conclusion of ovarian cancer essay

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Committee on the State of the Science in Ovarian Cancer Research; Board on Health Care Services; Institute of Medicine; National Academies of Sciences, Engineering, and Medicine. Ovarian Cancers: Evolving Paradigms in Research and Care. Washington (DC): National Academies Press (US); 2016 Apr 25.

Ovarian Cancers: Evolving Paradigms in Research and Care.

• Hardcopy Version at National Academies Press

Although recent years have seen many promising advances in cancer research, there remain surprising gaps in the fundamental knowledge about and understanding of ovarian cancer. Researchers now know that ovarian cancer cannot be categorized as a single disease; several distinct subtypes exist with different origins, risk factors, genetic mutations, biological behaviors, and prognoses. However, researchers do not have definitive knowledge of how and where these various ovarian cancers arise. Such unanswered questions impede progress in the prevention, early detection, treatment, and management of ovarian cancers. In particular, the failure to improve ovarian cancer morbidity and mortality during the past several decades is likely due to several factors, including

• A lack of research focusing on specific disease subtypes;
• An incomplete understanding of genetic and nongenetic risk factors;
• An inability to develop and validate effective screening and early detection tools;
• Inconsistency in the delivery of the standard of care;
• Limited precision medicine approaches tailored to the disease subtypes and tumor characteristics; and
• Limited attention paid to research on survivorship issues, including supportive care with long-term management of active disease.

The symptoms of ovarian cancers can be nonspecific, so they are often not seen as indicating a serious illness by women or their health care providers until the symptoms worsen, at which point the cancer is often widespread and difficult to cure. Late diagnosis is a major factor contributing to the high mortality rate. Indeed, roughly two-thirds of women with ovarian cancer are diagnosed with an advanced-stage cancer (or a cancer that has not been thoroughly staged), which is associated with less than 30 percent overall 5-year survival. Furthermore, although many ovarian cancers initially respond to treatment, the vast majority recur. Recurrent ovarian cancers may respond to further treatment, but virtually all of them will ultimately become resistant to current drug therapies. Overall, little attention has been paid to managing the acute and long-term physical and psychosocial effects of ovarian cancer diagnosis and treatment or understanding when to transition to appropriate end-of-life care.

This report gives a broad overview of the state of the science in ovarian cancer research, highlights major knowledge gaps, and provides recommendations to help reduce the incidence of and morbidity and mortality from ovarian cancers by focusing on promising research themes that could advance risk prediction, prevention, early detection, comprehensive care (e.g., treatment and supportive care), and cure.

• STUDY CONTEXT, CHARGE, AND APPROACH

Although ovarian cancer is relatively uncommon, it is one of the deadliest cancers. Each year in the United States, more than 21,000 women are diagnosed with ovarian cancer, and more than 14,000 women die from the disease. Ovarian cancer is the fifth leading cause of cancer deaths among American women, and the 5-year survival rate is just under 46 percent. By contrast, the 5-year survival rate is nearly 90 percent for breast cancer, more than 80 percent for endometrial cancer, and nearly 70 percent for cervical cancer. Indeed, although the estimated number of new cases of ovarian cancer among American women each year is only one-tenth the number of new cases of breast cancer, the death-to-incidence ratio for ovarian cancer is more than three times higher than that for breast cancer (see Figure S-1 ).

The ratio between the death and incidence rates for ovarian, breast, endometrial, and cervical cancers per 100,000 women in the United States, 2008–2012.

Ovarian cancer has been called a “silent killer” because no distinctive symptoms had been associated with the early stages of the disease. However, recent research shows that most women with ovarian cancer report symptoms such as bloating, pelvic or abdominal pain, and urinary symptoms, and many women recall having had these symptoms for an extended period of time before diagnosis. In 2006, the U.S. Congress passed the Gynecologic Cancer Education and Awareness Act of 2005 (known as Johanna's Law) to launch a campaign to “increase the awareness and knowledge of health care providers and women with respect to gynecologic cancers.”

Study Charge

In the fall of 2014, with support from the Centers for Disease Control and Prevention (CDC), the Institute of Medicine (IOM) formed the Committee on the State of the Science in Ovarian Cancer Research to examine and summarize the state of the science in ovarian cancer research, to identify key gaps in the evidence base and challenges to addressing those gaps, to consider opportunities for advancing ovarian cancer research, and to examine ways to disseminate new information to all stakeholders.

To guide its deliberative process, the committee developed a conceptual model to identify research gaps across the continuum of ovarian cancer care and also in critical areas of cross-cutting research (see Figure S-2 ).

Framework for research in ovarian cancer. NOTE: Colored figures represent phases of the ovarian cancer care continuum where research can be focused. Black boxes indicate critical areas of ongoing cross-cutting research that span these phases.

Defining Ovarian Cancer

“Ovarian cancer” is a generic term often used for any primary malignant ovarian tumor, but it is a misnomer in the sense that ovarian cancer is not just one disease. Rather, it refers to a constellation of distinct types of cancer involving the ovary. Ovarian cancers with epithelial differentiation (carcinomas) represent the majority of malignant tumors and are responsible for most ovarian cancer–related deaths. This classification is complicated by recent evidence suggesting that many ovarian carcinomas do not arise in the ovary per se. Instead they may, in fact, arise in other tissues (e.g., the fallopian tubes) and then metastasize to the ovary, or arise from cells that are not considered intrinsic to the ovary (see Figure S-3 ).

Potential cellular origins of ovarian carcinomas. NOTE: White arrows indicate ovarian surface epithelium (OSE); black arrows indicate fallopian tube epithelium (FTE). SOURCE: Photographs of pathology slides reprinted with permission from Kathleen Cho (more...)

Ovarian carcinomas themselves also represent a heterogeneous collection of different tumor types (see Figure S-4 ). Ovarian carcinomas account for more than 85 percent of ovarian cancers, and more than 70 percent of ovarian carcinomas are high-grade serous carcinomas (HGSCs). Consequently, this report focuses on ovarian carcinomas, with a particular emphasis on HGSCs, recognizing that other less common types of ovarian malignancies exist and are responsible for a smaller fraction of deaths.

Percentage of cases by major ovarian carcinoma subtype. NOTE: Other* refers to mixed or transitional carcinomas where it is not possible to categorize to a single subtype. SOURCES: Gilks et al., 2008; Seidman et al., 2003, 2004.

• RECOMMENDATIONS

The committee focused on identifying the research gaps that, if addressed, could have the greatest impact on reducing ovarian cancer morbidity or mortality. A wide variety of stakeholders are integral to ovarian cancer research, including the U.S. Congress, federal agencies (e.g., CDC, U.S. Department of Defense, U.S. Food and Drug Administration, National Institutes of Health), private foundations, industry, academic institutions, professional societies, and advocacy groups. Most of these stakeholders are engaged in research across the care continuum, and many are both funders and performers of research. The committee therefore concluded that directing research toward the gaps identified in the recommendations is the responsibility of all stakeholders in their individual and collaborative efforts to fund, perform, or advocate for ovarian cancer research.

The committee identified four overarching concepts that should be applied to each recommendation in this report:

• As the most common and lethal subtype, the study of HGSC needs to be given priority;
• Even so, more subtype-specific research is also needed to further define the differences among the various subtypes;
• Given the relative rarity and heterogeneity of ovarian cancers, collaborative research (including the pooling and sharing of data and biospecimen resources, such as through consortia) is essential; and
• The dissemination of new knowledge and the implementation of evidence-based interventions and practices are the final steps in the knowledge translation process.

These recommendations are intertwined and so need to be considered simultaneously, not sequentially. Their sequence should not be considered as indicating priority of importance or an order of implementation.

The Biology of Ovarian Cancer

Recent evidence suggests that many ovarian carcinomas do not arise in the ovary. Furthermore, researchers do not have a complete understanding for each subtype of how the disease progresses or the effects of the microenvironment. Without better model systems that replicate the manifestations of the human disease, the answers to many key questions will remain elusive. This research gap is further complicated by the significant degree of heterogeneity of ovarian carcinomas, including within and between subtypes. However, clinicians and researchers tend to combine them in many types of research. In spite of recent advances, the incomplete understanding of the basic biology of each subtype, including origin and pathogenesis, is an impediment to advances in prevention, screening and early detection, diagnosis, treatment, and supportive care.

RECOMMENDATION 1: Researchers and funding organizations should design and prioritize preclinical, clinical, and population-based research agendas that take into account the different ovarian cancer subtypes. A top priority should be elucidating the cellular origins and pathogenesis of each subtype. Particular attention should be paid to:

• Tumor characteristics such as microenvironment, intratumoral heterogeneity, and progression pathways;
• The development of experimental model systems that reflect ovarian cancer heterogeneity; and
• Incorporation of the multi-subtype paradigm into prevention, screening, diagnosis, and treatment research.

While it will be critical to apply this multi-subtype approach to research on ovarian cancer, an incomplete understanding of the biology of these cancers has prevented the emergence of uniform standards for describing the characteristics of the subtypes. Tumor classification, nomenclature, and grading systems have changed over time as new insights have emerged, and evidence suggests that there is substantial variability in current surgical and pathological practices for the reporting of ovarian cancers. The implementation of a single, uniformly implemented nomenclature and classification scheme (with standardized diagnostic criteria) is essential and will serve as the necessary foundation for all future research in ovarian cancer.

RECOMMENDATION 2: Pathology organizations, oncology professional groups, and ovarian cancer researchers should reach consensus on diagnostic criteria, nomenclature, and classification schemes that reflect the morphological and molecular heterogeneity of ovarian cancers, and they should promote the universal adoption of a standardized taxonomy.

Achieving this consensus will be complex. Multiple stakeholders will need to be engaged in an iterative process in which the schemes can change. Stakeholders can employ a variety of options for moving toward consensus, including the creation of ongoing working groups by subtype, as has been done in other diseases.

The committee again emphasizes that these recommendations about biology research and taxonomy need to be considered simultaneously. That is, a common taxonomy is needed based on the best currently available research, and research designs going forward will need to be based on this common taxonomy, but the taxonomy will also need to evolve as more is learned about the biology of the subtypes. For example, an improved understanding of molecular characterizations (see Recommendation 8) may, in fact, be more informative for classification than shared appearance. Simultaneously, an enhanced understanding of the characterizations of the subtypes will inform the development of targeted therapeutics (see Recommendation 9), and the drive for targeted therapeutics will, in turn, require more basic research on the biology of the ovarian cancer subtypes.

Risk Assessment, Screening, and Early Detection

Better methods for identifying high-risk women could facilitate the prevention or early detection of ovarian cancers. A family history of ovarian cancer, specific germline (inherited) genetic mutations, and certain hereditary cancer syndromes have strong associations with risk for ovarian cancer. The BRCA1 and BRCA2 genes are the most recognizable ovarian cancer risk-related genes, followed by the mismatch repair genes associated with Lynch syndrome. Several other risk-related genes have been identified but are less well studied. Although family history is linked to an increased risk for all ovarian cancer subtypes, it is most strongly linked with risk for HGSC, where up to 25 percent of women have a germline mutation. Multiple groups recommend that all women diagnosed with an invasive ovarian cancer receive genetic testing and counseling, for a variety of reasons, including to determine the appropriate therapies, to assess other health risks, and to estimate the risk for family members. Genetic counseling and testing are also recommended for the first-degree relatives of women with a hereditary cancer syndrome or germline mutation (i.e., cascade testing). For the first-degree relatives of women with ovarian cancer who have not had genetic testing, genetic counseling would be appropriate for assessing risk and the need for testing. Women without ovarian cancer who carry germline mutations associated with greatly increased risk for developing ovarian cancer (sometimes referred to as “previvors”) may benefit from enhanced screening, risk-reducing procedures, or chemoprevention. However, referrals for genetic counseling and testing are hindered by various patient-, provider-, and system-level barriers, such as a patient's lack of awareness of her family history, the limited time that providers generally have to collect a family history, and complex and inconsistent referral criteria. Furthermore, more research is needed to determine the significance of known mutations and to discover new significant mutations for all subtypes.

RECOMMENDATION 3: Researchers, public health practitioners, and clinicians should develop and implement innovative strategies to increase genetic counseling and testing, as well as cascade testing for known germline genetic predispositions in appropriate populations (e.g., untested ovarian cancer survivors and relatives of individuals who tested positive). Furthermore, researchers, clinicians, and commercial laboratories should determine the analytic performance and clinical utility of testing for other germline mutations beyond BRCA1 and BRCA2 and the mismatch repair genes associated with Lynch syndrome.

Risk cannot be fully assessed by relying on family history alone. Up to one-half of women with high-risk germline mutations do not have an apparent family history of breast or ovarian cancer, and family history may not identify risk for women with few female relatives or for women who do not know the family health history of one or both parents. Furthermore, as the majority of women with ovarian cancer do not appear to have a known high-risk germline mutation or a significant family history, it is critical to consider other potential risk factors. While several nongenetic factors are associated with either an increased or a decreased risk for developing ovarian cancer, the patterns of association are inconsistent, and the strongest factors to date are those associated with the less common and less lethal subtypes.

RECOMMENDATION 4: Researchers and funding organizations should identify and evaluate the underlying mechanisms of both new and established risk factors for ovarian cancers in order to develop and validate a dynamic risk assessment tool accounting for the various ovarian cancer subtypes. Furthermore, a spectrum of risk factors should be considered, including genetics, hormonal and other biological markers, behavioral and social factors, and environmental exposures.

Collaborations between clinicians and population and basic scientists will help identify potential new risk factors and also provide an opportunity to better understand how specific exposures influence disease development. Current research does not provide insight as into which risk factors need to be prioritized for future research. In light of the heterogeneity of the cell of origin, an emphasis on factors that influence early carcinogenesis may have the largest impact on identifying women at high risk.

Women known to be at high risk may benefit from nonsurgical and surgical preventive measures, but the risk–benefit ratios of these measures need to be better defined for different subtypes and at-risk populations. For example, the use of prescription medications (e.g., oral contraceptives) and risk-reducing surgeries (e.g., bilateral salpingo-oophorectomy and salpingectomy) need to be weighed against potential complications and long-term side effects (e.g., stroke risk, risk for other cancers, surgical complications, and overall mortality). As new prevention strategies are developed, researchers will need to amass an evidence base for their efficacy as well as their potential long-term harm.

RECOMMENDATION 5: Clinicians, researchers, and funding organizations should focus on quantifying the risk–benefit balance of nonsurgical and surgical prevention strategies for specific subtypes and at-risk populations.

Current approaches for early detection include assaying for biomarkers, often in combination with imaging technologies. While the use of these strategies in large screening trials has resulted in more ovarian cancers being detected at earlier stages, to date they have not had a substantial impact on overall mortality. Given the marked heterogeneity of ovarian cancers and the incomplete understanding of early disease development for each subtype, it is highly unlikely that a single biomarker or imaging modality will be sufficient to aid in the early detection of all the subtypes. While research on refining current methods may be fruitful, distinct multimodal approaches will likely be needed to detect each of the various subtypes at their earliest stages.

RECOMMENDATION 6: Researchers and funding organizations should focus on the development and assessment of early detection strategies that extend beyond current imaging modalities and biomarkers and that reflect the pathobiology of each ovarian cancer subtype.

Going forward, screening trials may be more informative if conducted in populations with elevated ovarian cancer risk. Research on the impact of earlier detection on quality of life will also be important.

