Cancer Treatment Reviews

Melanoma-associated antigen A4: A cancer/testis antigen as a target for adoptive T-cell receptor T-cell therapy

Induction chemotherapy followed by chemoradiotherapy for locally advanced cervical cancer: A systematic review and meta-analysis

The addition of induction chemotherapy (ICT) prior to concomitant chemoradiotherapy (CCRT) in the treatment of locally advanced cervical cancer (LACC) is controversial, as trials have yielded conflicting results. This study aims to evaluate the role of ICT followed by CCRT in LACC. We systematically searched PubMed, Embase and Cochrane for studies with patients diagnosed with LACC receiving ICT followed by CCRT. Studies that included surgery, definitive radiotherapy (without concurrent chemotherapy), or immunotherapy were excluded. Among 5,282 screened studies, 20 met the inclusion criteria, representing 1,543 patients treated with ICT. A meta-analysis of the five controlled studies exhibited high heterogeneity in progression-free survival (PFS) and overall survival (OS), driven by the CIRCE trial - a study employing a platinum-gemcitabine ICT regimen lasting > 6 weeks. Sensitivity analysis excluding this trial demonstrated a significant improvement in PFS (HR 0.46; 95 % CI 0.31-0.69; p = 0.0002) and OS (HR 0.68; 95 % CI 0.47-0.99; p = 0.049) with the addition of ICT to CCRT, compared to CCRT alone. Meta-analysis of proportions revealed a 2-year OS of 84.1 % for studies utilizing platinum-paclitaxel compared to 72.2 % for platinum-gemcitabine (p-value for subgroup difference = 0.022). Studies with ICT duration of ≤ 6 weeks showed a 2-year OS of 84.8 % compared to 71.7 % for ICT duration > 6 weeks (p = 0.003). In patients with LACC, ICT + CCRT significantly improves PFS and OS compared to CCRT alone, provided that the ICT involves a platinum doublet with paclitaxel and is administered within ≤ 6 weeks.

First-line treatment of locally advanced cervical carcinoma: An updated systematic review and Bayesian network meta-analysis

Locally advanced cervical carcinoma (LACC) remains a significant global health issue, particularly in low- and middle-income countries (LMICs), where disease burden is highest. While cisplatin-based chemoradiotherapy (CTRT) has long been the cornerstone of first-line treatment, its toxicities, including nephrotoxicity and hematologic adverse events, limit its use in certain patients. Advances in systemic therapies, including immune checkpoint inhibitors and induction chemotherapy, offer new avenues for improving outcomes. This study aimed to evaluate the efficacy of various first-line regimens for LACC through a systematic review and Bayesian network meta-analysis (NMA), focusing on overall survival (OS) and progression-free survival (PFS). This analysis adhered to PRISMA guidelines and included Phase III randomized controlled trials (RCTs) evaluating first-line treatments for LACC. The primary outcome was OS, expressed as hazard ratios (HRs) with 95% confidence intervals (CIs), while PFS was secondary. A comprehensive search of PubMed, EMBASE, and Cochrane Library was conducted through November 2024. Statistical analysis used a Bayesian NMA framework, with treatments ranked by surface under the cumulative ranking curve (SUCRA). Pembrolizumab + CTRT improved OS (HR, 0.67; 95 % CI, 0.50-0.90), while induction chemotherapy with carboplatin/paclitaxel followed by CTRT showed significant benefit (HR, 0.60; 95 % CI, 0.40-0.90). RT + cisplatin and 5-fluorouracil (5-FU) also improved OS (HR, 0.66; 95 % CI, 0.44-0.99), ranking highest in SUCRA analysis (98 %). Three promising strategies-pembrolizumab-based regimens, induction chemotherapy followed by CTRT, and RT + CDDP + 5-FU-offer substantial survival benefits, advancing treatment options for LACC.

Treatments for relapsed, BRCA-wild type, platinum-sensitive ovarian cancer: A systematic review and network meta-analysis

Although platinum-based chemotherapy (CT) is considered the standard treatment for relapsed platinum-sensitive ovarian cancer, there is currently no standard treatment for these patients. We compared the effectiveness of modern and older therapies in relapsed platinum-sensitive, BRCA-wild type, and ovarian cancers using a network meta-analysis (NMA). A systematic search of PubMed, EMBASE, and Cochrane Library was performed up to October 31, 2022. Randomized controlled trials (RCT) that compared different second-line approaches were included. The primary endpoint was overall survival (OS) and the secondary endpoint was progression-free survival (PFS). In total, 17 RCTs (n = 9405) comparing various strategies were included. The risk of death was significantly decreased with carboplatin + pegylated liposomal doxorubicin + bevacizumab compared to platinum-based doublet CT (hazard ratio [HR] = 0.59, 95%CI 0.35, 1). Various strategies, including secondary cytoreduction followed by platinum-based CT, carboplatin + pegylated liposomal doxorubicin + bevacizumab, and platinum-based CT with bevacizumab or cediranib, were better than platinum-based doublets alone for PFS. This NMA showed that carboplatin + pegylated liposomal doxorubicin + bevacizumab seems to increase the efficacy of standard second-line CT. These strategies can be considered when treating patients with relapsed platinum-sensitive ovarian cancer without BRCA mutations. This study provides systematic comparative evidence for the efficacy of different second-line therapies for relapsed ovarian cancer.

