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Background: Capecitabine (C) is an established agent in MBC & is being evaluated in anthracycline/taxane-based adjuvant (adj) & neoadjuvant (neoadj) regimens. Methods: We summarise available data for C from randomised phase III studies in EBC. Results: Significant efficacy benefits were reported with two C-based regimens in EBC: recurrence-free survival (RFS) was significantly improved when C was added to an adj regimen in the FinXX trial (3-year RFS: 93% vs 89% control; HR 0.66 [95% CI: 0.47-0.94]; p=0.02) [Lancet Oncol 2009;10:1145-51]. Pathological complete response (pCR) was significantly higher when C was integrated into a standard neoadj regimen in the ABCSG-24 study (24.3% vs 16.0% control; p=0.02) [ECCO-ESMO 2009; Abst 4BA]. Two studies were negative: one adj [Muss et al. NEJM 2009;360:2055-65] & one neoadj [GeparQuattro JCO 2010;2024-31]. D=docetaxel; Cyc=cyclophosphamide; E=epirubicin; F=5-FU; A=doxorubicin; P=paclitaxel; bev=bevacizumab; G=gemcitabine; M=methotrexate; DFS=disease-free survival; EFS=event-free survival Safety data are available from 3 other adj studies: in the GEICAM trial, ED→C was generally well tolerated and associated with significantly better hair recovery than control (incomplete hair recovery: 28% ECyc→D vs 11% ED→C; p=0.0004); in the GAIN study, haematological toxicities were more common in the E→P→Cyc arm & discontinuations more frequent with ECyc→CP; in the ICE study in pts aged >65 yrs, a low incidence of grade 3/4 AEs was reported with C & significantly higher global QoL scores were attained with C vs control (week 20, p=0.008). Several phase III trials are ongoing (table): US Oncology is conducting a study in high-risk EBC, which will report efficacy data shortly; CIBOMA collaborative group is conducting a trial of C maintenance therapy after adj anthracycline/taxane in triple-negative EBC; the TACT2 study has a 2x2 factorial design in resected/operable EBC; safety data are expected from both studies: MINDACT is an EORTC/collaborative group study in node-negative EBC and compares a 70-gene signature with traditional methods of risk evaluation; pts with high-risk disease receive anthracyclines or CD. Conclusions: The ongoing evaluation of C in EBC encompasses >20,000 pts. Following initial positive data for C in EBC, further results of these trials are eagerly awaited to define the clinical utility of C-based therapy in this setting. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-10-11.

SCC (squamous cell carcinoma) antigen is a subfraction of tumour antigen TA-4 isolated from cervical squamous cell carcinomas. Serum concentrations of SCC antigen were measured by radioimmunoassay in 382 control subjects, 70 women with cervical intraepithelial neoplasia (CIN), 517 with cervical carcinoma and 203 with other gynaecological carcinomas. Elevated SCC antigen levels (greater than 2.5 ng/ml) were found in 4% of normal controls, in 7% of women with CIN I-III, in 2%-23% with various forms of genital adenocarcinomas, in 55% with primary and in 76% of those with recurrent cervical squamous cell carcinoma. The positivity rate of the antigen was correlated with tumour stage (FIGO) and lymph node involvement of primary cervical squamous cell carcinomas. During long-term follow-up serum levels of SCC antigen were found to be concordant with tumour activity in 74% of cases. Patients with still elevated marker levels after therapy had twice the recurrence rate of women with normal serum values. Routine determination of SCC antigen during follow-up of cervical cancer is recommended.

The results of four randomized international multicentric trials evaluating the therapeutic benefit of Herceptin in the adjuvant treatment of HER2-neu positive primary breast cancer have been reported. These reports showed that even after short term follow up one year of Herceptin resulted in improved disease free, metastases free and overall survival. Design and results of these four studies and the recommendations of national and international societies for the use of Herceptin in the adjuvant setting will be discussed.