Diagnosis and Treatment

Compared to the situation over the past few decades, newly diagnosed ovarian cancers are now being more accurately and consistently staged, and a wider variety of treatment options exist. Most women with newly diagnosed ovarian cancer undergo primary debulking surgery (PDS) to remove as much of the grossly visible tumor as possible (cytoreduction), as well as to make it possible to determine a specific diagnosis (e.g., subtype, staging). Survival is markedly better for women who have complete (or optimal) tumor resection, yet great variability exists in the extent of tumor resection. For women in whom an optimal resection is not thought to be feasible, or who are unable to undergo PDS due to comorbidities, neoadjuvant chemotherapy (NACT) can reduce tumor size and facilitate subsequent resection. After surgery, women typically receive multiple cycles of chemotherapy. While the majority of women respond well to initial treatment, most will experience a recurrence of the disease, resulting in a cycle of repeated surgeries and additional rounds of chemotherapy.

Standard of Care

Several organizations have developed national clinical practice guidelines for the assessment and treatment of women with both newly diagnosed and recurrent ovarian cancers. While women who receive care in accordance with these guidelines have considerably better clinical outcomes (e.g., improved survival and fewer surgical complications), less than one-half of women with ovarian cancer receive such care. For example, while the intraperitoneal (IP) route for the delivery of chemotherapy offers notable advantages over intravenous (IV) and oral routes, the adoption of IP chemotherapy protocols is not widespread. However, this is due in part to concerns regarding the efficacy and potential adverse effects of IP administration, and the better side-effects profile associated with newer IV regimens. In addition to the variation in adherence to standards of care for surgery and chemotherapy, the guidelines for cancer genetics referrals are not routinely or widely implemented (see Recommendation 3). Testing for germline mutations among women newly diagnosed with ovarian cancer is important because the presence of certain mutations informs therapy decisions.

Being treated by a gynecologic oncologist and having treatment in a high-volume hospital or cancer center are the two most significant predictors of whether a woman with ovarian cancer will receive the standard of care, and both are associated with better outcomes, but access to such care can be a challenge. Significant predictors of nonadherence to the standard of care include the patient being of advanced age at diagnosis, the presence of treatment-limiting comorbidities, being of a nonwhite race, and having a lower socioeconomic status. Like most other cancers, ovarian cancer primarily affects older adults, but little is known about the care of older women with ovarian cancer. For example, older women with comorbidities may be precluded from receiving the standard of care, which, in turn, may lead to worse outcomes. Also, historical trends show differences in outcomes by race, but the reasons for this are unknown. Finally, more research is needed on how quality metrics (including measures of outcomes) can help drive continuous quality improvement in ovarian cancer care. The current patterns of care reveal inconsistencies in therapeutic approaches and disparities in care delivery, which may contribute to poorer outcomes.

RECOMMENDATION 7: To reduce disparities in health care delivery and outcomes, clinicians and researchers should investigate methods to ensure the consistent implementation of current standards of care (e.g., access to specialist care, surgical management, chemotherapy regimen and route of administration, and universal germline genetic testing for newly diagnosed women) that are linked to quality metrics.

However, no one model of care will serve all patients in all settings. For example, women in rural settings may not have access to a gynecologic oncologist or a high-volume cancer center. Therefore, it will be necessary to explore innovative models of care that can help deliver the standard of care, such as the use of telemedicine for consultation and the use of patient navigation systems to support self-management. The committee recognizes that, as is the case in other areas of health care, issues such as payment, policy, and education and training of the health care workforce affect the delivery of the standard of care, and so these issues will also need further examination as new models are developed.

Predicting Response

While adherence to standards of care leads to improved outcomes, little is known about why some women respond better to specific surgical and chemotherapeutic therapies, or about how age affects treatment. For example, the question of which women should receive initial PDS or NACT remains unresolved. It may be that women with certain subtypes respond better to different therapies or that women who respond particularly well to a given treatment may share characteristics that extend beyond their tumor subtype.

Current classification systems also do not, for the most part, help to tailor treatment regimens. Recurrent ovarian cancers have traditionally been categorized as platinum sensitive if recurrence is diagnosed more than 6 months from prior therapy or platinum resistant if recurrence is diagnosed less than 6 months from prior therapy, but this classification does not reflect the mechanisms of recurrent disease. Several assays have been developed (or are in development) to determine the likelihood of primary and recurrent tumors' ability to respond to various chemotherapeutic agents, but at this time none of them have been validated.

RECOMMENDATION 8: Clinicians and researchers should focus on improving current treatment strategies, including a. The development and validation of comprehensive clinical, histopathologic, and molecular characterizations that better inform precision medicine approaches for women with newly diagnosed and recurrent disease; b. Advancement in the understanding of the mechanisms of recurrent and drug-resistant (e.g., platinum-resistant) disease and the development of a more informative classification system; c. The identification of predictors of response to therapy and near-term indicators of efficacy; and d. The determination of the optimal type and timing of surgery in women newly diagnosed with ovarian cancer and of the efficacy of subsequent cytoreduction procedures for women with recurrent disease.

Several modalities can be used to match individual patients to specific procedures and treatments. The analysis of biomarkers, the determination of the molecular features of tumors, minimally invasive assessments (e.g., laparoscopy), and the use of imaging all provide insights. Similarly, a variety of approaches can be used to predict therapeutic efficacy, including scoring systems, genetic panel testing, and molecular profiling. The knowledge gained through these precision medicine approaches will also help to inform the development of new and better treatments.

Developing Better Treatments

While clinicians need better ways to select the most appropriate among existing treatments for individual patients, they also need more treatment options, and the development of better treatments depends in large part on the clinical trials system. The 2010 IOM report A National Cancer Clinical Trials System for the 21st Century outlined principles to improve the clinical trials system in general, including

• Improve collaboration among stakeholders, including the use of consortia;
• Define an effective mechanism for combining products in clinical trials;
• Develop and evaluate novel trial designs;
• Increase the accrual volume, diversity, and speed of clinical trials; and
• Educate patients about the availability, payment coverage, and value of clinical trials.

These principles are particularly relevant for ovarian cancer research, given the relative rarity of the disease combined with the diversity of subtypes. Comparative effectiveness studies, combination therapies, and multimodality strategies will all be important. This committee endorses these principles and suggests that they be applied to all recommendations related to clinical trials for ovarian cancer research.

Clinicians currently have few options for drug therapy, and the long-term efficacy of these agents is limited by a high rate of drug resistance. A better understanding of the diversity of ovarian cancers will offer the potential for targeted treatments. Innovative early phase clinical trial designs that incorporate biomarkers predictive of efficacy are needed to help identify which subtypes are likely to be responsive to specific new therapies. However, selecting clinically meaningful endpoints for trials in ovarian cancer can be challenging. For example, it may be difficult to determine the impact of a single agent on overall survival because women have typically had multiple previous therapies. Patient preferences also need to be considered in assessing the effectiveness of new therapies (e.g., the tolerable levels of side effects, given the expected outcomes). Furthermore, little research exists on nonpharmacologic therapies and interventions (e.g., diet, exercise, stress reduction) that might affect response to treatment. Overall, the current standard of care lacks precision medicine approaches to therapy.

RECOMMENDATION 9: Researchers should develop more effective pharmacologic and nonpharmacologic therapies and combinations of therapies that take into account the unique biology and clinical course of ovarian cancer. These approaches should include a. Developing immunologic and molecularly driven treatment approaches specific to the different ovarian cancer subtypes; b. Identifying markers of therapeutic resistance and exceptional response; and c. Using interdisciplinary teams to design and conduct statistically efficient and information-rich clinical studies.

The development of new approaches, however, will depend on developing a better understanding of the basic biology of the ovarian cancer subtypes (see Recommendation 1). As the committee did not find evidence for the superiority of any single treatment, it concluded that a variety of approaches need to be evaluated, including new combinations of existing drugs, new drug formulations, targeted biologics, protein inhibitors, TP53 -directed therapies, anti-angiogenics, immunotherapies, and nonpharmacologic interventions. All of these approaches have merit because their effectiveness may vary within and among subtypes.

Supportive Care Along the Survivorship Trajectory

Most research on ovarian cancers focuses on the treatment of the disease rather than on how to improve the management of the acute and long-term physical and psychosocial effects of diagnosis and treatment across the trajectory of survivorship. Although research on therapies that may provide life-saving benefit is crucial, complementary research on how to best support women living with ovarian cancer and improve their quality of life is also important for them and their families. Women with ovarian cancer require early and ongoing supportive care to ensure that aggressive, life-extending treatments are enhanced by multidisciplinary supportive care to maximize quality of life.

The 2013 IOM report Delivering High-Quality Cancer Care stated, “A high-quality cancer care delivery system depends on clinical research that gathers evidence of the benefits and harms of various treatment options so that patients, in consultation with their clinicians, can make treatment decisions that are consistent with their needs, values, and preferences.” However, for women with ovarian cancer, shared decision making and the management of the physical and psychosocial effects of diagnosis and treatment may be neglected in the effort to urgently address the disease, which is typically at an advanced stage at diagnosis. Also, a lack of professional expertise or resources may hinder joint decision making.

Current research provides little insight as to which women are most likely to suffer physical and psychosocial effects due to their diagnosis and treatment, or the best approaches for managing these effects. Furthermore, there may be differences in the needs of and best approaches for women of different demographic groups (e.g., older women versus younger women and women of different racial and ethnic groups). These research gaps may be addressed by more effective assessment of patient-reported symptoms and outcomes during treatment, especially on the outcomes that are most important to women (e.g., improved quality of life versus overall survival). Approaches to enhancing self-management, including leveraging mobile health technologies, need to be explored. Finally, as many women with ovarian cancer continue active treatment until the end of their lives, researchers need to help better define when disease-focused treatments are unlikely to be effective and the focus needs to shift to end-of-life care.

A majority of women with ovarian cancer require long-term active disease management, necessitating more effective approaches for supportive care and self-management.

RECOMMENDATION 10: Researchers and funding organizations should study the supportive care needs of patients with ovarian cancer throughout the disease trajectory, including a. Identifying the array of factors that put women at high risk for poor physical and psychosocial outcomes; b. Identifying and overcoming barriers to the systematic assessment of the physical and psychosocial effects of disease and treatment; c. Developing and implementing more effective supportive care and self-management interventions; and d. Defining the parameters that indicate when patients and their families would benefit from transitioning to end-of-life care.

Many of the supportive care needs of women with ovarian cancer are similar to those of women with other cancers. The committee endorses the following principles from previous IOM reports:

• Approaches for improving patient–provider communication and providing decision support,
• Screening instruments to identify psychosocial problems,
• Needs assessment instruments for psychosocial care planning, and
• Illness and wellness management interventions.
• Provide patients and their families with understandable information on cancer prognosis, treatment benefits and harms, palliative care, psychosocial support, and estimates of costs.
• Develop a common set of data elements that capture patient-reported outcomes, relevant patient characteristics, and health behaviors.
• Provide fact-based information to encourage advance care planning.
• Provide end-of-life care consistent with individual needs, values, and preferences.

Dissemination and Implementation

Amassing evidence on risk factors, treatments, and preventive strategies is not sufficient to ensure that this knowledge will be acquired and used by all stakeholders. A number of factors influence the movement of science into regular and effective use, including the complexity of health care systems, the capacity of practitioners and providers to absorb new knowledge, and the diversity of stakeholders. While the knowledge base on ovarian cancers has advanced, not all stakeholder groups are receiving important messages. This may contribute to the current variability seen in the delivery of the standard of care which, in turn, affects patient outcomes.

RECOMMENDATION 11: Stakeholders in ovarian cancer research, clinical care, and advocacy should coordinate the efforts to develop and implement efficient, effective, and reliable methods for the rapid dissemination and implementation of evidence-based information and practices to patients, families, health care providers, advocates, and other relevant parties. These efforts should include a. Researching impediments to adopting current evidence-based practices; b. Using multiple existing dissemination modalities (e.g., continuing education, advocacy efforts) to distribute messages strongly supported by the evidence base; and c. Evaluating newer pathways of dissemination and implementation (e.g., social media, telemedicine with specialists).

While progress has been made in understanding ovarian cancers over the past few decades, much remains to be learned, especially about the origins and mechanisms of development—fundamental knowledge that could change paradigms for prevention, screening and early detection, and treatment. Improved communication is also needed to recognize ovarian cancer as a constellation of many types of cancer involving the ovary. A focus on distinct areas of research within and across the continuum of ovarian cancer care will help improve the lives of all women at risk for or diagnosed with an ovarian cancer.

• Cite this Page Committee on the State of the Science in Ovarian Cancer Research; Board on Health Care Services; Institute of Medicine; National Academies of Sciences, Engineering, and Medicine. Ovarian Cancers: Evolving Paradigms in Research and Care. Washington (DC): National Academies Press (US); 2016 Apr 25. Summary.
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Paradigm Shift: A Comprehensive Review of Ovarian Cancer Management in an Era of Advancements

Valéria tavares, inês soares marques, inês guerra de melo, joana assis, deolinda pereira, rui medeiros.

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Correspondence: [email protected] ; Tel.: +351-22-508-4000

Received 2023 Dec 31; Revised 2024 Jan 30; Accepted 2024 Feb 2; Collection date 2024 Feb.

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/ ).

Ovarian cancer (OC) is the female genital malignancy with the highest lethality. Patients present a poor prognosis mainly due to the late clinical presentation allied with the common acquisition of chemoresistance and a high rate of tumour recurrence. Effective screening, accurate diagnosis, and personalised multidisciplinary treatments are crucial for improving patients’ survival and quality of life. This comprehensive narrative review aims to describe the current knowledge on the aetiology, prevention, diagnosis, and treatment of OC, highlighting the latest significant advancements and future directions. Traditionally, OC treatment involves the combination of cytoreductive surgery and platinum-based chemotherapy. Although more therapeutical approaches have been developed, the lack of established predictive biomarkers to guide disease management has led to only marginal improvements in progression-free survival (PFS) while patients face an increasing level of toxicity. Fortunately, because of a better overall understanding of ovarian tumourigenesis and advancements in the disease’s (epi)genetic and molecular profiling, a paradigm shift has emerged with the identification of new disease biomarkers and the proposal of targeted therapeutic approaches to postpone disease recurrence and decrease side effects, while increasing patients’ survival. Despite this progress, several challenges in disease management, including disease heterogeneity and drug resistance, still need to be overcome.

Keywords: ovarian neoplasms, biomarkers, early detection of cancer, diagnosis, antineoplastic protocols

1. Introduction

In 2020, ovarian cancer (OC) was the eighth most diagnosed malignancy worldwide, affecting approximately 314,000 women and also ranking as the eighth most deadly cancer, with over 207,000 attributed deaths [ 1 , 2 ]. Like other tumours, the incidence and mortality of OC vary worldwide. While the disease is more common in European countries with high Human Development Index (HDI) levels, the lowest incidence rates are observed in African countries with a low HDI. In opposition, the mortality rates tend to have a reversed inclination [ 2 , 3 ].

Worldwide, OC has consistently been regarded as the most lethal gynaecological tumour. Despite improvements in disease management, particularly in surgical techniques and maintenance therapy (treatment after the first-line therapeutic approach to delay disease recurrence), OC patients still have a 5-year survival rate lower than 50% in most countries [ 4 ]. This is primarily driven by late disease diagnosis, owing to its non-specific symptoms and the lack of appropriate screening methods, combined with the frequent acquisition of chemoresistance leading to disease recurrence [ 5 , 6 ].

