Treatment strategies in patients with gynecological sarcoma: Results of the prospective intergroup real-world registry for gynecological sarcoma in Germany (REGSA-NOGGO RU1).

OBJECTIVE: Gynecological sarcomas account for 3% of all gynecological malignancies and are associated with a poor prognosis. Due to the rarity and heterogeneity of gynecological sarcomas there is still no consensus on optimal therapeutic strategies. This study's objective was to describe the treatment strategies used in patients with gynecological sarcomas in the primary course of disease. METHODS: The German prospective registry for gynecological sarcoma (REGSA) is the largest registry for gynecological sarcomas in Germany, Austria and Switzerland. Primary inclusion criteria for REGSA are histological diagnosis of sarcoma of the female genital tract, sarcoma of the breast or uterine smooth muscle tumors of uncertain malignant potential (STUMP). We evaluated data of the REGSA registry on therapeutic strategies used for primary treatment from August 2015 to February 2021. RESULTS: A total of 723 patients from 120 centers were included. Data on therapeutic strategies for primary treatment were available in 605 cases. Overall, 580 (95.9%) patients underwent primary surgery, 472 (81.4%) of whom underwent only hysterectomy. Morcellation was reported in 11.4% (n=54) of all hysterectomies. A total of 42.8% (n=202) had no further surgical interventions, whereas an additional salpingo-ophorectomy was performed in 54% (n=255) of patients. An additional lymphadenectomy was performed in 12.7% (n=60), an omentectomy in 9.5% (n=45) and intestinal resection in 6.1% (n=29) of all patients. Among 448 patients with available information, 21.4% (n=96) received chemo- or targeted therapies, more commonly as single-agent treatment than as drug combinations. Information about anti-hormonal treatment was available for 423 patients, among which 42 (9.9%) received anti-hormonal treatment, 23 (54.8%) of whom with low-grade endometrial stroma sarcomas. For radiotherapy, data of 437 patients were available, among which 29 (6.6%) patients underwent radiotherapy. CONCLUSION: Our study showed that treatment of patients with gynecologic sarcomas is heterogeneous. Further trials are needed along with more information on treatment modalities, therapy response and patient-reported outcomes to implement new treatment strategies.

AEZS-108 : a targeted cytotoxic analog of LHRH for the treatment of cancers positive for LHRH receptors.

INTRODUCTION: Receptors for the luteinizing hormone-releasing hormone [LHRH, also known as gonadotropin-releasing hormone (GnRH)] can be regarded as an ideal target for a personalized medicine approach in cancer therapy. LHRH receptors are expressed in about 80% of human endometrial and ovarian cancers, 86% of prostate cancer, and about 50% of breast cancers including triple-negative breast cancer, as well as bladder, colorectal, and pancreatic cancers, sarcomas, lymphomas, melanomas, and renal cell carcinomas. Apart from the pituitary and reproductive organs, other organs and hematopoietic stem cells express LHRH receptors. Thus, a targeted cytotoxic LHRH analog such as AEZS-108 (formerly known as AN-152), in which doxorubin is linked to the LHRH agonist [D-Lys(6)]LHRH, appears to be a suitable drug for targeted chemotherapy of cancers expressing receptors for LHRH, which would be more efficacious and less toxic than standard systemic chemotherapy. AREAS COVERED: This review discusses the development of AEZS-108, its targeting mechanism, preclinical studies, and clinical trials in patients with endometrial, ovarian, prostatic, and bladder cancers. We emphasize its development as a personalized medicine approach. The studies reviewed demonstrate the effects of the cytotoxic LHRH analog, AEZS-108, mediated by LHRH receptors, in in vivo models of LHRH-receptor-positive human endometrial, ovarian, breast, prostatic, colorectal, pancreatic, and bladder cancers xenografted into nude mice. Intravenous administration of AEZS 108 inhibits the growth of LHRH-receptor-positive tumors better than equimolar doses of the cytotoxic agent doxorubicin and is far less toxic. AEZS 108 has no antitumor activity in cancers negative to LHRH receptor. This strongly supports the concept of targeting cytotoxic chemotherapy to tumor cells expressing LHRH receptors. Early clinical trials have demonstrated the efficacy of AEZS-108. A Phase I trial assessed the maximum tolerated dose and pharmacokinetics and pharmacodynamics of AEZS-108 given once every 3 weeks in patients with gynecological cancers. Two Phase II studies in heavily pretreated ovarian and recurrent endometrial cancers showed good clinical activity after a maximum of six courses of AEZS-108 as a single agent. Ongoing clinical studies with AEZS-108 in men with castration-resistant prostate cancer and patients with chemotherapy refractory bladder cancer had shown early signs of clinical efficacy. Side effects are moderate and easily manageable. In particular, no pituitary or cardiac toxicity is observed. EXPERT OPINION: AEZS-108 is a cytotoxic analog designed for receptor-mediated targeted chemotherapy and consists of an LHRH carrier linked to doxorubicin. Preclinical studies demonstrate that the uptake of AEZS-108 is achieved by receptor-mediated endocytosis. Results of Phase I and II clinical trials in patients with gynecological cancers demonstrated anticancer activity without cardiotoxicity even in highly pretreated patients. Phase I/II studies in castration-resistant prostate cancer and chemotherapy refractory bladder cancer are in progress. Targeted chemotherapy with a cytotoxic analog of LHRH, such as AEZS-108, is therefore being considered for Phase III studies in advanced endometrial cancers positive for LHRH receptor. LHRH receptors are also present in human colon cancers, melanomas, lymphomas, and sarcomas, and treatment of these cancers with AEZS-108 should also be undertaken. Before such treatment with AEZS-108 is begun, the status of tumoral LHRH receptors of patients must be determined.

