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Suggested Citation:"6 Recommendations." National Academies of Sciences, Engineering, and Medicine. 2016. Ovarian Cancers: Evolving Paradigms in Research and Care. Washington, DC: The National Academies Press. doi: 10.17226/21841.
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6

Recommendations

This report has provided a broad overview of the state of the science in ovarian cancer research, highlighting the major gaps in knowledge and the research challenges that may impede progress in preventing, detecting, and treating ovarian cancers. In assessing the evidence base, the committee focused its attention on identifying the particular research gaps that, if addressed, could have the greatest impact on reducing morbidity or mortality from ovarian cancer for the largest number of women. The committee identified four overarching concepts that should be applied to each recommendation in this report:

  • Because high-grade serous carcinoma (HGSC) is the most common and lethal subtype ovarian cancer, its study needs to be prioritized;
  • Even with a focus on HGSC, 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. (See Chapter 7.)

The following sections summarize the findings and conclusions of the previous chapters and outline the committee’s final recommendations across the spectrum of ovarian cancer research. The committee stresses that these

Suggested Citation:"6 Recommendations." National Academies of Sciences, Engineering, and Medicine. 2016. Ovarian Cancers: Evolving Paradigms in Research and Care. Washington, DC: The National Academies Press. doi: 10.17226/21841.
×

recommendations need to be considered simultaneously, not sequentially. The recommendations are often intertwined, and the sequence of their presentation here should not be considered as indicative of the priority of their importance or of the necessary order of their implementation.

THE BIOLOGY OF OVARIAN CANCER

As was noted earlier in this report, “ovarian cancer” is a generic term that can be used for any cancer involving the ovaries, but the term is a misnomer in the sense that ovarian cancer is not just one disease. The committee concludes that the term “ovarian cancer” refers to a constellation of several distinct types of cancer involving the ovary. Ovarian cancers can arise from many cell types, and even among ovarian carcinomas there are a number of distinct subtypes. For example, recent evidence suggests that many ovarian carcinomas do not arise in the ovary per se. Instead, these carcinomas may, in fact, arise in other tissues such as the fallopian tubes or ectopic endometrial-type tissue (e.g., endometriosis) and then metastasize to the ovary, or else arise from cells that are not considered intrinsic to the ovary (Brinton et al., 2005; DePriest et al., 1992; Erzen et al., 2001; Forte et al., 2014; Fujii et al., 2014; Kerr et al., 2013; Kindelberger et al., 2007; Kuhn et al., 2012; Kurman et al., 2011; Lee et al., 2006; Pavone and Lyttle, 2015; Przybycin et al., 2010; Robey and Silva, 1989; Rossing et al., 2008; Sainz de la Cuesta et al., 1996; Yoshikawa et al., 2000) (see Figure 2-1). The committee concludes that a substantial proportion of carcinomas labeled “ovarian” may actually originate outside the ovary or arise from cells that are not considered intrinsic to the ovary.

In addition to not having a complete understanding of the sites of origin for ovarian carcinomas, researchers do not have a complete understanding of the pathogenesis of the various subtypes or of the effects of the microenvironment on disease progression. 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 in ovarian carcinomas, including within and between subtypes. And while the subtypes are distinct, clinicians and researchers tend to combine them in many types of research. The committee concludes that an incomplete understanding of the basic biology of each subtype, especially its origin and pathogenesis, is an impediment to advances in prevention, screening and early detection, diagnosis, treatment, and supportive care. Therefore, the committee recommends the following:

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

Suggested Citation:"6 Recommendations." National Academies of Sciences, Engineering, and Medicine. 2016. Ovarian Cancers: Evolving Paradigms in Research and Care. Washington, DC: The National Academies Press. doi: 10.17226/21841.
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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.

