Current Treatment Options in Oncology

Current Treatment Options: Uterine Sarcoma

The cornerstone of treatment for uterine sarcoma, regardless of histologic type, remains en bloc surgical resection with total hysterectomy. In the case of incidental diagnosis during another procedure, such as myomectomy, where a hysterectomy was not performed initially, completion hysterectomy or cervical remnant removal is recommended. The completion of additional surgical procedures, including bilateral salpingo-oophorectomy and lymphadenectomy, remains nuanced. Bilateral salpingo-oophorectomy remains controversial in the setting of most subtypes of uterine sarcoma, except in the case of hormone-receptor positivity, such as in low grade endometrial stromal sarcoma, where it is indicated as part of definitive surgical treatment. In the absence of apparent nodal involvement, we do not recommend performing universal lymphadenectomy for patients with sarcoma. We recommend systemic therapy for patients with extra-uterine or advanced stage disease, high-grade histology, and recurrence. The most active chemotherapy regimens for advanced, high-grade disease remain doxorubicin or gemcitabine and docetaxol combination therapy. A notable exception is low grade endometrial stromal sarcoma, where we recommend anti-hormonal therapy in the front-line setting. Radiation therapy is reserved for selected cases where it can aid in palliating symptoms.

Management of Stage IVB Cervical Cancer Including the Role of Radiotherapy

The treatment of stage IVB cervical cancer is undergoing a paradigm shift, moving beyond palliation toward strategies that may improve survival rates in select patients. Radiation therapy is a key component of this shift, not only for local control, but also for enhancing systemic treatment efficacy and improving survival time. Stereotactic body radiation therapy (SBRT) for oligometastatic disease and image-guided brachytherapy improve tumor control while minimizing toxicity. The incorporation of immune checkpoint inhibitors into frontline therapy represents a significant advancement, particularly for PD-L1-positive tumors. However, durable responses remain a challenge, necessitating continued research into novel biomarkers and combination therapies. Personalized treatment approaches, integrating molecular profiling and adaptive therapy strategies, are essential for optimizing outcomes. Future clinical trials should evaluate the synergy between radiation and immunotherapy in order to refine curative approaches in stage IVB cervical cancer.

Frontiers of Ovarian Carcinosarcoma

Opinion statementOvarian carcinosarcoma (OCS), also known as a malignant mixed Müllerian tumour (MMMT), is a rare and aggressive form of cancer that accounts for less than 5% of ovarian cancers. It is characterized by high morbidity and mortality rates, with a median overall survival (OS) of less than 2 years. Several factors, including advancing age, nulliparity, reduced lactation rates, decreased use of oral contraceptive pills, genetic mutations in BRCA (breast cancer) genes, and the use of assisted reproductive technology, may increase the risk of OCS. Poor prognostic factors include an advanced stage at diagnosis, older age, lymph node metastasis, suboptimal surgical cytoreduction, the presence of heterologous features on histopathology, and increased expression of vascular endothelial growth factor (VEGF), tumour protein p53, and p53 alongside Wilms tumour 1 (WT1). The main treatment approach for OCS is cytoreductive surgery followed by platinum-based chemotherapy, although immunotherapy is showing promise. Homologous recombination deficiency (HRD) testing may enhance outcomes by enabling personalized immunotherapy and targeted therapies for specific patient groups, thereby reducing unnecessary side effects and healthcare costs. However, there is currently a lack of standardised treatment regimens for OCS patients, with most studies consisting of case reports and a shortage of suitable comparator groups. This article aims to provide clinicians with information on the epidemiology, risk factors, prognostic factors, and latest therapeutic advancements in OCS.

Recurrent Treatment in Ovarian Cancer Patients: What Are the Best Regimens and the Order They Should Be Given?

The choice of the right treatment regimen for recurrent ovarian cancer (rOC) remains a case-by-case decision. It is based on multiple factors that involve patient characteristics and biological factors at the same time. The prioritization of factors is still subject to changes with a trend towards a more personalized medicine. Therefore, participation and engagement in clinical studies constitutes a substantial need for the future development of the treatment algorithm of rOC.

Review of Bone Metastasis in Gynecologic Malignancies: Evaluation and Treatment

Metastatic bone disease (MBD) is a significant source of morbidity and mortality in cancer patients with solid tumors, including those with gynecologic malignancies. Infiltration of tumor cells within the bone microenvironment disrupts bone homeostasis and leads to osteoblastic, osteolytic, or mixed bone lesions. Greater than two thirds of those with MBD experience cancer-induced bone pain (CIBP) and one to two-thirds will develop a skeletal-related event (SRE). Various pharmacologic, surgical, and radiation treatments exist for the palliation of bone metastases and the prevention of SREs. It is paramount to understand the diagnostic evaluation and evidence-based treatment paradigms of bone metastases to decrease healthcare utilization, alleviate financial burden, mitigate disability, and improve quality of life.

Contemporary Review of Adenocarcinoma of the Cervix

Among cervical cancers, adenocarcinoma is less common than squamous cell carcinoma of the cervix; however, the incidence of these cancers is rising. The incidence has changed largely due to a shift in risk factors as well as the evolution of the diagnosis and classification of adenocarcinoma. Adenocarcinoma of the cervix is composed of a diverse group of neoplasms that can be classified by various factors. In this review article, preinvasive disease, updated classifications of adenocarcinoma, and treatment options for cervical adenocarcinoma are discussed with a focus on current and future therapies. Advances in antibody-drug conjugates (ADC) and immunotherapy have increased the treatment options available for usual-type adenocarcinoma but there is still a lack of variety of treatment options for the remaining 25% of non-usual-type adenocarcinomas.