Locally advanced and metastatic endometrial cancer: Current and emerging therapies

Until recently, patients diagnosed with locally advanced and metastatic endometrial cancer faced significant challenges in their treatment due to limited options and poor prognostic outcomes. The sequencing of tumors has been a major advancement in its management. It has led to The Cancer Genome Atlas classification currently used in clinical practice and the initiation of several clinical trials for innovative treatments targeting principally signaling pathways, immune checkpoints, DNA integrity, growth factors, hormonal signaling, and metabolism. Numerous clinical trials are investigating a combinatorial approach of these targeted therapies to counter tumoral resistance, cellular compensatory mechanisms, and tumor polyclonality. This review provides a comprehensive overview of historical, current, and promising therapies in advanced and metastatic endometrial cancer. It particularly highlights clinical research on targeted and hormonal therapies, but also immunotherapy, reflecting the evolving landscape of treatment modalities for this disease.

Therapeutic options following second-line platinum-based chemotherapy in patients with recurrent ovarian cancer: Comparison of active surveillance and maintenance treatment

Most women with advanced ovarian cancer respond to initial treatment, consisting of surgical resection and ≈6 cycles of platinum-based chemotherapy. However, disease recurrence occurs in most patients, and subsequent therapies become necessary. Historically, close monitoring following treatment (active surveillance) was the only available option, as continued maintenance chemotherapy treatment led to increased toxicity without providing any meaningful clinical benefit. Recently, targeted therapy with the angiogenesis inhibitor bevacizumab and the poly(ADP-ribose) polymerase (PARP) inhibitors olaparib, niraparib, and rucaparib have demonstrated significant clinical benefits as maintenance treatment for recurrent disease. Despite consensus guidelines recommending their use, maintenance treatments are currently underutilized. Here, we review evidence from pivotal clinical trials of approved second-line maintenance treatments demonstrating efficacy in terms of progression-free survival and postprogression efficacy outcomes for patients with recurrent ovarian cancer. Adverse events frequently associated with bevacizumab include hypertension, proteinuria, and non-central nervous system bleeding, whereas PARP inhibitors are associated with nausea, vomiting, fatigue, and anemia. Patient-centered outcomes analyses show that PARP inhibitors provide significant benefits to patient health status, even when accounting for the toxicities associated with treatment. Many factors influence the selection of second-line maintenance treatment for patients with recurrent ovarian cancer, including the maintenance treatment received in the first-line setting. Overall, targeted maintenance treatment represents a new standard of care for patients with ovarian cancer, and we recommend that maintenance treatment should be offered to all eligible patients with recurrent ovarian cancer.

Incorporating Parp-inhibitors in Primary and Recurrent Ovarian Cancer: A Meta-analysis of 12 phase II/III randomized controlled trials

The second decade of 2000s is witnessing a new ovarian cancer (OC) paradigm shift thanks to the results recently obtained by a new class of targeted agents: the Poly(ADP-ribose)polymerase (PARP)-Inhibitors (PARPi). Aim of this meta-analysis is to analyze available results obtained with PARPi, administered alone or in combination with chemo- and/or target-therapies in terms of efficacy and safety for the treatment of recurrent and primary advanced OC. On December 2019, all published phase II/III randomized clinical studies were systematically searched using the terms "[Parp-Inhibitor] AND [ovar*]". Twelve phase II/III randomized controlled trials were identified, with a total number of 5171 patients included. Results demonstrated that PARPi account for a significant improvement of PFS in both recurrent and primary OC setting, independently from their administration schedule and independently from patients' BRCA mutational status. Moreover, patients harboring a Homologous Recombination Deficiency (HRD) positive testing primary or recurrent OC progress significantly later after PARPi administration/association. Results also reported that PARPi increase the occurrence of severe (G3-G4) anemia. Furthermore, severe fatigue occurred more frequently among patients subjected to PARPi combined with chemotherapy and to PARPi plus Bevacizumab. Finally, a significant increase in severe high blood pressure occurrence was observed when PARPi was added to antiangiogenetics, compared to PARPi alone but a significant decrease in G3-G4 hypertension occurrence was found in PARPi plus bevacizumab users compared to Bevacizumab alone. PARPi are a valid option for the treatment of both primary and relapsed OC patients, with a relative low incidence of severe side effects.

PARP-inhibitors in epithelial ovarian cancer: Actual positioning and future expectations

Poly-(ADP)-ribose polymerase inhibitors (PARPi) are a class of oral anticancer drugs first developed as "synthetically lethal" in cancers harboring BRCA1/BRCA2 inactivating mutations. In high-grade serous or endometrioid ovarian cancers (HGOC), PARPi demonstrated benefit as maintenance therapy in relapsing BRCA-mutated and non-mutated tumors. Recently, they extended their indications to frontline maintenance therapy. This review summarizes the current place of PARPi (i) as maintenance or single agent in recurrent disease and (ii) frontline maintenance with different settings. We reviewed the course of biomarker identification, the challenge of overcoming resistance to PARPi and future combinations with targeted therapies, including anti-angiogenic, immune checkpoint inhibitors and DNA damage response inhibitors.