The committee re-emphasizes that the subsequent recommendations need to be interpreted in the context of the importance of understanding the distinct issues for each ovarian cancer subtype. However, the committee notes that in research that examines the individual subtypes of ovarian cancer, the rarity of cases of ovarian cancer overall limits the power of individual epidemiologic and treatment studies to draw accurate conclusions. Therefore, the use of consortia and the leveraging of existing data in pooled studies will be important for all types of studies in ovarian cancer. It will be necessary to develop the infrastructure to support such consortia, including data harmonization and the development of new statistical methods.

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 disease characteristics for each of the subtypes. Tumor classification, nomenclature, and grading systems have changed over time as new insights have emerged (Gurung et al., 2013; Kalloger et al., 2011; Shih and Kurman, 2004), and evidence suggests that there is great variability in current surgical and pathological practices for the reporting of ovarian cancers and that critical details are missing in a large percentage of reports (Donahoe et al., 2012; Gogoi et al., 2012; Verleye et al., 2011). The committee concludes that 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, including treatment course determination. Therefore, the committee recommends the following:

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, in part because this process cannot be static. Multiple stakeholders will need to be engaged in an

Suggested Citation:"6 Recommendations." National Academies of Sciences, Engineering, and Medicine. 2016. Ovarian Cancers: Evolving Paradigms in Research and Care. Washington, DC: The National Academies Press. doi: 10.17226/21841.
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iterative process in which the schemes can change as new evidence comes to light. Stakeholders can employ a variety of options for moving toward consensus, including the convening of experts to reach consensus on taxonomy or the creation of ongoing working groups by subtype. For example, in 2003 a workshop was co-convened by the National Institutes of Health Office of Rare Diseases, the National Cancer Institute’s (NCI’s) Office of Women’s Health, and the NCI Cancer Diagnosis Program to resolve conflicts regarding the characterization of borderline ovarian tumors (BOTs) (Berman, 2004). In an editorial about the workshop, Berman noted

In the past several years, pathologists have urged a BOT workshop, expressing the opinion that agreement could be reached on some issues that will help pathologists diagnose BOTs with higher consistency and that will guide clinicians toward a treatment commensurate with the expected clinical behavior of BOTs. For those areas where there is no agreement, a group would seek to develop a commonly accepted way of describing the basis of disagreement. By providing a thoughtful discussion of areas that lack agreement, new areas for future BOT research could be developed. (Berman, 2004)

Another example from a different field is the Lower Anogenital Squamous Terminology project, a consensus-based process co-sponsored by the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology to resolve concerns about multiple diagnostic terms being used by different specialties for human papillomavirus–associated squamous lesions of the lower anogenital tract (Darragh et al., 2013). This consensus process had multiple working groups to address the histopathologic nomenclature for these lesions and sought to “recommend terminology unified across lower anogenital sites” (Darragh et al., 2013, p. 1266). These two efforts—and others like them—can serve as examples for convening multiple stakeholders to reach consensus on taxonomy. Given the complexity of the multiple subtypes of ovarian cancer, such efforts will likely need to occur by subtype or other convention by which the overall taxonomy could be addressed.

The committee again stresses that these first two recommendations about biology research and taxonomy need to be considered simultaneously, not sequentially. 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 the 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

Suggested Citation:"6 Recommendations." National Academies of Sciences, Engineering, and Medicine. 2016. Ovarian Cancers: Evolving Paradigms in Research and Care. Washington, DC: The National Academies Press. doi: 10.17226/21841.
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therapeutics (see Recommendation 9). And, as a further example of the interconnection among this report’s recommendations, while Recommendation 9 calls for research on immunologic and molecularly driven treatment approaches, more basic research is needed to understand the immunologic and molecular characteristics of the individual ovarian cancer subtypes in order to drive the development of such novel therapeutics.