Navigating PARP Inhibitor Resistance in Ovarian Cancer: Bridging Mechanistic Insights To Clinical Translation

PARP inhibitors (PARPi) are increasingly vital in treating, particularly in individuals exhibiting homologous recombination deficiency (HRD), harnessing synthetic lethality to target tumor cells. However, PARPi resistance severely restricts their sustained efficacy, posing a significant clinical obstacle requiring a detailed exploration of its mechanisms and solutions. This review elucidates the underlying mechanisms of PARPi resistance, assesses biomarker-driven predictive tools, and explores novel strategies to improve therapeutic outcomes. This review critically assesses biomarker-driven strategies for resistance prediction, such as genomic profiling, functional assays, dynamic circulating tumor DNA (ctDNA) monitoring, and emerging markers, to refine patient stratification. Moreover, this review systematically dissects PARPi resistance, including genomic alterations, homologous recombination (HR) restoration, replication fork stabilization, enhanced drug efflux, reduced PARP1 trapping, and microenvironmental influences. In addition, therapeutic tactics to prevent or overcome resistance are evaluated, encompassing sequential PARPi use, combinations with chemotherapy, immunotherapy, antiangiogenic agents, and DNA damage response (DDR) inhibitors, alongside innovative approaches like antibody-drug conjugates (ADCs). Bridging mechanistic and clinical perspectives, this review promotes a multidisciplinary approach to optimize PARPi-based treatments, addressing current challenges in ovarian cancer management.

Updates in Systemic Treatment of Hormone Receptor-Positive Early-Stage Breast Cancer

Gynecologic Cancer Screening and Prevention: State of the Science and Practice

The Evolving Landscape of Ovarian Cancer: Innovations in Biotechnology and Artificial Intelligence- Based Screening and Treatment

Ovarian Cancer (OC) is a serious health problem that affects a great number of women globally. It is still one of the deadliest gynecological cancers due to restricted treatment choices and late-stage diagnosis. Worldwide, OC ranks as the seventh most commonly diagnosed kind of malignant neoplasm in women and the eighth leading cause of death in them. Because of several reasons such as genetic and economic ones, the epidemiology of OC shows disparities between races and countries. Lack of public screening program makes it difficult to diagnose this cancer earlier and as a result, most OCs are detected after they have progressed to other parts. However, advances in biotechnology and artificial intelligence (AI) are transforming both early detection and treatment strategies. Over the years, the application of AI in OC screening has shown promising results. The best way to get the drawbacks of traditional treatment methods is to combine newly developed strategies with existing treatment choices. Additionally, clinical researches are crucial to ensure the practical implementation of these advancements in healthcare settings. Utilizing state-of-the-art technologies and creative strategies will offer significant opportunity to lessen the worldwide impact of this curable cancer thereby enhancing women's quality of life in low and middle income countries (LMICs) and beyond. Hence, this review explores recent breakthroughs in ovarian cancer screening and therapy, highlighting the synergistic role of biotechnology and AI in improving patient outcomes that reshapes the ovarian cancer treatment landscape.

Chemoembolization, Radioembolization, and Percutaneous Ablation: New Opportunities for Treating Ovarian Cancer Liver Metastasis

Parenchymal liver metastases from ovarian cancer, occurring in 2-12.5% of cases, significantly worsen prognosis. While surgery and systemic treatments remain primary options, unresectable or chemotherapy-resistant multiple liver metastases pose a significant challenge. Recent advances in liver-directed therapies, including radiofrequency ablation, microwave ablation, cryoablation, transarterial chemoembolization (TACE), and radioembolization, offer potential treatment alternatives. However, the efficacy of these techniques is limited by factors such as tumor size, number, and location. The ideal candidate for tumor ablation is a patient with paucifocal disease, a single tumor up to 5 cm or up to 3 tumors smaller than 3 cm and tumors 1 cm away from major bile ducts and high-flow vessels. Transarterial chemoembolization could be performed in patients with less than 70% tumor load. Differently, radioembolization is available with less limitation on the sites or number of liver cancers. Radioembolization techniques are also able to downsize liver metastases. However, there are limited data regarding the outcomes of loco-regional therapy in patients with hepatic metastases from ovarian cancer. Advancing liver-directed therapies through interventional oncology, combined with robust data on the oncological efficacy of these local treatments, will validate their potential as effective locoregional therapies for liver metastases. This could offer a promising treatment option for patients with ovarian cancer and unresectable hepatic metastases.

Targeting BRCA and PALB2 in Pancreatic Cancer

An important subgroup of pancreatic ductal adenocarcinomas (PDACs) harbor pathogenic variants in BRCA1, BRCA2, or PALB2. These tumors are exquisitely sensitive to platinum-based chemotherapy and patients may experience deep and durable responses to this treatment. PARP inhibitors offer potential respite from the cumulative toxicities of chemotherapy as they significantly extend progression-free survival compared to a chemotherapy holiday. Given the lack of proven survival benefit, the decision to use a maintenance PARP inhibitor rather than continue chemotherapy should be individualized. Interestingly, in both published clinical trials of maintenance PARP inhibitors, there is a striking range of interpatient benefit: Even in the platinum-sensitive setting, roughly 25% of tumors appear to be PARP inhibitor refractory (progressive disease within 2 months of starting treatment), 50% sustain moderate benefit (up to 2 years), and 25% are hyper-responsive (more than 2 years of benefit). This finding highlights the need to refine our understanding of which patients will respond to maintenance PARP inhibitors, both by being able to identify biallelic loss and by deepening our knowledge of resistance mechanisms and who develops them. Recent data supports that reversion mutations are common in PARP inhibitor refractory patients, but we have little understanding of the mechanisms that drive delayed resistance and long-term responses. Identifying which patients are more prone to certain mechanisms of resistance and tackling them with specific treatment strategies are areas of active investigation. Additionally, given that PARP inhibitors have limited overall efficacy for most patients, upfront combination strategies are an important future strategy.