Die Effektivitat der adjuvanten Chemotherapie wie der antihormonellen Therapie sind in der letzten Dekade entscheidend verbessert worden. Sequenzielle chemoendokrine Therapien haben zu einer zusatzlichen Wirkungssteigerung bei hormonrezeptorpositiven Patientinnen gefuhrt. Wahrend CMF und anthrazyklinhaltige Schemata schon lange routinemasig eingesetzt werden, ist das „optimale“ anthrazyklinhaltige Regime durch St. Gallen 2005 erstmals klar benannt worden (6× FEC oder FAC). Nach Datenlage verfugen wir mittlerweile uber 4 Wirksamkeitsstufen der adjuvanten Chemotherapie (4× AC oder 6× CMF

Die Primartherapie beim Ovarialkarzinom setzt sich aus einer radikalen Operation, die moglichst eine komplette Tumorreduktion erbringen soll, und aus einer nachfolgenden systemischen Polychemotherapie zusammen. In Metaanalysen konnte gezeigt werden, dass platinhaltige Chemotherapien hinsichtlich Ansprechraten und Uberlebensdaten anderen Therapieschemata uberlegen sind. Eine Verlangerung des Gesamtuberlebens um 1 Jahr wurde durch die Kombination von Cisplatin und Paclitaxel erreicht, was erstmals im Jahre 1996 durch die GOG-Studiengruppe aus den USA gezeigt und vor kurzem durch die europaisch-kanadische Intergroup-Studiengruppe bestatigt werden konnte. In Deutschland konnte die AGO-Studiengruppe Ovar zeigen, dass die Kombination Carboplatin plus Paclitaxel dem Cisplatin/Paclitaxel-Schema in Bezug auf Toxizitat bei gleicher Ansprechrate uberlegen ist.

Since the publication of the Gynecologic Oncology Group (GOG) protocol 111 in 1996, and the results of the Arbeitgemeinschaft Gyna kologische Onkologie (AGO) trial Ovar-3 and the GOG protocol 158, the combination of platinum and paclitaxel has been adopted as the standard therapy in advanced ovarian cancer. One option for achieving further progress in the first-line treatment of advanced ovarian cancer might be the addition of noncross-resistant drugs to the two-drug regimen. Meta-analysis showed a survival benefit for platinum-anthracycline based combinations as compared to platinum-based combinations without anthracyclines. An AGO phase I/II trial compared epirubicin in combination with carboplatin and paclitaxel in untreated patients with gynecological malignancies. Based on the results of this study a randomized phase III trial together with the French GINECO group was conducted. The trial started 11/97 and was closed 11/99. All 1281 patients were randomized. Currently, 1132 end-of-therapy reports have been issued. Nine hundred eighty nine (87%) patients completed six cycles of treatment. Treatment and toxicity data are available for these patients. Three hundred thirty five patients had a measurable residual tumor after initial debulking surgery. Response data of 228 patients (111 ET-Carbo, 117 Carbo-T) are available.

The anthracycline doxorubicin plays a major role in the treatment of breast cancer due to its high activity. Phase I/II studies conducted with Caelyx, a PEG-liposomal formulation of doxorubicin, indicate comparable activity with doxorubicin but significantly less toxicity, including alopecia, nausea and vomiting, and myelosuppression. Of particular note, Caelyx is also devoid of any cardiotoxic potential. The dose-limiting toxicities of Caelyx are mucositis and foot-hand syndrome, the latter being more pronounced with short treatment intervals. Both toxicities are tolerable, however, when Caelyx is given at a dose of 45–50 mg/m2 every 4 weeks. Because of its efficacy and favorable toxicity profile, Caelyx was combined in phase II studies with several other drugs with established activity in breast cancer, including cyclophosphamide, the taxanes, and vinorelbine. Response rates of up to 70% were achieved. The combination of Caelyx and paclitaxel was shown to be also highly effective and, in contrast to doxorubicin/paclitaxel, not cardiotoxic. In a recently completed randomized phase III trial Caelyx was found to be equieffective with vinorelbine or mitomycin/vinblastine in the salvage treatment of patients with metastatic breast cancer who had failed prior taxane therapy. In another ongoing phase III study Caelyx is compared with doxorubicin in the first-line treatment of metastatic breast cancer.

Chemotherapy-induced febrile neutropenia makes the immuncompromized cancer patient even more susceptible to severe infections. The risk of infections correlates with grade and duration of febrile neutropenia. Empiric antibiotic treatment can diminish the high infection-associated mortality. There are guidelines for antimicrobial treatment and modifications of therapy. To individualize therapy decisions, it is helpful to characterize high- and low-risk patients. Antibiotic prophylaxis in afebrile neutropenic patients is only indicated in special cases. Use of G-CSF for prophylaxis of neutropenia can be recommended for high-risk patients, but it should not be used for the treatment of infection.