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 and specific germline (inherited) genetic mutations and hereditary cancer syndromes have strong associations with risk for ovarian cancer (Jervis et al., 2014; Shulman and Dungan, 2010; Soegaard et al., 2009; Stratton et al., 1998; Werness and Eltabbakh, 2001). 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 genes have been identified but are less well studied (Hampel et al., 2015; Hendriks et al., 2006; Lu and Daniels, 2013; Shulman, 2010). 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 genetic mutation (most commonly in BRCA1 or BRCA2) (Schrader et al., 2012; Walsh et al., 2011). Multiple professional groups recommend that all women diagnosed with an invasive ovarian cancer receive genetic testing and counseling with a cancer genetics professional for a variety of reasons, including to determine appropriate therapies, assess other health risks, and determine the risk for family members (ACS, 2012; Hampel et al., 2015; Lancaster et al., 2015; NCCN, 2015). 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 potential 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”) can benefit from enhanced screening, risk-reducing procedures, or chemoprevention (Leonarczyk and Mawn, 2015). 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 (Hampel et al., 2015). Furthermore, more research is needed to determine the significance

Suggested Citation:"6 Recommendations." National Academies of Sciences, Engineering, and Medicine. 2016. Ovarian Cancers: Evolving Paradigms in Research and Care. Washington, DC: The National Academies Press. doi: 10.17226/21841.
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of known mutations and to discover new significant mutations for all subtypes. Therefore, the committee recommends the following:

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.

The committee recognizes that relying on family history alone may lead clinicians to overlook some women with germline mutations that put them at higher risk for ovarian cancer. Up to one-half of women with high-risk germline mutations do not have an apparent family history of breast or ovarian cancer (Schrader et al., 2012; Walsh et al., 2011). Also, family history may not identify high risk for women with few female relatives, for women who were adopted and do not know their biological family’s cancer history, or for women who otherwise do not know the family health history of one or both parents. (Lancaster et al., 2015).

Furthermore, as the majority of women with an ovarian cancer do not appear to have a known high-risk germline mutation or a significant family history, it is critical to also consider other potential risk factors. While several nongenetic factors are associated with either an increased or a decreased risk for developing ovarian cancers (see Table 3-1), the patterns of association are inconsistent. For example, some risk factors may affect risk in the same way for all subtypes, whereas other factors may increase risk for some subtypes while decreasing risk for other subtypes. The strongest known risk factors to date are those associated with the less common and less lethal subtypes. Therefore, the committee recommends the following:

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

Suggested Citation:"6 Recommendations." National Academies of Sciences, Engineering, and Medicine. 2016. Ovarian Cancers: Evolving Paradigms in Research and Care. Washington, DC: The National Academies Press. doi: 10.17226/21841.
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to better understand how specific exposures influence disease development. Current research does not provide insight 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. Furthermore, consortia will be again needed in order to provide sufficient power to evaluate potential risk factors, particularly for the less common subtypes and rare exposures.

Women known to be at high risk may benefit from surgical and nonsurgical preventive measures, but the risk–benefit ratios of these measures need to be better defined for different tumor subtypes and at-risk populations. For example, risk-reducing surgeries (e.g., bilateral salpingo-oophorectomy and salpingectomy) and the use of prescription medications (e.g., oral contraceptives) 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) (Bassuk and Manson, 2015; Beral et al., 2008; Cibula et al., 2011; Daly et al., 2015; Evans et al., 2009; Falconer et al., 2015; Finch et al., 2014; Guldberg et al., 2013; Havrilesky et al., 2013; Madsen et al., 2015; McAlpine et al., 2014; Nelson et al., 2014; Walker et al., 2015). 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. Collaborative research and longitudinal sampling will again be important when performing these types of studies, especially in the determination of the long-term impact of these interventions..The committee concludes that much remains to be learned about risk assessment and prevention strategies for specific subtypes and in specific populations. Therefore, the committee recommends the following:

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.