Evaluation of Homologous Recombination Deficiency in Ovarian Cancer

Homologous recombination deficiency (HRD) is an important biomarker guiding selection of ovarian cancer patients who will derive the most benefit from poly(ADP-ribose) polymerase inhibitors (PARPi). HRD prevents cells from repairing double-stranded DNA damage with high fidelity, PARPis limit single-stranded repair, and together these deficits induce synthetic lethality. Germline or somatic BRCA mutations represent the narrowest definition of HRD, but do not reflect all patients who will have a durable PARPi response. HRD can also be defined by its downstream consequences, which are measured by different metrics depending on the test used. Ideally, all patients will undergo genetic counseling and germline testing shortly after diagnosis and have somatic testing sent once an adequate tumor sample is available. Should barriers to one test be higher, pursuing germline testing with reflex to somatic testing for BRCA wildtype patients or somatic testing first strategies are both evidence-based. Ultimately both tests offer complementary information, germline testing should be pursued for any patient with a history of ovarian cancer, and somatic testing is valuable at recurrence if not performed in the upfront setting. There is a paucity of data to suggest superiority of one germline or somatic assay; therefore, selection should optimize turnaround time, cost to patients, preferred result format, and logistical burden. Each clinic should implement a standard testing strategy for all ovarian cancer patients that ensures HRD status is known at the time of upfront chemotherapy completion to facilitate comprehensive counseling about anticipated maintenance PARPi benefit.

Options for the Treatment of Mucinous Ovarian Carcinoma

Complete surgical resection is the gold-standard treatment for all mucinous ovarian carcinoma (MOC) cases. Advanced-stage disease is often additionally treated with adjuvant platinum-based chemotherapy; however, these were developed largely against the more common high-grade serous ovarian carcinoma and have low efficacy in treating MOC. More effective therapeutics are needed to treat late-stage and platinum-resistant tumors; however, traditional drug development and clinical trial paradigms are a major challenge for such a rare disease. New approaches to support evidence-based treatment decisions are required, such as registry trials. Recently, a number of targeted therapies have emerged as viable treatment options in other cancer types, and for some of these, the actionable tumor mutations are also seen in MOC. Thus, a promising alternative approach to provide benefit to current MOC patients involves DNA sequencing to identify a tumor's unique mutational profile and allow matching to available targeted agents. Such a pipeline can involve special approval to administer a drug already approved for clinical use in other cancer types to a given MOC patient, or their inclusion in existing ongoing clinical trials, such as basket trials encompassing patients with tumors from a range of anatomical sites. Implementation of such personalized medicine can be boosted using improved pre-clinical models, where through a clinical research collaboration a patient's own tumor cells can be used to a test a range of putative therapies prior to administration in the clinic, enabling selection of the available pharmaceutical/s that give any given patient the best possible chance of cancer remission.

Appropriate Selection of PARP Inhibitors in Ovarian Cancer

Poly-ADP-ribose polymerase inhibitors (PARPi) are a class of anti-cancer drugs that target DNA repair pathways and have shown promising efficacy in patients with ovarian cancer in recent clinical trials. To date, there have been 9 FDA PARPi approvals/indications in ovarian cancer since 2014, highlighting the importance of this class of agents in the treatment of ovarian cancer. BRCA1/2-mutated tumors or other forms of homologous recombination deficient (HRD) tumors are particularly susceptible to PARP inhibition and have seen the greatest benefits of improvement in response rate and progression-free survival (PFS) in clinical trials. Patients with homologous recombination-proficient tumors also receive benefit, especially when a nice response to paltinum is noted, but to a lesser extent. PARP inhibitors now have FDA approval and indications in first-line and recurrent maintenance, and treatment. PARP inhibitor use as maintenance therapy in the front-line setting is now considered the standard of care in patients with BRCA1/2 mutations based on the SOLO-1/GOG-3004/ENGOT study. PARP inhibitors are also recommended per ASCO guidelines in all patients with ovarian cancer as front-line maintenance therapy based on the PRIMA/ENGOT-OV26/GOG-3012 trial. The combination of PARP inhibitor, olaparib, and the anti-angiogenesis inhibitor bevacizumab is also approved as maintenance therapy after front-line chemotherapy treatment in patients with HRD tumors and is an option for patients who have initiated bevacizumab with their chemotherapy treatment. PARPi are also FDA approved and can be utilized as a treatment in third-line and beyond in recurrent ovarian cancer patients with BRCA1/2 mutations and HRD tumors. In this review, we will cover in detail when PARP inhibitor use is appropriate in ovarian cancer, as well as the various clinical factors to take into consideration when selecting a PARP inhibitor regimen.

