Quality of therapy in early ovarian cancer: results of the quality assurance program of the AGO Study Group.

OBJECTIVE: The quality assurance program for ovarian cancer (QS-OVAR) evaluates the implementation of treatment standards and impact on survival for International Federation of Gynecology and Obstetrics (FIGO) stage I ovarian cancer. METHODS: Patients with a first diagnosis of ovarian cancer, diagnosed in the third quarter of 2004, 2008, 2012, and 2016, were documented. Surgical quality was categorized as optimal (maximum one surgical item missing) versus suboptimal (≥2 surgical items missing). Chemotherapy was defined as optimal according to national guidelines. Treatment quality was classified into four categories: surgery and chemotherapy were optimal, optimal surgery and suboptimal chemotherapy, suboptimal surgery and optimal chemotherapy, and surgery and chemotherapy were suboptimal. RESULTS: In total, 19.9% (n=700) of ovarian cancer patients were diagnosed with FIGO stage I. Median age was 60 years (range 18-96), 47.1% had FIGO stage IA and 47.9% had stage IC, with 37.1% high grade serous histology. Optimal surgical quality increased over time from 19.9% to 54.1%. The optimal surgery population increased from 42.2% to 70.9%. Disease free survival improved significantly in the optimal surgery population (84% after 48 months vs 71% in the suboptimal surgery population). Overall survival increased with 91% after 48 months in the optimal surgery population versus 76% in the suboptimal surgery population. In total, 20.7% of patients were undertreated concerning systemic treatment and 1% overtreated. Optimal chemotherapy standard was administered increasingly over time (71.4-80.8%). Disease free survival and overall survival were prolonged with adjuvant chemotherapy. The optimal surgery/chemotherapy subgroup increased from 37.9% to 54.1% with significantly longer disease free survival and overall survival (overall survival at 48 months: optimal surgery and chemotherapy 93%; suboptimal surgery and chemotherapy 68%). CONCLUSION: Although QS-OVAR data showed that the quality of therapy has improved over the years, not all surgical standards were met in nearly 50% of patients. The steady increase in the optimal surgery and chemotherapy collective is an important tool for improvement of prognosis of ovarian cancer patients.

Prevalence of deleterious germline variants in risk genes including BRCA1/2 in consecutive ovarian cancer patients (AGO-TR-1).

BACKGROUND: Identification of families at risk for ovarian cancer offers the opportunity to consider prophylactic surgery thus reducing ovarian cancer mortality. So far, identification of potentially affected families in Germany was solely performed via family history and numbers of affected family members with breast or ovarian cancer. However, neither the prevalence of deleterious variants in BRCA1/2 in ovarian cancer in Germany nor the reliability of family history as trigger for genetic counselling has ever been evaluated. METHODS: Prospective counseling and germline testing of consecutive patients with primary diagnosis or with platinum-sensitive relapse of an invasive epithelial ovarian cancer. Testing included 25 candidate and established risk genes. Among these 25 genes, 16 genes (ATM, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, NBN, PMS2, PTEN, PALB2, RAD51C, RAD51D, STK11, TP53) were defined as established cancer risk genes. A positive family history was defined as at least one relative with breast cancer or ovarian cancer or breast cancer in personal history. RESULTS: In total, we analyzed 523 patients: 281 patients with primary diagnosis of ovarian cancer and 242 patients with relapsed disease. Median age at primary diagnosis was 58 years (range 16-93) and 406 patients (77.6%) had a high-grade serous ovarian cancer. In total, 27.9% of the patients showed at least one deleterious variant in all 25 investigated genes and 26.4% in the defined 16 risk genes. Deleterious variants were most prevalent in the BRCA1 (15.5%), BRCA2 (5.5%), RAD51C (2.5%) and PALB2 (1.1%) genes. The prevalence of deleterious variants did not differ significantly between patients at primary diagnosis and relapse. The prevalence of deleterious variants in BRCA1/2 (and in all 16 risk genes) in patients <60 years was 30.2% (33.2%) versus 10.6% (18.9%) in patients ≥60 years. Family history was positive in 43% of all patients. Patients with a positive family history had a prevalence of deleterious variants of 31.6% (36.0%) versus 11.4% (17.6%) and histologic subtype of high grade serous ovarian cancer versus other showed a prevalence of deleterious variants of 23.2% (29.1%) and 10.2% (14.8%), respectively. Testing only for BRCA1/2 would miss in our series more than 5% of the patients with a deleterious variant in established risk genes. CONCLUSIONS: 26.4% of all patients harbor at least one deleterious variant in established risk genes. The threshold of 10% mutation rate which is accepted for reimbursement by health care providers in Germany was observed in all subgroups analyzed and neither age at primary diagnosis nor histo-type or family history sufficiently enough could identify a subgroup not eligible for genetic counselling and testing. Genetic testing should therefore be offered to every patient with invasive epithelial ovarian cancer and limiting testing to BRCA1/2 seems to be not sufficient.