Bis Mitte der 70er Jahre spielte die Chemotherapie im gesamten Behandlungskonzept nur eine marginale Rolle. Auch heute sind Operation und Strahlentherapie unverandert die Eckpfeiler der Behandlung. Fur den Einsatz der Chemotherapie gibt es prinzipiell folgende Indikationsbereiche

Background The GeparQuinto study showed that adding bevacizumab to 24 weeks of anthracycline–taxane–based neoadjuvant chemotherapy increases pathological complete response (pCR) rates overall and specifically in patients with triple-negative breast cancer (TNBC). No difference in pCR rate was observed for adding everolimus to paclitaxel in nonearly responding patients. Here, we present disease-free (DFS) and overall survival (OS) analyses. Patients and methods Patients (n = 1948) with HER2-negative tumors of a median tumor size of 4 cm were randomly assigned to neoadjuvant treatment with epirubicin/cyclophosphamide followed by docetaxel (EC-T) with or without eight infusions of bevacizumab every 3 weeks before surgery. Patients without clinical response to EC ± Bevacizumab were randomized to 12 weekly cycles paclitaxel with or without everolimus 5 mg/day. To detect a hazard ratio (HR) of 0.75 (α = 0.05, β = 0.8) 379 events had to be observed in the bevacizumab arms. Results With a median follow-up of 3.8 years, 3-year DFS was 80.8% and 3-year OS was 89.7%. Outcome was not different for patients receiving bevacizumab (HR 1.03; P = 0.784 for DFS and HR 0.974; P = 0.842 for OS) compared with patients receiving chemotherapy alone. Patients with TNBC similarly showed no improvement in DFS (HR = 0.99; P = 0.941) and OS (HR = 1.02; P = 0.891) when treated with bevacizumab. No other predefined subgroup (HR+/HER2-; locally advanced (cT4 or cN3) or not; cT1–3 or cT4; pCR or not) showed a significant benefit. No difference in DFS (HR 0.997; P = 0.987) and OS (HR 1.11; P = 0.658) was observed for nonearly responding patients receiving paclitaxel with or without everolimus overall as well as in subgroups. Conclusions Long-term results, in opposite to the results of pCR, do not support the neoadjuvant use of bevacizumab in addition to an anthracycline–taxane-based chemotherapy or everolimus in addition to paclitaxel for nonearly responding patients. Clinical trial number NCT 00567554, www.clinicaltrials.gov .

Introduction: At present the topic “feminisation” in medicine, in other words the increasing number of female staff members is under heavy discussion; however, there are only few data upon the basis of which a scientific discussion can be held. The question arises as to the possibility of problems arising therefrom for the specialty gynaecology and obstetrics. Methods: With the help of a questionnaire the directors of departments of gynaecology and obstetrics were questioned about the various aspects of the topic feminisation in gynaecology and obstetrics. Results: Among current applications the proportion of female applicants is estimated to be 84.2 %. Reasons given most frequently for the feminisation in the specialty include low income, loss of face of the medical profession and the poor career chances. Among the spontaneously mentioned reasons were the increasingly female dominated image of gynaecology and the working conditions in hospitals. Whereas the taking on of surgical duties and of directing functions was less markedly desired by women than by men, the questioned directors found that male and female staff members were equally motivated to take on duties outside of their working hours or to engage in research work. Discussion: Feminisation in medicine represents a challenge. It seems to be important to evaluate and investigate the motivation of staff members with regard to their wishes in professional life and thus to be able to offer an appropriate working environment based on the survey results.

Hintergrund: Fruhdiagnostik und Pravention gehoren zu den Eckpfeilern der Medizin. Aufgrund ihrer unterschiedlichen anatomischen Zuganglichkeit und Pathogenese stehen das Zervix- und das Korpuskarzinom beispielhaft fur je eine dieser Moglich-keiten. Methodik: Die Voraussetzungen fur ein effektives Fruherkennungsprogramm, Fehler-moglichkeiten und Schwachstellen werden fur beide Karzinome diskutiert. Ihre Berucksichtigung sowie die Moglichkeiten der hormonellen Pravention des Endometriumkarzinoms sind wesentliche Voraussetzungen zur weiteren Steigerung der Effektivitat und damit Akzeptanz der Vorsorge. Schlusfolgerungen: Systematisch durchgefuhrte Vorsorgeuntersuchungen fuhren zu einer effektiven Senkung der Morbiditat und Mortalitat des Zervixkarzinoms. Vorsorgeuntersuchungen sollten bei sexuell aktiven Frauen mit dem 20. Lebensjahr beginnen. Die Frage des Untersuchungsintervalls wurde in den verschiedenen Screeningprogrammen sehr unterschiedlich diskutiert. Haben die drei ersten Untersuchungen Normalbefunde ergeben, so kann als Ergebnis verschiedener Studien das Screeningintervall auf 2 Jahre ausgedehnt werden. Auch wenn das routinemasige ljahrige Intervall verschiedentlich in Frage gestellt wird, so empfehlen wir trotzdem seine Beibehaltung. Das Korpuskarzinom entzieht sich einer effektiven Screening-moglichkeit. Dafur besitzen wir die Moglichkeit, durch Verordnung von Kontrazepti-va und kombinierter Ostrogen/Gestagen-Substitutionstherapie in der Peri-/Postmenopause die Inzidenz signifikant zu senken. Unabhangig von einer stattfindenden Substitutionstherapie ist der Einsatz der transvaginalen Sonographie in jahrlichen Abstanden zur Beurteilung der Endometriumsdicke indiziert, auch wenn die Datenlage eine verbindliche Beurteilung dieser Masnahme zum jetzigen Zeitpunkt noch nicht erlaubt.

