Chemotherapy for 70-Year-Old Women with Breast Cancer in Germany: A Survey by the German Breast Group.

Aim: Around half of all women in Germany with breast cancer are older than 65 and approximately one third of them is older than 70 years of age. In theory, the preferred therapeutic management of women with breast cancer aged 65 and above corresponds to that formulated for younger patients and complies with the S3 Guidelines and the therapy recommendations formulated by AGO. To study the current therapies used to treat women with breast cancer aged 70 and above in Germany, a survey of the clinics of the German Breast Group (GBG) was done. Method: An online survey was carried out with requests sent to 599 physicians registered as principal investigators in the database of the GBG. The 12-item questionnaire was used to investigate the systematic therapeutic management of 70-year-old patients in different settings. The indication for chemotherapy was taken as a given. Results: In a neoadjuvant setting, 62 % of physicians opted for anthracycline and taxane-based therapy as did 56.6 % of physicians in an adjuvant setting. One third of physicians preferred a taxane-based therapy with the anti-angiogenesis inhibitor bevacizumab as first-line therapy for primary metastatic cancer and after anthracycline-based therapy. Capecitabine (around 30 %) and navelbine (around 20 %) were proposed as second-line neoadjuvant and adjuvant therapies after prior anthracycline- and taxane-based therapy. Conclusion: The chemotherapy regimen prescribed for women with breast cancer aged 70 and above in Germany appears to be relatively standardised and corresponds to the recommendations given in the S3 Guidelines and by the AGO Breast Committee.

A phase II trial (AGO 2.11) in platinum-resistant ovarian cancer: a randomized multicenter trial with sunitinib (SU11248) to evaluate dosage, schedule, tolerability, toxicity and effectiveness of a multitargeted receptor tyrosine kinase inhibitor monotherapy.

BACKGROUND: Recurrent platinum-resistant ovarian cancer usually has a poor outcome with conventional chemotherapeutic therapy and new treatment modalities are warranted. This phase II study was conducted to evaluate sunitinib, an oral antiangiogenic multitargeted tyrosin kinase inhibitor, in this setting. MATERIAL AND METHODS: The primary end point of this randomized phase II trial was the objective response rate according to RECIST criteria and/or Gynecologic Cancer InterGroup CA125 response criteria to sunitinib in patients with recurrent platinum-resistant ovarian cancer who were pretreated with up to three chemotherapies. A selection design was employed to compare two schedules of sunitinib (arm 1: 50 mg sunitinib daily orally for 28 days followed by 14 days off drug; and arm 2: 37.5 mg sunitinib administered daily continuously). RESULTS: Of 73 patients enrolled, 36 patients were randomly allocated to the noncontinuous treatment arm (arm 1) and 37 patients were randomly allocated to the continuous treatment arm (arm 2). The mean age was 58.8 and 58.5 years, respectively. We observed six responders (complete response + partial response) in arm 1 (16.7%) and 2 responders in arm 2 (5.4%). The median progression-free survival (arm 1: 4.8 [2.9-8.1] months; arm 2: 2.9 [2.9-5.1] months) and the median overall survival (arm 1: 13.6 [7.0-23.2] months; arm 2: 13.7 [8.4-25.6] months) revealed no significant difference. Adverse events included fatigue as well as cardiovascular, gastrointestinal and abdominal symptoms, hematologic and hepatic laboratory abnormalities. Pattern and frequency of adverse events revealed no substantial differences between both treatment groups. CONCLUSIONS: Sunitinib treatment is feasible and moderately active in relapsed platinum-resistant ovarian cancer. The noncontinuous treatment schedule should be chosen for further studies in ovarian cancer.

Immunhistochemical analysis for expression of calpain 1, calpain 2 and calpastatin in ovarian cancer.