Natural Killer Cells: the Missing Link in Effective Treatment for High-Grade Serous Ovarian Carcinoma

Ovarian cancer (OC), especially high-grade serous cancer (HGSC), is a highly heterogeneous malignancy with limited options for curative treatment and a high frequency of relapse. Interactions between OC and the immune system may permit immunoediting and immune escape, and current standard of care therapies can influence immune cell infiltration and function within the tumor microenvironment. Natural killer (NK) cells are involved in cancer immunosurveillance and immunoediting and can be activated by therapy, but deliberate approaches to maximize NK cell reactivity for treatment of HGSC are in their infancy. NK cells may be the ideal target for immunotherapy of HGSC. The diverse functions of NK cells, and their established roles in immunosurveillance, make them attractive candidates for more precise and effective HGSC treatment. NK cells' functional capabilities differ because of variation in receptor expression and genetics, with meaningful impacts on their anticancer activity. Studying HGSC:NK cell interactions will define the features that predict the best outcomes for patients with the disease, but the highly diverse nature of HGSC will likely require combination therapies or approaches to simultaneously target multiple, co-existing features of the tumor to avoid tumor escape and relapse. We expect that the ideal therapy will enable NK cell infiltration and activity, reverse immunosuppression within the tumor microenvironment, and enable effector functions against the diverse subpopulations that comprise HGSC.

The Potential of Immune Checkpoint Blockade in Cervical Cancer: Can Combinatorial Regimens Maximize Response? A Review of the Literature

Cervical cancer (CC) is most often caused by the human papillomavirus (HPV). In principle, these ties to the virus should make HPV tumors a relatively easy target for clearance by the immune system. However, these HPV-associated tumors have evolved strategies to escape immune attack. Checkpoint inhibition immunotherapy, which has had remarkable success in cancer treatment, has the potential to overcome the immune escape in CC by harnessing the patient's own immune system and priming it to recognize and kill tumors. Recent work involving PD-1/PD-L1 inhibitors in CC lends credence to this belief, as pembrolizumab has shown evidence of clinical efficacy and consequently been granted accelerated approval by the FDA. That being said, the oncologic outcomes following monotherapy with these biologics have mostly been modest and variable, and this can be attributed to alternative resistance mechanisms to tumor response. The use of therapies that stimulate immune responses via checkpoint-independent activation will therefore augment release of T cell inhibition by checkpoint inhibitors for stronger and more sustained clinical responses. Such a combinatorial approach holds promise for weak- or non-responders to checkpoint therapies as supported by evidence from various, recent pre-clinical, and preliminary clinical studies.

Radical Hysterectomy After the LACC Trial: Back to Radical Vaginal Surgery

Classical radical vaginal hysterectomy first performed by Anton Pawlik in Prague in 1888 and popularized by Frederic Schauta is now a historical technique virtually abandoned due to painful perineal incision, a high rate of urinary dysfunction, and the inability to perform lymph node assessment. However, the heritage of this approach has been still used and taught in a few centers outside their Austrian birthplace. A combined vaginal and laparoscopic approach was developed in the 1990s by French and German surgeons who designed diverse surgical techniques for which a novel classification is proposed. All these techniques are different from the so-called laparoscopically assisted radical vaginal hysterectomy (LARVH), a term widely used for laparoscopic radical hysterectomies with vaginal extraction of the specimen. Interestingly, after the publication of the LACC trial (Laparoscopic Approach to Cervical Cancer), the radical vaginal approach has found a very timely application. The creation of a vaginal cuff before performing radical laparoscopic hysterectomy described in 2007 by Leblanc as "Schautheim" operation can be used as a protective maneuver to avoid tumor spillage and potentially overturn the negative outcome of minimally invasive surgery in early-stage cervical cancer. As a result, the combination of radical vaginal and laparoscopic steps of surgery is one possible evolution after the LACC trial that needs further investigation. The forgotten vaginal surgical technique needs a specific learning curve. The creation of a vaginal cuff should be mastered by every gynecological oncologist.

Radical Hysterectomy for Cervical Cancer: the Right Surgical Approach

Radical hysterectomy with pelvic lymph node assessment is the standard initial therapy for early-stage cervical cancer. Radical hysterectomy via laparotomy (an "open" approach) was first described more than 100 years ago and has been the standard for decades. Minimally invasive surgery (MIS) has been increasingly adopted by many surgeons due to its reported perioperative benefits. MIS was deemed safe for radical hysterectomy for many years based on multiple retrospective publications. Recently, the Laparoscopic Approach to Cervical Cancer (LACC) trial reported that patients randomized to MIS had inferior oncologic outcomes. The results of the LACC trial and subsequent retrospective studies led multiple professional societies to state that open radical hysterectomy should remain the gold standard surgical approach. We acknowledge that the open approach for radical hysterectomy is an appropriate option for all cervical cancer patients eligible for surgical treatment. However, considering the limitations of the LACC trial and the available data from other retrospective studies, we feel the MIS approach should not be simply abandoned. There may still be a role for MIS in cervical cancer surgery for properly and carefully selected cases and with detailed counseling; surgeons should analyze their own outcomes closely in order to perform such counseling. Modification of surgical technique and maintaining proper oncologic surgical principles are key for MIS to remain a viable option. Tumor manipulation and contamination should be avoided. Transcervical uterine manipulators should not be used. Cervical and tumor containment prior to colpotomy, as is performed during an open approach, is required. This will all require validation in future trials. We await the results of ongoing randomized trials to further inform us. A one-size-fits-all approach may be short-sighted; we may need to decide treatment strategy based on the notion of the right surgical approach for the right patient by the right surgeon.