HPV vaccination and HPV-related malignancies: impact, strategies and optimizations toward global immunization coverage

HPV-related diseases represent a major cause of morbidity and mortality, although effective HPV vaccines are available, potentially allowing for the elimination of these malignancies. Historically, most of the available literature has focused on cervical cancer, the fourth commonest cause of cancer-related death worldwide, whose incidence is heterogeneous mirroring the inequitable distribution of facilities for screening and treatment and vaccination programs. A broader vision of HPV vaccination impact is needed to understand the potential effect of a global high immunization coverage on both cervical cancer and other HPV-associated malignancies, in women and men. Five HPV vaccines are currently available, all inducing antibody response against the most frequent high-risk HPV types (HPV16 and 18). They are safe and strongly reduce the incidence of HPV-related diseases in clinical trials and in real-world studies, among both women and men. Therefore, WHO has set an ambitious goal for the global elimination of cervical cancer. The WHO global strategy has been launched to accomplish this goal and is supported by multiple organizations, governments, and donors, aiming at vaccinating 90% of young girls worldwide by 2030. In this setting, it is vital to optimize vaccination programs, with a focus on delivery approaches, target populations, increasing financial support, and awareness. In conclusion,HPV vaccination is safe and effective and can lead to the first case of cancer elimination worldwide. A sustained joint effort is fundamental for this goal to be reached, with optimization of this strategy and adaptation of vaccination programs to country-specific infrastructure.

Immunotherapy with anti-PD-1 or PD-L1 in advanced ovarian cancer: A meta-analysis of randomized trials

Ovarian cancer remains the gynecological malignancy with the highest mortality rate. Despite advances in treatment, the median overall survival remains suboptimal. Although there is strong biological rationale for the use of immune checkpoint inhibitors (ICIs), their clinical efficacy in ovarian cancer remains uncertain. This study aimed to evaluate the effectiveness of anti-PD-1/PD-L1 agents in advanced ovarian cancer by reviewing randomized trials. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs). Data sources included PubMed, EMBASE, the Cochrane Library, and major conference abstracts, with searches conducted up to July 1, 2025. Eligible studies included RCTs comparing anti-PD-1/PD-L1 agents (with or without chemotherapy) to standard treatments in patients with advanced ovarian cancer (first-line, platinum-sensitive, or platinum-resistant). Trials with fewer than 50 patients or non-randomized designs were excluded. Two authors independently extracted summary-level data. The primary outcome measure was progression-free survival (PFS) in the intention-to-treat population. A random-effects model was used to estimate pooled hazard ratios (HRs). Risk of bias was assessed using the Cochrane RoB 2 tool. (Supplementary, Fig. S1) The meta-analysis was registered with PROSPERO (CRD420251112816). Ten RCTs (n = 7,847 patients) met the inclusion criteria. Overall, ICIs did not significantly improve PFS compared to control treatments (HR 0.98, 95% CI 0.85-1.12; I Anti-PD-1/PD-L1-based ICI strategies have not led to significant improvements in outcomes for ovarian cancer. Future studies should focus on optimizing biomarker selection, evaluating combination therapies, and targeting the tumor microenvironment to enhance the efficacy of immunotherapy. This research received no external funding.

Revisiting ovarian function suppression with GnRH agonists for premenopausal women with breast cancer: Who should use and the impact on survival outcomes

Integration of immunotherapy into treatment of cervical cancer: Recent data and ongoing trials

Cervical cancer constitutes a significant health burden for women globally. While most patients with early-stage disease can be cured with radical surgery or chemoradiotherapy, patients with high-risk locally advanced disease or with recurrent/metastatic disease have a poor prognosis with standard treatments. Immunotherapies are a rational treatment for this HPV-driven cancer that commonly expresses programmed cell death ligand-1. Before 2021, pembrolizumab was the only United States Food and Drug Administration-approved immunotherapy in cervical cancer, specifically for the second-line recurrent or metastatic (r/m) setting. In late 2021, the antibody-drug conjugate tisotumab vedotin was approved for second-line r/m cervical cancer and pembrolizumab combined with chemotherapy ± bevacizumab was approved for first-line r/m disease based on results from KEYNOTE-826. Moreover, with at least 2 dozen additional immunotherapy clinical trials in the second-line and first-line r/m setting, as well as in locally advanced disease, the treatment landscape for cervical cancer may eventually encounter a potential paradigm shift. Pivotal trials of immunotherapies for cervical cancer that were recently approved or with the potential for regulatory consideration through 2024 are reviewed. As immunotherapy has the opportunity to establish new standards of care in the treatment of cervical cancers, new biomarkers to identify the ideal patient populations for these therapies may also become important. However, issues with access, affordability, and compliance in low- and middle-income countries are anticipated.

Overview of BH3 mimetics in ovarian cancer

Ovarian carcinoma is the leading cause of gynecological cancer-related death, still with a dismal five-year prognosis, mainly due to late diagnosis and the emergence of resistance to cytotoxic and targeted agents. Bcl-2 family proteins have a key role in apoptosis and are associated with tumor development/progression and response to therapy in different cancer types, including ovarian carcinoma. In tumors, evasion of apoptosis is a possible mechanism of resistance to therapy. BH3 mimetics are small molecules that occupy the hydrophobic pocket on pro-survival proteins, allowing the induction of apoptosis, and are currently under study as single agents and/or in combination with cytotoxic and targeted agents in solid tumors. Here, we discuss recent advances in targeting anti-apoptotic proteins of the Bcl-2 family for the treatment of ovarian cancer, focusing on BH3 mimetics, and how these approaches could potentially offer an alternative/complementary way to treat patients and overcome or delay resistance to current treatments.