Although ovarian tumourigenesis is poorly comprehended, the disease is thought to arise from the ovarian surface epithelium. Also, it is closely related to tumours originating from the peritoneum and the fallopian tube, according to the serous tubal intraepithelial carcinoma (STIC) theory [ 7 ]. Indeed, the three primary tumours are typically deemed as a single tumour entity classified as “ovarian or tubal cancers” [ 8 , 9 ]. Ovarian tumours constitute a heterogeneous group of malignant diseases with distinct aetiology, origin, pathogenesis, differentiation, patterns of spread, and molecular profiles [ 10 ]. According to the 2020 World Health Organization (WHO) classification, OC includes epithelial (EOC; 90%), germ cell (5%), and sex cord–stromal tumours (2–5%). EOCs (i.e., ovarian carcinomas) are the most common OC type, encompassing five main subtypes that are distinguished based on molecular analysis, histologic and immune profile: high-grade serous (HGSC; 70%), endometrioid (EC; 10%), clear cell (CCC; 10%), low-grade serous (LGSC; 5%) and mucinous (MC; 3%) carcinomas ( Figure 1 ) [ 11 , 12 ]. According to the dualistic carcinogenesis model, these subtypes can be further subdivided into type I and type II according to specific histological and molecular features [ 13 , 14 , 15 ]. Type I tumours (~25% of EOCs) typically exhibit slow growth and tend to be diagnosed at earlier stages (stages I/II). Furthermore, these tumours appear to be associated with endometriosis and usually present a genetic stability phenotype with a pattern of mutations in BRAF , KRAS , PTEN , CTNNB1 , ARID1A , PIK3CA, and PPP2R1A . Type II tumours (75% of EOCs), on the other hand, generally have rapid growth, with the disease being diagnosed at advanced stages (stages III/IV). These tumours also display a high degree of genetic instability, frequently exhibiting BRCA and TP53 mutations. Despite the recognised clinical value of this classification system, it does not always reflect tumour aggressiveness, as even type I tumours can be very aggressive [ 14 , 15 , 16 , 17 , 18 ]. Not surprisingly, this heterogeneity impacts treatment response and clinical outcomes [ 10 ].

Subtypes of ovarian cancer. Figure created with BioRender.com (accessed on 28 December 2023). Ovarian cancer is a heterogeneous disease, encompassing numerous malignant subtypes with distinct aetiology, origin, pathogenesis, differentiation, spread patterns, and molecular profiles. The most common subtype is epithelial ovarian cancer (~90%), which can be further subclassified into type I and type II according to specific histological and molecular features [ 10 , 11 , 12 , 14 , 15 ].

A paradigm shift has been observed in OC research with the evolution to a better disease understanding, aiming for effective screening, early diagnosis, and personalised treatment strategies. This shift was catalysed by innovations in genomics, including the widespread use of microarrays and next-generation sequencing (NGS), which have enabled cost-effective germline and tumour genomic profiling [ 19 ]. Notably, the available technology has led to the identification of more disease subtypes related to the molecular and genetic makeup of ovarian tumours (see Section 3 ) [ 20 ]. Furthermore, progress in molecular pathology, particularly integrating artificial intelligence and machine learning technologies, is shown to be determined [ 21 ]. Not dismissing technical and ethical challenges, existing data advocate that artificial intelligence models may aid in early and accurate OC diagnosis while providing important prognostic information to guide disease treatment [ 22 ].

Given the recent advancements in OC management, an in-depth overview of the current knowledge is critical for researchers and healthcare professionals to stay updated with the latest developments. Furthermore, it could help pinpoint research gaps and guide future investigations. Therefore, this comprehensive narrative review article aims to discuss the current body of evidence on the aetiology, prevention, diagnosis, and treatment of OC, highlighting recent progress in disease management and future directions for OC research. To perform this, a search in the PubMed database was conducted using combinations of the terms “ovarian cancer”, “ovarian tumour”, “ovarian carcinoma”, “advances”, “updates”, “overview”, “screening”, “prevention”, “diagnosis”, “prognosis”, “therapy” and “treatment” that appeared anywhere in the article. The retrieved papers were published between 2013 and 2023. Additional relevant publications were identified in the references list of the retrieved papers.

2. Disease Aetiology and Prevention

Various aetiological determinants are thought to impact ovarian tumourigenesis showing heterogeneity depending on tumour histology [ 3 , 23 , 24 ]. The most impactful ones are advanced age, genetic predisposition, and a family history of cancer. These factors are particularly related to continuous ovulation, hormonal changes, cumulative genetic damage, and chronic inflammation [ 3 , 25 , 26 , 27 ]. Ovarian tumours are rare among young women, particularly those under the age of 30. After the age of 50, especially following menopause, OC risk drastically increases, with the average diagnosis occurring between 50 and 70 years [ 12 ]. Concerning the genetic component, OC is one of the most heritable tumours, mainly linked to germline genetic mutations associated with the hereditary breast and OC syndrome (predominantly mutations in BRCA1 and BRCA2 ) and hereditary nonpolyposis colorectal cancer syndrome (mutations in MLH1 , MSH2 , MSH6, and PMS2 ) [ 25 , 28 ]. Thus, a family history of breast, ovarian, and colorectal tumours, particularly at young ages, could be indicative of a high risk of OC onset [ 29 , 30 ]. For instance, while the risk of developing OC in the general population is <2%, women with BRCA1 and BRCA2 mutations have an overall lifetime risk of 20–40% and 10–20%, respectively [ 31 ].

Despite inconsistent data, reproductive factors such as early menarche, late menopause onset, long-term hormone replacement therapy, and nulliparity also constitute risk factors [ 32 , 33 , 34 , 35 , 36 ]. In opposition, pregnancy, breastfeeding, and the use of oral contraceptives are considered to be protective factors [ 37 , 38 , 39 ]. The impact of these determinants on a predisposition for OC is commonly attributed to the cumulative number of ovulatory cycles, as fewer cycles are associated with a lower OC risk [ 12 , 40 , 41 ]. Also, oestrogen exposure could be a contributing factor [ 42 , 43 ]. Other important risk determinants include lifestyle-related factors (e.g., diet, tobacco use, high body mass index, and obesity), a history of gynaecological conditions (e.g., endometriosis, ovarian cysts, and pelvic inflammatory disease), a personal history of endometrial, breast or colorectal cancers and ethnicity [ 44 , 45 , 46 , 47 ].

Identifying predisposing factors for OC development is important for tailoring prevention measures. However, there is no effective method for OC’s primary prevention. Nonetheless, tubal sterilisation and salpingo-oophorectomy for women at high risk, particularly those with hereditary syndromes, are possible prophylactic options. As such, according to the National Comprehensive Cancer Network (NCCN) guidelines (version 2.2021, 2021), genetic testing should be offered to women with a family history of the disease [ 48 , 49 , 50 ]. Furthermore, although conflicting, some studies have found that low-dose aspirin and other anti-inflammatory medications may decrease the risk of OC [ 40 , 51 , 52 , 53 ].

The secondary prevention of OC, which refers to disease screening, has also been challenging [ 54 , 55 ]. Ideally, an adequate screening exam should be easy to conduct, steadily reliable, inexpensive, and induce minimal discomfort. Importantly, it must have high sensitivity and specificity. For instance, an adequate test to screen for OC should have a sensitivity and specificity superior to 75% and 99.6%, respectively, to reach a positive predictive value (PPV) of 10% [ 56 ]. Also, a suitable exam should target the subpopulation with the highest prevalence of this condition of interest to establish an adequate PPV. Lastly, it should improve the morbimortality rates in the target population [ 54 , 57 ]. Several potential methods for OC screening have been reviewed, including serum CA-125 measurement, a transvaginal ultrasound, colour Doppler ultrasonography, and pelvic examination. However, none of them have shown adequate performance in trials involving the general population and high-risk groups [ 57 , 58 , 59 , 60 ]. For instance, CA-125 (also known as mucin 16 or MUC16), which is widely used in the clinical setting for OC monitoring, exhibits limited sensitivity in early disease stages. Also, its levels can be elevated in benign conditions such as ovarian cysts and endometriosis [ 24 , 61 , 62 , 63 ]. More recently, novel molecular markers have been proposed, including HE4, CA 72-4, CA 19-9, folate receptor alpha (FRα), microRNA profiles, DNA methylation patterns, circulating tumour DNA and antibodies in liquid biopsies, particularly blood and cervical mucus and swabs [ 62 , 64 , 65 , 66 , 67 , 68 ]. The use of liquid biopsies in disease screening is attractive since they can capture the disease’s heterogeneity through minimally invasive sample collection and at a low cost. However, the tumour material in these biopsies is usually scarce and does not provide information about the tumour’s architecture or its primary site [ 68 ]. According to existing data, a multimodal approach combining several tests might be the most effective tool to screen OC accurately [ 69 ]. In this context, several multivariate index assays have been proposed to help detect early-stage OC, including the risk of malignancy index (RMI), OVA1, and risk of ovarian malignancy algorithm (ROMA) [ 70 , 71 , 72 , 73 ]. Another advancement in this field is the development of new imaging techniques, namely auto-fluorescence and magnetic relaxometry, which could help detect the disease at earlier stages, enabling timely therapeutic intervention and better outcomes [ 67 ]. Despite these improvements, screening for asymptomatic and average-risk women is still controversial, given the low prevalence of this disease and the high probability of false-positive findings, which may lead to excessive interventions [ 74 , 75 ]. Consequently, 60–70% of OC patients are diagnosed at advanced stages upon symptom presentation, which, as formerly mentioned, significantly impacts their prognosis [ 5 , 12 , 76 ]. Of note, the list of possible symptoms encompasses vaginal bleeding, diarrhoea, constipation, abdominal distension allied to pain, eating difficulties, urinary frequency, fatigue, nausea, anorexia, dyspepsia, and early satiety [ 24 ]. The time of presentation of these symptoms may vary depending on the histological nature of the disease [ 77 ].

Given their implications, education on the risk factors underlying OC onset is crucial to increase patients’ health awareness and self-advocacy.

3. Disease Diagnosis and Prognosis Assessment

Current strategies to diagnose OC include a medical history evaluation combined with the gynaecological exam, serum CA-125 quantification, and imaging tests (transvaginal ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), and/or positron emission tomography (PET)), while also demanding a histopathological examination from either a diagnostic biopsy or, if possible, a surgical specimen for a definitive diagnosis and staging [ 78 , 79 , 80 ]. For MC, the evaluation of the tumour markers CEA and CA 19-9 is also recommended according to the European Society for Medical Oncology (ESMO) 2023 guidelines for OC management [ 24 ].

At diagnosis, the International Federation of Gynecology and Obstetrics (FIGO) staging system is one of the most important tools to predict the clinical outcomes of OC patients and evaluate their therapeutical options [ 81 ]. This system, first published in 1973 and last revised in 2021, includes four stages, each with subdivisions ( Figure 2 ) [ 75 , 81 , 82 ]. Ovarian carcinomas can also be subclassified based on histologic grading, with two systems being applied [ 60 ]. For non-serous tumours, according to cell architecture, the disease can be deemed as GX (grade not determined), G1 (well differentiated), G2 (moderately differentiated), and G3 (poorly differentiated). On the other hand, serous carcinomas can be categorised as low or high-grade based on their distinct cellular characteristics and behaviours [ 60 , 82 ].

Stages of ovarian cancer. Figure created with BioRender.com (accessed on 28 December 2023). The FIGO staging system for ovarian cancer (OC) includes four stages that address the disease’s extent and severity by evaluating the tumour burden, dissemination within the abdomen, and the secondary involvement of distant organs. Stage I integrates tumours confined to either the ovary (one or both ovaries) or the fallopian tubes, while, at stage II, the tumour has already spread beyond the ovaries or fallopian tubes, with pelvic extension or primary peritoneal cancer. In stage III, OC cells spread to the peritoneum outside the pelvis, and there might be metastasis to the retroperitoneal lymph nodes. Lastly, stage IV is characterised by OC’s dissemination to other body parts beyond the pelvis and abdomen, namely the liver and lungs [ 82 ]. Abbreviations: FIGO, International Federation of Gynecology and Obstetrics.

Regarding the prognosis assessment, the FIGO stage, histologic subtype, grade, baseline serum CA-125 levels, the extent of debulking surgery, and chemotherapy schemes are traditionally deemed the most relevant independent prognostic factors of OC. For instance, those with early disease stages, type I tumours and lower baseline CA-125 levels usually have higher survival [ 12 , 83 , 84 , 85 , 86 , 87 , 88 ]. However, ongoing research has recently identified several molecular biomarkers associated with OC treatment response and prognosis, including mutations, gene expression patterns, and/or epigenetic changes [ 89 , 90 , 91 ]. This is particularly relevant given the high heterogeneity that characterises HGSC, with the predominant and most lethal OC subtype accounting for 70% of OC-related deaths [ 92 ]. Notably, Tothill et al., (2008) [ 93 ] were the first to propose HGSC subtypes based on the following genomic signatures: C1 (high stromal response), C2 (high immune signature), C4 (low stromal response) and C5 (mesenchymal). Next, Kurman and Shih (2010) [ 13 ] proposed the classic dualist model—type I vs. type II. Later, in 2011, data on histological structure and gene expression profile from the Cancer Genome Atlas (TCGA) Research Network led to the recognition of four HGSC subtypes: mesenchymal (with a gene expression profile that resembles mesenchymal tissues with increased cell motility and invasiveness), proliferative (displaying a molecular pattern indicative of high cell proliferation and limited inflammatory infiltration), differentiated (with a gene expression profile related to more specialised cell types) and immunoreactive (tumours with high infiltration of immune cells and with a gene expression profile characteristic of immune activation) [ 15 , 94 ]. Although not mutually exclusive, these subgroups correlate with prognosis. According to the “Classification of Ovarian Cancer” (CLOVAR) signature, the mesenchymal subtype is the most lethal with a related five-year OS of 18%, followed by the proliferative, differentiated, and, finally, the immunoreactive subtype, which is associated with a survival rate of 45% [ 95 ]. Importantly, these signatures also influence therapy response [ 96 ]. Since the proposal of these models, the integrative analysis of tumour (epi)genetic and molecular signatures has more or less confirmed the existence of these four HGSC subtypes with an impact on prognosis and/or treatment response ( Table 1 ). This is anticipated to change OC management by facilitating personalised treatment [ 91 ].

(Epi)genetic and molecular signatures of high-grade serous ovarian carcinoma (HGSC) with implications for therapy response and patients’ clinical outcomes.

Abbreviations: HRR, homologous recombination repair; NGS, next-generation sequencing; PFS, progression-free survival; TCGA, The Cancer Genome Atlas.

4. Current Treatments and Innovations

The therapeutic management of OC mainly relies on the disease stage, with tumour histology, molecular profile, and the patient’s medical background also being relevant determinants. Traditionally, the front-line approach involves cytoreductive surgery followed by intravenous chemotherapy with platinum-containing drugs (cisplatin or carboplatin) typically combined with taxane agents (paclitaxel and docetaxel) every 21 days for six cycles [ 79 , 103 , 104 , 105 , 106 ]. According to ESMO 2023 guidelines, for patients at stage I and with low-grade tumours, chemotherapy can be omitted [ 24 ]. As for those with advanced disease, the complete resection of macroscopic disease (i.e., complete debulking) is often not conceivable. As such, these patients might first be treated with neoadjuvant (induction) chemotherapy, and if there is a treatment response, an interval debulking resection can be conducted, followed by adjuvant chemotherapy [ 75 , 107 ]. Radiotherapy is also a possible therapeutic approach; however, due to its high toxicity and low effectiveness compared to platinum-based chemotherapy, its use is often limited to palliative care [ 108 , 109 , 110 ].

