Chinese Clinical Oncology

Radiotherapy in women with epithelial ovarian cancer: historical role, current advances, and indications

Epithelial ovarian cancer (OC) is known to be a neoplasm responsive to radiotherapy (RT). Nevertheless, the role of RT in the management of this disease represent a topic of controversy, and the indications for its use are not fully established. Initial studies suggested that the addition of RT in the form of intraperitoneal (IP) radioisotopes was useful. Indications for this treatment were peritoneal cytology with tumor cells, peritoneal implants, and capsule rupture. The instillation of radioisotopes was contraindicated when macroscopic residual disease was present. Pelvic RT was used after surgery in patients with an absence of gross residual disease. Early studies established the inadequacy of this technique and the need for treating the whole abdomen. Whole abdominal irradiation (WAI) was a therapeutic tool used in the prechemotherapy era to eradicate large amounts of microscopic peritoneal disease. Ideal candidates for WAI were stage I patients with grade 2 or 3 tumors; stage II patients with grade 1 or 2 tumors and residual disease, and stage III, grade 1 patients with <2 cm residual disease. The disadvantages of WAI were the dose-limiting toxicities, which were predominantly acute hematologic and late gastrointestinal. The era of aggressive debulking and platinum agents made WAI fall out of favor as a treatment of OC. Selective approaches with highly conformal radiotherapy (CRT) have been used in case of limited recurrent or unresectable disease with the potential for long-term disease control. Currently, the role of RT in OC applies for patients with recurrent oligometastatic or oligoprogressive disease and in the palliative setting for symptom control. We performed a nonsystematic review and included data from both retrospective and prospective studies focusing on the use of RT for OC and its biological rationale. Furthermore, ongoing trials on this issue are reported.

Systemic therapy for non-serous ovarian carcinoma

Ovarian cancer is one of the top ten most common cancers in women around the world, with high-grade serous epithelial cancer being the most frequent type. However, around a quarter of cases consist of non-serous epithelial ovarian cancer (EOC), which is a heterogeneous group of malignancies that includes endometroid, mucinous, clear cell carcinoma (CCC), and carcinosarcoma. Another relevant group of nonepithelial tumors are those arising from germ cells or sex-cord stromal cells, which account for about 10% of all ovarian cancers. Although there are similarities in the presentation, evaluation, and management of these tumors, they have unique characteristics in terms of epidemiology, tumor biology, tumor marker expression, and response to treatment, warranting a different approach to each one of them. Collectively, the treatment of most of EOC include surgical cytoreduction followed by adjuvant systemic platinum-based chemotherapy. The most common chemotherapy and route of administration for systemic treatment is paclitaxel plus carboplatin given intravenously. However, the treatment of EOC has been rapidly evolving and emerging targeted therapies such as poly (adenosine diphosphate-ribose) polymerase inhibitors, immune checkpoint inhibitors, and antiangiogenic agents are also available. On the other hand, non-EOC responds well to combination chemotherapy used to treat testicular cancer (bleomycin, etoposide, cisplatin) and has a good prognosis. Frontline chemotherapeutic regimen selection differs according to histological subtype, molecular alterations, and patient characteristics. Here, we review specific characteristics of non-serous and non-EOC emphasizing the peculiarities of systemic therapy for each subtype.

Epidemiology of ovarian cancer

Worldwide, ovarian cancer (OC) is the seventh most common type of malignant neoplasm in women and the eighth cause of mortality in them. The classification of OC is made by the possible origin of one of the three main components of the ovary: epithelium, stroma, and germinal cells. Due to this the main malignant tumors arising from the ovary are epithelial carcinoma, germ cell tumor, sex cord-stromal tumor, and Krukenberg's tumor. The most common are the epithelial carcinomas, in which the most prevalent is serous ovarian carcinoma. Nevertheless, the subtype of OC varies according to the age of appearance. The global incidence of OC has been stable during the last decades, but, it´s still a disease that has contributed to a considerable number of deaths around the world. The epidemiology of this cancer shows differences between races and countries due to several factors including genetic and economic. The detection of this cancer has been problematic as there is no screening public program for its early detection and as a consequence, most OCs are detected in an advanced stage where most of the time it has already spread to other parts different from the ovary. The purpose of this article is to present a comprehensive review of the general epidemiology, incidence rates, prevalence rates, mortality, and survival of the different types of OC worldwide and in certain regions.