Better methods for identifying high-risk women would likely affect the morbidity and mortality of ovarian cancer by helping to prevent or detect ovarian cancers as early as possible. Current approaches for early detection include assaying for biomarkers (e.g., CA-125), 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 these methods have not had a substantial impact on overall mortality (Buys et al., 2011; Jacobs et al., 2015; Kobayashi et al., 2008; Menon et al., 2015; van Nagell et al., 2007). Given the marked heterogeneity of ovarian cancers and the incomplete understanding of early disease devel-

Suggested Citation:"6 Recommendations." National Academies of Sciences, Engineering, and Medicine. 2016. Ovarian Cancers: Evolving Paradigms in Research and Care. Washington, DC: The National Academies Press. doi: 10.17226/21841.
×

opment 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. The committee concludes that current screening strategies have not had a substantial impact on reducing mortality in the general population and that 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. Therefore, the committee recommends the following:

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. Trials could be conducted in populations of women identified to be at high genetic risk and also in high-risk populations that are newly identified as a result of using the risk assessment tool from Recommendation 4. 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. Thanks both to better characterization of tumor biology and to a precision medicine approach in the development of therapeutics, a wider variety of treatment options now 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). Progression-free survival and overall survival are markedly better for women who have complete (or optimal) tumor resection, yet great variability exists in the extent of tumor resection (Chi et al., 2012; du Bois et al., 2009; Hacker, 2013). 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 burden and facilitate subsequent resection (Morrison et al., 2012; Vergote et al., 2013). 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 (Coleman et al., 2013), resulting in cycles of repeated surgeries and additional rounds of chemotherapy. Women with recurrent disease have better outcomes when all grossly visible

Suggested Citation:"6 Recommendations." National Academies of Sciences, Engineering, and Medicine. 2016. Ovarian Cancers: Evolving Paradigms in Research and Care. Washington, DC: The National Academies Press. doi: 10.17226/21841.
×

tumor is removed during the subsequent surgical resections (Al Rawahi et al., 2013; Harter et al., 2006).

Standard of Care

Several organizations have developed standards of care for the assessment and treatment of women with both newly diagnosed and recurrent ovarian cancers. Women who receive care in accordance with National Comprehensive Cancer Network (NCCN) clinical practice guidelines have considerably better clinical outcomes (e.g., improved survival and fewer surgical complications) than patients who do not receive the standard of care (Bristow et al., 2013b; Chan et al., 2007; Eisenkop et al., 1992; Goff, 2015). However, less than half of women with ovarian cancer nationwide receive care that adheres to NCCN guidelines (Cliby et al., 2015). 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 (Armstrong et al., 2006; Hess et al., 2007; Jaaback et al., 2011; Tewari et al., 2015). 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 (Katsumata et al., 2009; Wright et al., 2015).

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 at this time (see Recommendation 3) (Febbraro et al., 2015; HHS, 2013; Powell et al., 2013). Testing for germline genetic mutations among women already diagnosed with ovarian cancer is important because the presence of certain mutations informs the decision-making process and helps clinicians determine the most appropriate therapy.

Being treated by a gynecologic oncologist and having treatment in a high-volume (often urban) instead of a low-volume (often rural) 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 (Bristow et al., 2013a, 2014). Significant predictors of nonadherence to the standard of care include the patient being of advanced age at diagnosis, having one or more treatment-limiting comorbidities, being of a non-white race, and having a lower socioeconomic status (Bristow et al., 2013a,b; Chase et al., 2012; Du et al., 2008; Erickson et al., 2014; Goff et al., 2007; Harlan et al., 2003; Howell et al., 2013; Jordan et al., 2013; Joslin et al., 2014; Thrall, 2011). Like most other cancers, ovarian cancer primarily affects older adults, but little is known about the care needs of older women with ovarian cancer. For example, older women are more likely to have comorbidities that may

Suggested Citation:"6 Recommendations." National Academies of Sciences, Engineering, and Medicine. 2016. Ovarian Cancers: Evolving Paradigms in Research and Care. Washington, DC: The National Academies Press. doi: 10.17226/21841.
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preclude them from receiving care in accordance with NCCN guidelines, which, in turn, may lead to worse outcomes. In addition to the disparities in how care is delivered, historical trends show considerable differences in outcomes by race (Howlader et al., 2015). Furthermore, some studies show geographic variations in the patterns of cancer care, which may be due to socioeconomic or other factors (Fairfield et al., 2010; Polsky et al., 2006; Ulanday et al., 2014). Finally, more research is needed on how quality metrics can be used to help promote the delivery of the standard of care. The committee concludes that the current patterns of care for women with newly diagnosed and recurrent ovarian cancers reveal inconsistencies in therapeutic approaches and disparities in care and subsequent outcomes. Therefore, the committee recommends the following:

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 genetic germline testing for newly diagnosed women) that are linked to quality metrics.

