Primary cytoreductive surgery followed by chemotherapy has been considered standard management for patients with advanced ovarian cancer over decades. An alternative approach of interval debulking ...surgery following neoadjuvant chemotherapy was subsequently reported by two randomized phase III trials (EORTC-GCG, CHORUS), which were criticized owing to important limitations, especially regarding the rate of complete resection.
To clarify the optimal timing of surgical therapy in advanced ovarian cancer.
Primary cytoreductive surgery is superior to interval cytoreductive surgery following neoadjuvant chemotherapy for overall survival in patients with advanced ovarian cancer.
TRUST is an international open, randomized, controlled multi-center trial investigating overall survival after primary cytoreductive surgery versus neoadjuvant chemotherapy and subsequent interval cytoreductive surgery in patients with FIGO stage IIIB-IVB ovarian, tubal, and peritoneal carcinoma. To guarantee adequate surgical quality, participating centers need to fulfill specific quality assurance criteria (eg, ≥50% complete resection rate in upfront surgery for FIGO IIIB-IVB patients, ≥36 debulking-surgeries/year) and agree to independent audits by TRUST quality committee delegates. Patients in the primary cytoreductive surgery arm undergo surgery followed by 6 cycles of platinum-based chemotherapy, whereas patients in the interval cytoreductive surgery arm undergo 3 cycles of neoadjuvant chemotherapy after histologic confirmation of the disease, followed by interval cytoreductive surgery and subsequently, 3 cycles of platinum-based chemotherapy. The intention of surgery for both groups is complete tumor resection according to guideline recommendations.
Major inclusion criteria are suspected or histologically confirmed, newly diagnosed invasive epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal carcinoma FIGO stage IIIB-IVB (IV only if resectable metastasis). Major exclusion criteria are non-epithelial ovarian malignancies and borderline tumors; prior chemotherapy for ovarian cancer; or abdominal/pelvic radiotherapy.
Overall survival.
772 patients.
Accrual completion approximately mid-2019, results are expected after 5 years' follow-up in 2024.
NCT02828618.
Abstract Objective Since almost two decades standard 1st-line chemotherapy for advanced ovarian cancer (AOC) has been a platinum/taxane combination. More recently, this general strategy has been ...challenged because different types of AOC may not benefit homogenously. Low-grade serous ovarian cancer (LGSOC) is one of the candidates in whom efficacy of standard chemotherapy should be revised. Methods This study is an exploratory case control study of the AGO-metadatabase of 4 randomized phase III trials with first-line platinum combination chemotherapy without any targeted therapy. Patients with advanced FIGO IIIB IV low-grade serous ovarian cancer were included and compared with control cases having high-grade serous AOC. Results Out of 5114 patients in this AGO database 145 (2.8%) had LGSOC and of those thirty-nine (24.1%) had suboptimal debulking with post-operative residual tumor > 1 cm, thus being eligible for response evaluation. An objective response was observed in only 10 patients and this 23.1% response rate (RR) was significantly lower compared to 90.1% RR in the control cohort of high-grade serous ovarian cancer (HGSOC) (p < 0.001). Both, LGSOC and HGSOC patients who underwent complete cytoreduction had significantly better progression free survival (PFS) and overall survival (OS) in comparison to those with residuals after primary surgery, accordingly (p < 0.001). Conclusions Our observation indicates that low-grade serous cancer is not as responsive to platinum-taxane-based chemotherapy as high-grade serous AOC. In contrast, surgical debulking showed a similar impact on outcome in both types of AOC thus indicating different roles for both standard treatment modalities. Systemic treatment of low grade serous AOC urgently warrants further investigations.
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.
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.
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.
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.
Primary surgery followed by platinum/taxane-based chemotherapy is the standard therapy in advanced ovarian cancer. The prognostic role of complete debulking has been well described; however, the ...impact of systematic pelvic and para-aortic lymphadenectomy and its interaction with biologic factors are still not fully defined.
This was an exploratory analysis of three prospective randomized trials (Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom trials 3, 5, and 7) investigating platinum/taxane-based chemotherapy regimens in advanced ovarian cancer conducted between 1995 and 2002.
One thousand nine hundred twenty-four patients were analyzed. Lymphadenectomy was associated with superior survival in patients without gross residual disease. In patients with and without lymphadenectomy, the median survival time was 103 and 84 months, respectively, and 5-year survival rates were 67.% and 59.2%, respectively (P = .0166); multivariate analysis confirmed a significant impact of lymphadenectomy on overall survival (OS; hazard ratio HR = 0.74; 95% CI, 0.59 to 0.94; P = .0123). In patients with small residual tumors up to 1 cm, the effect of lymphadenectomy on OS barely reached significance (HR = 0.85; 95% CI, 0.72 to 1.00; P = .0497). For patients with small residual tumors and clinically suspect nodes, lymphadenectomy resulted in a 16% gain in 5-year OS (log-rank test, P = .0038).