Sentinel lymph node in cervical cancer: time to move forward

In early-stage cervical cancer, lymph node status is of paramount importance to determine the best therapeutic strategy and is one of the most important prognostic factors of survival. According to main international guidelines, pelvic full lymphadenectomy is recommended for lymph node staging. Sentinel lymph node (SLN) biopsy is an accurate method for the assessment of lymph nodal involvement and has been suggested instead of systematic pelvic lymph node dissection (PLND). The SLN technique requires a learning-curve to be well performed. Combined detection with technetium-99 and blue dye has been widely used but the recent introduction of indocyanine green (ICG) is of growing interest since it could improve SLN detection. SLN biopsy offers a more accurate anatomical staging by finding potential metastatic nodes outside of usual lymphadenectomy areas. SLN biopsy improves the diagnostic value of lymph node staging with ultrastaging and detection of low-volume nodal metastases [isolated tumor cells (ITCs) and micrometastases]. Appropriate selection of patient and minimal training combined with some simple rules may guarantee a low false negative rate. Several studies have shown that SLN mapping in these patients is feasible, with excellent detection rates and sensitivity. Less-radical lymph node dissection decreases the associated morbidity of PLND, especially the risk of lower-limb lymphoedema, which severely affects patient quality of life. Some points are still subject to debate such as the low accuracy of intraoperative SLN status assessment by frozen section and the impact of micrometastasis on prognosis. Although international guidelines consider SLN biopsy as an alternative to PLND, SLN biopsy alone is not the gold-standard yet due to lack of prospective evidence on long-term oncological safety. The 3 ongoing prospective trials SENTIX, PHENIX and SENTICOL III will most probably give an answer to these issues.

Sentinel lymph node in vulvar cancer

Lymph node removal as a part of surgical management is a standard of care in vulvar cancer patients. Due to patient morbidities and difficulties in treatment of inguinal healing after lymph nodes removal, lymphatic mapping has emerged as an increasingly popular option over the past few years. At this time several different techniques have been described and variety of different dyes were used. In addition, an important aspect of the use of the sentinel lymph node (SLN) technique is the removal of a limited number of lymph nodes, which allows more detailed pathological examination. Moreover, the interpretation of pathological ultra-staging of SLNs, which can identify low-volume metastases for which the clinical significance and the ideal management, remain uncertain. Despite differences in techniques and dyes used, this minimally invasive procedure is currently recommended as an alternative to full inguinofemoral lymph node dissection in selected cases by all major international societies. As for now SLN concept became a standard of care in vulvar cancer. This technique, though simple as a concept, requires a learning curve and should only be used in expert centers. This article provides a review on literature on SLN technique in vulvar cancer, current recommendations and future lines of investigation.

Discrepancy between recommendations regarding hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer management: a narrative review

Hyperthermic intraperitoneal chemotherapy (HIPEC) is still controversial in ovarian cancer (OC) management. Doubts are related mainly to HIPEC effectiveness, but also to its safety. European Society of Medical Oncology and European Society of Gynecologic Oncology do not consider HIPEC as a standard of care. Opposite to European recommendations, National Comprehensive Cancer Network found HIPEC as a treatment option in patients undergoing interval debulking surgery in first-line treatment. This may be confusing for oncologists in clinical practice. The aim of this narrative review is to present literature review focusing on efficacy, confounding factors, complications and immunological issue of HIPEC in OC management. PubMed was searched for meta-analyses, randomized trials, observational studies, experimental studies to outline the role of HIPEC in OC management since January 2015 until August 2023. Keywords included "hyperthermic intraperitoneal chemotherapy", "HIPEC", "ovarian cancer", "immune response". References from full-text articles were screened for additional studies. Most meta-analyses found that HIPEC improved survival in patients with OC and none of the meta-analyses showed that addition HIPEC to surgery was associated with a worse treatment outcome compared to surgery alone. Positive effect on treatment outcome was found more common in first-line treatment than recurrent disease. Positive effect on treatment outcome was more common in first-line treatment (especially during interval debulking surgery) than recurrent disease. HIPEC efficacy can be affected by patients' characteristics (BRCA status, platinum sensitivity), cytostatic type and dose, intensity of hyperthermia and peritoneal flow characteristics. Apart from strict cytotoxic effect, HIPEC can induce anti-cancer immune response. Although factors confounding HIPEC efficacy are not well-defined, survival improvement, related to addition HIPEC to surgery in OC, was observed. Future studies should focus on determining a subgroup of patients, who benefit from HIPEC. This will contribute to the unification of European and American recommendations.

Interleukine-10 in ovarian cancer

Interleukins serve as communicating molecules between cells, mediating key interactions in the tumor microenvironment (TME) between immune cells and non-immune cells. Interleukin-10 (IL-10), a multifunctional cytokine with multiple properties, has been extensively studied in various aspects of immunology and cancer biology. IL-10 is pleiotropic, promotes cytotoxicity, yet inhibits antitumor-responses. In recent years, the role of IL-10 in ovarian cancer (OC) progression and treatment has gained significant scientific attention, elucidating the signaling pathways triggered by IL-10 action. OC, the leading cause of gynecologic cancer-related deaths, is characterized by ascites, which hosts an intricate TME that is not responsive to treatment by immune checkpoint inhibition. IL-10, known for its immunosuppressive and anti-inflammatory properties, plays a complex role in OC progression, immune modulation, and therapeutic response and has a potential therapeutic property as a target and as an effector. As the literature of basic science research studying the role of IL-10 in the TME of OC scopes a few decades and some data is contrasting, it is important to review the literature and provide concise input derived from it. This review aims to provide a comprehensive overview of the current understanding of IL-10 in OC, highlighting its influence on tumor growth, immune evasion, and potential as a therapeutic target.