Communicating BRCA research results to patients enrolled in international clinical trials: lessons learnt from the AGO-OVAR 16 study.

BACKGROUND: The focus on translational research in clinical trials has the potential to generate clinically relevant genetic data that could have importance to patients. This raises challenging questions about communicating relevant genetic research results to individual patients. METHODS: An exploratory pharmacogenetic analysis was conducted in the international ovarian cancer phase III trial, AGO-OVAR 16, which found that patients with clinically important germ-line BRCA1/2 mutations had improved progression-free survival prognosis. Mechanisms to communicate BRCA results were evaluated, because these findings may be beneficial to patients and their families. RESULTS: Communicating individual BRCA results was not anticipated during clinical trial design. Consequently, options were not available for patients to indicate their preference for receiving their individual results when they signed pharmacogenetic informed consent. Differences in local requirements, clinical practice, and opinion regarding the ethical aspects of how to convey genetic results to patients are all potential barriers to returning individual BRCA results to patients. Communicating the aggregate BRCA result from this study provided clinical investigators with a mechanism to disseminate the overall study finding to patients while taking individual circumstances, local guidelines and clinical practice into account. CONCLUSION: This study illustrates the importance of increasing the clarity and scope of informed consent and the need for patient engagement to ensure clinical trial participants can indicate their preference regarding receipt of potentially important individual pharmacogenetic results. TRIAL REGISTRATION: This study was registered in the NCT Clinical Trial Registry under NCT00866697 on March 19, 2009, following approval from participating ethics committees (Additional file 1).

Addition of vandetanib to pegylated liposomal doxorubicin (PLD) in patients with recurrent ovarian cancer. A randomized phase I/II study of the AGO Study Group (AGO-OVAR 2.13).

BACKGROUND: PLD is a standard treatment in patients with recurrent platinum-resistant or refractory ovarian cancer. Vandetanib is an oral once daily administered inhibitor of VEGFR-, EGFR- and RET-signaling with activity in combination with chemotherapy in some solid tumours. We aimed to establish a feasible combination therapy of PLD and vandetanib in ovarian cancer. METHODS: Eligible patients were treated with PLD 50 mg/m(2) q28 and vandetanib 100 mg/d po. It was planned to recruit at least 10 patients evaluable for toxicity over 2 treatment cycles. Primary endpoints were tolerability and safety; secondary endpoint was efficacy. RESULTS: Fourteen of 15 registered patients started treatment and were evaluable for toxicity. Three patients (21%) stopped after first cycle (PD, withdrawal of consent, nausea/vomiting). The remaining 11 patients were treated for at least 2 cycles. Dose reductions of PLD and vandetanib were indicated in 4 (29%) and 5 patients (36%), respectively. The following G3/4 toxicities occurred per patient: 2 (14%) elevated liver enzymes G3, 2 (14%) neutropenia G3/4, 5 (36%) PPE G3/4, 2 (14%) mucositis G3. Tyrosine kinase inhibitor attributed side effects like hypertension or bowel perforations were not reported. Toxicity led to cessation of treatment in 4 patients (29%). Ten patients were evaluable for response: PR 1, SD 4. The median PFS was 6.7 months and median OS was 11.1 months. CONCLUSIONS: The combination of PLD 50 mg/m(2)q28 and vandetanib 100 mg/d is feasible, but may be intolerable due to reported toxicity.

Roadmap for the European Network of Gynaecological Trial groups (ENGOT) Trials.

The European Network for Gynaecological Oncological Trial groups (ENGOT) is a research network of the European Society of Gynaecological Oncology and was founded in Berlin in October 2007. Earlier, we reported on the ENGOT minimal requirements for trials between academic groups and pharmaceutical companies. In this paper, we summarize the roadmap for performing trials in the ENGOT framework. In this roadmap, we define how an ENGOT trial should be set up and discuss the following items: What are the conditions to classify a study as an ENGOT trial? What is an ENGOT protocol? How are an ENGOT protocol, informed consent (ICF), and case report form (CRF) produced? How is the center selection and feasibility performed in ENGOT trials? How are regulatory and operational tasks handled? How should a confidentiality agreement between the industry and the whole ENGOT network be negotiated? How are contracts made between the industry and ENGOT and between ENGOT groups? How are funding, insurance, and communication flow arranged in ENGOT trials? What are the requirements for conducting substudies and what are the tasks for the leading group in an ENGOT trial? A template of a confidentiality agreement, a checklist of ENGOT criteria for new study proposals, and guidelines for authorship are also provided.