Although the majority of OC patients (~80%) have a complete response after front-line treatment, over 60% of the patients with <1 cm of residual disease (optimal debulking) and about 80% of those with >1 cm of residual disease (suboptimal debulking) progress to around 18 months, often due to chemoresistance [ 12 , 105 , 111 , 112 , 113 , 114 ]. At a phase of disease recurrence, OC treatment commonly consists of second-line chemotherapy, which depends on platinum sensitivity [ 114 ]. Based on the period between the completion of first-line platinum-based chemotherapy and disease recurrence (i.e., platinum-free interval (PFI)), OC can be classified as platinum-refractory (when it occurs during the first-line chemotherapy), resistant (within 6 months after treatment completion), partially sensitive (between 6 and 12 months) or highly sensitive (beyond 12 months) [ 104 , 114 , 115 ]. According to ESMO 2023 guidelines for recurrent OC management, patients with sensitive disease can benefit from second-line chemotherapy with a combination of platinum compounds with paclitaxel, gemcitabine or pegylated liposomal doxorubicin (PLD), followed by treatment with bevacizumab (see Section 4.1 ) or poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) (see Section 4.2 ). In the event of platinum-hypersensitivity reaction/intolerance, PLD might be combined with trabectedin [ 24 ]. As for those refractory or resistant to platinum, the best therapeutical option is monotherapy with paclitaxel, gemcitabine, PLD, or topotecan, although the overall response rate with these agents is relatively small (8 to 20%) [ 24 , 114 , 116 ]. In this setting, bevacizumab can also be added if not contraindicated [ 24 ]. It is worth mentioning that most OC patients with recurrent disease eventually develop platinum resistance [ 117 ].

The disease heterogenicity complicates OC treatment. The acquisition of chemoresistance can arise due to tumour microenvironmental, cancer cell-specific, and pharmacokinetic aberrations [ 116 ]. Additionally, chemotherapy is associated with adverse events, including but not limited to alopecia, neuropathy, neutropenia, palmar-plantar erythrodysesthesia, ototoxicity, and bone marrow depression, all of which negatively impact the patient’s quality of life [ 118 , 119 , 120 , 121 ]. Consequently, over the past few decades, a framework change has been observed, transitioning from an era of first-line treatment mainly centred around cytoreductive surgery followed by platinum and taxane-based chemotherapy to a new phase with improved upfront interventions, such as hyperthermic intraperitoneal chemotherapy (HIPEC), to delay the disease’s recurrence, reduce adverse effects and prolong patients’ survival. This evolution also encompasses broadening the treatment options to include more targeted approaches, namely the use of antiangiogenic agents, DNA damage repair-based therapeutics, hormone receptor modulators, and FRα-targeting drugs ( Figure 3 ). These novel therapeutical agents target signalling pathways that are central to the progression of OC and/or its mechanism of drug resistance [ 87 ].

Pivotal gene discoveries and the approval of therapeutic agents and approaches to treat ovarian cancer. Figure created with BioRender.com (accessed on 28 December 2023). Several therapeutical agents and approaches for ovarian cancer management have emerged in recent decades due to a better understanding of the disease’s pathogenesis [ 122 , 123 ]. Abbreviations: EMA, European Medicine Agency; FDA, Food and Drug Administration; HIPEC, hyperthermic intraperitoneal chemotherapy; HT, hormonal therapy; NCCN, National Comprehensive Cancer Network.

4.1. Antiangiogenic Agents

Tumours release proangiogenic factors, including VEGFA, which can activate the proliferation of vascular endothelial cells, fuelling tumour neoangiogenesis [ 124 ]. VEGFA and angiogenesis are crucial promoters of ovarian tumourigenesis. Both correlate directly with the disease’s extent and inversely with progression-free survival (PFS) and overall survival (OS), usually regardless of other prognostic determinants [ 125 , 126 ].

In 2011, after the results of the GOG-0218 ( NCT00262847 ) and ICON7 ( NCT00483782 ) trials, bevacizumab, a recombinant humanised anti-VEGFA monoclonal antibody, was approved by the European Medicine Agency (EMA) for the first-line and maintenance treatment of advanced-stage OC in combination with platinum-taxane-based chemotherapy [ 125 , 126 ]. Subsequently, in 2014, the US Food and Drug Administration (FDA) granted approval for this drug to be used in the second-line therapy of platinum-resistant-recurrent OC [ 127 ]. By neutralising all active forms of VEGFA, bevacizumab suppresses angiogenesis, inhibiting tumour growth and metastatic dissemination [ 128 ]. Additionally, it is thought to enhance the delivery of chemotherapeutic agents to their designated targets by normalising the tumour’s vasculature, decreasing the interstitial fluid pressure, and increasing the tumour’s oxygenation [ 129 ]. This agent was the first biological drug to show a promising therapeutic response in the frontline intervention (first-line therapy) and recurrent OC (second-line therapy) [ 125 , 130 ]. However, its effect on PFS is limited and does not prolong OS [ 131 , 132 ]. Also, bevacizumab is associated with considerable toxicity, with a list of adverse events including hypertension, thrombotic events, gastrointestinal perforation, and renal and central nervous system disorders [ 125 , 133 , 134 ].

There is no unanimous agreement on the prescription of bevacizumab, given the lack of validated predictive biomarkers of response [ 76 ]. Nevertheless, those with molecular subtypes associated with poor survival, namely proliferative and mesenchymal tumours, are known to benefit most from bevacizumab-based treatment [ 135 ]. More recently, its use in combination with PARPi has proven to be beneficial, receiving approval from both the EMA and the FDA in 2020 [ 123 , 136 ]. Furthermore, in addition to bevacizumab, small-molecule kinase inhibitors targeting VEGFA receptors (VEGFRs) are currently under investigation (see Section 5.4 ).

4.2. DNA Damage Repair-Based Therapeutics

Since 2014, the landscape of OC management has been revolutionised with the approval of PARPi by the EMA and FDA for disease treatment in different settings [ 137 , 138 ]. These therapeutic agents inhibit the activity of PARPs, which are proteins crucial for DNA damage repair. In malignancy, PARPs facilitate the repair of DNA damage, particularly single-strand breaks, which are induced by antineoplastic treatments [ 12 , 137 ]. Tumour cells with a deficient homologous recombination repair (HRR) pathway, mainly due to mutations in BRCA1/2 , are unable to repair DNA double-strand breaks. In these cells, PARPi have a negative effect, rendering the repair of DNA damage unfeasible. Consequently, these therapeutic agents promote the apoptosis of tumour cells through a process known as synthetic lethality [ 12 , 137 , 139 , 140 ]. As anticipated, PARPi are particularly relevant for HGSC, given the high rate of HRR deficiencies [ 141 ].

For OC management, PARPi were initially proposed for patients with recurrent platinum-sensitive disease after the outstanding improvement in PFS observed in three randomised phase III trials—SOLO-2/ENGOT-OV21 ( NCT01874353 ), NOVA/ENGOT-OV16 ( NCT01847274 ) and ARIEL3 ( NCT01968213 ) [ 137 , 142 , 143 , 144 ]. The results of these trials led to the approval of olaparib (2014), niraparib (2017), and rucaparib (2016–2018), respectively [ 137 ]. Early clinical data supported the effectiveness of these agents among those with germline or somatic BRCA1/2 mutations. However, in the maintenance setting for those with platinum sensitivity, more recently, these drugs have shown clinical benefits even among those without these mutations [ 141 ]. Indeed, other genes implicated in the HRR pathway are known to be mutated in OC. The list includes BARD1 , BRIP1 , RAD50 , RAD51 paralogs ( RAD51C and RAD51D ), MRE11 and PALB2. Curiously, OC patients present germline mutations in HRR-related genes more often than somatic tumour mutations (<10% of cases) [ 145 ]. In addition to recurrent disease, PARPi have been suggested to be beneficial in first-line therapy, which could affect subsequent treatment choices [ 137 ].

Despite these clinical benefits, the therapeutical impact of olaparib, niraparib, and rucaparib is constrained, translating into only a short-term survival extension as most patients inevitably develop drug resistance [ 146 , 147 ]. Therefore, other PARPi have emerged, including veliparib, pamiparib, fuzuloparib (formerly known as fluzoparib), and talazoparib. Veliparib is still under investigation, pamiparib and fuzuloparib were recently approved for OC treatment in China, and talazoparib was approved by the FDA in 2018 to manage HER2-negative-advanced breast cancer [ 148 , 149 ]. Moreover, the panorama of DNA damage repair-based therapies for OC management has evolved beyond PARPi with the development of pharmaceutical agents targeting the cell cycle checkpoint protein kinases ATR (ceralasertib), CHK1 (prexasertib) and WEE1 (adavosertib) [ 150 ]. These agents are still being investigated in clinical trials and promise to overcome PARPi-resistant ovarian tumours [ 150 , 151 ].

4.3. Hyperthermic Intraperitoneal Chemotherapy (HIPEC)

HIPEC involves the intraperitoneal delivery of chemotherapeutic agents after cytoreductive surgery and under hyperthermic conditions to improve patients’ outcomes by more effectively removing residual disease. This is partially due to hyperthermia, which increases the penetration of chemotherapeutic drugs at the peritoneal surface while enhancing the sensitivity of the tumour to treatment. These two factors, however, notably depend on the selected drug and the achieved temperature [ 152 , 153 ].

While HIPEC has been adopted in the management of malignant diseases such as colorectal, gastric, and primary peritoneal carcinomatosis, for OC, its implementation has been a subject of intense debate [ 154 ]. Only in 2019 was it integrated as an optional form of treatment for the interval debulking of OC patients in the NCCN guidelines (version 1.2019, 2019) [ 155 ]. In part, this delay was due to questions on optimal patient selection, the protocol for drug delivery (open versus closed), the timing of the treatment, the choice of drug regimen, and, importantly, the risk of complications [ 156 ]. Currently, according to the NCCN guidelines, HIPEC is recommended for OC patients with peritoneal carcinomatosis (FIGO stage III) and with response or stable disease after undergoing neoadjuvant chemotherapy [ 155 ]. For these patients, the treatment has been associated with a trend towards improved PFS and OS [ 157 ]. However, for various reasons, despite the demonstrated benefits, the acceptance and implementation of HIPEC by gynaecologic oncology and surgeons have been challenging [ 24 , 158 , 159 ].

4.4. Hormone Receptor Modulators

Oestrogen is known to drive the proliferation of OC cells [ 160 ]. Oestrogen signalling is mediated by oestrogen receptor(ER)-alpha (ERα) and ER-beta (ERβ), each with different isoforms, which are further amplified by G protein-coupled oestrogen receptor 1 (GPER1) [ 42 ]. In vitro and in vivo studies show that oestrogen via ERα regulates OC growth and promotes cell migration and epithelial–mesenchymal transition (EMT), influencing cell motility and survival [ 161 , 162 , 163 , 164 ]. These modifications proceed through the downregulation of E-cadherin: a process that ERβ inhibits [ 165 ]. Indeed, ERβ, the most common ER form in normal ovary tissue, is thought to be an OC suppressor [ 166 , 167 , 168 , 169 ]. As for GPER1, both suppressive and promotor roles have been proposed among OC patients, indicating a likely complex function [ 170 , 171 , 172 , 173 , 174 ]. Contrary to MC (21%) and CCC (20%), over 80% of serous EOCs (HGSC and LGSC) and EC express ERα and have demonstrated response to hormonal therapy with aromatase inhibitors (for instance, letrozole) and tamoxifen in multiple clinical studies [ 42 , 50 , 76 , 175 , 176 ]. While aromatase inhibitors block oestrogen synthesis, tamoxifen directly competes with oestrogen in order to bind to ER [ 177 ]. Progesterone, gonadotropins, androgens, and the gonadotropin-releasing hormone (GnRH) also play a role in the endocrine regulation of the ovary mediated by the hypothalamic–pituitary–ovary axis. While GnRH and progesterone seem protective against OC, gonadotropins, and androgens favour its progression [ 111 , 178 ].

The restricted therapeutic options for the management of recurrent and platinum-resistant OC and the favourable safety profile combined with its convenient and inexpensive use make hormonal therapy an attractive option [ 117 ]. According to the ESMO-European Society of Gynaecological Oncology guidelines (ESMO-ESGO) of 2019 and the NCCN guidelines (version 2.2021) of 2021, hormonal therapy is recommended as an alternative approach to treat those with recurrent and platinum-resistant OC [ 50 , 76 ]. However, the clinical benefit of hormonal therapy in OC management has not been systematically evaluated in large trials (arzoxifene, an ER modulator, in NCT00003670 ; fulvestrant, an ER degrader, in NCT00617188 , tamoxifen in NCT02728622 and NCT00041080 ; and mifepristone, a progesterone receptor modulator, in NCT00459290 and NCT02046421 ). Currently, efforts are being made to identify biomarkers that can stratify responsive OC subgroups [ 42 ].

4.5. FRα-Targeting Drugs

The folate metabolism is essential in DNA synthesis, methylation, and repair [ 179 ]. The transmembrane glycoprotein FRα transports folic acid (folate) and its derivatives into cells via endocytosis [ 180 ]. In normal tissues, its expression is restricted to the intestine, kidney, retina, lung, choroid plexus, and placenta [ 181 ]. Except for the kidney (which does not retain folate), FRα in normal tissues is only presented in polarised epithelial cells, which are inaccessible to circulating pharmaceutical agents [ 181 , 182 ]. On the other hand, its elevated expression is demonstrated in most carcinomas, including endometrial, breast, lung, and ovarian tumours. This selective expression and its ability to be internalised after ligand-binding makes FRα an attractive target for cancer drug delivery [ 179 ].

Most ovarian carcinomas overexpress FRα, while this receptor is absent in normal ovarian epithelium [ 182 , 183 ]. The synthesis of FRα is particularly common in advanced and high-grade serous EOC, which is sustained even in recurrent diseases and within metastatic niches [ 184 ]. Importantly, this receptor is reported to shed from the cell membrane into circulation [ 66 ]. In EOC patients, circulating receptor (sFRα) levels correlate with tumour FRα expression, disease burden, and treatment outcomes [ 66 , 185 ]. Thus, sFRα might be an attractive biomarker of early EOC. Inclusively, this marker has exhibited higher accuracy than serum CA-125 levels [ 66 ].

In the treatment setting, FRα-targeting drugs have emerged as potential therapeutic agents for OC. Antibody-drug conjugates (ADCs) are a group of agents designed to selectively deliver chemotherapeutic agents to the site of tumours by targeting cancer-specific antigens [ 186 ]. Mirvetuximab soravtansine, one of the most extensively studied FRα-targeting ADCs, is composed of an anti-FRα antibody coupled to a potent tubulin-targeting agent named DM4. Mechanistically, the drug binds to FRα in EOC, delivering DM4 directly to the tumour cells, providing a positive balance between efficacy and toxicity. Currently, mirvetuximab soravtansine is being tested for EOC management in platinum resistance [ 186 , 187 ]. Based on the positive findings of the phase III trial SORAYA ( NCT04296890 ), this drug received accelerated approval in 2022 by the FDA for the treatment of patients with FRα-positive and platinum-resistant EOC previously treated with systemic anticancer regimens [ 188 ]. Another FRα-based therapeutic strategy involves farletuzumab, a humanised monoclonal antibody to FRα. Particularly in low-folate environments, FRα provides a growth advantage to cancer cells. As expected, farletuzumab demonstrated growth-inhibitory effects on FRα-expressing OC cells in preclinical models [ 189 , 190 ]. Yet, clinical trials managing platinum-sensitive EOC with this drug in combination with other therapeutical approaches have shown conflicting results ( NCT00318370 and NCT02289950 ) [ 191 , 192 ].

5. Emerging Therapies

The existing evidence indicates a stagnation in OC therapies, failing to extend the OS of patients significantly. As a result, there is a pressing demand for novel treatment approaches. Several therapeutical agents and schemes are being developed or are currently undergoing clinical trials, displacing encouraging preliminary results.