Tumor treating fields: narrative review of a promising treatment modality for cancer

Anatomical basis of lymph node detection in gynecologic cancers: a review from a surgical perspective

Pelvic and para-aortic lymphadenectomy are associated with increased risk of complications and are responsible for a significant proportion of morbidity and impaired quality of life following surgical management of pelvic malignancies. Sentinel lymph node (SLN) was developed as a trade-off between systematic and no lymphadenectomy to limit morbidity while conserving good oncological staging and outcomes. In this comprehensive review, we aimed to synthetize the anatomical basis of the SLN procedure in patients with pelvic malignancies from a surgical perspective. The reliability of the SLN procedure is based on the knowledge of the dissemination pathways for each type of tumors. The most recent understanding of the uterine lymphatic anatomy defined three consistent channels: an upper paracervical pathway (UPP) with draining medial external and/or obturator lymph nodes; a lower paracervical pathway (LPP) with draining internal iliac and/or presacral lymph nodes and the infundibulo-pelvic pathway (IPP) with a course along the fallopian tube and upper broad ligament via the infundibulo-pelvic ligament to its origin. In patients with endometrial cancer, most SLNs are located on the UPP pathway: obturator and external iliac whereas 80% of the SLNs in patients with cervical cancer are located in the external iliac, interiliac and obturator area. Surgical training is a key step toward improving detection rates and exhaustiveness of SLN research while reducing overall morbidity. This is all the more important that the indications for performing complete lymphadenectomy are becoming increasingly rare.

Paclitaxel and carboplatin combination therapy-induced pure red cell aplasia in endometrial cancer patient and favorable response to low-dose corticosteroid treatment: a case report

Endometrial cancer, the sixth most common malignancy in women, is frequently treated with carboplatin-paclitaxel chemotherapy. While myelosuppression is a common adverse effect, drug-induced pure red cell aplasia (PRCA) is exceedingly rare. This report presents a case of refractory PRCA induced by this regimen, which was successfully reversed with low-dose corticosteroids, underscoring its clinical significance. A postmenopausal patient with endometrial cancer (stage IA, high p53 expression) received adjuvant paclitaxel and carboplatin chemotherapy. She subsequently developed severe anemia (reticulocytes 0.001×1012/L). Bone marrow examination revealed an absence of erythroid precursor cells. PRCA was diagnosed after excluding hemolysis, hematologic malignancies, infections, and autoimmune disorders. Given normal pre-chemotherapy hemoglobin (Hb) levels, drug-induced PRCA was suspected. Chemotherapy was discontinued, and stanozolol was initiated; however, Hb remained stable at 60 g/L without improvement. Low-dose corticosteroids (0.5 mg/kg) were added one week later, resulting in Hb increasing to 82 g/L within 2 weeks. Levels normalized within four weeks and remained stable after corticosteroid taper. This case highlights PRCA as a potential complication of carboplatin-paclitaxel therapy, emphasizing the importance of obtaining reticulocyte counts and bone marrow studies in cases of refractory chemotherapy-induced anemia. Early low-dose corticosteroid intervention proved effective and safe. Clinicians should include PRCA in the differential diagnosis during chemotherapy toxicity surveillance to optimize supportive care in cancer patients.

From systematic lymphadenectomy to sentinel lymph node mapping: a review on transitions and current practices in endometrial cancer staging

Endometrial cancer care has undergone major changes in the past 30 years. In 1988, staging transitioned from clinical to surgical. Moreover, the surgical approach of choice is no longer open surgery, but minimally invasive surgery. An improvement in terms of nodal evaluation followed. Full systematic lymphadenectomy has been continuously replaced by sentinel lymph node mapping. Although sentinel lymph node mapping with a cervical injection of indocyanine green dye is rapidly gaining clinical acceptance, we lack consistent recommendations on a well-defined procedure that accurately and indolently assesses the lymph node status. Such recommendations are indispensable, as nodal status is the most important predictive factor of survival and is essential for tailoring adjuvant treatment to the risk of recurrence. This paper focuses on transitions in endometrial cancer care and highlights current data on sentinel lymph node mapping in endometrial cancer. We demonstrate that sentinel lymph node mapping is a safe and accurate strategy for nodal status evaluation with appropriate sensitivity, false-negative rate and negative predictive value in high- as well as low-risk settings. Furthermore, we elaborate on type and dose of tracer, site of injection, number of sentinel lymph nodes to be removed, sentinel lymph node mapping learning curve, operation mode and sentinel lymph node ultrastaging. In the future, guidelines with consistent recommendations on the above outlined features of sentinel lymph node mapping should be established to allow for a uniform and wide-spread application of the sentinel lymph node mapping procedure.