Advances in treatment strategies for low-grade serous ovarian cancer

Low-grade serous ovarian carcinoma (LGSOC) represents a unique therapeutic challenge in gynecologic oncology. While it accounts for a minority of epithelial ovarian cancers (EOC), its distinct molecular landscape and limited sensitivity to conventional chemotherapy underscore the urgent need for alternative treatment paradigms. Over the past decade, advances in genomic profiling have led to a deeper understanding of its biology, revealing recurrent alterations in key signaling pathways such as (mitogen-activated protein kinase) MAPK, PI3K, and cell cycle regulators. These insights have catalyzed a shift toward precision medicine, with targeted agents and endocrine strategies emerging as promising avenues. However, despite encouraging signals from clinical trials, the rarity of LGSOC continues to hinder the development of robust, evidence-based standards. In this review, we critically examine the current treatment landscape and explore evolving therapeutic strategies, including ongoing efforts to integrate molecular biomarkers into clinical decision-making. By synthesizing recent evidence and highlighting key areas of unmet need, this review aims to provide a forward-looking perspective on the treatment of LGSOC. Future progress will depend on collaborative research, biomarker-driven clinical trial design, and a commitment to tailoring therapy based on the unique biology of this rare tumor type.

Engineering strategies to optimise adoptive cell therapy in ovarian cancer

Ovarian cancer is amongst the ten most common cancer types in women, and it is one of the leading causes of death. Despite the promising results of targeted therapies, including anti-angiogenic agents and poly (ADP-ribose) polymerase inhibitors (PARPi), the majority of patients will relapse and develop treatment resistance, implying that novel therapeutic strategies are required. Adoptive cell therapy (ACT) refers to the process by which autologous immune cells are used to eliminate cancer. Examples include tumour infiltrating lymphocytes (TILs), T cells genetically engineered with T cell receptors (TCR), or chimeric antigen receptor (CAR)-T cells. Recently, ACT has revealed promising results in the treatment of haematological malignancies, however, its application to solid tumours is still limited due to lack of functionality and persistence of T cells, prevalence of an exhausted phenotype and impaired trafficking towards the tumour microenvironment (TME). In this review we explore the potential of ACT for the treatment of ovarian cancer and strategies to overcome its principal limitations.

Recent advancements of antiangiogenic combination therapies in ovarian cancer

Ovarian cancer is a deadly malignancy with a growing therapeutic armamentarium, though achieving sustained benefit in the clinic remains largely elusive. Through biomarker and genetic analysis, several pathways of resistance and sensitivity to commonly used therapeutics have been identified, expanding the potential of identifying unique drug combinations and indicating new directions for improving clinical outcomes. Here, we review the mechanisms of angiogenic response and antiangiogenic therapy in ovarian cancer, as well as the interactions it exhibits with the immune and DNA damage response pathways. We discuss results from clinical trials examining the combinations of antiangiogenics, PARP inhibitors, and immune checkpoint inhibitors are also discussed, as well as several ongoing trials.

Exploiting somatic alterations as therapeutic targets in advanced and metastatic cervical cancer

It is estimated that 604,127 patients were diagnosed with cervical cancer worldwide in 2020. While a small percentage of patients will have metastatic disease at diagnosis, a large percentage (15-61%) later develop advanced disease. For this cohort, treatment with systemic chemotherapy remains the standard of care, with a static 5-year survival rate over the last thirty years. Data on targetable molecular alterations in cervical cancer have lagged behind other more common tumor types thus stunting the development of targeted agents. In recent years, tumor genomic testing has been increasingly incorporated into our clinical practice, opening the door for a potential new era of personalized treatment for advanced cervical cancer. The interim results from the NCI-MATCH study reported an actionability rate of 28.4% for the cervical cancer cohort, suggesting a subset of patients may harbor mutations which that are targetable. This review sets out to summarize the key targeted agents currently under exploration either alone or in combination with existing treatments for cervical cancer.

Immunotherapy in cervix cancer

The treatment approach to cervix cancer has remained unchanged for several decades and new therapeutic strategies are now required to improve outcomes, as the prognosis is still poor. In the last years, a better understanding of HPV tumor-host immune system interactions and the development of new therapeutics targeting immune checkpoints generated interest in the use of immunotherapy in cervix cancer. Preliminary phase I-II trials demonstrated the efficacy, the duration of responses and the manageable safety of this approach. Currently, many phase II and III studies are ongoing in both locally advanced and metastatic cervical cancer, assessing immunotherapy as a single agent or in combination with chemotherapy and radiotherapy. We reviewed the published data and the therapeutic implications of the most promising novel immunotherapeutic agents under investigation in cervix cancer.

Survival and toxicity in neoadjuvant chemotherapy plus surgery versus definitive chemoradiotherapy for cervical cancer: A systematic review and meta-analysis

Neoadjuvant chemotherapy followed by surgery (NACT + S) has been compared with definitive chemoradiothherapy (CRT) in randomized clinical trials (RCTs) in stage IB2, IIA and IIB cervical cancer (1994 Figo stage). Our aim was to evaluate efficacy and toxicity of NACT + S and CRT and identify differences in clinical outcomes and severe toxicity frequency. The PRISMA statement was applied. Random-effects models were used. Two RCTs representing 1259 patients were identified. NACT + S was not associated with significant OS improvement compared with CRT, with HR of 1.08 (95% CI = 0.86-1.36; p = 0.51). The HR of relapse was 1.32 (95%CI = 1.07-1.62) in favor of CRT. Severe acute toxicity was lower in CRT group. This meta-analysis showed similar OS rates between treatment and CRT superiority over NACT + S in terms of DFS and severe acute toxicity. Impact on long term toxicity and quality of life remain to be proven.