Antibody-Drug Conjugates in Gynecologic Cancers

Antibody-drug conjugates (ADCs) are a novel class of targeted cancer therapies with the ability to selectively deliver a cytotoxic drug to a tumor cell using a monoclonal antibody linked to a cytotoxic payload. The technology of ADCs allows for tumor-specificity, improved efficacy, and decreased toxicity compared to standard chemotherapy. Common toxicities associated with ADC use include ocular, pulmonary, hematologic, and neurologic toxicities. Several ADCs have been approved by the United States Food and Drug Administration (FDA) for the management of patients with recurrent or metastatic gynecologic cancers, a population with poor outcomes and limited effective treatment options. The first FDA-approved ADC for recurrent or metastatic cervical cancer was tisotumab vedotin, a tissue factor-targeting agent, after demonstrating response in the innovaTV 204 trial. Mirvetuximab soravtansine targets folate receptor alpha and is approved for use in patients with folate receptor alpha-positive, platinum-resistant, epithelial ovarian cancer based on results from the SORAYA trial. While there are no FDA-approved ADCs for the treatment of uterine cancer, trastuzumab deruxtecan, an anti-human epidermal growth factor receptor 2 (HER2) agent, is actively being investigated. In this review, we will describe the structure and mechanism of action of ADCs, discuss their toxicity profiles, review ADCs both approved and under investigation for the management of gynecologic cancers, and discuss mechanisms of ADC resistance.

Updates in Hormone Replacement Therapy for Survivors of Gynecologic Cancers

Opinion Statement Symptoms of menopause and the sequelae of gynecologic cancer treatment can be severe in their physical and mental impact on patient quality of life. Survivors of certain gynecologic cancers – namely, early-stage, low-grade endometrial cancers; epithelial and germ cell ovarian cancers; and early-stage squamous cell cervical, vulvar, and vaginal cancers – as well as those who have undergone risk-reducing surgery for BRCA or Lynch syndrome mutations may safely use hormone replacement therapy (HRT). Treatment is ideally initiated in patients younger than age 60 or within ten years of menopause. The decision to start treatment should be made on an individualized basis after discussion of risks, benefits, and symptom severity with patients. Data suggest that the safest HRT regimens in this population include low-dose vaginal estrogen for the treatment of vulvovaginal symptoms, or low-dose systemic estrogen for the treatment of vasomotor symptoms, combined with progesterone in patients with an intact uterus. Therapies such as SSRIs/SNRIs, vaginal moisturizers, pelvic floor physical therapy, and psychosocial counseling should also be considered when appropriate for their effectiveness in managing menopausal symptoms without the potential risk of hormones.

Intraperitoneal and Hyperthermic Intraperitoneal Chemotherapy for the Treatment of Ovarian Cancer

In our clinical practice, we have shifted away from the use of adjuvant normothermic intraperitoneal (IP) chemotherapy, particularly following the publication of GOG 252. Our decision is rooted in the accumulating evidence indicating a lack of demonstrable superiority, alongside the recognized toxicities and logistical challenges associated with its administration. This strategic departure is also influenced by the rising utilization of maintenance therapies such as bevacizumab and PARP inhibitors, which present viable alternatives for improving patient outcomes. Our utilization of hyperthermic IP chemotherapy (HIPEC) is currently reserved for a specific cohort of patients, mirroring the patient population studied in the OVHIPEC-1 trial. Specifically, our HIPEC protocol applies to patients presenting with newly diagnosed stage IIIC high-grade epithelial ovarian cancer who are deemed ineligible for primary debulking surgery. Patients must exhibit at least stable disease with neoadjuvant platinum-based chemotherapy, maintain a favorable performance status (ECOG score 0-1), possess good nutritional reserves (with no evidence of protein-calorie malnutrition and an albumin level exceeding 3.5), and not have chronic kidney disease. When HIPEC is planned, it is administered at the time of interval debulking surgery, contingent upon the attainment of optimal surgical outcomes (< 1 cm of residual disease). Our HIPEC protocol adheres to the original OVHIPEC-1 trial guidelines, employing cisplatin at a dosage of 100 mg/m

Targeted Therapies in Low-Grade Serous Ovarian Cancers

Opinion StatementLow grade serous carcinoma of the ovary has been delineated as a separate entity from its counterpart high grade serous carcinoma of the ovary. Molecular profiling has helped to further characterize this disease process and has led to new and exciting treatment options. Surgery has always been a cornerstone of management both in primary and recurrent disease settings. Chemotherapy has been a long-standing backbone of adjuvant treatment, but its efficacy continues to be questioned. Hormonal therapy for upfront and recurrent disease is an effective treatment option with a high response rate and minimal side effects. Newer therapies including MEK, CDK 4/6, and PI3KCA inhibitors have emerged as exciting options for recurrent disease. Ongoing clinical trials will hopefully lead to additional therapeutic opportunities based on novel biomarkers in this disease.