Up-to-date in ovarian cancer

Controversies on the treatment of ovarian cancer with dose-dense chemotherapy

Epithelial ovarian cancer is the most lethal gynaecological malignancy with an estimated 295,414 new cases and 184,799 deaths around the world. Cytoreductive surgery and combination chemotherapy have remained a standard therapy for decades. The majority of women diagnosed with ovarian cancer will receive systemic chemotherapy for recurrent or advanced diseased. In recent years, therapies such as anti-angiogenics, PARP inhibitors, and dose-dense chemotherapy have emerged as novel strategies against ovarian cancer. Dose-dense chemotherapy, usually with a carboplatin and paclitaxel regimen, has been proposed as an alternative to conventional chemotherapy for these patients. However, the results for different trails are inconsistent and dose-dense chemotherapy remains controversial. Results from the JGOG 3016 study showed a progression free survival and overall survival benefit, with increased neurotoxicity and anaemia. While the GOG 262, MITO-7, GOG 252 and ICON8 studies found no benefit on progression free survival, with a recent meta-analysis concluding that three weekly chemotherapy remains the standard of care. Ovarian cancer molecular subtypes and differences in pharmacogenetics between populations may explain the differences in response to dose dense chemotherapy, however our understanding of this factors is still lacking. Here, we reviewed the evidence for and against dose-dense chemotherapy and the possible factors for the different results among trials.

Clinical evidence on a Coriolus versicolor-based vaginal gel for HPV-related cervical disease: a narrative review

Human papillomavirus (HPV) infection is the most common sexually transmitted disease worldwide. Its persistence may lead to cervical dysplasia and, eventually, cervical cancer. Currently, there are no approved treatments specifically targeting HPV infection or low-grade squamous intraepithelial lesions (LSILs). A multicomponent vaginal gel containing Trametes versicolor extract, prebiotics, moisturizing agents, and anti-inflammatory coadjuvants has been developed to support natural HPV clearance and promote lesion healing or regression. The aim of this review is to summarize the available evidence regarding a multi-ingredient vaginal gel for HPV infection and cervical low-grade dysplasia treatment and to provide a critical review of the literature. A structured literature search was performed in MEDLINE, Embase, and Scopus without language or date restrictions. Additional records were identified through ClinicalTrials.gov and Google Scholar. Both peer-reviewed publications and conference abstracts reporting clinical outcomes of Trametes versicolor-based vaginal gel (Papilocare® or Palomacare®) were included. Papilocare®/Palomacare® is available in over 65 countries across Europe, Africa, Asia, and Latin America. The clinical evidence includes two pilot studies, two prospective non-controlled interventional studies, one randomized clinical trial, and one retrospective observational study. This narrative review summarizes their design, results, strengths, and limitations. Ethical issues related to trial design, lack of biopsy confirmation, absence of blinding, and retrospective registration are discussed. Although some preliminary data suggest potential benefits in epithelial repair and HPV clearance, current evidence remains insufficient to support its routine clinical use. Further independent, well-designed, and adequately powered randomized trials are required to confirm the safety and efficacy of this formulation. Strengthening methodological rigor will be essential to define its role in HPV-related cervical disease management.

Narrative review of the utility of magnetic resonance imaging in radiotherapy for cervical cancer

In radiotherapy (RT) for locally advanced cervical cancer, high soft tissue contrast on magnetic resonance imaging (MRI) can ensure accurate delineation of target volumes (TVs) and optimal dose distribution to the RT target and organs at risk (OAR). MRI-guided adaptive RT (MRIgART) is a novel technology that revises RT plans according to anatomical changes occurring throughout the treatment to improve target coverage and minimise OAR toxicity. This review aims to assess the evidence and gaps of MRI use in RT planning and MRIgART in the treatment of cervical cancer, as well as challenges in its clinical implementation. Ovid Medline and PubMed were searched using keywords for MRI in RT for cervical cancer. After applying the inclusion and exclusion criteria, the initial search was deduced to 32 studies. A total of 37 final studies were reviewed, including eight additional articles from references. In the primary studies, TVs and organ motion were assessed before, during, and after treatment. MRI was used to investigate dose distribution and therapeutic response to the treatment in association with its outcome. Lastly, rationales for MRIgART were evaluated. It was concluded that MRI enables accurate target delineation, assessment of organ motion and interfraction changes, and monitoring of treatment response through dynamic parameters. Enhanced target coverage and reduced OAR irradiation through MRIgART can improve local control and the overall outcome, although its rationales against the logistical challenges need to be evaluated on further research.