5.1. Immunomodulators

One of the emerging therapies for OC is cancer immunotherapy. This therapeutic method harnesses the power of the patient’s immune system to eliminate the tumour [ 193 ]. Numerous immune-based interventions have been approved to treat solid and haematologic tumours, including immune checkpoint inhibitors, nonspecific immune stimulation, adoptive cell therapy, and cancer vaccines [ 194 ]. The involvement of the immune system in OC patients’ outcomes is demonstrated by the observation that tumour-infiltrating lymphocytes and the lower expression of PD-L1 are associated with improved survival [ 195 , 196 , 197 , 198 ]. Considered an “inflamed tumour”, OC could benefit from these immune-based interventions, yet data are insufficient and inconsistent [ 199 , 200 ]. Thus, multiple clinical trials have explored the role of OC immunotherapy as a standalone treatment and in combination with other therapeutical approaches, namely chemotherapy, the use of antiangiogenic agents, and PARPi [ 199 , 200 ]. The studies actively recruiting are described in Table 2 . Current studies, including (epi)genetic and molecular profiling, are also focused on identifying predictive biomarkers to assess the responsiveness of OC to immune-based interventions and improve patient selection criteria [ 199 , 201 ]. Namely, tumour mutational burden (TMB), meaning the number of somatic mutations per unit of a tumour-interrogated genome, has surfaced as an important marker of response to immune checkpoint inhibition [ 202 ]. In 2020, the FDA granted accelerated approval to pembrolizumab (anti-PD-1 agent) for the treatment of unresectable and/or disseminated solid tumours with high TMB (≥10 mut/Mb) [ 203 ]. The exploration of immunotherapy and the integration of predictive biomarkers in clinical decision-making represent promising strides in the personalised management of OC.

Actively recruiting clinical trials of immunotherapy for OC management.

Data available at “clinicaltrials.gov” (accessed on 29 December 2023) until December 2023 using the terms “ovarian cancer” and “immunotherapy” as keywords. Maintenance therapy was deemed a treatment strategy employed after the first-line therapy but preceding any disease recurrence. * Estimated. Abbreviations: NA, non-applicable; NR, non-restrictive; PLD, pegylated liposomal doxorubicin.

5.2. Gene Therapies

Gene therapy is generally defined as the replacement of an abnormal gene with a functional copy of that gene aiming to correct an underlying disorder [ 204 ]. Different gene therapy strategies have been explored for OC management in preclinical studies, including the replacement of tumour suppressor genes to restore cell control (e.g., TP53 ), oncogene inhibition strategies (e.g., EGFR ), suicide gene therapy with the delivery of genes encoding for toxins (e.g., HSV-TK ), genetic immunopotentiation to reinforce immune response against tumour cells (e.g., IL-12A/B ), antiangiogenic gene therapy (e.g., COL18A1 ), strategies to restore pharmacological sensitivity (e.g., survivin ( BIRC5 )) and cancer virotherapy (e.g., vesicular stomatitis virus). Furthermore, some of these approaches have also been investigated in clinical trials ( Table 3 ). Despite continuous progress and promising results, several challenges prevent the clinical implementation of gene therapy, including low efficiency in the delivery of therapeutic genes, an unspecific expression allied to biosafety concerns, and ethical and financial issues. In addition, OC, like other malignant diseases, is a polygenic disease characterised by a higher degree of heterogeneity between individuals and even tumours in the same patient [ 204 , 205 , 206 ]. Thus, more clinical trials are required to explore the current preclinical strategies and the correct way to translate gene therapy to the clinical setting.

Active and completed clinical trials of gene therapy for OC management.

Data available at “clinicaltrials.gov” (accessed on 29 December 2023) until December 2023 using the terms “ovarian cancer” and “gene therapy” as keywords. Maintenance therapy was deemed a treatment strategy employed after the first-line therapy but preceding any disease recurrence. Completed trials with results are highlighted in bold. * Estimated. Abbreviations: MOv-PBL, MOv-gamma chimeric receptor gene; MV-CEA, Carcinoembryonic antigen-expressing measles virus; MV-NIS, oncolytic measles virus encoding thyroidal sodium iodide symporter; NA, non-applicable; NR, non-restrictive.

5.3. Drug Repurposing

Drug repurposing (also known as drug reprofiling, re-tasking, or repositioning) consists of identifying alternative uses for approved therapeutical agents that are outside the original prescription scope, even regarding non-cytotoxic drugs [ 207 ]. This strategy cuts research costs and speeds up drug usage as the repurposed drugs have already been deemed safe in preclinical models and humans. As a result, drug repurposing has achieved great success, leading to the identification of candidate drugs for a pleura of diseases [ 208 ].

Focusing on the therapeutic agents approved for non-oncological diseases, one of the repurposed drugs under investigation for OC management is vitamin D (VD) and its analogues. VD consists of a group of steroid-like molecules, namely cholecalciferol (vitamin D3), ergocalciferol (vitamin D2), calcidiol (25-hydroxy-vitamin D) and calcitriol (with the active form also known as 1,25-dihydroxy vitamin D3 or 1,25D3), with the latter binding to the vitamin D receptor (VDR) to modulate the expression of several genes [ 209 ]. The most studied role of VD and its analogues is the maintenance of serum calcium and phosphorus homeostasis. Beyond their functions in physiological conditions, these steroid-like molecules are also reported to have antitumour effects in preclinical models. Namely, they can induce tumour cell differentiation and apoptosis while reducing the cells’ proliferation and dissemination potential [ 209 , 210 , 211 ]. Consequently, synthetic VD analogues, which do not possess the side effect of hypercalcemia, have been developed to target malignant diseases [ 212 ]. Many epidemiological studies have linked VD deficiency to cancer risk and mortality [ 213 , 214 , 215 ]. The implications of VD are best characterised by breast, colorectal, and prostate cancers [ 212 ]. Regarding OC, although in vitro and in vivo studies have obtained promising results, the impact of VD and its analogues is still blurred. Current evidence suggests that VD-based therapy could potentiate the activity of chemotherapeutic agents and PARPi [ 216 , 217 , 218 , 219 , 220 , 221 ]. The combination of VD with immunotherapy has also been considered potentially beneficial, given its immunomodulatory effect [ 222 ]. However, clinical trials assessing the efficacy of VD-based therapy in OC are lacking.

Other repurposed drugs have been investigated in clinical trials to help manage OC. This list includes statins (hypercholesterolemia; NCT04457089 and NCT00585052 ), hydroxychloroquine (malaria, rheumatoid arthritis and lupus erythematosus; NCT03081702 ), metformin (type 2 diabetes mellitus; NCT02312661 and NCT01579812 ), itraconazole (fungal infections; NCT03081702 ), beta-blockers (hypertension; NCT01504126 ) and sodium valproate (bipolar disorder and epilepsy; NCT00529022 ) [ 223 , 224 ]. Of note, the off-labelled use of drugs approved for other malignant diseases in OC management is beyond the scope of this review.

Given the implications of drug repurposing, more investigation in this field is needed to better understand the underlying mechanisms.

5.4. Small-Molecule Kinase Inhibitors

Kinases are implicated in several signalling pathways that are often deregulated in cancer. These proteins regulate cell survival and growth, promoting tumour progression [ 225 ]. In OC, the kinases involved in angiogenesis (e.g., VEGFRs), cell growth (e.g., EGFR), and intracellular signalling (e.g., PI3K/AKT/mTOR pathway) are reported to be overactivated, being attractive therapeutic targets [ 226 ]. Numerous small-molecule kinase inhibitors have been evaluated in clinical trials for OC management ( Table 4 ). Despite their potential, the high heterogeneity of ovarian tumours and drug resistance are significant obstacles to the implementation of these drugs [ 226 , 227 , 228 , 229 ]. Nevertheless, progress in disease (epi)genetic and molecular profiling may help solve some of the current issues [ 91 ].

Active and completed clinical trials of small-molecule kinase inhibitors for OC management.

Data available at “clinicaltrials.gov” (accessed on 29 December 2023) until December 2023 using the terms “ovarian cancer” and “small-molecule kinase inhibitor” as keywords. Also, the term of each inhibitor was used. Maintenance therapy was deemed a treatment strategy employed after the first-line therapy but preceding any disease recurrence. Completed trials with results are highlighted in bold. * Estimated. Abbreviations: NA, non-applicable; NR, non-restrictive; OC, ovarian cancer; PLD, pegylated liposomal doxorubicin.

5.5. Coagulation-Targeting Approaches

Patients with ovarian tumours are commonly diagnosed with venous thromboembolism (VTE), with an incidence ranging from 10 to 30% [ 239 ]. This thrombotic event constitutes the second cause of death among oncological patients [ 240 ]. Importantly, even in the absence of VTE, most cancer patients present a state of blood hypercoagulation. Cumulative evidence suggests that underling this state, deregulated haemostatic components—endothelial cells, platelets, and coagulation/fibrinolysis systems—exhibit protumourigenic functions, including tumour cell growth, survival, proliferation, and invasion while also supporting cancer neoangiogenesis and metastatic dissemination [ 226 ]. Several haemostatic components have been suggested to play critical roles in OC progression and ascite formation, creating potential avenues for therapeutic intervention [ 241 ]. Namely, the overexpression of coagulation factor 3, commonly known as the tissue factor (TF), and the presence of tumour-educated platelets are some of the most studied mechanisms in this interface of VTE and OC progression [ 239 , 241 , 242 ].

Regarded as the initiator of the extrinsic coagulation pathway, TF is released into the blood circulation following vascular damage to trigger fibrin deposition at the injury site. This mechanism is vital to stop blood loss and restore haemostasis [ 243 , 244 , 245 ]. Cancer cells constitutively express TF and induce its synthesis in normal cells in the tumour microenvironment, which generates a prothrombotic cascade that favours tumour progression [ 246 ]. Inclusively, the overexpression of this coagulation factor in several tumour types, including OC, is linked to poor prognosis [ 247 , 248 , 249 , 250 ]. The protumourigenic roles of TF encompass tumour cell proliferation, cancer stemness, angiogenesis, immune evasion, and metastasis through clotting-dependent and independent processes [ 243 , 251 , 252 , 253 ]. Recently, tisotumab vedotin (Tivdak™), a TF-specific human ADC conjugated to the tubulin-targeting agent called monomethyl auristatin E (MMAE), was approved by the FDA for the management of recurrent or metastatic cervical tumour [ 254 , 255 , 256 ]. According to the results of phase I/II innovaTV-201 ( NCT02001623 ), this drug showed promising antitumour activity and a convenient safety profile in platinum-resistant OC, which supports the continued investigation of tisotumab vedotin in this population [ 255 ].

Platelets, also known as thrombocytes, are megakaryocyte-derived haemostatic key players in the bloodstream [ 257 , 258 , 259 ]. Apart from their role in haemostasis, platelets promote tumour growth and dissemination, and, in turn, tumour cells stimulate platelet production and activation, creating a feedback loop that fuels tumourigenesis and leads to paraneoplastic thrombocytosis (i.e., an elevated platelet count >450,000 per cubic millimetre) [ 260 , 261 ]. This well-recognised phenomenon is often associated with many solid tumours [ 257 , 262 ]. In the context of OC, the interaction of thrombocytes and tumour cells is so evident that one-third of women with newly diagnosed OC have paraneoplastic thrombocytosis. However, data on the impact of thrombocytosis on the patient’s clinical outcomes is inconsistent [ 261 , 263 , 264 ]. Some studies have demonstrated that when considering other clinical factors, such as cancer burden, thrombocytosis in advanced OC-stage patients does not independently impact prognosis [ 261 , 265 ]. Others, nevertheless, have shown that this condition is associated with an advanced disease stage, high grade, and elevated preoperative CA-125 levels, which are all known OC prognostic factors [ 259 , 261 ]. When focusing on early stages, thrombocytosis seems to be a powerful prognostic factor, with affected patients exhibiting approximately an eightfold increase in the risk of recurrence and a fivefold increase in the risk of death. Moreover, this condition in these patients seems to correlate with disease burden, residual disease, and postoperative complications [ 265 ]. On the other hand, thrombocytosis was also found to be an independent prognostic factor, regardless of disease stage, tumour grade, histologic type, and the extent of surgical intervention ( p < 0.001). Namely, affected patients presented a median OS of 2.65 years compared to the 4.65 years exhibited by their counterparts [ 261 ]. Thus, designing therapeutic agents to target platelets at the tumour microenvironment (i.e., tumour-educated platelets) can provide a promising breakthrough in OC treatment [ 266 ]. Epidemiological studies have suggested that acetylsalicylic acid (also known as aspirin), a non-steroidal anti-inflammatory drug, may have anticancer properties [ 267 , 268 ]. By inhibiting cyclooxygenase-2 (COX-2), aspirin exerts antiplatelet and anti-inflammatory effects. Although the cumulating data on aspirin’s impact on OC patients’ survival is conflicting, preclinical data show that aspirin exerts anti-tumoural effects when combined with bevacizumab [ 269 , 270 ]. Thus, the phase II trial EORTC-1508 ( NCT02659384 ) is currently evaluating the efficacy and safety of combining atezolizumab (monoclonal antibody targeting PD-L1), bevacizumab and aspirin to treat recurrent platinum-resistant OC. Moreover, an ongoing phase I trial ( NCT05080946 ) aims to evaluate the effectiveness of aspirin with neoadjuvant chemotherapy for decreasing markers of immune suppression (M2 tumour-associated macrophages and immunosuppressive T-regulatory cells) within the tumour. More studies on aspirin’s effect and the development of other antiplatelet agents for OC treatment should be evaluated.

6. Conclusions

Despite significant strides in disease management, OC remains the most lethal female reproductive cancer. Not dismissing the potential publication and selection bias, which is characteristic of narrative reviews, this comprehensive overview provides an in-depth analysis of the recent evidence regarding OC management, identifying gaps in the literature and suggesting future directions for disease research. Briefly, ongoing research focuses on dissecting OC pathogenesis to refine screening techniques and seek innovative and more targeted treatments to manage this malignant disease effectively, decrease side effects, and enhance OC patient outcomes. Due to a better understanding of OC’s (epi)genetic and molecular profiling, several therapeutical approaches have been recently approved, with others in development. Notably, (epi)genetic and molecular changes in ovarian tumours have been found to correlate with drug efficacy and resistance, particularly in HGSC heterogeneity. Thus, integrating molecular insights might have significant implications for clinical decision-making. Future investigation endeavours should be directed at OC’s heterogeneity and drug resistance challenges. Likewise, there should be an emphasis on identifying more accurate diagnostic tools, prognostic indicators, and predictive biomarkers of response for current and emerging therapies. Furthermore, more data should be collected on the impact of combining diverse treatment modalities, as it holds promise in elevating treatment effectiveness and conquering drug resistance, enhancing patient outcomes by leveraging the synergistic actions of multiple therapies.

Acknowledgments

The authors would like to thank Ministério da Saúde de Portugal, Instituto Português de Oncologia do Porto (IPO Porto), Fundação para a Ciência e Tecnologia (FCT) and the Portuguese League Against Cancer (LPCC-NRNorte).

Abbreviations

CCC: clear cell carcinoma; EC, endometrioid carcinoma; EMA, European Medicine Agency; EOC, epithelial ovarian cancer; ESMO, European Society for Medical Oncology; FDA, Food and Drug Administration; FRα, folate receptor alfa; HGSC, high-grade serous carcinoma; HIPEC, hyperthermic intraperitoneal chemotherapy; LGSC, high-grade serous carcinoma; MC, mucinous carcinoma; NCCN, National Comprehensive Cancer Network; OC, ovarian cancer; OS, overall survival; PARP, poly (ADP-ribose) polymerase; PARPi, Poly (ADP-ribose) polymerase inhibitors; PFS, progression-free survival.

Author Contributions

Conceptualisation, V.T.; Methodology, V.T.; Writing—Original Draft Preparation, V.T.; Writing—Review and Editing, V.T., J.A., I.S.M., I.G.d.M., D.P. and R.M.; Supervision, J.A., D.P. and R.M.; Funding Acquisition, V.T. and J.A. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

Funding Statement

V.T. is a Ph.D. scholarship holder (No. 2020.08969.BD) supported by FCT, co-financed by the European Social Funds (FSE) and national funds of MCTES. J.A. has a junior researcher contract (UIDB/00776/2020-3) funded by FCT/MCTES. The funders had no role in the decision to write or publish the manuscript.