In order to meet the standard of care, 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 alternative models of care that may help to meet the standard of care, such as the use of telemedicine for consultation and the use of patient navigation systems to allow women to be more engaged in their own care. The committee recognizes that, as is the case in other areas of health care, changes in payment, policy, education and training, and other areas will likely be needed to effectively implement these models of care.

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, some research shows that PDS and NACT have similar outcomes, but these studies have come under criticism for their study design (Dai-yuan et al., 2013; Hacker, 2013; Vergote et al., 2010). As such, 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.

Suggested Citation:"6 Recommendations." National Academies of Sciences, Engineering, and Medicine. 2016. Ovarian Cancers: Evolving Paradigms in Research and Care. Washington, DC: The National Academies Press. doi: 10.17226/21841.
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Current classification systems also do not, for the most part, help to tailor treatment regimens. For women with recurrent disease, the traditional classification system of platinum sensitive or platinum resistant does not reflect the improved understanding of recurrent disease, particularly given the ability to diagnose these recurrences at earlier time points, the improved understanding of the impact of BRCA mutation status on response to therapy for recurrence, and the heterogeneous response noted in patients with platinum-resistant tumors (Davis et al., 2014; Guth et al., 2010). 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 (Rutherford et al., 2013). Therefore, the committee recommends the following:

RECOMMENDATION 8: Clinicians and researchers should focus on improving current treatment strategies, including

  • 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;
  • 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;
  • The identification of predictors of response to therapy and near-term indicators of efficacy; and
  • 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.

Improvements in the clinical, histopathologic, and molecular characterizations of tumors will help inform the iterative process of developing the standardized taxonomy (see Recommendation 2). Furthermore, this improved understanding may help to improve outcomes, as certain characterizations may help clinicians to determine which women are more likely to have positive outcomes, or which treatments are most likely to be beneficial. 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. Furthermore, a variety of approaches can be used to predict therapeutic efficacy, including scoring systems, genetic germline testing, and molecular profiling. For example, the committee notes that trials in other cancers commonly rec-

Suggested Citation:"6 Recommendations." National Academies of Sciences, Engineering, and Medicine. 2016. Ovarian Cancers: Evolving Paradigms in Research and Care. Washington, DC: The National Academies Press. doi: 10.17226/21841.
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ommend tumor biopsy to better direct recurrent disease treatment. 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 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 Institute of Medicine (IOM) report A National Cancer Clinical Trials System for the 21st Century noted that individual companies may have less incentive to conduct studies to compare the effectiveness of treatment options, combine novel therapies developed by different sponsors, test multimodality strategies, or develop therapies for rare diseases (IOM, 2010). The report outlined goals and recommendations to improve the clinical trials system in general, including

  • Streamline and harmonize government oversight (e.g., U.S. Food and Drug Administration regulations);
  • Improve collaboration among stakeholders, including through 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 translational research in ovarian cancer, 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 to reducing morbidity and mortality in ovarian cancer. Therefore, this committee endorses these goals and recommendations and suggests that these principles be applied to all recommendations of this report related to clinical trials for ovarian cancer research.