Bioinformatics identification of characteristic genes of cervical cancer via an artificial neural network

Artificial neural networks (ANNs) have been extensively used in the field of medicine. The present hypothesis-free study sought to use an ANN to identify the characteristic genes of cervical cancer (CC). RNA sequencing profiles were obtained from the GSE7410, GSE9750, GSE63514, and GSE52903 datasets. The differentially expressed genes (DEGs) were identified and compared between the normal and CC tissues. An ANN analysis was conducted to obtain the random-forest tree and to examine differences in gene filtering. A neural network model was established using the characteristic genes of CC, while the verification accuracy of the model was examined by Cox regression. The differences in the immune infiltrating cells between the normal cervical and CC tissues were compared by CIBERSORT (an analytical tool can provide an estimation of the abundances of member cell types in a mixed cell population). Nine genes' characteristics for CC were identified: cyclin-dependent kinase inhibitor 2A (CDKN2A), chromosome 1 open reading frame 112 (C1orf112), helicase, lymphoid-specific (HELLS), mini-chromosome maintenance protein 5 (MCM5), mini-chromosome maintenance protein 2 (MCM2), kinetochore associated 1 (KNTC1), cysteine-rich secretory protein 3 (CRISP3), phytanoyl-CoA 2-hydroxylase interacting protein (PHYHIP), and cornulin (CRNN). ANN is a robust neural network model that can be used to potentially predict CC based on the gene score. It can provide novel insights into the pathogenesis and molecular mechanisms of CC.

Comparison of PARPi efficacy according to homologous recombination deficiency biomarkers in patients with ovarian cancer: a systematic review and meta-analysis

Mutations in the BRCA1/2 (BRCA) genes are associated with response to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi). In addition, there are different homologous recombination deficiency (HRD) biomarkers available in clinical practice [e.g., genome-wide loss-of-heterozygosity (gLOH) and myChoice® score] that identify patients who can benefit from PARPi. Inconsistencies in biomarkers used in PARPi clinical trials make it challenging to identify clinically relevant predictive biomarkers. This study aims to compare clinically available HRD biomarkers in terms of benefits from PARPi. We performed database search for phase II or III randomized clinical trials comparing PARPi versus chemotherapy, and meta-analysis using generic inverse variance and a Random Effects model. Patients were classified according to their HRD status: (I) BRCAm (patients with BRCA mutation of germline or somatic origin); (II) non-BRCA HRD [patients BRCA wild-type (wt) with another HRD biomarker-gLOH or myChoice®]; and (III) homologous recombination proficiency (HRP) (BRCAwt and without HRD biomarkers). From those that were BRCAwt, we compared myChoice®+ with gLOH-high. Five studies (3,225 patients) analyzing PARPi in first line setting were included. Patients with BRCAmut had progression-free survival (PFS) with hazard ratio (HR) 0.33 [95% confidence interval (CI): 0.30-0.43]; patients with non-BRCA HRD had a PFS HR 0.49 (95% CI: 0.37-0.65), and patients with HRP had a PFS HR 0.78 (95% CI: 0.58-1.03). Eight studies (5,529 patients) with PARPi including first line and recurrence settings were included. BRCAmut had PFS HR 0.37 (95% CI: 0.30-0.48), BRCAwt & HRD 0.45 (95% CI: 0.37-0.55) and HRP 0.70 (95% CI: 0.57-0.85). Patients with BRCAwt & myChoice® ≥42 had PFS HR 0.43 (95% CI: 0.34-0.56), similar to patients with BRCAwt & gLOH-high with PFS HR 0.42 (95% CI: 0.28-0.62). Patients with HRD derived significantly more benefit from PARPi when compared to patients with HRP. The benefit of PARPi in patients with HRP tumors was limited. Careful cost-effectiveness analysis, and alternative therapies or clinical trial enrollment should strongly be considered for patients with HRP tumors. Among patients with BRCAwt, a similar benefit was found in patients with gLOH-high and those myChoice®+. The clinical development of further HRD biomarkers (e.g., Sig3) may help identify more patients who benefit from PARPi.

Efficacy and safety of PD-1 inhibitor combined with concurrent chemoradiotherapy in locally advanced cervical cancer with pelvic and/or para-aortic lymph node metastases: a retrospective cohort study