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Ovarian Cancer: An Integrated Review

Affiliations.

• 1 Carolina's Medical Center, Charlotte, NC. Electronic address: [email protected].
• 2 Assistant Vice President Patient Care Services, Carolina's Medical Center, Rock Hill, SC.
• 3 Interim Dean, Harris College of Nursing & Health Sciences, Associate Dean for Nursing & Professor, Texas Christian University, Ft Worth, TX.
• PMID: 30867104
• DOI: 10.1016/j.soncn.2019.02.001

Objective: To provide an overview of the risk factors, modifiable and non-modifiable, for ovarian cancer as well as prevention, diagnostic, treatment, and long-term survivorship concerns. This article will also examine current and future clinical trials surrounding ovarian cancer.

Data sources: A review of articles dated 2006-2018 from CINAHL, UpToDate, and National Comprehensive Cancer Network guidelines.

Conclusion: There is no screening test for ovarian cancer and with diagnosis often in the late stages, recurrence is high in this population. Early identification can range from knowing the vague symptoms associated with the cancer to prophylactic surgical removal of at-risk tissue. Standard treatment for ovarian cancer is surgery followed by combination chemotherapy. Although advances are being made, ovarian cancer remains the most fatal female gynecologic cancer.

Implications for nursing practice: Becoming familiar with and educating women about risk factors and the elusive symptoms of ovarian cancer can increase patient autonomy and advocacy, as well as potentially improve patient outcomes for those affected by ovarian cancer.

Keywords: BRCA; gynecologic; oncology; ovarian cancer; prevention; risk factors.

Copyright © 2019 Elsevier Inc. All rights reserved.

Publication types

• Ovarian Neoplasms / diagnosis
• Ovarian Neoplasms / epidemiology*
• Ovarian Neoplasms / prevention & control
• Ovarian Neoplasms / therapy
• Risk Factors

Ovarian Cancer: Risk Factors, Health Disparities, and Preventive Measures Essay

Introduction, prominent aspects of ovarian cancer, current data and statistics related to ovarian cancer, health disparities associated with ovarian cancer, prevention strategies, contemporary research and clinical studies on ovarian cancer, pathophysiologic effects of stress and evidence-based interventions.

Ovarian cancer is a common gynecologic cancer worldwide, accounting for a high mortality rate. It is primarily associated with the growth and multiplication of cells that form in the ovaries, invading and destroying healthy body tissue. The traditional view of this type of cancer is that it forms on the ovarian surface mesothelium and continues to grow to a large extent (Stewart et al., 2020). However, alternative views have challenged the idea, arguing that ovarian cancer tumors develop from cysts in areas such as the fallopian tube and spread to the ovaries. Ovarian cancer is a prevalent illness that requires keen understanding and research to develop long-lasting solutions.

Ovarian cancer is associated with risk factors that increase the disease’s chances. The risk factors for the disease include age, family history cancer, endometriosis, and being obese or overweight (CDC, 2022). In the past, ovarian cancer was mostly misdiagnosed, but modern technology and other alternative procedures have significantly assisted in creating a distinction. The most common signs and symptoms of ovarian cancer include weight loss, pain in the pelvic region, swelling and bloating in the abdomen, low appetite, and increased urination.

In the most recent statistics, there have been more than three hundred thousand new cases worldwide, and about twenty thousand of these new cases were reported in the United States (Siegel et al., 2020). More research has shown that the risk of developing the disease stands at one in seventy-eight, and most women affected are aged fifty-five to sixty-four years (Siegel et al., 2020). The risk of an individual dying from ovarian cancer is about one in a hundred, and about fourteen thousand people die yearly in the United States (Siegel et al., 2020). In the past, the diagnosis was often made when the illness had progressed, but in recent times, approximately sixteen percent of patients are diagnosed early enough. Early diagnosis increases the chances of an individual surviving five years later, slowly reducing cases over the past twenty years (Healthy People 2020, 2018). Such positive trend is definitely welcome by patients and doctors alike.

Health disparities associated with ovarian cancer have recently become more recognized and are linked to ethnicity and race. In the past, more incidences were recorded among white individuals than other ethnic groups. However, African American women experience the highest risk factors of mortality and morbidity associated with ovarian cancer. Research has shown that the survival rates among white populations have increased because they have access to better healthcare services than the African American population, who are affected by various socio-economic problems that hinder them from acquiring and affording proper treatment (Siegel et al., 2020). However, the disease is associated with other factors such as genetics, making genetic counseling crucial in determining the most effective treatment methods.

There are still no specific practical ways to prevent ovarian cancer cases hence many healthcare providers only advise on ways to help reduce the risk of developing the disease. Women can lower the risk by chemotherapy, maintaining a healthy weight, using oral contraceptives, tubal ligation, or removing both ovaries through surgery if necessary (Kuroki & Guntupalli, 2020). There are various complementary therapies that are used alongside conventional treatment, for instance, self-help groups, support groups, and relaxation techniques. Alternative therapies primarily encourage replacing prescribed treatment procedures, for instance, through dietary supplements such as quercetin found in vegetables and fruits. Researchers, scientists, and physicians are collaborating to determine whether these therapies are worthwhile in managing the disease.

Contemporary research and clinical studies on ovarian cancer are crucial to detect high-risk genes and increase comprehension of the interaction between hormonal and genetic factors to help develop effective ways of preventing this type of cancer (CDC, 2022). In addition, numerous clinical trials frequently determine whether new treatment procedures such as anti-angiogenic are safer than the ones currently available. These studies suggest that soon, there is a higher chance of creating a substantial mode of treatment for ovarian cancer.

Increased stress levels can result in cancer progression or trigger its reoccurrence. Patients are advised to stay active and seek counseling services to lower stress and depression, which may lead to additional complications (CDC, 2022). Evidence-based stress management interventions that may help include frequent screening, support groups, and stress management training (Healthy People 2020, 2018). It is important that the psychological health of patients is addressed so they can cope with the physical challenges they experience.

In developing countries, governments must improve healthcare conditions and partner with international organizations to acquire necessary medication and equipment. The success of ovarian cancer treatment depends on early diagnosis, which is why evidence-based interventions should include effective population education so that individuals know how to act when they suspect ovarian cancer. Support groups and community resources should be made available to people so that they are well-informed for effective decision-making.

To conclude, ovarian cancer is a prevalent disease that requires intensive research to develop better preventative measures and treatments. People should take a personal initiative to ensure they lead healthy lifestyles and exercise regularly to lower the disease’s chances. Community health programs and awareness campaigns can help spread vital information about the available preventative measures and treatment procedures, and encourage regular screening to detect changes in the body.

Centers for Disease Control and Prevention. (2022). Ovarian cancer. Web.

Healthy People 2020. (2018). Ovarian cancer: Screening. Web.

Kuroki, L., & Guntupalli, S. (2020). Treatment of epithelial ovarian cancer. BMJ Healthcare Research , 371. Web.

Siegel, L., Miller, D., & Jemal, A. (2020). Cancer statistics. A Cancer Journal for Clinicians, 70 (1), 7-30. Web.

Stewart, C., Ralyea, C., & Lockwood, S. (2020). Ovarian cancer: An integrated review. Seminars in Oncology Nursing, 35 (2), 20-45. Web.

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1. IvyPanda . "Ovarian Cancer: Risk Factors, Health Disparities, and Preventive Measures." October 20, 2023. https://ivypanda.com/essays/ovarian-cancer-risk-factors-health-disparities-and-preventive-measures/.

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Ovarian Cancer: A Comprehensive Essay Sample

A wide spectrum of cancerous diseases drastically deteriorates the quality of life and considerably reduces the life span of a human. The growing incidence, increased morbidity, and mortality rates associated with various malignancies make them a serious health issue and challenge for healthcare organizations worldwide. Moreover, specific cancers can tremendously affect female reproductive and overall health, and ovarian cancer is in this category. Sufficient knowledge regarding the stated disease, its etiology, preventive care, and treatment modalities can benefit any female, particularly from the risk group.

Ovarian cancer is a serious, life-threatening cancerous disease that can largely compromise a woman’s health and cause negative implications for the one. It is characterized by excessive and uncontrollable multiplication of malignant cells, eventually becoming tumors (U.S. National Library of Medicine, 2017). The discussed malignancy can be fatal without appropriate preventive strategies and therapeutic interventions.

For the reason of developing efficient preventive measures, researchers have closely scrutinized the etiology of the given pathology. It allowed the conclusion that old age, family history, genetic mutations, previous cancer-related status, and long-term estrogen replacement therapy are the major precipitating factors that increase the risk of developing ovarian cancer. Moreover, intrauterine device use, endometriosis, fertility medication, abnormal weight, excessive smoking, and no pregnancy history can ultimately facilitate the disease’s progression (Mayo Clinic Staff, 2014). All the factors above contribute to the pathophysiology of the stated malignancy to different extents. However, numerous studies have asserted a strong association of ovarian cancer with significant mutations in the BRCA1 and BRCA2 genes, which are responsible for providing cellular stability, securing genetic information, and fixing DNA impairments. Severe mutations in the stated genes can disturb the cellular balance and compromise DNA-repairing abilities.

Consequently, such imbalance triggers the proliferation of the mutated cells which can result in ovarian cancer. Furthermore, “mutations in the TP53 and MLN1 or MLN2 genes” prevent from production of proteins that can suppress abnormal proliferation of the malignant cells and inhibit tumor growth (U.S. National Library of Medicine, 2017). Excessive weight or obesity is also responsible for harmful, malignant changes in the ovaries. The given disorder is largely associated with hormonal and physiologic alterations contributing to ovarian cancer pathogenesis.

Ovarian cancer preventive strategies can be effective by diminishing or eliminating the adverse effects of risk factors. In the case of having a family history and adverse genetic predisposition, it is highly recommended to have genetic counseling and BRCA gene testing. Furthermore, gynecologists can advise the conduction of “bilateral salpingo-oophorectomy to females with revealed BRCA1 or BRCA2 mutations after having pregnancy and completing childbearing” (Green, 2018). Post-operative surveys and investigations show that such a radical strategy can be efficacious in preventing ovarian cancer progression. It is estimated that “pregnancies, lactation, and hormonal contraceptives” can ultimately suppress ovulation and minimize ovarian cancer risk (McCance & Huether, 2014, p.831). In addition, an appropriate lifestyle, regular physical training, healthy nourishment with low consumption of saturated fat and red meat, and increased intake of fruits, vegetables, and fish can significantly decrease excessive weight in high-risk women and improve their endocrine profile. Such measures can considerably reduce the risks of acquiring ovarian cancer in prospect.

Moreover, regular “vaginal examination” and transvaginal ultrasound are critical preventive measures for preventing the reviewed disease in genetically predisposed females. Both visual studies can reveal “visible abnormalities in the uterus or ovaries” that can be managed at the earliest (Nordqvist, 2016). A specific blood test that measures serum cancer antigen 125 (CA-125) levels largely assists in detecting cancer-related abnormalities.

Gynecologists are involved in various treatment options for managing ovarian cancer. The treatment regimen may include surgical interventions, chemotherapy, and radiation therapy. Simultaneously, they actively use medication to alleviate the symptoms, enhance the overall condition, and eradicate impairments caused by the disease under scrutiny. Furthermore, targeted drug therapy is also a part of the drug treatment that can effectively eradicate malignant cells, and suppress their multiplication and growth without injuring healthy cells. It may include the administration of such relatively novel drugs as “bevacizumab and olaparib” (Pietrangelo & Cafasso, 2017). The latter medication is effective for treating female patients with mutated BRCA genes.

Furthermore, prescription “protein tyrosine kinase and angiogenesis inhibitors” effectively treat tumors and ovarian cancer cases (Zhang, Tian, & Sun, 2017). Clinical trials of apatinib intake and conventional chemotherapeutics show positive therapeutic efficiency in managing ovarian cancer patients. Oncologists involve carboplatin and a taxane drug, such as paclitaxel or docetaxel, in chemotherapy sessions to cease cancerous cell proliferation and suppress their multiplication and spread.

Presently, researchers continue improving the pharmaceutical properties of existing medications and developing new ones that can efficiently combat symptoms associated with ovarian cancer. Thus, clinicians continue studying the efficacy and applicability of “small-molecular-weight inhibitors, monoclonal antibodies, epidermal growth factor receptors, and gene therapy” in managing the discussed cancer type (McCance & Huether, 2014, p. 834). Finally, the recent discovery of PARP inhibitors, in other words, “poly (ADP-ribose) polymerase inhibitors with cytotoxic effects on mutated BRCA1- and BRCA2 cells,” demonstrate positive dynamics and therapeutic effects (Osman, 2014, p. 5).

Therefore, ovarian cancer is a serious cancerous disease that can significantly deteriorate a woman’s overall and reproductive health. Age, genetic mutations, strong family history, syndromes associated with genetic mutations, unhealthy lifestyle and nutrition, and inflammatory diseases increase the risk of developing ovarian cancer. However, genetic abnormalities related to mutations in certain genes and unfavorable lifestyle and dieting habits are major precipitating factors that can precede the pathology. Pharmacotherapy is one of the primary treatment modalities in combatting the discussed malignancy that can provide sufficient therapeutic effect and positive outcomes. Medication is ultimately a part of targeted drug therapy, hormone therapy, and chemotherapy that assists in eliminating cancerous cells and ceasing their multiplication. The ongoing research on novel medications can improve the efficacy of drug treatment with less detrimental consequences and side effects.

📎 References:

1. Green, A. (2018, January 5). Ovarian cancer treatment and management. Retrieved from https://emedicine.medscape.com/article/255771-treatment#d29?form=fpf 2. Mayo Clinic Staff. (2014a, June 12). Ovarian cancer. Risk factors. Retrieved from https://www.mayoclinic.org/diseases-conditions/ovarian-cancer/symptoms-causes/syc-20375941 3. McCance, K. L., & Huether, S. E. (Eds.). (2014). Pathophysiology: The biologic basis for disease in adults and children (7th ed.). St Louis, MO: Mosby. 4. Nordqvist, C. (2016, August 11). Ovarian cancer: Causes, symptoms, and treatment. Medical News Today. Retrieved from https://www.medicalnewstoday.com/articles/159675 5. Osman, M. A. (2014, December). Genetic cancer ovary. Clinical Ovarian and Other Gynecologic Cancer, 7(1/2), 1-7. 6. Pietrangelo, A., & Cafasso, J. (2017, July 3). Ovarian cancer: Early symptoms, detection, and treatment. Healthline. Retrieved from https://www.healthline.com/health/cancer/ovarian-cancer-early-signs#overview1 7. Stöppler, M. C., & Davis, C. P. (2018, January 24). Ovarian cancer (Cancer of the ovaries). Retrieved from https://www.medicinenet.com/ovarian_cancer/article.htm 8. Zhang, M., Tian, Z., & Sun, Y. (2017). Successful treatment of ovarian cancer with apatinib combined with chemotherapy. Medicine, 96(45). Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5690771/pdf/medi-96-e8570.pdf 9. U.S. National Library of Medicine. (2017). Ovarian cancer. Retrieved from https://medlineplus.gov/genetics/condition/ovarian-cancer/#genes

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• Published: 13 November 2024

Nutritional status and daily habits as determinants of hospitalization duration in ovarian cancer patients undergoing chemotherapy

• Xin Dan 1 , 4   na1 ,
• Ya-Lin Tian 1 , 4   na1 ,
• Yan Huang 2 , 4 ,
• Ya-Lin He 1 , 4   na2 &
• Jian-Hua Ren 3 , 4   na2  

Scientific Reports volume  14 , Article number:  27841 ( 2024 ) Cite this article

Metrics details

• Health care

Adequate nutrition in a hospital setting is essential for achieving optimal health outcomes in oncology patients. This study specifically investigated the interrelationships between nutritional status, daily habits, and hospital length of stay (LOS) in ovarian cancer patients undergoing chemotherapy. A prospective longitudinal study was conducted from August 2019 to January 2022 in a tertiary hospital. Throughout the study, nutritional status, biochemical indicators, diet, and physical activity were meticulously recorded at different stages of chemotherapy: before chemotherapy (T 0 ), the first course (T 1 ), third course (T 2 ), and fifth course (T 3 ). To determine the factors influencing LOS, a generalized estimation equation (GEE) was employed. A total of 460 patients completed the follow-up period. The findings revealed a decline in nutritional risk among patients by 9.90% at T 1 , 17.62% at T 2 and 18.26% at T 3 ( χ 2   =  79.220, P <  0.001). The proportion of people receiving enteral nutrition showed an upward trend ( χ 2   =  15.202, P  < 0.001). Notably, the proportion of patients adhering to a healthier diet increased by 40.44% by the study’s conclusion, while the number of patients abstaining from physical activity or engaging in solely low-intensity activities decreased by 21.08%. Moreover, as the chemotherapy cycle progressed, daily activity steps exhibited an upward trajectory ( F =  5.986, P <  0.001), while the LOS experienced a significant reduction ( F =  21.298, P <  0.001). This study identified hypoproteinemia (protein level < 34 g/L), a high nutritional risk (NRS 2002 score ≥ 3), a short duration of sleep (≤ 7 h/day), and a lower daily activity level as risk factors for LOS. Receiving enteral nutrition support is a protective factor for LOS. Significant improvements in nutritional status, diet, and physical activity have been observed among ovarian cancer patients during their chemotherapy cycles. Reduced nutritional risks, implementation of nutritional support, good physical activity, and adequate sleep were associated with a shorter LOS.