Calpains, also called calcium activated neutral proteases (CANP), are expressed ubiquitously. They are intracellular, non-lysosomal cytoplasmic cysteine endopeptidases. Calcium is required for their activation. Their endogenous specific inhibitor is calpastatin, which is expressed ubiquitously and coexists within cells besides calpain. When calcium is present, calpastatin and calpain attach to each other inhibiting the protease. The calpain system plays an important role in many processes including apoptosis, necrosis, ischemia formation and exocytosis. So far, many reports exist on studies about the influence of calpains in different tumors (skin, breast, renal cell and prostate cancers). The role of calpains in pathogenesis or further tumor progression has always been proved in related studies, but their exact function could not be demonstrated. So far, no studies on calpains being involved in the pathogenesis of ovarian cancer have been published. In our study we focused on the expression of the enzymes calpain 1, calpain 2 and their inhibitor calpastatin in normal and malign ovarian tissue. Therefore, we performed immunohistochemical stainings of paraffin slices and evaluated staining intensity (SI), percentage of positive cells (PP) and immunoreactive score (IRS). We evaluated the correlation between enzyme expression in malign and benign ovarian tissues. In malignant ovarian tissue, we found decreased expression, staining intensity and immunoreactive score of calpastatin. With higher grading of the ovarian carcinoma, staining intensity and immunoreactive score of calpain 1 decreased. Staining intensity of calpain 2 in ovarian carcinoma decreased with increasing lymph node status. We clearly demonstrated differences between enzyme expressions in malign and benign tissue. This study could not find any specific function of calpains. Only few studies in the literature have been found that deal with calpain evaluation of ovarian cancer. Additional studies including more patients are required to elucidate the functional role and impact of calpain in tumors in detail.

Heterogeneous expression of serine protease inhibitor maspin in ovarian cancer.

UNLABELLED: Ovarian cancer (OC) is a disease with poor prognosis, and molecular markers are needed to improve understanding of disease progression and resultant treatment. Only limited data concerning the expression of maspin, a serine protease inhibitor, in ovarian cancer (OC) are available. This study investigates the prognostic value of maspin expression (ME) in various OC cell lines and clinical tissue specimens from OC patients. PATIENTS AND METHODS: Tumour purified mouse anti-human maspin monoclonal antibody was applied to tissue specimens from 87 OC patients. ME was recorded by an immunoreactive score, which was correlated with grading, stage, histopathological subtypes and overall survival. Additionally ME was evaluated in established ovarian cancer cell lines (HEY, SKOV3, OVCAR3/8) and paclitaxel- and docetaxel-resistant HEY cells by QRT-PCR. RESULTS: There was significant correlation between cytoplasmatic ME and overall survival (p<0.05). OC patients with high levels of ME had a median survival of 28 vs. 57 months for those with low levels. Significant differential ME was detected between benign, borderline ovarian lesions and OC, as well as among different tumour gradings. Normal ovarian epithelial cells expressed less maspin than ovarian cancer cells as measured by QRT-PCR. Docetaxel- and paclitaxel-resistant ovarian cell lines showed an even higher level of ME, suggesting an unfavourable role of ME in OC cell lines. CONCLUSION: Maspin is expressed differentially in OC, and low expression levels of maspin are correlated with a longer survival.

[Coagulation and formation of malignant effusions]. / Die Rolle des Gerinnungssystems bei der Entstehung maligner Ergüsse.

Malignant effusions are a frequent problem for cancer patients. Due to the high resistance of tumor cells within these effusions, no effective treatment has been defined yet. Most patients exhibit additional phenomena related to hyper-coagulability such as elevated levels for d-dimers and prothrombin fragments f1.2; half of them suffer from manifest thrombosis or complications. We followed the hypothesis that the activated coagulation system contributes to the resistance of tumor cells and analyzed the effusions from cancer patients. The majority of isolated tumor cells aberrantly expressed PAR-1 thrombin receptors. In vitro pre-incubation of PAR-1 expressing human leukemia cells with thrombin resulted in a dose-dependent resistance to idarubicin. Within the effusions, we did not only find high concentrations of VEGF and tissue factor, but also all coagulation factors of the tissue factor pathway. Very high levels of prothrombin fragments f1.2 indicate constant thrombin generation. Upon the basis of these findings, we developed a multistep model elucidating the pathophysiological generation of malignant effusions, which might serve as a basis for further examinations.

[Benign and borderline tumors of the ovary]. / Benigne und Borderline-Tumoren des Ovars.