Phase III placebo-controlled oncology trials in the last decade: evolution, methodological foundations, and clinical impact

KELIM score: A marker of chemosensitivity in ovarian cancer

Ovarian cancer is the gynecological cancer with the worst prognosis and the highest mortality rate, primarily because 75% of patients are diagnosed with advanced FIGO stage III-IV disease. About 50% of patients are now treated with neoadjuvant chemotherapy followed by interval debulking surgery. In that context, there is a need for accurate predictors of tumor primary chemosensitivity, as it may impact the feasibility of subsequent interval debulking surgery. The cancer antigen 125 ELIMination rate constant K (KELIM) score, a modeled kinetic parameter, is a potential marker of tumor chemosensitivity in patients with ovarian cancer treated with adjuvant or neoadjuvant chemotherapy before interval debulking surgery. This review aims to provide a comprehensive overview of potential predictive factors for response to platinum therapy, focusing on the KELIM score, a marker increasingly used in clinical practice.

Clearer Horizons: The latest advances in clear cell ovarian cancer treatment

This review aims to consolidate the current understanding of Clear Cell Ovarian Carcinoma (CCOC), a rare yet distinct subtype of epithelial ovarian cancer. CCOC exhibits unique epidemiological, clinical and molecular features, being one of the most frequent subtypes in East Asia, often diagnosed at an early stage and frequently affecting younger women. Its hallmark characteristics include high resistance to conventional chemotherapy, poor prognosis in advanced stage and a molecular profile distinct from high-grade serous histotype. Specifically, CCOC is characterized by a low prevalence of TP53 mutations, BRCA1/2 mutations and homologous-recombination deficiency, but a high frequency of ARID1A, along with other SWI/SNF alterations, and PIK3CA mutations, both of which represent promising therapeutic targets. Despite the absence of validated therapies for CCOC so far, significant advancements in preclinical research and emerging clinical strategies including immunotherapy combinations offer hope for improved outcomes. Given the rarity of this cancer type, collaborative research and global partnerships have enabled robust studies and the implementation of trials with innovative personalized therapeutic approaches. The objective of this report is to explore the epidemiology, clinical and molecular characteristics, current standard of care and evolving therapeutic strategies for CCOC patients. It will not only highlight the progress made so far, but most importantly identifies critical research priorities to optimizing patient outcomes.

A systematic review of phase I trials in patients with ovarian cancer

Ovarian cancer (OC) is the leading cause of death among gynecological malignancies, with limited treatment options for advanced and platinum-resistant disease. This systematic review analyzes phase I trials to assess recent therapeutic advancements. We performed a systematic review of phase I trials in OC, published between 2012 and 2023, retrieving data on trial characteristics and outcomes. Studies were classified according to the tested treatment strategies into chemotherapy-only (CO), chemotherapy + non-chemotherapy agents (CNC) and chemotherapy-free (CF). 78 trials were included, with more than 50 % of them published in the last four years. Overall, chemotherapy and immunotherapy were the most investigated agents. Fourteen trials (17.9 %) evaluated a CO strategy, 42 (53.8 %) a CNC combination and 22 (28.2 %) a CF therapy. Dose-limiting toxicities and toxic deaths were observed in 71 % and 100 % of CO studies, in 45.2 % and 21 % of CNC trials and in 37.4 % and 13.6 % of CF trials, respectively. CNC regimens outperformed the other treatment types in terms of efficacy outcomes, including overall response rate (11.5 % CO; 32.2 % CNC; 25.5 % CF), clinical benefit rate (40 % CO; 62 % CNC; 52 % CF) and median progression free survival (mPFS 5.9 months CO; 6.45 months CNC; 4.85 months CF). Trials enrolling platinum resistant or agnostic patients displayed worse clinical outcomes. In the last years, there has been an increasing number of phase 1 trials assessing new agents and new combinations in patients with OC. Chemotherapy-free strategies display a more favorable safety profile, while regimens combining CNC agents seem to be more effective compared to CO approaches.

Ovarian escape in premenopausal breast cancer: Challenges and strategies for optimizing hormone suppression

Optimal bevacizumab treatment strategy in advanced ovarian cancer: A review

Bevacizumab was the first targeted therapy developed for newly diagnosed and recurrent advanced ovarian cancer (AOC). Although bevacizumab has been approved for the treatment of AOC for several years, identifying patients who may benefit most from this treatment is still debated. Bevacizumab has been associated with improved progression-free survival (PFS) regardless of clinical risk, but in some countries the use of bevacizumab in the treatment of newly diagnosed AOC has been restricted to higher-risk patients (stage III inoperable or suboptimally debulked disease, or stage IV disease); this is primarily due to the findings of exploratory subgroup analyses from phase III trials that suggest only higher-risk patients derive an overall survival (OS) advantage with bevacizumab. Recently reported post hoc analyses from the PAOLA-1 trial of maintenance olaparib plus bevacizumab versus bevacizumab alone for patients with newly diagnosed AOC and homologous recombination deficiency-positive tumors suggested PFS and OS benefit was achieved in both lower-risk (with stage III disease who had undergone upfront surgery and had complete resection) and higher-risk (with stage III disease who had undergone upfront surgery and had residual disease or who had received neoadjuvant chemotherapy, or with stage IV disease) patients, prompting reassessment of the role of bevacizumab in lower-risk patients. This review examines the role of bevacizumab in the AOC treatment pathway by discussing its efficacy and safety in the first-line, maintenance and recurrent settings, and evaluates the clinical implications of bevacizumab use across risk groups and lines of therapy.

