimen (CHT) with acceptable side effects, consisting of the two most potent drugs used as single agents in breast cancer. We tested the combination of an anthracycline, epirubicin (A) at 70 mg/m2 i.v. on day 1 or (B) at 120 mg/m2 i.v. on day 1 with an alkylating drug ifosfamide (IFO), (C) at 2.5 g/m2 in an i.v. infusion given over 4 h on days 1–3 or (D) at 5 g/m2 in a 24-h i.v. infusion given on day 1. Courses were repeated every 4 weeks. The combinations were given as first-line therapy as follows: CHT (A, C) in six cases and CHT (B, C) in five cases of advanced breast carcinoma, and CHT (B, D) in seven patients with primary inflammatory breast cancer. Due to side effects (e.g., stomatitis, mental disturbances) and applicability, CHT regimen (B, D) was preferred. Responses (12/18) occurred 1–3 cycles earlier than those previously achieved using the conventional epirubicin/cyclophosphamide CHT. We conclude that 5 g/m2 IFO given i.v. over 24 h with uroprotection (mesna) in a two-drug regimen is an effective dose with tolerable toxicity. Alopecia was seen in all cases. However, according to our experience, myelotoxicity is the dose-limiting factor for both of these drugs.