In order to understand further the effects of Newcastle-disease-virus(NDV)-modified tumour vaccines we investigated the feasibility of isolating lymphocytes from the site of injection of patients undergoing postoperative active specific immunization (ASI) with autologous NDV-modified tumour cells. Delayed-type-hypersensitivity(DTH)-like reactions from five cancer patients were surgically removed, minced and the tissue particles were digested with collagenase and DNase. Lymphoid cells recovered were expanded in a highly efficient limiting-dilution analysis system optimized for T cell growth [Moretta et al. (1983) J Exp Med 157: 743] and lymphocyte microcultures (clonal probability > 0.8) could be grown for up to 1 year. Analysis of the microcultures for phenotype and function showed that the majority were positive for CD4 (92%) and TCR alpha beta (96%). Concanavalin-A-induced production of interleukin-2 (IL-2), IL-6, interferon gamma and tumour necrosis factor alpha was detected in more than 70% of the microcultures. Lectin-dependent cytotoxicity was only very rarely observed. The general characteristics of the microcultures obtained support the notion of a DTH-like reaction taking place at the site of tumour cell challenge. The possibility of in vitro expansion and cultivation of T lymphocytes from ASI vaccination sites should help to elucidate further the role of these cells in active specific immunization against autologous tumour cells.

The new progestagen dihydrospirorenone (ZK30595) known to have no estrogenic androgenic or glucocorticoid biological activity was characterized at the receptor level for estrogenic progestogenic mineralocorticoid and adrenocorticoid binding. This progestin (6beta7beta15beta 16beta-dimethylen-3-oxo-17alpha-pregn-4-ene-2117-carbolactone) is a testosterone derivative with a carbolactone ring at C-17. It is 8 times as potent as spironolactone as an aldosterone antagonist and 0.3 times as potent as cyproterone acetate as an antiandrogenic agent. The receptors used for these assays were human uterine estrogen receptor adrenalectomized rat mineralocorticoid and glucocorticoid receptors and castrated rat prostate androgen receptor. In a study of kinetics of association and dissociation of dihydrospirorenone progesterone and the progestin R5020 after saturation binding all 3 progestins showed first-order dissociation kinetics and remained stable for 6 hours. The dissociation half-lives of dihydrospirorenone and progesterone were 33 and 61 minutes compared to 295 minutes for R5020. The dissociation constant (K-value) by Scatchard analysis was 1.09 x 10 (-8) mol/l about 10 times less than that of R5020 and the binding capacity was 465 fmol/l protein. The binding affinity of dihydrospirorenone for the androgen receptor was high 65% of that of R1881. Binding to the glucocorticoid receptor was low 5% of that of dexamethasone. Binding to the mineralocorticoid receptor was high 230% of that of aldosterone. Binding to estrogen receptor could not be defined. On sucrose density gradients dihydrospirorenone-receptor ligand sedimented in the 8S and 4S region. Generally receptor binding of steroid hormones correlated well with biological activity in vivo but receptor binding analysis will not predict whether a given steroid will have agonist or antagonist activity at the cellular level. This agent is typical of progestins of its series for binding to progesterone and mineralocorticoid receptors; it is unique for binding to androgen receptors but having potent anti-androgenic biological activity.