Lymphadenectomy in advanced ovarian cancer might offer benefit mainly to patients with complete intraperitoneal debulking. However, this hypothesis should be confirmed in the context of a prospectively randomized trial.
The DESKTOP I trial proposed a score for the prediction of complete cytoreduction in recurrent ovarian cancer. Resectability was assumed if 3 factors were present: (1) complete resection at first ...surgery, (2) good performance status, and (3) absence of ascites. The DESKTOP II trial was planned to verify this hypothesis prospectively in a multicenter setting.
Participating centers prospectively enrolled all consecutive patients with platinum-sensitive first or second relapse. The score was applied to all patients, but centers were free to decide on therapy. All further therapies were documented, and the outcome of patients was analyzed. A 75% complete resection rate in 110 prospectively classified patients had to be achieved to confirm a positive predictive value of 2 or higher of 3 with 95% probability.
A total of 516 patients were screened within 19 months; of these, 261 patients (51%) were classified as score positive, and 129 patients with a positive score and first relapse were operated on. The rate of complete resection was 76%, thus confirming the validity of this score regarding positive prediction of complete resectability in 2 or more of 3 patients. Complication rates were moderate including second operations in 11% and perioperative mortality in 0.8%.
This score is the first prospectively validated instrument to positively predict surgical outcome in recurrent ovarian cancer. It can aid in the selection of patients who might benefit from secondary cytoreductive surgery and will be enrolled in the recently started randomized prospective DESKTOP III trial investigating the role of surgery in recurrent platinum-sensitive ovarian cancer.
Immunosuppression including high-dose calcineurin inhibitors (CNI) is essential after lung transplantation. Dosing is usually guided by therapeutic drug monitoring adjusted to target trough levels of ...CNIs to keep the balance between over-dose causing severe toxicity and increased risk of infections or under-dose with a risk of graft injury. Adaptation of CNI-based immunosuppression by monitoring of torque teno virus (TTV), a latent nonpathogenic DNA virus, measured in the whole blood in addition to conventional therapeutic drug monitoring may reduce the toxicity of immunosuppression with similar efficacy.
An open-label, randomized, controlled, parallel-group, multicenter trial in lung transplant recipients will be conducted to investigate the safety and efficacy of immunosuppression guided by TTV monitoring as an add-on to conventional therapeutic drug monitoring. Adult lung transplant recipients 21 to 42 days after transplantation are eligible to participate. Patients (N = 144) will be randomized 1:1 to the experimental intervention (arm 1: immunosuppression guided by TTV monitoring in addition to conventional therapeutic drug monitoring of tacrolimus trough levels) and control intervention (arm 2: conventional therapeutic drug monitoring). Outcomes will be assessed 12 months after randomization with the change in glomerular filtration rate as the primary endpoint. Secondary endpoints will be additional measurements of renal function, allograft function, incidence of acute rejections, incidence of chronic lung allograft dysfunction, graft loss, and infections.
The results of this randomized controlled trial may reduce the toxicity of immunosuppression after lung transplantation while maintaining the efficacy of immunosuppression. Study results are transferable to all other solid organ transplantations.
ClinicalTrials.gov NCT04198506 . Registered on 12 December 2019.
A high percentage of epithelial ovarian cancers (EOC) express the estrogen receptor (ER), which is an ideal target for endocrine therapy. Letrozole is a proven, potent aromatase inhibitor, ...extensively tested and used in the treatment of ER positive breast cancer. In addition, it seems a potent drug for patients with heavily pre-treated OC as demonstrated in several distinctive settings. However, it has never been evaluated prospectively in a maintenance setting for ovarian cancer after standard of care. The here proposed trial aims to define a population of EOC patients, who would benefit from the effectiveness of the generic agent letrozole, with little expected toxicity and thus beneficial impact on overall quality of life (QoL).
In this international multicenter randomized, placebo-controlled phase III trial at clinical centers in Switzerland, Germany and Austria, we plan to include 540 patients with primary, newly diagnosed FIGO Stage II to IV and histologically confirmed low- or high-grade serous or endometrioid epithelial ovarian/fallopian tube/peritoneal cancer. Patients are randomized in a 1:1 ratio into two groups: receiving blinded study treatment (letrozole or placebo tablets). When assuming a HR of 0.7, a median PFS of 18 months in the control arm and a median PFS of 25.7 months in the treatment arm, a two-sided alpha level of 5%, 3.5 years recruitment and 1.5 years observation time, we expect 330 events to have occurred within these 5 years in the total cohort yielding a power of 90%. Follow-up data for the whole cohort will be collected for up to 10 years and for the low-grade cancer for up to 12 years.
The here proposed randomized phase III trial aims to identify patients with EOC in the maintenance setting, who benefit from the effectiveness of the letrozole, by proving its efficacy whilst maintaining a high standard of QoL due to the limited toxicity expected in comparison to the current alternative drugs on the market for this treatment phase.
This trial is registered at clinicaltrials.gov under the identifier NCT04111978 . Registered 02 October 2019.
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