Fertility Sparing Medical Management Options in Gynecologic Cancers

Opinion Statement There is an increasing use of medical management for gynecologic cancers given the rise in neoadjuvant therapies, delayed childbearing, and use of assisted reproductive technology. Chemotherapy, albeit broadly used in most gynecologic cancers, lacks long term data with respect to its associated gonadotoxicity and potential adverse pregnancy outcomes. Immunotherapy and other targeted therapies that have demonstrated promising responses in other tumor types are increasingly being studied in gynecologic malignancies. These therapies may offer opportunities for enhanced treatment response in an effort to minimize more toxic, invasive, or surgical management approaches that could have significant negative implications on fertility. Given that some of these therapies do not represent the standard of care and currently only exist in the experimental setting, detailed counseling and careful selection of patients for fertility sparing treatment remains critical. It is reasonable for patients with early stage, low-risk endometrial cancers to attempt conservative management while establishing clear treatment objectives. Early involvement of fertility specialists is necessary in order to optimize these patients’ pregnancy goals. An emphasis on lifestyle changes and in particular weight loss should also be discussed with these patients. Neoadjuvant chemotherapy followed by fertility sparing surgery in cervix cancer patients with low-risk, small tumors shows promising results that suggest this can be a safe treatment option. Patients with advanced stage disease of any primary tumor or aggressive histology such as in many cases of ovarian cancer are not appropriate candidates for prioritization of fertility sparing treatment options. Ongoing and future studies will help to better identify appropriate patients and maximize medical management options in early-stage gynecologic cancers.

Ovarian Suppression: Early Menopause and Late Effects

Opinion statementAround 90% of breast tumours are diagnosed in the early stage, with approximately 70% being hormone receptor-positive. The cornerstone of adjuvant therapy for early-stage hormone receptor-positive breast cancer is endocrine therapy, tailored according to disease stage, biological characteristics of the tumour, patient’s comorbidities, preferences and age. In premenopausal patients with hormone receptor-positive breast cancer, ovarian function suppression is a key component of the adjuvant endocrine treatment in combination with an aromatase inhibitor or tamoxifen. Moreover, it can be used during chemotherapy as a standard strategy for ovarian function preservation in all breast cancer subtypes. In the metastatic setting, ovarian function suppression should be used in all premenopausal patients with hormone receptor-positive breast cancer to achieve a post-menopausal status. Despite its efficacy, ovarian function suppression may lead to several side effects that can have a major negative impact on patients’ quality of life if not properly managed (e.g. hot flashes, depression, cognitive impairment, osteoporosis, sexual dysfunction, weight gain). A deep knowledge of the side effects of ovarian function suppression is necessary for clinicians. A correct counselling in this regard and proactive management should be considered a fundamental part of survivorship care to improve treatment adherence and patients’ quality of life.

Treatment of node-positive endometrial cancer: chemotherapy, radiation, immunotherapy, and targeted therapy

Opinion StatementThe standard of treatment for node-positive endometrial cancer (FIGO Stage IIIC) in North America has been systemic therapy with or without additional external beam radiation therapy (RT) given as pelvic or extended field RT. However, this treatment paradigm is rapidly evolving with improvements in systemic chemotherapy, the emergence of targeted therapies, and improved molecular characterization of these tumors. The biggest question facing providers regarding management of stage IIIC endometrial cancer at this time is: what is the best management strategy to use with regard to combinations of cytotoxic chemotherapy, immunotherapy, other targeted therapeutics, and radiation that will maximize clinical benefit and minimize toxicities for the best patient outcomes? While clinicians await the results of ongoing clinical trials regarding combined immunotherapy/RT as well as management based on molecular classification, we must make decisions regarding the best treatment combinations for our patients. Based on the available literature, we are offering stage IIIC patients without measurable disease postoperatively both adjuvant chemotherapy and IMRT with carboplatin, paclitaxel, and with or without pembrolizumab/dostarlimab as primary adjuvant therapy. Patients with measurable disease post operatively, high risk histologies, or stage IV disease receive chemoimmunotherapy, and vaginal brachytherapy is added for those with uterine risk factors for vaginal recurrence. In the setting of endometrioid EC recurrence more than 6 months after treatment, patients with pelvic nodal and vaginal recurrence are offered IMRT and brachytherapy without chemotherapy. For measurable recurrence not suitable for pelvic radiation alone, chemoimmunotherapy is preferred as standard of care.

Combining Radiotherapy with Immunotherapy in Cervical Cancer: Where Do We Stand and Where Are We Going?

Combining immunotherapy and radiotherapy as a treatment strategy for cervical cancer has attracted increasing attention. The primary objective of this review is to provide an up-to-date summary of the knowledge regarding the combined use of radiotherapy and immunotherapy for treating cervical cancer. This review discusses the biological rationale combining immunotherapy with radiotherapy in a clinical setting and presents supporting evidence for the combination strategy based on both safety and effectiveness data. Additionally, we discuss the potential and challenges of combining radiotherapy and immunotherapy in clinical practice.