The prognosis remains poor after standard chemoradiotherapy in locally advanced cervical cancer patients with pelvic and/or para-aortic lymph node metastases. Programmed cell death receptor-1 (PD-1) inhibitors have been recommended as the first-line treatment for recurrent cervical cancer. The efficacy of PD-1 inhibitor combined with concurrent chemoradiotherapy in locally advanced cervical cancer was still uncertain. This study aimed to explore the efficacy and safety of PD-1 inhibitors combined with concurrent chemoradiotherapy in locally advanced cervical cancer patients with pelvic and/or para-aortic lymph node metastases. This retrospective study included patients with pelvic and/or para-aortic lymph node positive diseases [International Federation of Gynecology and Obstetrics (FIGO) stage IIB-IVA] who had received PD-1 inhibitors plus chemoradiotherapy/radiotherapy between April 1, 2020, and March 31, 2022 at the Hunan Cancer Hospital. The baseline clinicopathological characteristics, treatment, and clinical outcomes were collected. The major clinical outcomes were objective response rate (ORR), progression-free survival (PFS), and treatment-related adverse events (TRAEs). A total of 29 patients were included. The mean age was 55.8 [standard deviation (SD): 8.8] years. Most patients had stage IIIA-IIIB disease (72.4%) and squamous cell carcinoma (93.1%). All patients had lymph node metastases, including 24 (82.8%) with multiple metastases and 11 (37.9%) with para-aortic lymph node metastases. Among the 29 patients, 18 received sintilimab and 11 received camrelizumab concurrently with chemoradiotherapy or radiotherapy. The ORR was 96.6% [95% confidence interval (CI): 0.828, 0.993] at 3 months after radiotherapy (including 15 complete responses and 13 partial responses). At the data cutoff (August 31, 2022), the median follow-up was 14 (range, 5-30) months. The median PFS was not mature. The estimated 1- and 2-year PFS rates were 85.3% (95% CI: 60.1%, 95.2%) and 76.8% (95% CI: 47.0%, 91.2%), respectively. TRAEs of any grade occurred in 27 (93.1%) patients, most commonly as a decrease in white blood counts (82.8%), anemia (58.6%), and fatigue (48.3%). TRAEs of grade 3 or greater occurred in eight (27.6%) patients. There were no treatment-related deaths. PD-1 inhibitor combined with concurrent chemoradiotherapy showed potential benefit in term of tumor response and PFS in locally advanced cervical cancer patients with pelvic and/or para-aortic lymph node metastases.

How far should we go in optimal cytoreductive surgery for ovarian cancer?

The treatment of ovarian cancer should be appropriate, since clinical and surgical decisions may affect the prognosis; the surgery must be performed by an expert oncological surgeon or gynecological oncologist, it's fundamental roles are cancer staging and cytoreduction. The concept of staging surgery in early stages has its justification in the fact that up to 11% of "early ovarian cancers" will have metastasis in different sites of the peritoneal cavity at the time of diagnosis. In advanced stages of epithelial ovarian cancer, the goal is the complete cytoreduction of all visible macroscopic disease, since this variable is the most strongly associated with increased overall survival and disease-free period. The ideal time for cytoreductive surgery in relation to chemotherapy (before or after) is still under debate. In 2010 a randomized trial (EORTC) was published, comparing 310 patients initially operated (followed by adjuvant chemotherapy) versus 322 patients initially treated with neoadjuvant chemotherapy (followed by cytoreductive surgery); no significant differences in overall survival between groups were found. Another important factor playing a role in survival and in the probability of surgical cytoreductive success is tumor biology; there has been described a clear difference between serous and mucinous tumors, but some groups advocate that maximal surgical effort in mucinous tumors may compensate morbidity with an increase in survival. The extension of resection in cytoreduction is still controversial; some authors have confirmed that the most important factor is the residual disease and that radical surgery is superior to non-radical surgery in terms of overall survival. The need and extent of lymphadenectomy in advanced cancer will be treated in another chapter of this issue. Undoubtedly, an important factor is to perform procedures in specialized centers.

PARP inhibitors in ovarian cancer: evidence for maintenance and treatment strategies

Ovarian cancer is the most lethal gynecologic malignancy. The long-established primary treatment for ovarian cancer consisted of surgical cytoreduction followed by platinum-based chemotherapy. Unfortunately, this therapeutic approach is related to a high frequency of early relapses. Further chemotherapy is necessary for recurrent disease, but very few patients can be cured. Poly (ADP-ribose) polymerase (PARP) is a family of proteins involved in various DNA repair activities. PARP inhibition leads to synthetic lethality in BRCA mutated or homologous recombination deficient tumors. The development of PARP inhibitors has changed the way ovarian cancer patients are treated. Olaparib, niraparib and rucaparib are orally active and have demonstrated efficacy for both maintenance and treatment settings. These three drugs have gained regulatory approval for different clinical circumstances. They have an acceptable toxicity profile and are generally well tolerated. Common class toxicities include hematologic effects, gastrointestinal effects and fatigue. Moreover, new treatment strategies that combine PARP inhibitors with other drugs, such as angiogenic agents, are being explored. The purpose of this review is to describe the evidence that define the current clinical role of PARP inhibitors in ovarian cancer. The implementation of rationally designed new clinical trials will be crucial to facilitate the best selection of patients and to continue improving clinical outcomes.

Breast cancer (BRCA) gene testing in ovarian cancer

The discovery of cancer-causing BRCA1/2 mutations and the emergence of genetic testing have brought precision in patient selection for poly-(ADP)-ribose polymerase inhibitor (PARPi) treatment. Interestingly, patients who are carriers of BRCA1/2 mutations have a higher risk for developing cancer, but respond better to DNA-damaging cytotoxic therapy, such as platinum-based chemotherapy. The distinctive biology of ovarian cancer involves high genomic instability consisting of gene amplification, gene deletion, oncogene hypomethylation, loss of heterozygosity, and tumor suppressor gene promoter hypermethylation in many of the DNA damage response (DDR) genes, including BRCA1/2. Several of these genetic abnormalities can impair high fidelity DNA damage repair increasing the therapeutic audience for PARPi's. This is especially important given the clinical development over the last decade of this group of agents and the dramatic increase in progression free survival among ovarian cancer patients who received PARPi, both in treatment or maintenance setting. In this review, we summarize our current understanding of the role of BRCA1/2 mutations in ovarian cancer and present relevant clinical trials in which BRCA1/2 was investigated as biomarker for therapy. We also outline the role of homologous recombination (HR) deficiency as biomarker by presenting the recent clinical development and recent approvals PARPi for firstline maintenance in ovarian cancer.

