Federica Martorana

Can we learn from failures? A systematic review of phase III trials in platinum-resistant ovarian cancer

This systematic review analyzed phase III trials in platinum-resistant ovarian cancer to understand their poor outcomes and guide future trials. A systematic review adhering to PRISMA guidelines was conducted. PubMed/Medline, Cochrane Library CENTRAL, and EMBASE were searched for randomized phase III trials (2010-January 2024) involving patients with platinum-resistant ovarian cancer. Fifteen studies (5,468 patients) were included. Platinum resistance was defined by the interval between last platinum administration and recurrence/progression. Heterogeneity existed in defining platinum-refractory patients. Experimental arms included chemotherapy (4 trials), immune checkpoint inhibitors, anti-angiogenic agents, targeted agents, or antibody-drug conjugates (2 trials each), and others (3 trials). Control arms consistently used single-agent chemotherapy (paclitaxel, gemcitabine, pegylated liposomal doxorubicin, or topotecan). Only four trials had biomarker-selected populations. Most trials (except TRINOVA1, AURELIA, and MIRASOL) showed no progression-free survival benefit. Only MIRASOL had statistically significant overall survival improvement. Negative outcomes likely stem from various factors, including inconsistent platinum resistance definitions, inadequate control arm benchmarks, and suboptimal biomarker use. A deeper understanding of tumor biology and its integration into trial design is crucial to enhance drug development in this patient population, aiming for improved efficacy while preserving quality of life.

A review and metanalysis of metronomic oral single-agent cyclophosphamide for treating advanced ovarian carcinoma in the era of precision medicine

Objective Oral metronomic cyclophosphamide has been used as a single agent or in combination with other drugs for several solid tumors with interesting results in disease palliation and mild to moderate toxicity, notably in patients with recurrent epithelial ovarian cancer (EOC) progressing after systemic chemotherapy. In this paper, we report a review and a metanalysis of heterogeneous data published up to date. Data sources The literature search was restricted to single-agent MOC. The analysis was conducted through March 2023 by consulting PubMed, Embase, Google Scholar, and The Cochrane Library databases. Research string and Medical Subject Headings included “ovarian tumor,” “ovarian carcinoma,” or “ovarian cancer,” “fallopian tube cancer,” “primary peritoneal cancer,” “oral chemotherapy,” and “metronomic cyclophosphamide.” All articles were assessed for quality by at least two investigators independently, and a < 18 patients sample size cutoff was chosen as a lower limit with a Cohen's kappa statistical coefficient for accuracy and reliability. Metanalysis of selected papers was carried out according to a fixed model. Data summary The percentage of agreement between investigators on literature study selection was very high, reaching 96.9% with a Cohen's k of 0.929. MOC pooled objective response rate (ORR) and disease control rate for recurrent or platinum-refractory ovarian cancer were 18.8% (range 4–44%) and 36.2% (range 16–58.8%), respectively. The mean progressive-free survival and overall survival were 3.16 months (range 1.9 to 5.0 months) and 8.7 months (range 8 to 13 months), respectively. The fixed model metanalysis of selected studies showed a 16% median ORR (12–20% CI, p < 0.001). Conclusions Single-agent oral cyclophosphamide in EOC holds promise as a treatment option, even in the era of precision medicine. Genetic factors, such as DNA repair gene polymorphisms, may influence treatment response. Combining cyclophosphamide with biological agents such as PARP inhibitors or immunotherapy agents is an area of active investigation.

Entangled Connections: HIV and HPV Interplay in Cervical Cancer—A Comprehensive Review

Cervical cancer (CC) remains a prevalent malignancy and a significant global public health concern, primarily driven by persistent human papillomavirus (HPV) infections. The infectious nature of HPV underscores the preventability of CC through vaccination and screening programs. In addition to HPV, factors such as age, parity, smoking, hormonal contraceptives, and HIV co-infection elevate the risk of CC. HIV-associated immunodeficiency exacerbates susceptibility to infections and cancers, making CC a defining condition for acquired immune deficiency syndrome (AIDS) and one of the most commonly diagnosed cancers among women living with HIV (WLWH). These women face higher risks of HPV exposure due to sexual behavior and often encounter economic, social, and psychological barriers to screening. HIV and HPV co-infection can potentially accelerate CC carcinogenesis, with WLWH typically being diagnosed with CC earlier than their HIV-negative counterparts. Antiretroviral therapy (ART), which reduces AIDS-related mortality, also lowers the risk of invasive CC. The interaction between HIV and HPV is intricate and bidirectional. This summary reviews current evidence on HPV infection and CC in WLWH, highlighting the connections across pathogenesis, prevention, diagnosis, and treatment.

A retrospective, real-life analysis of metronomic oral single-agent cyclophosphamide for the treatment of platinum-pretreated advanced ovarian carcinoma in Italy

Introduction Metronomic oral cyclophosphamide (MOC) presents many potential advantages, such as significantly less severe side effects than standard regimens, ease of administration, and the delivery of a dose-dense but not necessarily dose-intense treatment. These observations prompted us to evaluate in a retrospective, multicenter study the efficacy and toxicity of MOC in a real-life series of pretreated cancer patients. Methods The study is a multicenter, retrospective analysis of the activity of single-agent MOC in patients with recurrent or residual epithelial ovarian, fallopian tube, or primary. Eligible patients were continuously treated with MOC at 50 mg/day until progression, toxicity, or death. Overall response rate (ORR), stable disease (SD), and disease control rate (DCR) were reported. Results The study included 62 patients. Three patients reached a complete response rate (5%), 11 had a partial response rate (18), and 15 had stabilization of disease (24) for an ORR of 23% and a DCR of 47%. Patients with low-grade indolent tumors showed an ORR and an SD rate higher than that observed in non-indolent ones (33% vs. 18% and 28% vs. 14%, respectively). Overall, progression-free survival was 3.5 months (range 1–9 months). Conclusion Single-agent MOC is active and very well tolerated in a significant fraction of patients with refractory, recurrent, or residual epithelial ovarian, fallopian tube, or primary peritoneal cancer. In the vision of a practical approach, single-agent MOC may be a useful palliative treatment option for patients with poor tolerance to high-dose regimens or widely pretreated. Further studies are needed better to characterize the role of such an approach in clinical practice.

The Consistency and Quality of ChatGPT Responses Compared to Clinical Guidelines for Ovarian Cancer: A Delphi Approach

Introduction: In recent years, generative Artificial Intelligence models, such as ChatGPT, have increasingly been utilized in healthcare. Despite acknowledging the high potential of AI models in terms of quick access to sources and formulating responses to a clinical question, the results obtained using these models still require validation through comparison with established clinical guidelines. This study compares the responses of the AI model to eight clinical questions with the Italian Association of Medical Oncology (AIOM) guidelines for ovarian cancer. Materials and Methods: The authors used the Delphi method to evaluate responses from ChatGPT and the AIOM guidelines. An expert panel of healthcare professionals assessed responses based on clarity, consistency, comprehensiveness, usability, and quality using a five-point Likert scale. The GRADE methodology assessed the evidence quality and the recommendations’ strength. Results: A survey involving 14 physicians revealed that the AIOM guidelines consistently scored higher averages compared to the AI models, with a statistically significant difference. Post hoc tests showed that AIOM guidelines significantly differed from all AI models, with no significant difference among the AI models. Conclusions: While AI models can provide rapid responses, they must match established clinical guidelines regarding clarity, consistency, comprehensiveness, usability, and quality. These findings underscore the importance of relying on expert-developed guidelines in clinical decision-making and highlight potential areas for AI model improvement.