Six permanent human tumor cell lines (OV-MZ-1 to 6) were established from 6 patients with serous adenocarcinomas of the ovary. These cell lines were derived from both solid tumors and ascites, from pre-treated and untreated patients, and are available over a range of in vitro passage numbers. The tumor cells grow its monolayers and develop foci of “piled-up” cells in confluent cultures. Flow cytophotometry showed that all the lines exhibited DNA hyperdiploidy with DNA tetraploidy in one cell line and DNA aneuploidy in the other cell lines. The mean population doubling time ranged from 24 to 52 hr. Transmission electron microscopy demonstrated that the tumor cells of all cell lines exhibited features of epithelial differentiation such as desmosomes and intracellular gland-like lumina. Immunocy- tochemical analysis showed that the co-expression of cytokeratins and vimentin, which is a feature of ovarian serous cystadeno- carcinomas; in situ, was fully preserved in the majority of cell lines. The main cytokeratin polypeptides expressed were numbers 7, 8, 17, 18 and 19. The tumor-associated antigen CA-125, but not CEA, was shed in the culture supernatant. This was in accordance with FACScan analysis of the cell lines and the level of CA-125 and CEA in the patients' serum. The estrogen and progesterone receptors were negative both in the cell lines and in the original tumors. These new ovarian carcinoma cell lines will be valuable models for further investigations into a variety of biological properties. © 1992 Wiley-Liss, Inc.

Different studies have demonstrated epidermal growth factor receptor (EGFR) status as an independent prognostic factor for ovarian cancer (OC). Recent studies in non-small cell lung cancer suggest that the presence of a clinical response to tyrosine kinase inhibitors correlates with somatic mutations in the kinase domain of EGFR, exons 18-21. For patients with OC, data are not available on EGFR gene mutation.Shock-frozen samples from 32 patients with OC were screened for L858R deletion mutations of EGFR within exon 21 of the kinase domain and 15 bp deletion in exon 19. Additionally, nine commercially available OC cell lines and 32 established OC lines were analysed.In cell lines, as well as in tumor samples, stratified to platinum-free therapy interval, no mutation of the EGFR gene was observed.Mutations in the kinase domain of the EGFR, exons 19 and 21, are absent or very infrequent in patients with OC.

Ovarian cancer is chemosensitive, but most patients with advanced disease die from tumor progression. As 25% of the patients can be cured by chemotherapy, it is reasonable to evaluate high-dose chemotherapy (HDCT). Forty-eight patients with untreated ovarian cancer were entered in a multicenter phase I/II trial of multicycle HDCT. Median age was 46 (19–59 years); International Federation of Gynecology and Obstetrics-stage was III in 79% and IV in 21%; 31% had residual disease >1 cm after surgery. Two courses of induction/mobilization therapy with cyclophosphamide (250 mg/m2) and paclitaxel (250 mg/m2) were used to collect peripheral blood stem cells. HDCT consisted of two courses of carboplatin (area under curve (AUC) 18–22) and paclitaxel followed by one course of carboplatin and melphalan (140 mg/m2) with or without etoposide (1600 mg/m2). Main toxicity was gastrointestinal. Limiting carboplatin to AUC 20 and eliminating etoposide resulted in manageable toxicity (69% without grade 3/4 toxicity). One patient died from treatment-related pneumonitis. At 8 years median follow-up, median progression-free-survival (PFS) and overall survival (OS) is 13.3 and 37.0 months. Five-years PFS and OS is 18 and 33%. Multicycle HDCT is feasible in a multicenter setting. A European phase III trial based on this regimen is evaluating the efficacy of HDCT.

The results of four randomized international multicentric trials evaluating the therapeutic benefit of Herceptin in the adjuvant treatment of HER2-neu positive primary breast cancer have been reported. These reports showed that even after short term follow up one year of Herceptin resulted in improved disease free, metastases free and overall survival. Design and results of these four studies and the recommendations of national and international societies for the use of Herceptin in the adjuvant setting will be discussed.

Laparoscopy using subcostal insertion is particularly mentioned in the literature in connection with cholecystectomies and nephrectomies. Subcostal access was chosen for placement of the Veress needle and the primary trocar in 72 patients. The following indications have been considered: prior midline vertical abdominal incisions, previous described periumbilical adhesions, prior peritonitis, umbilical hernias, obesity. The location of the incision was subcostal of the 9th rib in the midclavicular line. 28 patients (43.1%) had periumbilical, 23 (32.0%) had subumbilical omental adhesions. Periumbilical bowl adhesions have been described for 12 patients (16.7%) and 20 (27.8) had subumbilical bowl adhesions. One patient required laparotomy. There have been no complications during the operation or postoperative in the remaining 71 patients. The subcostal insertion is a safe location for primary trocar placement and can possibly help to prevent serious omental or bowl lesions.