Fertility-sparing treatment for epithelial ovarian cancer: a literature review

Epithelial ovarian cancer is more common in postmenopausal women, with a mean age at diagnosis of 65 years; however, it has been documented that 3% to 17% of epithelial ovarian cancer cases are diagnosed in women younger than 40 years, with an overall survival of up to 90% when diagnosed in early-stage disease. The development of fertility-sparing approaches represents one of the most significant advances in the gynecologic oncology field. These approaches can have satisfactory outcomes on fertility with excellent oncological results in premenopausal women with early-stage epithelial ovarian cancer and the desire to preserve fertility. Because of the low occurrence of this specific population, randomized trials have not been performed. However, several retrospective series suggest that in certain cases, fertility-sparing surgery is safe, with low rates of recurrence and favorable reproductive outcomes in accordance to the new techniques in reproductive biology; therefore, fertility-sparing approaches must be discussed with young female patients with epithelial ovarian cancer or in patients that desire to preserve fertility or to maintain ovarian function and to improve quality of life in this particular group of individuals. In this review, we present the published evidence, including oncologic and reproductive results, as well as fertility-sparing surgical options, in the field in the last 10 years.

Non-epithelial ovarian carcinoma: what is the optimal staging surgery?

Non-epithelial ovarian neoplasms are a group of infrequent, heterogenous clinical and histological tumors that account from 6% to 10% of ovarian malignancies, the two most common non-epithelial ovarian neoplasms are germ cell tumors and sex cord-stromal cell tumors, each of these classifications is divided in multiple histologic subtypes. In the case of epithelial ovarian tumors comprehensive surgical staging has remained as the gold standard for staging, nonetheless for non-epithelial ovarian neoplasms the use of staging surgery has remained debatable and controversial throughout the years in order to correctly stage non-epithelial ovarian carcinomas. Despite the fact that the role of surgery remains critical in the adequate management of all ovarian tumors, there are several manners to surgically approach an ovarian tumor depending on the type of tumor, risk factors and staging of disease. There are multiple reasons why the use of surgery in non-epithelial ovarian tumors is still debatable nowadays, for instance the main reason relies in the low prevalence of this disease, therefore there are few studies that actually offer a clear and sufficient overview to this issue. The objective of this manuscript is to present a comprehensive review of the non-epithelial carcinoma and to focus in the latest information, evidence and recommendations about the optimal treatment and staging surgery for these tumors.

Role of hyperthermic intraperitoneal chemotherapy in ovarian cancer

Epithelial ovarian cancer (EOC), has the highest worldwide mortality of all gynecological tumors, in 75% of cases is diagnosed in advanced stages. Despite of treatments with maximal cytoreductive surgery (CRS) and platinum-based chemotherapy (CT), approximately 70% of patients with advancedstage disease relapse within 18 months, given this high number of recurrences, new approaches are needed to improve outcomes for these patients. Hyperthermic intraperitoneal chemotherapy (HIPEC) has fundamentally changed the treatment of patients with ovarian cancer, with complete CRS and locoregional administration of chemotherapy. The purpose of this review is to find the most relevant, reliable published evidence of the use of HIPEC in ovarian cancer, together with an overview of peritoneal carcinomatosis (PC), procedures, therapeutic approaches in first-line and recurrent disease, the benefit of hyperthermia, selection of the ideal patient for the HIPEC procedures as well to analyze the disease free survival (DFS), morbidity, mortality and overall survival (OS) in patients with ovary cancer. So far, the small amount of evidence points favorably to the use of CRS and HIPEC as a first line of therapy, but more prospective randomized trials are needed to officially adopt this procedure as a standard of care, additionally patients need to know this option exists.

The prognostic nomogram in platinum-resistant ovarian cancer: how to develop and validate?

Can lymphadenectomy be omitted in advanced ovarian cancer?—a brief review

The indication of systematic lymphadenectomy in advanced ovarian cancer without apparent macroscopic lymph node involvement has been controversial over the past three decades, and the recommendation to perform it or not has been based on multiple retrospective studies, small cohort studies, and few randomized studies with several biases; however, it seems that this controversy has come to an end after the recent publication of a randomized clinical trial. The study of lymph node disease in ovarian cancer has intensified in the last two decades, so far that it was part of the changes of the last update of the International Federation of Gynecology and Obstetrics (FIGO) staging; In this review, a search was made of the available literature to understand the evolution of knowledge about the implications of the realization or not of lymphadenectomy in two scenarios of advanced ovarian cancer (namely, the presence or not of lymph node disease macroscopic), without losing the landscape of the importance of peritoneal disease in these stages, which, as we will see throughout the review, the complete cytoreduction of the tumor remains an integral part of the treatment, since residual disease is one of the most relevant prognostic factors. Nowadays, we can confidently state that systematic lymphadenectomy in patients with advanced ovarian cancer without clinically apparent nodal disease is not necessary, and the presence of macroscopic retroperitoneal lymph node disease should be resected as part of cytoreductive surgery since it will be this and the residual disease that determine the prognosis of the patients.