Alterations of the ovaries easily cause diagnostic uncertainty about relevance and consequence. Palpable or sonographic ovarian tumors are reason for various differential diagnoses. Therefore the clarification of ovarian lesions is one of the main duties in daily gynaecological practice. Although diagnostic procedures might be supplemented by CT-Scan or MRI techniques, classical bimanual examination and vaginal ultrasound scan will determine the diagnosis in most cases comparably accurate. The suspected diagnosis concerning benign or malignant lesions, should take the palpable and sonographic feature, as well as the information from the patients medical history (e.g. family history of malignant diseases (BRCA 1/2 mutations) into account. In this regard, there are no other additional parameters established. Serum tumormarkers (CA 12.5) or sonographic examinations (including Doppler) have low sensitivity and specificity. Clinical diagnostic experience seems to be crucial. Cystic lesions mostly occur in premenopausal women and commonly relapse. They are mostly normal follicle cysts, but may also be a tumor of low malignant potential (LMP-tumor) or even an invasive cancerous lesion. 20-30% of all ovarian tumors are malignant and by the time of primary diagnosis already in a about 60-70% incurable due to intraabdominal dissemination. Benign or malignant lesions may occur in every age group. Ovarian tumors at infantile age are malignant in about 15%. Most malignant tumors occur between the age of 50 to 70. The LMP-tumors occur in average 10 years earlier. Malignant ovarian lesions represent about 15-30% of all genital malignant tumors. Hormonal contraceptives, pregnancy and breast feeding seem to be protective. The persistence of ovarian cysts and tumors will be mostly examined by laparoscopic surgery. In that respect the diagnosis of LMP-tumors might be incidentally and will then have a substantial impact on the extent of the surgery and the follow up. This compilation overviews the spectrum of benign and low malignant potential tumors of the ovary and their different tissues of origin.

[Malignant tumors of the uterus]. / Maligne Tumoren des Uterus.

Malignant uterine tumors are responsible for up to 9% of all new cancer cases and for 4.5% of all cancer related deaths in women. The three important uterine cancers are endometrial cancers, uterine sarcomas and cervical cancers. Endometrial cancers are typically found in elderly women and are > 70% hormone sensitive (type I), type II is often less differentiated and not hormone sensitive. Diagnosis can be achieved by vaginal ultrasound and by histology after hysteroscopy and curettage of the uterine cavity. Therapy of choice is the stage related radical hysterectomy (incl. lymphnode dissection). Postoperatively and at progressive stages endocrine and radiation therapies can be useful. Chemotherapy is only useful in not hormone sensitive and in progressive tumors. Uterine sarcomas are a rare and heterogeneous group of tumors. Therefore no clinical guidelines are available for this entity. These often aggressive tumors are hardly responding to systemic and radiation therapy. Therefore radical tumor surgery plays the main therapeutic role. Cervical carcinomas are usually growing on an underlying chronic infection with oncogenic HPV subtypes. Important co-factors for carcinogenesis are tobacco smoking, an immunodeficiency and chronic genital infections of other causes. Cervical carcinomas and their precursor lesions are easily accessible for screening tests. Many tumors are detected in early tumor stages. Preoperatively diagnostic procedures are performed to examine local and distant tumor growth. In early stages a radical hysterectomy (incl. pelvine (+paraaortal) lymphonodectomy) and in rare cases an uterus preserving surgery should be performed. Alternatively a primary radiochemotherapy can be applied. Patients with tumors in stages > or = FIGO IIb receive a primary combined radiochemotherapy.

[Aromatase inhibitors in the adjuvant therapy of breast cancer]. / Aromataseinhibitoren in der adjuvanten Therapie des Mammakarzinoms.

Breast cancer is a hormone-sensitive cancer and in most post-menopausal women hormone receptor positive. The hormone receptor status is a highly valid predictive marker of responsiveness to endocrine therapy. The standard adjuvant therapy in patients with hormone-receptor-positive breast cancer is the selective estrogen receptor modulator tamoxifen. Third-generation aromatase inhibitors are accepted as a treatment option for metastatic breast cancer. However, results from recent studies show also a benefit of this type of drugs for disease-free survival with fewer adverse reactions in the adjuvant therapy. Therefore a new therapeutic field opens for the use of 3rd-generation aromatase inhibitors. This will lead to an expansion of the indication, but the question of modality -- up-front, switch or extended therapy -- remains to be resolved.