Assessing risks and knowledge gaps on the impact of systemic therapies in early breast cancer on female fertility: A systematic review of the literature

Primary or adjuvant chemoradiotherapy for cervical cancer with intraoperative lymph node metastasis – A review

Upon discovery of lymph node metastasis during radical hysterectomy with pelvic lymphadenectomy in early-stage cervical cancer, the gynaecologist may pursue one of two treatment strategies: abandonment of surgery followed by primary (chemo)radiotherapy (PRT) or completion of radical hysterectomy, followed by adjuvant (chemo)radiotherapy (RHRT). Current guidelines recommend PRT over RHRT, as combined treatment is presumably associated with increased morbidity. However, this review of literature suggests there are no significant differences in survival and recurrence and total proportions of adverse events between treatment strategies. Additionally, both strategies are associated with varying types of adverse events, and affect quality of life and sexual functioning differently, both in the short and long term. Although total proportions of adverse events were comparable between treatment strategies, lower extremity lymphoedema was reported more often after RHRT and symptom experience (e.g. distress from bladder or bowel problems) and sexual dysfunction more often after PRT. As reporting of adverse events, quality of life and sexual functioning were not standardised across the articles included, and covariate adjustment was not conducted in most of the analyses, comparability of studies is hampered. Accumulating retrospective evidence suggests no major differences on oncological outcome and morbidity after PRT and RHRT for intraoperatively discovered lymph node metastasis in cervical cancer. However, conclusions should be considered cautiously, as all studies were of retrospective design with small sample sizes. Still, treatment strategies seem to affect adverse events, quality of life and sexual functioning in different ways, allowing room for shared decision-making and personalised treatment.

The role of the tumor primary chemosensitivity relative to the success of the medical-surgical management in patients with advanced ovarian carcinomas

In patients with advanced ovarian carcinomas, the first-line treatment has historically relied on debulking surgery and platinum-based chemotherapy. If the major therapeutic/prognostic role of the surgery part is well understood, and integrated in disease-management algorithms, the impact of chemotherapy efficacy has been insufficiently addressed. This review describes the main indicators of the chemosensitivity reported in the literature (pathological response score & biomarkers; genomic alterations; DNA scars; imaging; and circulating tumor markers), and investigates the respective roles of the debulking surgery and tumor primary chemosensitivity relative to the success of the comprehensive medical-surgical treatment. The tumor primary chemosensitivity exhibits a major independent prognostic impact on the feasibility of complete interval debulking surgery after neoadjuvant chemotherapy, risk of subsequent platinum-resistant relapse, efficacy of subsequent maintenance therapies with bevacizumab or PARP inhibitors, progression-free survival, overall and long-term survival. While both the completeness of the surgery and the tumor primary chemosensitivity are undoubtedly major prognostic factors, the impact of the surgery may differ according to the primary chemosensitivity. This assumption raises a potential new concept: in patients with advanced ovarian carcinomas, the maximum tumor debulking should ideally be both biological (induced by systemic treatments) and physical (induced by surgery) for maximizing patient survival. Besides BRCA and HRD biomarkers, future trials and algorithms may integrate indicator(s) of the tumor primary chemosensitivity for guiding more subtly the surgical and medical management in first-line setting. Moreover, such a parameter would help in the development of novel approaches meant to reverse the resistance to chemotherapy and PARP inhibitors.

Practical clinical management of ocular adverse events related to Antibody-Drug Conjugates in gynaecological malignancies

The advent of Antibody-Drug Conjugates (ADC) represents a significant advancement in targeted therapy for gynaecological malignancies. However, the ocular toxicities associated with ADCs, particularly Tisotumab Vedotin (TV) and Mirvetuximab Soravtansine (MIRV) necessitate effective mitigation in order to optimise patient care. This review synthesises findings from clinical trials to delineate the spectrum of ocular adverse events induced by ADCs. The analysis focuses on the incidence, onset, severity and reversibility of adverse events. It examines the underlying mechanisms of toxicity and provides management strategies based on study protocols. Adverse events mainly impact the anterior ocular segment, resulting in conjunctivitis and keratopathy. They affect up to 56 % of patients treated with MIRV and 50 to 60 % of those receiving TV. Symptoms like blurred vision, dryness and pain hinder the patient's quality of life. Events are CTCAE grade 3 or higher in less than 10 % of cases. The median time to onset is 1.3 months. However, ocular toxicity may appear up to 10 months after treatment initiation, indicating a need for prolonged vigilance. Primary prophylaxis calls for local corticotherapy, lubricants and in some cases, vasoconstrictors. Despite the potential for severity, most cases are reversible with local treatment and transient dose reduction and/or delay. Close monitoring is crucial for early detection and subsequent management. Clinicians ought to be cognizant of the potential ocular toxicity of ADCs. Proactive prophylaxis, patient education and a multidisciplinary approach involving ophthalmologists are paramount to minimising the impact of these AEs. Further research is essential to measure the real outcome of preventive strategies and balance their benefits with potential short and long-term risks.

Low grade serous ovarian cancer – A rare disease with increasing therapeutic options

High-grade serous ovarian cancers (HGSOCs) most commonly arise from the fimbrial end of the fallopian tube and harbor TP53 gene mutations. In contrast, low-grade serous ovarian cancers (LGSOCs) appear to have different pathological, epidemiological, and clinical features and should be seen as a distinct serous epithelial ovarian cancer subtype. Our current understanding of LGSOC is limited, and treatment has generally been derived from the more common HGSOCs due to a lack of separate trial data. LGSOCs are characterized by slow tumor growth and are assumed to develop from serous borderline ovarian tumors as precursors. These cancers are often estrogen-receptor positive and show an activated mitogen-activated protein kinase pathway together with KRAS and BRAF mutations and, rarely, TP53 mutations. These characteristics are now commonly used to guide therapeutical decision making and, consequently, a substantial part of treatment consists of maintenance with endocrine treatment, thus balancing disease stabilization and mild toxicity. Additionally, new trials are ongoing that examine the role of targeted therapies such as MEK inhibitors in combination with endocrine treatments. The purpose of this work is to summarize current knowledge and present ongoing trial efforts for LGSOCs.