The Role of PARP Inhibitors in Patients with Primary Malignant Central Nervous System Tumors

Primary malignant central nervous (CNS) tumors are a devastating group of diseases with urgent need for improved treatment options. Surgery, radiation, and cytotoxic chemotherapy remain the primary standard treatment modalities, with molecularly targeted therapies having proven efficacy in only small subsets of cases. Poly(ADP-ribose) polymerase (PARP) inhibitors, which have had immense success in the treatment of extracranial cancers with homologous recombination deficiency (HRD), are emerging as a potential targeted treatment for various CNS tumors. Although few primary CNS tumors display canonical BRCA gene defects, preclinical evidence suggests that PARP inhibitors may benefit certain CNS tumors with functional HRD or elevated replication stress. In addition, other preclinical studies indicate that PARP inhibitors may synergize with standard therapies used for CNS tumors including radiation and alkylating agents and may prevent or overcome drug resistance. Thus far, initial clinical trials with early-generation PARP inhibitors, typically as monotherapy or in the absence of selective biomarkers, have shown limited efficacy. However, the scientific rationale remains promising, and many clinical trials are ongoing, including investigations of more CNS penetrant or more potent inhibitors and of combination therapy with immune checkpoint inhibitors. Early phase trials are also critically focusing on determining active drug CNS penetration and identifying biomarkers of therapy response. In this review, we will discuss the preclinical evidence supporting use of PARP inhibitors in primary CNS tumors and clinical trial results to date, highlighting ongoing trials and future directions in the field that may yield important findings and potentially impact the treatment of these devastating malignancies in the coming years.

Sentinel Lymph Node Evaluation in Early-Stage Vulvar Cancer

Sentinel lymph node mapping (SLNM) and dissection (SLND) should be used as an alternative to full inguinofemoral lymph node dissection (IFLND) in select patients with early-stage vulvar cancer. IFLND is associated with high postoperative complications such as wound breakdown, lymphedema, lymphocyst formation, and infection. SLND in select patients offers a safe, effective, and less morbid alternative. Candidates for SLND include patients with a unifocal vulvar tumor less than four centimeters, clinically negative lymph nodes, and no prior inguinofemoral surgeries. SLND should ideally be performed by a high-volume SLN surgeon. Most commonly, SLND is performed using both radiocolloid lymphoscintigraphy (e.g., Technetium-99) and a visual tracer such as blue dye; however, near infrared imaging with indocyanine green injection is becoming more widely adopted. Further prospective studies are needed to examine the safety and efficacy of various techniques for SLND. SLND has been demonstrated to be cost-effective, especially when including perioperative complications. Further studies are needed to demonstrate quality of life differences between IFLND and SLND.

Contemporary Use of Hormonal Therapy in Endometrial Cancer: a Literature Review

Most endometrial cancers are estrogen receptor and progesterone receptor positive. Hormonal therapy in endometrial cancer is best used in patients with low-grade disease and hormone receptor positivity. Though not standard of care, hormonal treatment can be considered in endometrial cancer treatment in both the early-stage upfront setting for patients who are not surgical candidates and in advanced and recurrent endometrial cancer. In patients who desire fertility preservation or who are not surgical candidates, levonorgestrel intrauterine device and oral progesterone are preferred treatment options. In patients with advanced and metastatic disease, there is no standard-of-care second-line treatment, and hormonal treatment is a widely accepted option for low-grade disease. Beyond progesterone, selective estrogen receptor modulators, aromatase inhibitors, gonadotropin-releasing hormone agonists, and fulvestrant are hormonal treatment options. New therapies, such as MTOR inhibitors and CDK 4/6 inhibitors, have been extensively studied in breast cancer and are shown to be useful in conjunction with hormonal therapies particularly when there is suspected resistance to anti-estrogen treatment. Hormonal therapies also tend to be better tolerated than chemotherapy agents, making them a desirable option particularly in patients with lower performance status. Results from ongoing clinical trials will hopefully help shed light on the use of combination treatment in patients with hormone receptor-positive, low-grade metastatic, and recurrent endometrial cancer.

Circulating Tumor DNA (ctDNA) and Its Role in Gynecologic Malignancies

From Fallopian Tube to Ovarian Cancer: Understanding the Evaluation and Management of Serous Tubal Intraepithelial Carcinoma Lesions

Opinion Statement Ovarian cancer, particularly high-grade serous carcinoma (HGSC), remains a leading cause of mortality in gynecologic oncology. Emerging research identifies serous tubal intraepithelial carcinoma (STIC) as a precursor lesion in many HGSC cases, highlighting its role in ovarian cancer pathogenesis and prevention. Management of STIC is challenging, as there is only limited data available to guide clinical decision-making. For average-risk women, opportunistic salpingectomy is increasingly being adopted during routine procedures such as hysterectomy or cesarean section. This intervention has demonstrated significant potential in reducing ovarian cancer incidence while maintaining safety and feasibility. For high-risk individuals, particularly BRCA mutation carriers, risk-reducing salpingo-oophorectomy (RRSO) remains the gold standard. RRSO significantly lowers ovarian cancer risk, though alternative approaches like salpingectomy alone or radical fimbriectomy are under investigation to preserve ovarian function in younger patients. To improve STIC detection, SEE-FIM pathology protocol is recommended when patients are undergoing risk-reducing surgery to prevent ovarian cancer, but challenges such as diagnostic variability and limited data persist. When STIC is detected incidentally, management varies based on risk factors and lesion characteristics. Genetic counseling and testing are essential when STIC is identified, as hereditary predisposition may guide further management. Surgical management is advised for cases of STIC with microinvasive carcinoma, but routine use of surgical management for STIC is not clearly defined in the literature. Bilateral oophorectomy is generally recommended when STIC is identified, and adnexal structures have not yet been removed. Chemotherapy is not recommended for treatment of STIC. Surveillance is suggested when STIC has been diagnosed, but there are no set guidelines as to the frequency and type of monitoring. Future directions include refining molecular profiling to predict progression and conducting randomized studies to establish evidence-based guidelines. Multidisciplinary collaboration is essential to optimize prevention and treatment, ultimately reducing HGSC incidence and improving patient outcomes.