In several phase II and III topotecan studies the large number of patients with stable disease is striking. Since no severe organ toxicity has been described for topotecan, long-term therapy with topotecan seems to be reasonable. In this summary we present evidence, that long-term topotecan therapy can be managed without cumulative hematological and non-hematological toxicity.Thirty-three patients with recurrent ovarian cancer, who were treated with at least 7 courses of topotecan, were evaluated in this retrospective study (patient database from SmithKline Beecham, Germany). Most of the patients had more than 2 previous courses of chemotherapy. The starting dose was between 1.0 and 1.5 mg/m2 topotecan administered for 5 days every 3 weeks as an i.v. infusion. All patients were evaluated for toxicity, 32 patients for response.The 33 patients received 343 courses of topotecan, an average of more than 10 courses per patient. The highest number of courses given to a single patient was 33. The hematotoxicity was in the expected range, but toxicity was not cumulative. The number of interventions for growth factors and blood cell transfusions were constant over the whole therapy. Dose reductions were conducted in more than 75% of the patients as early as in course two. There was no grade 3 or 4 non-hematological toxicity. Alopecia was the only toxicity to be cumulative. Remissions were observed in 12 out of 32 eligible patients. The remissions were achieved after an average of 4.3 courses (range 2-7). The median time to progression was 33 weeks.Long-term therapy with topotecan is reasonable and can be conducted without cumulative hematological toxicity.

Bis heute gilt das Dogma, dass das metastasierte Mammakarzinom nicht mehr kurativ behandelt werden kann. Die mittlere Uberlebenszeit nach Feststellung der Metastasierung betragt im Median 2 Jahre. Sie ist etwas langer bei Patientinnen, deren Tumor hormonrezeptorpositiv ist oder die eine klinisch komplette Remission unter konventioneller Chemotherapie erzielen. Beim Nachweis viszeraler Metastasen ist die Prognose deutlich ungunstiger als bei einer ausschlieslichen Knochen- oder Weichteilmetastasierung, was in den Therapieempfehlungen des Possinger-Score Berucksichtigung findet. Ob das Dogma der Inkurabilitat, z. B. durch den Einsatz der Hochdosischemotherapie fur ein zu definierendes Kollektiv, aufgehoben werden kann, ist unwahrscheinlich.

Since the publication of the Gynecologic Oncology Group (GOG) protocol 111 in 1996, and the results of the Arbeitgemeinschaft Gyna kologische Onkologie (AGO) trial Ovar-3 and the GOG protocol 158, the combination of platinum and paclitaxel has been adopted as the standard therapy in advanced ovarian cancer. One option for achieving further progress in the first-line treatment of advanced ovarian cancer might be the addition of noncross-resistant drugs to the two-drug regimen. Meta-analysis showed a survival benefit for platinum-anthracycline based combinations as compared to platinum-based combinations without anthracyclines. An AGO phase I/II trial compared epirubicin in combination with carboplatin and paclitaxel in untreated patients with gynecological malignancies. Based on the results of this study a randomized phase III trial together with the French GINECO group was conducted. The trial started 11/97 and was closed 11/99. All 1281 patients were randomized. Currently, 1132 end-of-therapy reports have been issued. Nine hundred eighty nine (87%) patients completed six cycles of treatment. Treatment and toxicity data are available for these patients. Three hundred thirty five patients had a measurable residual tumor after initial debulking surgery. Response data of 228 patients (111 ET-Carbo, 117 Carbo-T) are available.

The aim of the present study was to assess whether the induction of specific immune responses by vaccination with the murine monoclonal anti-idiotypic antibody ACA125, which imitates the tumor-associated antigen CA125, has a positive influence on the survival of patients with recurrent ovarian carcinoma. Forty-two patients with platinum-pretreated recurrences were included in a clinical Phase I/II trial of consolidation in third-line therapy. Patients initially received four immunizations with 2 mg of alum-precipitated anti-idiotype ACA125 every 2 weeks and then monthly applications. No serious allergic reactions could be detected within a maximal control period of 56 months. Hyperimmune sera of 27 of 42 patients (64.2%) showed increased concentrations of human antimouse antibodies. Specific anti-anti-idiotypic antibodies as a marker for induced immunity were detected in 28 of 42 patients (66.7%). The survival of the whole ACA125-treated collective of patients after a mean of 12.6 antibody applications was 14.9 +/- 12.9 months. The survival of patients with a positive immune response was 19.9 +/- 13.1 months in contrast with 5.3 +/- 4.3 months in those patients without detectable anti-CA125 immunity (P0.0001). According to these results, vaccination with a suitable anti-idiotypic antibody offers an effective way to induce specific immunity against a primarily nonimmunogenic tumor antigen such as CA125 and is associated with a positive impact on the survival of patients with recurrent ovarian cancer with few side effects, which warrants a Phase III trial for ovarian cancer patients after primary therapy.