Targeting NaPi2b in ovarian cancer

Novel biomarkers are needed to direct new treatments for ovarian cancer, a disease for which the standard of care remains heavily focused on platinum-based chemotherapy. Despite the success of PARP inhibitors, treatment options are limited, particularly in the platinum-resistant setting. NaPi2b is a cell surface sodium-dependent phosphate transporter that regulates phosphate homeostasis under normal physiological conditions and is a lineage marker that is expressed in select cancers, including ovarian, lung, thyroid, and breast cancers, with limited expression in normal tissues. Based on its increased expression in ovarian tumors, NaPi2b is a promising candidate to be studied as a biomarker for treatment and patient selection in ovarian cancer. In preclinical studies, the use of antibodies against NaPi2b showed that this protein can be exploited for tumor mapping and therapeutic targeting. Emerging data from phase 1 and 2 clinical trials in ovarian cancer have suggested that NaPi2b can be successfully detected in patient biopsy samples using immunohistochemistry, and the NaPi2b-targeting antibody-drug conjugate under evaluation appeared to elicit therapeutic responses. The aim of this review is to examine literature supporting NaPi2b as a novel biomarker for potential treatment and patient selection in ovarian cancer and to discuss the critical next steps and future analyses necessary to drive the study of this biomarker and therapeutic targeting forward.

AMH as a marker for resumption of ovarian function after chemotherapy: an IPD meta-analysis and systematic review

Emerging molecular alterations leading to histology-specific targeted therapies in ovarian cancer beyond PARP inhibitors

After more than 30 years of a one-size-fits-all approach in the management of advanced ovarian cancer, in 2018 the SOLO1 trial results have introduced a new era of personalized medicine. A deeper knowledge of ovarian cancer biology and the development of new drugs targeting specific molecular pathways have led to biomarker-driven phase 3 trials with practice changing results. Thereafter, platinum-based combinations are no longer the only therapeutic options available in first line setting and poly-ADP ribose polymerase inhibitors maintenance therapy has become the mainstay in patients with tumor harboring a homologous recombination defect. However, most of the recent therapeutic breakthroughs regard high grade serous carcinoma, the most frequent ovarian cancer subtype, and only few improvements have occurred in the management of less common histotypes. Moving towards the next challenges, we aimed to investigate and review new potential molecular targets in ovarian cancer, according to histotype, starting from promising molecular drivers and matched drugs that have been investigated in early and late-stage clinical trials or conceptualized in preclinical studies.

Targeting the PI3K pathway and DNA damage response as a therapeutic strategy in ovarian cancer

Ovarian cancer is the most lethal gynecological malignancy worldwide although exponential progress has been made in its treatment over the last decade. New agents and novel combination treatments are on the horizon. Among many new drugs, a series of PI3K/AKT/mTOR pathway (referred to as the PI3K pathway) inhibitors are under development or already in clinical testing. The PI3K pathway is frequently upregulated in ovarian cancer and activated PI3K signaling contributes to increased cell survival and chemoresistance. However, no significant clinical success has been achieved with the PI3K pathway inhibitor(s) to date, reflecting the complex biology and also highlighting the need for combination treatment strategies. DNA damage repair pathways have been active therapeutic targets in ovarian cancer. Emerging data suggest the PI3K pathway is also involved in DNA replication and genome stability, making DNA damage response (DDR) inhibitors as an attractive combination treatment for PI3K pathway blockades. This review describes an expanded role for the PI3K pathway in the context of DDR and cell cycle regulation. We also present the novel treatment strategies combining PI3K pathway inhibitors with DDR blockades to improve the efficacy of these inhibitors for ovarian cancer.

PARP inhibitors for metastatic castration-resistant prostate cancer: Biological rationale and current evidence

Poly(ADP-ribose) polymerase inhibitors (PARPi) are the first clinically approved agents designed to exploit synthetic lethality. Based on the recent approvals, PARPi became available for patients with metastatic castration-resistant prostate cancer (mCRPC). Unlike breast or ovarian cancers, where the approvals are limited to patients with BRCA1/2 alterations, in mCRPC PARPi are offered to patients with a broader spectrum of aberrations. A growing body of data indicates that alterations in specific homologous recombination repair (HRR) genes may confer different sensitivities to PARPi. Another challenging issue is the optimal testing methodology for identifying these aberrations. This comprehensive review presents the current place of PARPi in the treatment of mCRPC, provide biological rationale explaining mechanisms of their action and resistance, and discuss current clinical challenges along with avenues for future research.

Challenges and advances in cervix cancer treatment in elder women

With population ageing, cancer treatments in elder patients is becoming a true public health care issue. There is an authentic dilemma between patient's frailty, residual life expectancy and the toll that take anticancer treatments. Since elder patients are almost always excluded from clinical trials, it is hard to get robust scientific data on the tolerability of oncologic treatments and to set in place recommendations. Cervix cancer is traditionally diagnosed in younger women but it has a 2nd incidence peak between 60 and 70 years old. Cervix cancer in elder patients is a subject to many questions in terms of screening and is a therapeutic challenge. This article reviews literature data on these different aspects, from screening to surgery, from radiotherapy to brachytherapy, from chemotherapy to supportive care, from immunotherapy to geriatric assessment. We tried to show how modern therapeutic innovations may benefit elder patients. Expected benefits in terms of efficacy and toxicity may overcome the long-lasting tendency to undertreatment in elder patients and improve their quality of life after cancer treatment. In 2020, there seems to be less and less reasons justifying that elder women with cervix cancer may not receive the appropriate treatment.