Therapeutic Challenges in the Management of Serous Endometrial Intraepithelial Carcinoma (SEIC)

Serous endometrial intraepithelial carcinoma (SEIC) is an aggressive precursor and a similar biology to uterine serous carcinoma (USC). Patients diagnosed with SEIC should undergo surgical staging that includes total hysterectomy with bilateral salpingo-oophorectomy, lymph node sampling, and omentectomy. With trends in lymph node evaluation shifting towards sentinel lymph node sampling, we recommend bilateral sentinel lymph node sampling as a reasonable alternative to full pelvic and para-aortic lymphadenectomy. There is limited data to support the use of adjuvant chemotherapy, however, it is apparent that those with extrauterine disease have a higher likelihood of recurrence and decreased overall survival. Those with stage IVB SEIC have similar rates of survival to those with stage IVB USC and may be a population that could benefit from newer regimens for advanced stage endometrial cancer including immunotherapy and maintenance therapy. Unfortunately, strong data to support this will continue to be a challenge given the rare incidence of isolated SEIC without concurrent USC. The utility of adjuvant radiotherapy remains unclear and given its noninvasive nature and propensity for distant recurrence, may be of little utility. Regardless of the adjuvant therapies selected, routine surveillance like that of USC should be followed as recurrences are often noted greater than one year after initial surgery. Unlike other precursor lesions, SEIC behaves similarly to invasive carcinoma and ultimately should be treated as such for optimal disease control and outcomes.

Beyond Serous: Treatment Options for Rare Endometrial Cancers

Rare endometrial cancers are high-grade, aggressive malignancies which are often diagnosed at an advanced stage, and account for disproportionately more deaths than their more common low-grade counterparts. Standard of care includes a combination of surgery, radiation, and chemotherapy. Surgery consists of complete hysterectomy, and more recent evidence supports replacing a full lymphadenectomy with sentinel node mapping. Paclitaxel and carboplatin remain the mainstays of chemotherapy, while current studies incorporating immunotherapy will inform future practice. Whether and how to incorporate radiation remains controversial, and certain histologic subtypes, such as carcinosarcomas, may benefit from radiation more than others. Owing to their relative rarity, it is difficult to conduct clinical trials in this patient population, which has hindered the development of effective therapies for rare malignancies. Molecular profiling has offered insight into the pathogenesis of rare endometrial cancers, providing actionable targets for personalized therapy.

Management of Advanced Stage Endometrial Cancer With Non-Measurable Disease After Surgery

Patients with advanced stage completely resected endometrial cancer represent a heterogeneous group and decision-making regarding adjuvant treatment for this patient population is complex. When considering this cohort of patients, factors such as histologic subtype and molecular classification impact decision-making on adjuvant therapy. Options include systemic chemotherapy with or without immunotherapy or HER2-targeted therapy, chemoradiotherapy and radiation alone. We recommend tailoring treatment for patients with advanced-stage, non-measurable endometrial cancer based on HER2 status, mismatch repair (MMR) proficiency, disease stage and histology. For HER2-positive cases, we recommend carboplatin, paclitaxel, and trastuzumab. For HER2-negative, MMR-proficient disease, Stage 3 patients we recommend that have stage IIIB or IIIC disease AND grade 1 or 2 endometrioid histology OR grade 3 endometrioid histology p53 wild-type, we recommend carboplatin and paclitaxel, with consideration of the addition of pelvic radiationFor patients with stage IIIA disease OR grade 3 p53 aberrant endometrioid OR non-endometrioid histology, we recommend carboplatin and paclitaxel, with consideration of brachytherapy for patients with uterine risk factors such as lymphovascular space invasion, cervical stromal involvement, or lower uterine segment involvement. For Stage 4 patients with Her2 negative, MMRp disease, we recommend carboplatin and paclitaxel, with optional brachytherapy. For HER2-negative, MMR-deficient disease, the recommended regimen includes carboplatin, paclitaxel, and immunotherapy, with consideration of brachytherapy for patients with the uterine risk factors listed above.

The Role of Sentinel Lymph Node Mapping in High-grade Endometrial Cancer

Total hysterectomy with lymph node assessment is the current standard-of-care for surgical staging in apparent early-stage endometrial cancer. Compared to the traditional complete pelvic lymphadenectomy with or without para-aortic lymphadenectomy, sentinel lymph node (SLN) mapping results in fewer surgical complications, decreased operative time, and lower rates of chronic lymphedema. The technique is endorsed by the National Comprehensive Cancer Network and the Society of Gynecologic Oncology guidelines, and over the past two decades the majority of gynecologic oncologists worldwide have adopted SLN mapping into their practice. However, as the results of the initial SLN studies were mostly based on low-grade tumors, adoption of the technique in high-grade tumors has been slower and more controversial. In this review, we discuss the most recent studies evaluating the SLN mapping in high-grade endometrial cancers. The results of these studies suggest that the SLN detection rate is acceptably high and the negative predictive value is sufficiently low to support the use of SLN mapping in high-grade endometrial tumors to replace complete lymphadenectomy. Validity of SLN mapping techniques does, however, require following a standard algorithm, and success depends also on surgeon expertise. Moreover, the impact of SLN mapping on overall survival in high-grade tumors requires future prospective randomized studies. Finally, a transition toward near-universal SLN mapping techniques for endometrial cancers could significantly impact on the adequacy of gynecologic oncology fellows' surgical training and competency in lymphadenectomy.