The standard treatment for ovarian cancer consists of staging laparotomy with aggressive debulking, a pelvic and paraaortal lymphadenectomy if indicated and a postoperative chemotherapy. A reappraisal of primary high dose chemotherapy in advanced ovarian cancer seems warranted because of high remission rates of such schedules in palliative situations. For a nation-wide interdisciplinary phase I/II multi-center-study 49 patients were recruited. Induction for stem cell mobilization consists of two cycles of cyclophosphamide and taxol. Three high dose cycles follow with a steady dose-escalation of carboplatin by a factor of 4, this is contrast to a conventionally dosed chemotherapy. During the first two cycles taxol is added, during the third etoposide and melphalane. The plan of primary sequential high dose therapy proved feasible in this study. In a prospective randomized follow-up study primary high dose therapy is compared to conventional chemotherapy (AGO-Ovar-5-study). It results will answer the question whether primary high dose chemotherapy with stem cell support improves the course of ovarian cancer compared to conventional treatment.

Recently, a randomized study conducted by the Gynecologic Oncology Group (GOG 111) demonstrated that, given by a 24-hour infusion, the combination of cisplatin and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is superior to combination cisplatin/cyclophosphamide in previously untreated patients with advanced ovarian cancer. This combination, however, necessitates hospitalization. Combination paclitaxel/carboplatin would be expected to induce fewer nonhematologic side effects but may be more myelotoxic. Thus, we started a phase I dose-escalation study to determine the maximal tolerated dose of paclitaxel given as a 3-hour infusion in combination with carboplatin, both drugs administered every 21 days. The paclitaxel dose was escalated by increments of 25 mg/m2, starting at 135 mg/m2 (level 1), 160 mg/m2 (level 2), 185 mg/m2 (level 3), and 210 mg/m2 (level 4). Carboplatin was administered to achieve an area under the concentration-time curve of 5, using the Calvert formula For study levels 5 and 6, the carboplatin dose was targeted at area under the concentration-time curves of 6 and 7.5, respectively, and was combined with a fixed paclitaxel dose of 185 mg/m2. Thirty previously untreated patients with stage IIC to IV ovarian cancer were enrolled. Nonhematologic toxicity, including nausea/vomiting and arthralgia/myalgia, was mild. Across all dose levels, a total of 16 patients developed peripheral neurotoxicity (World Health Organization grades 1 and 2). At dose level 5, one patient experienced reversible grade 4 neurotoxicity. Neutropenia was the principal dose-limiting hematologic toxicity. During 33 (31%) of 106 courses, World Health Organization grade 4 neutropenia was observed. Granulocyte colony-stimulating factor was required in only 7.6% of courses. Thrombocytopenia was less than that expected when carboplatin is given alone. Clinical responses were observed in eight of 14 patients, for an overall response rate of 57%. The combination of carboplatin plus paclitaxel was found to be an active regimen. This trial demonstrates that carboplatin dosed by the Calvert equation and 3-hour paclitaxel can be combined safely at full therapeutic doses for six or more courses in patients with advanced epithelial ovarian cancer.

The use of hematopoetic growth factors and stem cell support reduces the dose limiting hematopoetic toxicity's, resulting in a remarkable increase in dose intensity of chemotherapy. As far as data from phase I/II trials are available high dose chemotherapy (HDC) may be integrated in the systemic treatment of breast and ovarian cancers. In metastatic breast cancer HDC may induce fairly high but short response rates. Long term survival is expected in 20% of the cases. Patients with limited metastatic disease, without significant prior chemotherapy, partial or complete response to induction chemotherapy and complete remission after HDC may benefit from HDC. In phase I/II trials HDC improved recurrence free survival in high risk patients (e.g.9 positive LN) compared to historic controls and may therefore be a curative approach. Ovarian cancer is very chemosensitive. Conventional chemotherapies induce multidrug resistance rapidly. Just as in breast cancer-Phase I/II trials demonstrated high response rates to HDC, which again were short of duration.