Theranostic biomarkers and PARP-inhibitors effectiveness in patients with non-BRCA associated homologous recombination deficient tumors: Still looking through a dirty glass window?

Breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2) deleterious variants were the first and, still today, the main biomarkers of poly(ADP)ribose polymerase (PARP)-inhibitors (PARPis) benefit. The recent, increased, numbers of individuals referred for counseling and multigene panel testing, and the remarkable expansion of approved PARPis, not restricted to BRCA1/BRCA2-Pathogenic Variants (PVs), produced a strong clinical need for non-BRCA biomarkers. Significant limitations of the current testing and assays exist. The different approaches that identify the causes of Homologous Recombination Deficiency (HRD), such as the germline and somatic Homologous Recombination Repair (HRR) gene PVs, the testing showing its consequences, such as the genomic scars, or the novel functional assays such as the RAD51 foci testing, are not interchangeable, and should not be considered as substitutes for each other in clinical practice for guiding use of PARPi in non-BRCA, HRD-associated tumors. Today, the deeper knowledge on the significant relationship among all proteins involved in the HRR, not limited to BRCA, expands the possibility of a successful non-BRCA, HRD-PARPi synthetic lethality and, at the same time, reinforces the need for enhanced definition of HRD biomarkers predicting the magnitude of PARPi benefit.

Molecular characterization as new driver in prognostic signatures and therapeutic strategies for endometrial cancer

Endometrial cancer (EC) incidence and mortality rates have been increasing, particularly among young females. Although more than 90% of ECs are sporadic, 5-10% are hereditary, a majority of which occurs within Hereditary Non-Polyposis Colorectal Cancer syndrome (HNPCC) or Lynch syndrome. The traditional histopathological classification differentiates EC between two main groups: type I (or endometrioid) and type II (including all other histopathological subtypes). However, this classification lacks reproducibility and does not account for the emerging molecular heterogeneity. In 2013, The Cancer Genome Atlas (TCGA) project proposed EC molecular classification defining four groups with different prognostic and predictive values and the current international guidelines are progressively establishing EC risk stratification and treatment based on both histopathological and molecular criteria. Our manuscript aims to summarize the current state of EC molecular characterizations, including germline alterations at the basis of hereditary EC predisposition, to discuss their clinical utility as prognostic and predictive markers.

Incorporation of anti-PD1 or anti PD-L1 agents to platinum-based chemotherapy for the primary treatment of advanced or recurrent endometrial cancer. A meta-analysis

Various randomized trials have explored the efficacy of combining immune checkpoint inhibitors (ICIs) with first-line chemotherapy in advanced endometrial cancer. We aimed to summarize available data and clarify the benefit of adding immunotherapy according to the DNA mismatch repair status (deficient, dMMR or proficient, pMMR) and the specific type of agent used (anti-PD1 or anti-PD-L1). To assess whether the addition of ICIs to standard platinum-based chemotherapy enhances progression-free survival (PFS) for patients with advanced endometrial cancer both overall and based on DNA mismatch repair status. Electronic databases (PubMed, Embase and Cochrane Library) and conference proceedings were searched for first line, randomized and controlled trials integrating ICIs with chemotherapy for the treatment of advanced endometrial cancer published or presented by November 1, 2023. Five studies, comprising 2456 patients (1308 received ICIs with chemotherapy and 1148 treated with chemotherapy alone) met the selection criteria and were included in the analysis. Experimental arms included pembrolizumab, dostarlimab (anti-PD1) and durvalumab, atezolizumab and avelumab (anti-PD-L1) combined with standard three-weekly carboplatin-paclitaxel chemotherapy backbone. Endometrial carcinosarcoma were included in 3 out of 5 trials. For comparison of PFS outcomes, extrapolation of hazard ratios (HRs), 95% confidence intervals (CI) and PFS events was performed for each included study in the overall population and according to subgroups. Data analysis was conducted using a random-effects model. The addition of ICIs to chemotherapy improved PFS compared to chemotherapy alone in the overall population (pooled HR, 0.63; 95 % CI, 0.52--0.76; P <.001). In the dMMR subgroup the benefit was more pronounced (pooled HR, 0.34; 95 % CI, 0.27--0.44; P <.001) and not affected by drugs used with pooled HRs of 0.39 (95 % CI, 0.28--0.55; P <.001) and 0.34 (95 % CI, 0.27--0.44; P <.001) for PD-L1 and PD1 inhibitors, respectively. For pMMR patients, a statistically significant benefit in terms of PFS was confirmed only when anti-PD1 were used (anti-PD-1: HR 0.64, 95 % CI: 0.46-0.90, P =.010 vs anti-PD-L1: HR 0.87, 95 % CI: 0.73-1.03, P =.104) CONCLUSIONS AND RELEVANCE: This meta-analysis confirmed the advantage in terms of PFS of adding ICIs to standard platinum-based chemotherapy. While dMMR patients benefit from the incorporation of both anti PD-1 or anti PD-L1, this benefit is confined to the association of anti-PD1 agents in pMMR patients. Updated analysis of trials is awaited to clarify the impact of immunotherapy on overall survival.