Ovarian cancer is a prevalent malignancy in the female reproductive system. Ovarian cancer has the highest mortality rate among gynecologic malignancies and poses a significant threat to women’s health 1 . According to the most recent data from the International Agency for Research on Cancer (IARC), there were over 310,000 new cases of ovarian cancer reported worldwide in 2020. This included approximately 60,000 new cases in China, which accounts for roughly 20% of the global total 2 . Due to the slow and inconspicuous development of ovarian cancer, around 70% of patients are diagnosed at an advanced stage, leading to a considerable decrease in the five-year survival rate 3 . The unique stress response of cancer patients, along with surgical and chemotherapy-related inflammation and high protein breakdown, causes lowered protein utilization efficiency, leading to weight loss and decreased muscle mass, making patients more vulnerable to malnutrition 4 . A meta-analysis showed that the different rates of muscle atrophy in critically ill patients (ranging from 1.6 to 6%) were closely related to the hospital length of stay (LOS) 5 . Supplementing enteral nutrition to cancer patients at high nutritional risk can improve biochemical and immune indicators, reduce postoperative lung infection rates, and shorten LOS 6 . Statistics indicate that 30% of cancer cases can be attributed to poor dietary habits, and dietary and nutritional interventions can improve the survival rate of ovarian cancer patients 7 . Medical institutions are encouraged to promptly assess cancer patients’ dietary status to reduce their impact on the disease 7 . In addition, exercise oncology, as an emerging field, has been widely proven to benefit cancer patient’s physical and mental health and quality of life 8 . The Netherlands Cohort Study on Diet and Cancer demonstrated that women who exercised for 60, 90, and over 90 min each day had ovarian cancer rate ratios of 0.78, 0.86, and 0.72, respectively, when compared to those who exercised for less than 30 min per day, which indicates that appropriate physical activity can reduce the risk of ovarian cancer 9 .

The nutritional status, dietary habits, and physical activity of patients with ovarian cancer have been found to influence several clinical outcomes, including quality of life, complications, and LOS 10 , 11 . Consequently, it is crucial to regularly assess ovarian cancer patients’ nutrition and daily living habits in clinical practice. However, there are no standardized criteria for selecting evaluation time points. Additionally, most existing studies are limited to simultaneous cross-sectional surveys, requiring ongoing and dynamic evaluation 12 . Patients with ovarian cancer undergoing chemotherapy typically require a minimum of six cycles. Patients’ nutritional status, dietary habits, and physical activity throughout chemotherapy may fluctuate due to disease progression, overall health, and response to treatment. Assessing these factors through a single point-in-time survey is limited and fails to capture the changing trends during chemotherapy 13 . Thus, we conducted a longitudinal survey to monitor patients’ evolving nutritional status and daily living habits at different time points during chemotherapy. The aim was to examine how these factors impact the LOS and provide a basis for healthcare professionals to implement targeted interventions.

The objectives of this study were threefold. Firstly, we aimed to identify the distribution of ovarian cancer patients based on general demographic and disease-related characteristics. Secondly, we sought to determine the dynamic changes in nutritional risk, biochemical indicators, dietary habits, and physical activity at four specific time points: before chemotherapy (T0), the first course of chemotherapy (T 1 ), the third course of chemotherapy (T 2 ), and the fifth course of chemotherapy (T 3 ). Lastly, we aimed to investigate the impact of nutrition, dietary habits, and physical activity on the LOS in ovarian cancer patients undergoing chemotherapy. Given the established links between poor nutrition and adverse treatment outcomes in cancer patients, we expect that improved nutritional status, healthier dietary habits, and increased physical activity will be associated with shorter hospital stays and better clinical outcomes. These findings will provide essential insights for personalized nutritional interventions during chemotherapy for ovarian cancer patients.

Materials and methods

Study design.

This study employed a prospective longitudinal design, utilizing a questionnaire survey to collect data from ovarian cancer patients receiving inpatient chemotherapy at the gynecological chemotherapy ward of a specialized maternity and children’s hospital in Sichuan Province. The data collection period spanned from August 2019 to January 2022.

Sample size

According to the recommendations made by Bentler and Chou 14 , it is advised to determine the sample size as 5 to 10 times the number of parameters. In this study, 55 parameters were considered, encompassing the patient’s general information, nutritional status, and daily living habits questionnaire. Considering a 25% dropout rate and a 10% questionnaire invalidity rate and employing a standard of six times the number of parameters, a sample size of 508 is deemed necessary.

Participant recruitment

The study recruited volunteers who met the following inclusion criteria: (1) being aged 18 years or older, (2) having a pathological diagnosis of ovarian cancer, (3) receiving chemotherapy for the first time, (4) being conscious and aware of their condition, and (5) expressing a willingness to participate. Patients were excluded from the study if they met any of the following exclusion criteria: (1) having recurrent ovarian cancer, (2) receiving radiotherapy, biotherapy, or other adjuvant treatments, (3) experiencing cognitive barriers that hindered the ability to complete the questionnaire independently, or (4) being unable to cooperate with the investigation due to severe organ injuries or significant physical illnesses. 565 patients who fulfilled the inclusion and exclusion criteria were recruited for this study. Among them, 42 patients dropped out at T 2 for reasons such as refusal to continue the investigation, transfer to another hospital, or inability to complete the questionnaire due to physical constraints. Additionally, 63 patients dropped out at T 3 due to refusal to continue the investigation, initiation of radiotherapy or biological therapy, transfer to the intensive care unit, or death resulting from their illness. Consequently, 460 participants completed T 0 –T 3 , resulting in a questionnaire recovery rate of 81.42%. Statistical analysis revealed no statistically significant differences in general demographic data and disease-related data between the patients who withdrew and those who completed all surveys.

The following tools and instruments were used in this study for data collection and variable measurement: nutritional risk screening (NRS 2002) scale, used to screen the nutritional risk of hospitalized patients; Laboratory biochemical indicators (such as albumin, prealbumin) were measured using the hospital’s standard equipment, using the Roche Diagnostics Cobas ® 8000 fully automatic biochemical analyzer; Height and weight were measured using the SECA electronic height and weight scale (model SECA 220) to calculate body mass index(BMI); Daily activity monitoring was done using the Fitbit smart bracelet, recording daily steps and activity levels; Sleep duration was assessed through a patient-reported sleep log questionnaire.

Clinical and demographic information sheet

The clinical and demographic information sheet was designed by the researchers and included height, weight, age, marital status, nation, education level, habitation, per capita monthly income, medical insurance, complication, cancer stage, chemotherapy setting, chemotherapeutic regimen, radiation history, surgical history, Karnofsky level, and Barthel status, etc.

Nutritional status sheet

With a total of 20 questions, we obtained the following four dependent contents: NRS 2002 scores, nutrition intake assessment form, BMI and laboratory indicators.

The nutritional risk screening tool selected for this study was the NRS 2002, as recommended by the European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines for identifying nutritional risk and malnutrition in hospitalized patients. The NRS 2002 scale comprises three components: age score (ranging from 0 to 1 point), disease severity score (ranging from 0 to 3 points), and nutritional status score, which considers BMI, weight loss, and dietary intake (ranging from 0 to 3 points). The NRS 2002 score is obtained by summing up the scores of these three components, with a score of ≥ 3 points indicating nutritional risk 15 .

The nutrition intake assessment form includes the nutritional support received by ovarian cancer patients at different stages of chemotherapy (e.g., enteral and parenteral nutrition), as well as the collection of disease information that may related to nutritional status, including gastrointestinal decompression, abrosia, blood transfusion, nausea and vomiting.

The classification of BMI adheres to the Asian standards proposed by the World Health Organization in 2002. BMI is categorized into four groups based on the following criteria: underweight (BMI < 18.5 kg/m 2 ), average weight (BMI 18.5 kg/m 2 − 22.99 kg/m 2 ), overweight (BMI 23 kg/m 2 − 24.99 kg/m 2 ), and obesity (BMI ≥ 25 kg/m 2 ). For albumin and prealbumin, the latest medical testing standards are utilized. The average values for albumin and prealbumin are 34–55 g/L and 180–350 mg/L, respectively. Current research showed that albumin and prealbumin levels are highly likely to be biochemical indicators reflecting nutritional status 16 .

Daily living habit sheet

Patients with ovarian cancer were also asked to answer 11 other questions reflecting their daily lifestyle: diet taboos (yes, no), diet regular (yes, no), extra meal (never, once in a while, 3–4 times/week, or every day), dietary changes (eat more fruits and vegetables, eat less red meat, eat less fat, or eat more healthily), dietary intake (unchanged, increase (≤ 50%), reduce (≤ 50%), or reduce(>50%)), coffee drinking habits (yes, no), main types of physical activity (never, low intensity activities, moderate intensity activities, or strenuous activities), moderate or above intensity activity frequency (never, ≤ 3 times/week, 4–6 times/week, every day), average daily sleep duration, average daily activity steps, and average daily sitting time. The items were evaluated using the single-choice format, except for the dietary change question, which utilized the multiple-choice format.

The current study’s questionnaire displayed a Cronbach’s α of 0.80, indicating acceptable internal consistency. Furthermore, the content validity index was measured at 0.85, signifying strong content validity.

Ethical considerations

The ethics committee of the research hospital approved this study, and all survey participants were provided comprehensive information regarding the research’s purpose and methods. Additionally, they willingly signed an informed consent form.

The data for this study was collected by nurses and research assistants who had received standardized training and possessed extensive clinical nursing experience, especially in oncology nursing. The data collectors underwent standardized training before the start of this study to ensure the accuracy and consistency of the data collection process. Upon admission, demographic and disease-related data, nutritional intake, and daily lifestyle habits were collected through reviewing medical records or face-to-face interviews. To recall their habits from the preceding month, research assistants aided patients. Biochemical markers, nutritional scores, and LOS were retrieved by examining medical records on the day of discharge. All personnel involved in the data collection completed uniform training and utilized standardized instructions while administering the questionnaire to patients. Investigators utilized impartial and objective language for patients unable to self-evaluate to elaborate on survey items and support completion.

Data analyses

This study ensures the accuracy of the data and minimizes the possibility of underreporting or overreporting through the following measures. Standardized training: All data are collected by nurses and research assistants who have received standardized training. The data collection process strictly follows standardized operating procedures to ensure the collected data is consistent and accurate. Data review: Questionnaire data for all patients are reviewed twice to ensure the accuracy of data entry and reduce the possibility of human input errors.

Cross-validation

Our goal is to reduce reporting bias and improve data reliability. We cross-validate objective data such as biochemical indicators (e.g., albumin, BMI, etc.) with patients’ self-reported data to achieve this. Structured questionnaire design: To reduce the influence of subjective factors on data by patients, we designed closed-ended and structured questions to ensure standardized processing of all patients’ responses, thereby reducing the risk of underreporting or overreporting. Data entry and statistical analysis were conducted using SPSS Version 22.0 (SPSS, Inc., Chicago, IL, USA). The counting data were reported as frequency (percentage), while the measurement data, with a normal distribution, were presented as mean ± standard deviation. Repeated measurement variance analysis, chi-square tests, and the Kruskal-Wallis test were employed to investigate the dynamic changes in NRS 2002 scores, nutrition intake, biochemical indicators, dietary habits, physical activity, and LOS at four-time points during chemotherapy. If performing repeated measurement variance analysis and the spherical hypothesis is valid, we used the uncorrected coefficient. If it was not valid ( P  < 0.05), we used the Greenhouse-Geisser correction coefficient and the corrected coefficient. A univariate setting and multivariate multi-level GEE model were used to determine the relationship between nutritional status, lifestyle and LOS indicators while controlling for the cluster effect of location and the confounding effects of demographic characteristics. Variables whose P -value for a significance test is less than 0.1 in univariate setting were selected to build up the multivariable model. All statistical tests were conducted using a bilateral test, with a statistically significant difference of P  < 0.05.

Demographic and disease-related characteristics

Four hundred sixty patients with ovarian cancer undergoing chemotherapy were included in this study. Patients aged > 65 years old accounted for 61 individuals (13.3%), while there were 399 patients aged ≤ 65, with the majority falling between 41 and 60 years old (65.4%). the education level is mainly junior high school or below (57.2%), the majority of patients were married (85.5%), and the nationality is Han (98.0%). The majority of patients live in cities (54.6%). Nearly half (41.1%) reported earning a family income of 3001–5000 yuan per month. 94.3% of the patients have medical insurance. The cancer stage is mainly III or IV (73.0%). 80.9% of patients receive adjuvant chemotherapy. Paclitaxel plus Cisplatin / Carboplatin is the main chemotherapeutic regimen (87.4%). Most patients have no history of complications and radiotherapy (71.7%, 98.7%, respectively), and 92.4% have undergone ovarian cancer surgery. The majority of patients have high levels of daily living ability and Karnofsky level (75.4%, 80.2%, respectively). The details are shown in Table  1 .

Nutrition risk

The NRS 2002 scores of 460 patients at T 0 , T 1 , T 2 , and T 3 were (1.72 ± 1.14), (1.57 ± 1.03), (1.29 ± 0.84), and (1.25 ± 0.79) respectively, for the whole cohort ( F  = 15.644, P  < 0.001). The Chi-square test results showed a significant effect of time ( χ 2  = 79.220, P  < 0.001). The patient’s nutritional risk was highest at T 0 , 25.65%, 15.75% at T 1 , 8.03% at T 2 , and 7.39% at T 3 , indicating a decreased nutrition risk over time (Table  2 ).

Nutritional support and disease status

Table  3 shows that the distributions of nutritional support and disease status related to nutritional damage at T 1 -T 3 . As the chemotherapy course progresses, the number of people receiving enteral nutrition showed an upward trend ( χ 2   =  15.202, P  < 0.001). At the three time points of chemotherapy, the proportion of people receiving parenteral nutrition, abrosia, blood transfusion, and gastrointestinal decompression was all less than 20%. The proportion of people who experience grade 2 or above nausea and vomiting is less than 17%, and the severity distribution at each level is relatively stable, with no statistically significant differences.