Surgery in recurrent ovarian cancer: the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) DESKTOP OVAR trial.

BACKGROUND: The role of cytoreductive surgery in relapsed ovarian cancer is not clearly defined. Therefore, patient selection remains arbitrary and depends on the center's preference rather than on established selection criteria. The Descriptive Evaluation of preoperative Selection KriTeria for OPerability in recurrent OVARian cancer (DESKTOP OVAR) trial was undertaken to form a hypothesis for a panel of criteria for selecting patients who might benefit from surgery in relapsed ovarian cancer. METHODS: The DESKTOP trial was an exploratory study based on data from a retrospective analysis of hospital records. Twenty-five member institutions of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Committee (AGO OC) and AGO-OVAR boards collected data on their patients with cytoreductive surgery for relapsed invasive epithelial ovarian cancer performed in 2000-2003. RESULTS: Two hundred and sixty-seven patients were included. Complete resection was associated with significantly longer survival compared with surgery leaving any postoperative residuals [median 45.2 vs. 19.7 months; hazard ratio (HR) 3.71; 95% confidence interval (CI) 2.27-6.05; P < .0001]. Variables associated with complete resection were performance status (PS) [Eastern Cooperative Oncology Group (ECOG) 0 vs. > 0; P < .001], International Federation of Gynecology and Obstetrics (FIGO) stage at initial diagnosis (FIGO I/II vs. III/IV, P = .036), residual tumor after primary surgery (none vs. present, P <.001), and absence of ascites > 500 ml (P < .001). A combination of PS, early FIGO stage initially or no residual tumor after first surgery, and absence of ascites could predict complete resection in 79% of patients. CONCLUSIONS: Only complete resection was associated with prolonged survival in recurrent ovarian cancer. The identified criteria panel will be verified in a prospective trial (AGO-DESKTOP II) evaluating whether it will render a useful tool for selecting the right patients for cytoreductive surgery in recurrent ovarian cancer.

Targeted deletion of murine coagulation factor XII gene-a model for contact phase activation in vivo.

To analyze the biological role of factor XII (FXII, Hageman Factor) in vivo, we generated mice deficient for FXII using a gene targeting approach on two distinct genetic backgrounds, i.e. mixed C57Bl/6J X 129X1/SvJ and inbred 129X1/SvJ. Homozygous FXII knockout (FXII(-)/(-)) mice showed no FXII plasma activity and had a markedly prolonged activated partial thromboplastin time (aPTT). In contrast, coagulation factors XI, VIII, IX, X,VII, V, II and fibrinogen did not differ between FXII(-/-) mice and their wild-type littermates. Heterozygous matings segregated according to the Mendelian inheritance indicating that FXII deficiency does not increase fetal loss. Furthermore, matings of FXII(-/-) males and FXII(-/-) females resulted in normal litter sizes demonstrating that total FXII deficiency in FXII(-/-) females does not affect pregnancy outcome. Also, gross and histological anatomy of FXII(-/-) mice was indistinguishable from that of their wild-type littermates on both genetic backgrounds. Thus it appears that deficiency of murine FXII does not cause thrombophilia or impaired fibrinolysis in vivo. These results indicate that FXII deficiency does not affect hemostasis in vivo and we anticipate that the FXII(-/-) mice will be helpful to elucidate the biological role(s) of FXII in health and disease.