Das Mammakarzinom ist die haufigste Krebserkrankung bei Frauen. Eine Senkung der Mortalitat ist derzeit nur durch eine Verbesserung der Fruhdiagnostik zu erzielen. Bislang galt die Mammographie als einzige Methode, die eine Fruherfassung des Mammakarzinoms erlaubt. Die hierdurch zu erzielende Senkung der Mortalitat wurde in den letzten dreisig Jahren weltweit durch zahlreiche Mammographie-Screeningstudien belegt [1]. Insgesamt erlaubt die Mammographie eine Mortalitatssenkung um etwa 30 % im Screening-Kollektiv. In einigen Studien wurde nach pra- und postmenopausalen Patientinnen gesondert untersucht. Bei Frauen ab dem 50. Lebensjahr zeigt sich ein noch deutlicherer Screeningerfolg. Dagegen erzielt die Mammographievorsorge bei Frauen vor dem 50. Lebensjahr keine Effektivitat. Dies liegt daran, das bei jungen Frauen das Drusengewebe meistens dichter ist und eine hohere Strahlenabsorption aufweist. Dadurch verbergen sich haufig tumorose Verdichtungen und sogar MikroVerkalkungen. Dies reduziert die Sensitivitat der Mammographie bei pramenopausalen Frauen [10].

A randomized phase III trial was conducted in patients with advanced ovarian cancer FIGO IIB–IV in order to determine whether epirubicin (E) in addition to paclitaxel (T) and carboplatin (C) will increase survival in comparison to TC alone. The rationale of this study was based not only on the evidence of activity of free and liposomal anthracylins in patients who have been pretreated with the platinum–paclitaxel regimen but also on the evidence of meta-analyses performed before the taxane era of a 7% improvement in survival when doxorubicin was added as the third agent in first-line treatment (Ovarian Cancer Meta-analysis Project. J Clin Oncol 1991;9:1668–74). In addition, there were some reports suggesting a synergistic activity between paclitaxel and anthracylins (Ray-Coquard I et al. Gynecol Oncol 2003;88:351–7) in patients with ovarian cancer in relapse. Between November 1997 and February 2000, 1282 patients were randomized to receive six cycles of either T 175 mg/m2 3 h iv + C area under curve 5 (according to the Calvert formula) + E 60 mg/m2 iv (TEC) or TC at same doses, both in 3-week intervals. Patients were stratified per centre and into one of two strata according to FIGO stage and residual tumor size: stratum I includes patients with FIGO IIB–IIIC and residual tumor ≤1 cm and stratum II patients with FIGO IIB–IIIC and residual tumor >1 cm or FIGO IV. The primary end point was overall survival (OS). Secondary end points included toxicity, response to treatment, quality of life, and progression-free survival (PFS). Median follow-up at the time of analysis was 51.9 months. The whole population is available for PFS and OS analysis. A total of 1264 patients received at least one cycle of treatment and are evaluable for toxicity. Patient characteristics are well balanced between the two arms with respect to median age, performance status, FIGO stage, histology, and stratification, with less than one third of the patients suboptimally debulked. The three-drug combination induced a markedly higher myelotoxicity resulting in increased demand on supportive care. Grade 3/4 febrile neutropenia occurred in 5.5% patients in TEC and in 1.3% patients in TC (P

Der Variationskoeffizient (VK) ist ein wenig anschauliches und zudem von der Substratkonzentration abhangiges Mas fur die Genauigkeit einer Mesmethode. Wunschenswert ist ein methodenspezifisches Mas fur die Trennscharfe. Versuchsanordnungen fur die Performanceevaluierung bieten die Moglichkeit, die Gesamtvarianz der Messungen eines Labors aufzugliedern in eine Varianzkomponente zwischen den Konzentrationen der Testseren S A 2 und eine Komponente der Varianz innerhalb der Mesreihen S E 2 . Der Quotient Q = S A 2 /S E 2 ist ein solches Kriterium fur die Trennscharfe. Vertrauensintervalle fur eine solche Maszahl konnen allerdings bei unrationeller Versuchsanordnung (zu wenig Testseren, zu grose Konzentrationsunterschiede, zu viele Meswiederholungen) riesig werden und bestehende Unterschiede zwischen den Mesmethoden kaschieren. In jedem Fall sollte ein Biometriker im Stadium der Versuchsplanung hinzugezogen werden. Die Studie zeigt eine deutliche Uberlegenheit des Enzymun-Tests bzgl. der Trennscharfe gegenuber den Parallelmessungen mit anderen Methoden fur die Marker CA 72–4, CA 19–9 und CEA. Ob sich diese Uberlegenheit auf die prognostische Treffsicherheit auswirkt, ist durch eine klinische Langzeitstudie zu prufen.