Ovarian carcinoma: pathology review with an emphasis in their molecular characteristics

Ovarian carcinoma is highly aggressive and difficult to treat neoplasm, which is usually detected in advanced stages where most patients recur. Extensive investigation about several treatment modalities has been performed but this neoplasm has poor benefits from such treatments including targeted therapy. Recent data have begun to highlight the histological and molecular heterogeneity of these tumors defining this neoplasm, not as a single disease but a group of heterogeneous histological subtypes with important differences in terms of genetics, morphology, oncogenesis, prognosis, chemosensitivity and especially molecular characteristics that are likely to be targets of new molecules. In general, high-grade serous carcinomas are characterized by great genomic instability and frequent amplifications and deletions; lowgrade ovarian neoplasms are genomically stable. On this phytopathogenic basis, recent findings suggest a dual model of carcinogenesis consisting of two large groups named types I and II. Type I cancers (serous, mucinous, and low-grade endometrioid) commonly arise from well-described, genetically stable precursor lesions (usually borderline tumors); manifests as large adnexal masses with the early-stage disease, and they have a good overall prognosis. In contrast, type II carcinomas (serous, high-grade endometrioid, mixed, and undifferentiated carcinomas) originate de novo from the adnexal epithelium, often demonstrate chromosomal instability, and have aggressive biological behavior. Surprisingly, most of the genomic abnormalities detected encode known oncogenic proteins for which there is targeted therapy. Then, there is a real potential for personalized medicine adapted to the molecular portrait of tumors. In this review, I synthesize the histology and molecular pathology of ovarian carcinomas and possible strategies to reach targeted therapy.

Integrating PARP inhibitors into the management of breast cancer: where are we?

During the last 2 decades, extensive research has focused on the molecular functions of BRCA1 and BRCA2 genes. This has led to the development of Poly(ADP-ribose) polymerase inhibitors (PARPi), as effective target therapies, based on their preferential cytotoxicity in tumor cells harboring germline BRCA1 and BRCA2 mutations. At the present time, 2 PARPi (Olaparib and Talazoparib) are approved as single agent for the treatment of patients with metastatic HER2-ve breast cancer, who have BRCA germline mutations. The clinical benefit of these agents might be also anticipated in patients harboring germline mutations in some additional genes involved in the process of homologous recombination repair (HRR) other than BRCA1/BRCA2. In this review, we summarize the molecular rational for the therapeutic development of PARPi and the clinical evidence supporting their use as anticancer drugs in breast cancer patients with BRCA1/BRCA2 germline mutations. We also discuss the role of platinum-based chemotherapy and how it compares with PARPi in the management of these patients. We will go through some relevant clinical trials of various combinations of PARPi with cytotoxic or immunotherapeutic agents, which may potentially provide better treatment results, compared to what is already achieved with their use as monotherapy.

Clinical analysis of patients with skin metastasis of cervical squamous cell carcinoma

Cancers that metastasize to the skin are rare, especially cervical squamous cell carcinoma to the skin. Here, we have reported clinical analysis of patients with cervical squamous cell carcinoma metastasize to skin, to obtain a general understanding of this malignancy for clinicians. A retrospective analysis of patients with skin metastasis from cervical squamous cell carcinoma was conducted, focusing on clinical manifestations, histopathology, diagnosis, treatment, and prognosis. The average age of onset for the six patients with skin metastasis from cervical squamous cell carcinoma was 55.17±17.08 years, with four cases presenting as solitary lesions and two cases as multiple lesions. Treatment strategies included local excision for isolated lesions, chemotherapy, radiotherapy, or targeted therapy based on the extent of skin involvement, and immunotherapy was proved to have promising results in our cases. Among the six patients, three have passed away with a diagnosis-to-death time of approximately 5-6 months, while three patients are alive, with survival times ranging from 30 to 72 months. Skin metastasis from cervical squamous cell carcinoma is rare and often accompanies recurrent metastases to other visceral sites, necessitating early and accurate diagnosis. For isolated metastatic lesions, early detection followed by wide excision surgery and adjuvant radiotherapy can yield favorable outcomes. However, in cases of multiple skin metastases or concurrent metastases to multiple organs, treatment is challenging with a poor prognosis. Nevertheless, with advancements in medicine, combination chemotherapy, immunotherapy, and targeted therapy can effectively prolong survival, offering new hope for patients with skin metastasis from cervical cancer.