BMI and biochemical indicators

Table  4 presents the longitudinal results for BMI and biochemical indicators. In particular, the indicators albumin and prealbumin significantly improved as the chemotherapy course progressed ( F =  27.569, P <  0.001; F =  38.600, P <  0.001, respectively). Although body weight and BMI showed a slight upward trend, no statistically significant difference was observed ( F =  0.882, P >0.05; F =  0.531, P > 0.05, respectively). Hemoglobin and total lymphocyte count followed a slightly different pattern, with a reduction but maintaining levels within the normal range at T 0 , T 1 , T 2 , and T 3 ( F =  8.743, P <  0.001; F =  0.237, P > 0.05, respectively). Serum calcium exhibited an irregular change trend, initially increasing from T 0 to T 2 and then decreasing at T 3 , but no significant statistical difference in these changes was found ( F =  0.319, P > 0.05).

Daily living habits

The study revealed regular diet and physical activity changes throughout the chemotherapy cycles, as presented in Table  5 . Notable differences were observed in dietary taboos over time. The proportion of participants with no dietary taboos increased by 6.09% at T 2 (90.22%) and remained relatively stable until the study’s conclusion (92.83%). In the initial chemotherapy phase, the dietary changes index indicated low frequencies of consuming more fruits and vegetables (26.52%), reducing red meat intake (29.78%), decreasing fat consumption (25.87%), and adopting a healthier eating pattern (22.39%). However, these frequencies increased to 38.70%, 39.57%, 34.57%, and 62.83%, respectively, before the fifth chemotherapy session. Similar improvements were observed in the type and frequency of physical activity. The proportion of participants who reported no engagement in any activity and those who did not engage in moderate or intense activities decreased from 35.43% to 59.78% at the early stage of chemotherapy to 6.96% and 38.70% at the study’s conclusion. Analysis of daily step counts indicated an enhancement in health status after five cycles of chemotherapy ( F  = 3.986, P  < 0.05).

The overall situation of LOS at different chemotherapy time points

The LOS for patients in this study at three-time points, T 1 , T 2 , and T 3 , was (4.96 ± 1.08), (3.82 ± 1.01), and (3.26 ± 0.95), respectively. The LOS showed a downward trend; the difference was statistically significant ( F  = 21.298, P  < 0.001) with increased chemotherapy cycles.

Effects of nutrition and daily living habits on LOS

Univariate and multivariate multi-level GEE model were utilized to examine the impact of nutrition and daily living habits on LOS at different time points (Table  6 ). After controlling for the cluster effect of location and the confounding effects of other covariates (e.g., cancer stage, monthly income, medical insurance, chemotherapy setting, chemotherapeutic regimen, complication, baseline assessment, Karnofsky level, and activity of daily living), as these factors have been suggested in the literature to influence LOS potentially 17 . The findings revealed that patients with normal serum albumin levels experienced shorter LOS than those with hypoproteinemia ( β = -2.482, P <  0.001). Moreover, patients with a nutritional risk were associated with a longer LOS than those without a nutritional risk ( β = -1.298, P =  0.018). Patients who received enteral nutrition showed shorter LOS compared to those who did not receive treatment ( β = -0.973, P =  0.013). Notably, patients with shorter daily sleep duration (≤ 7 h/d) and a lower number of daily activity steps exhibited prolonged LOS ( β =  1.382, P =  0.014; β = -1.492, P <  0.001, respectively).

This study employed a prospective longitudinal design to investigate the dynamic changes in nutritional status, dietary habits, and physical activity throughout chemotherapy in a substantial sample of ovarian cancer patients who received chemotherapy exclusively. Moreover, it aimed to assess the impact of these factors on LOS. Despite the efforts of NCCN guidelines and international agencies to enhance the evaluation and management of malnourished patients 18 , 19 , 20 , few studies have explored the dynamic changes in nutrition among ovarian cancer patients undergoing chemotherapy. Our study revealed that patients had a lower risk of malnutrition, and as the number of chemotherapy sessions increased, high-risk nutrition and relevant biochemical indicators (albumin and prealbumin) demonstrated a satisfactory change trend. The risk of malnutrition was notably lower than the findings reported by Pressoir and Hébuterne et al. 21 , 22 , and higher than those reported by Salas et al., 23 which might be attributed to the high heterogeneity of the sample.

Typically, patients who have undergone surgery tend to have a higher likelihood of experiencing malnutrition. In this study, over 90% of the participants underwent ovarian cancer radical surgery, followed by chemotherapy scheduled approximately one month later. Previous studies on ovarian cancer have highlighted that weight fluctuations in patients during the perioperative period are more pronounced due to surgical stress and chemotherapy-related inflammation. This difference may be attributed to acute stress and metabolic changes triggered by surgery, short-term fasting, and impaired gastrointestinal function 23 , 24 , 25 . As anticipated, nutritional scores and relevant biochemical markers showed a slight deterioration in the initial phases of chemotherapy. The administration of chemotherapy drugs, known for their toxic side effects, can further elevate the risk of malnutrition during this stage 26 . However, as patients progress through subsequent chemotherapy cycles, the lower malnutrition risk can likely be attributed to adherence to standardized nutrition management protocols, which involve regular weight monitoring and at least one dietary assessment during inpatient chemotherapy.

Our research findings reveal that more than 40% of patients diagnosed with ovarian cancer have significantly modified their diet and exercise regimens. These modifications predominantly involve adopting healthier habits, such as consuming higher quantities of fruits and vegetables, decreasing their intake of high-fat foods, and engaging in essential aerobic exercises. These observed changes follow the ESPEN practical guideline and the American Cancer Society’s advocacy for improving cancer patients’ nutrition and lifestyle 20 , 27 . In addition, most patients believe that this lifestyle is beneficial for the prognosis of the disease and physical health, and some patients indicate that after adhering to this lifestyle for some time, symptoms of anxiety and depression have been alleviated. Studies have revealed that tumors or chemotherapy can cause oxidative stress and changes in the levels of inflammatory markers in the body, leading to an imbalance of pro-inflammatory cytokines (such as hypersensitive c-reactive protein, interleukin − 6, tumor necrosis factor-α) 28 , 29 . Patients exhibit a persistent low-grade pro-inflammatory state after chemotherapy, even lasting for several years of treatment. Consumption of anti-inflammatory foods, including whole grains, vibrant vegetables and fruits, as well as foods rich in n-3 polyunsaturated fatty acids, along with engaging in suitable aerobic exercise, can effectively stimulate adenylate kinase activity and diminish the levels of inflammatory factors among these patients 30 . Malnutrition can arise from various factors, including tumor consumption, stress states, and inflammatory reactions 31 . Notably, malnutrition diminishes the body’s capacity to withstand surgical procedures and chemotherapy, resulting in unfavorable treatment outcomes, such as surgical incision infections, delayed surgical site healing, and heightened toxic side effects of chemotherapy.

In addition, malnutrition can accelerate disease deterioration and result in patients exhibiting symptoms of weakness, fatigue, edema, and even cachexia, ultimately affecting the patient’s quality of life 32 , 33 . Research has indicated that patients with a stable BMI display prolonged survival times and shorter LOS 34 . Therefore, enhancing screening for nutritional risks and implementing timely nutritional interventions is crucial in clinical practice. Standardized nutritional therapy should be based on the patient’s nutritional status, dietary habits, physical activity, and cultural preferences 35 .

According to nutrition guidelines, cancer patients are advised to distribute their daily energy intake as follows: less than 30% fat/d, consisting mainly of monounsaturated and polyunsaturated fatty acids; approximately 55% carbohydrates, primarily sourced from whole foods like oats, brown rice, and fruits; and a protein intake of 1.2–1.5 g per kilogram of body weight per day, to prevent muscle wasting and obesity. A healthy dietary pattern involves avoiding or reducing the consumption of red meat, processed meat, sugary beverages, highly processed foods, and refined grain products. Alcohol consumption is not recommended, but for those who choose to drink alcohol, it should be consumed in moderation. Women should be at most 1 glass (12 ounces) of regular beer, 5 ounces of wine, or 1.5 ounces of 80-proof distilled spirits daily. It is essential to include a variety of colorful vegetables and fruits in the diet, as well as garlic and cruciferous vegetables, as part of nutritional therapy. Consuming foods rich in β-Carotenoids and vitamins A, E, and C, along with essential micronutrients, can contribute to the prevention of disease progression in cancer patients and improve overall health and prognosis 35 , 36 . Enteral immune nutrition is increasingly utilized as an innovative nutritional support in adjuvant therapy for cancer patients, especially those with impaired immune function 6 .

The results of this study indicated that as the chemotherapy course progresses, the number of people receiving parenteral nutrition, gastrointestinal decompression, abrosia, and blood transfusion remains relatively stable and in a relatively low proportion. It may be related to the fact that chemotherapy is recommended for patients who are in good physical health. The proportion of enteral nutrition intake, mainly based on oral nutritional supplements, is gradually increasing, which may be related to oncologists receiving professional nutrition training and providing nutritional support and education to potential malnourished patients during the research process. Enteral nutrients entering the gastrointestinal tract can stimulate intestinal peristalsis, promote the growth of intestinal mucosal cells and secretion of gastrointestinal hormones, facilitate the normal operation of the gastrointestinal mucosal barrier, prevent abnormal transfer of intestinal flora, and reduce the probability of enterogenous infections 37 . In addition, enteral nutrition can maintain immune balance in the intestine, and promote the normal metabolic recovery of the body, which is beneficial for the patient’s disease recovery and shortens the LOS 38 .

Sleep disorders, particularly insomnia, are highly prevalent among cancer patients. A meta-analysis reveals that around 95% of cancer patients encounter sleep disorders and disturbances 39 . Moreover, research indicates that cancer can initiate sleep disorders, accelerating cancer progression 39 , 40 . Additionally, sleep disorders can give rise to several adverse consequences, including fatigue, anxiety, depression, decreased pain tolerance, and weakened immunity 41 . Our study found that many patients reported experiencing worsened insomnia before hospital admission. Further analysis has revealed that the most common causes of sleep disruption were the uncomfortable hospital environment, fear of treatment and adverse drug reactions, and financial stress. Intervention lighting systems should be deployed in wards to address potential medical barriers, while measures to reduce unnecessary noise should be implemented. For patients with anxiety and depression, psychological counseling or relaxation training should be rendered, and if necessary, drug intervention should be considered, especially for long-term hospitalized patients.

The study’s results revealed that activity steps were independently predictive of LOS. Previous research has demonstrated that being overweight and leading a sedentary lifestyle contribute to about 25% of cancer cases worldwide 42 . Physical exercise can mitigate the risk of developing cancer by impacting multiple mechanisms, such as decreasing sex and metabolic hormones, suppressing inflammatory reactions, and enhancing immune function 43 . Hence, physical exercise constitutes a crucial intervention for preventing and treating cancer. While there is no conclusive evidence of an interaction between physical activity and chemotherapy, various clinical trials have reported no detrimental effects of exercise on chemotherapy patients 44 , 45 , 46 .

Patients who participated in aerobic exercises or comprehensive rehabilitation programs, which included resistance and fitness training, massage, relaxation, and body awareness training, exhibited notable enhancements in fatigue, pain symptoms, happiness index, and overall quality of life 46 . Furthermore, a multicenter randomized controlled trial indicated that incremental load aerobic exercise and strength training positively influenced chemotherapy completion rates among cancer patients while avoiding complications such as lymphedema and other side effects 45 . When initiating physical activity, the timing and approach should be tailored to the patient’s physical condition and preferences. According to physical activity guidelines, individuals undergoing chemotherapy and radiation therapy should commence with lower intensity and shorter duration exercise, gradually increasing frequency according to their ability, striving to maintain optimal activity levels 27 .

There are several limitations in this study. Firstly, the analysis was limited to data collected from only one specialized tertiary hospital in Chengdu, which may hinder the generalizability of the results. Hence, future investigations should encompass multiple hospitals from diverse regions and varying levels of treatment facilities to enhance the accuracy of the findings. Secondly, the study did not monitor changes in the patient’s nutritional status and lifestyle habits after the chemotherapy course and during long-term follow-up. Consequently, future studies should extend the follow-up period to offer more compelling data support for intervention studies related to this topic.

Ovarian cancer patients have significantly improved their nutritional status, diet, and physical activity following their fifth round of chemotherapy. This study identified hypoproteinemia (protein level < 34 g/L), a high nutritional risk (NRS 2002 score ≥ 3), a short duration of sleep (≤ 7 h/day), and a lower daily activity level as risk factors for LOS. Receiving enteral nutrition support is a protective factor for LOS. The findings of this study indicate that the nutritional status, sleep patterns, and daily activities of cancer patients impact their quality of life and disease prognosis. Consequently, healthcare professionals in clinical settings should prioritize monitoring the nutritional status of these patients and provide appropriate dietary and exercise guidance to optimize the effectiveness of chemotherapy. This study has a large sample size, including a total of 460 ovarian cancer patients, providing representative statistical data; secondly, a longitudinal study design was adopted to systematically follow up on the nutritional status and daily habit changes of patients at different stages of chemotherapy, dynamically revealing the impact of these factors on the length of hospital stay; finally, using Generalized Estimating Equations (GEE) for multifactor analysis, controlling for confounding variables to ensure the scientific and accurate results. Therefore, the experimental results of this study provide a solid basis for nutritional intervention and inpatient management for ovarian cancer patients.

Data availability

The datasets generated and/or analysed during the current study are not publicly available due to the personal information protection law in China but are available after the permission from the institutional review board and the corresponding author on reasonable request.

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Acknowledgements

The authors gratefully acknowledge the hospital supervisors, the 460 patients who volunteered to participate in the study and the experts and members of the group for their help and advice.

This study was supported by the Science and Technology Project of the Health Planning Committee of Sichuan (no.20PJ083).

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These authors contributed equally : Xin Dan and Ya-Lin Tian.

These authors contributed equally : Ya-Lin He and Jian-Hua Ren.

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Department of Radiation Therapy and Chemotherapy for Cancer Nursing, West China Second University Hospital, Sichuan University, Chengdu, China

Xin Dan, Ya-Lin Tian & Ya-Lin He

Department of Nursing, West China Second University Hospital, Sichuan University, Chengdu, China

Department of Obstetrics and Gynecology Nursing, West China Second University Hospital, Sichuan University, Chengdu, China

Jian-Hua Ren

Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, 610041, Sichuan, China

Xin Dan, Ya-Lin Tian, Yan Huang, Ya-Lin He & Jian-Hua Ren

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Xin Dan wrote the main manuscript and analyzed the data. Ya-Lin Tian and Yan Huang coordinated the study and collected and prepared the data. Ya-Lin Tian helped interpret the results. Xin Dan, Ya-Lin He and Jian-Hua Ren revised and supervised the manuscript.

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Correspondence to Ya-Lin He or Jian-Hua Ren .

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This study obtained approval from the Ethics Committee of West China Hospital, Sichuan University, with approval number 2019071 on July 1, 2019. All participants signed informed consent forms before participating in the study. The research process strictly adhered to the Helsinki Declaration’s ethical principles to ensure the participants’ privacy and data security and to prevent any potential harm to them.

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Dan, X., Tian, YL., Huang, Y. et al. Nutritional status and daily habits as determinants of hospitalization duration in ovarian cancer patients undergoing chemotherapy. Sci Rep 14 , 27841 (2024). https://doi.org/10.1038/s41598-024-78941-y

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DOI : https://doi.org/10.1038/s41598-024-78941-y

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