Clinicians currently have limited 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 histologic subtypes and molecular features of the range of ovarian cancers has led to a more targeted approach for the use and development of new therapeutic treatments. To address the growing number of new therapeutics, innovative early phase clinical trials that

Suggested Citation:"6 Recommendations." National Academies of Sciences, Engineering, and Medicine. 2016. Ovarian Cancers: Evolving Paradigms in Research and Care. Washington, DC: The National Academies Press. doi: 10.17226/21841.
×

incorporate biomarkers predictive of efficacy are needed to help identify which ovarian cancer histologic and molecular subtypes are likely to be resistant or 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 typically have had multiple previous therapies. Patient preferences also need to be considered in assessing the effectiveness of new therapies (e.g., what level of side effects is considered tolerable for a woman, given the expected improvement in outcomes associated with a new drug). Yet another issue is that little research has been done on nonpharmacologic therapies and interventions (e.g., diet, exercise, stress reduction) that might affect response to treatment. Overall, the committee concludes that the current standard of care lacks precision medicine approaches to therapy. Therefore, the committee recommends the following:

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

  • Developing immunologic and molecularly driven treatment approaches specific to the different ovarian cancer subtypes;
  • Identifying markers of therapeutic resistance and exceptional response; and
  • Using interdisciplinary teams to design and conduct statistically efficient and information-rich clinical studies.

The development of new immunologic and molecularly driven treatment approaches depends largely on improving our understanding of the immunologic and molecular characteristics of ovarian cancer at a basic science level (see Recommendation 1). However, research on such newer treatment options is once again complicated by the relative rarity of the disease overall and by the heterogeneity of the subtypes. 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.

Suggested Citation:"6 Recommendations." National Academies of Sciences, Engineering, and Medicine. 2016. Ovarian Cancers: Evolving Paradigms in Research and Care. Washington, DC: The National Academies Press. doi: 10.17226/21841.
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SUPPORTIVE CARE ALONG THE SURVIVORSHIP TRAJECTORY

Most research on ovarian cancer 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 obviously 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, even those with recurrent disease, often live many years following diagnosis. These women require early and ongoing supportive care to ensure that aggressive, life-extending treatments are enhanced by multidisciplinary supportive care to maximize quality of life.

A 2013 IOM report stated, “A high-quality cancer care delivery system depends upon 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” (IOM, 2013, p. 207). However, for women diagnosed 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 primary 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 as a result of their diagnosis and treatment or on 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 versus younger women and women in different racial and ethnic groups). Traditionally, the systematic assessment of symptoms and quality of life in ovarian cancer has not been a major focus in clinical practice. In 2010, the IOM called on the Patient-Centered Outcomes Research Institute (PCORI)1 and others to “develop a common set of data elements that captures patient-reported outcomes, relevant patient characteristics, and health behaviors that researchers should collect from randomized clinical trials and observational studies” (IOM, 2009, p. 12). Furthermore, the optimal medical management of treatment side effects requires an iterative approach with in-depth conversations between the patient and her interdisciplinary team of clinicians. Given the current structure of the health care system and the time pressures to move patients through clinics, these types of interactions are

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1 For more information, see http://www.pcori.org (accessed July 22, 2015).

Suggested Citation:"6 Recommendations." National Academies of Sciences, Engineering, and Medicine. 2016. Ovarian Cancers: Evolving Paradigms in Research and Care. Washington, DC: The National Academies Press. doi: 10.17226/21841.
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difficult to achieve. Approaches to enhancing self-management, including leveraging mobile health technologies, need to be explored.

Research gaps may in part be addressed by more effective clinical assessment of patient-reported symptoms and outcomes during treatment, especially the outcomes that are most important to women with ovarian cancer (e.g., improved quality of life versus longer survival). Furthermore, because 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 should shift to high-quality end-of-life care. The committee concludes that a majority of women with ovarian cancer require long-term active disease management, necessitating more effective approaches for supportive care and self-management across the survivorship trajectory. Therefore, the committee recommends the following:

RECOMMENDATION 10: Researchers and funding organizations should study the supportive care needs of patients with ovarian cancer throughout the disease trajectory, including

  • Identifying the array of factors that put women at high risk for poor physical and psychosocial outcomes;
  • Identifying and overcoming barriers to the systematic assessment of the physical and psychosocial effects of disease and treatment;
  • Developing and implementing more effective supportive care and self-management interventions; and
  • Defining the parameters that indicate when patients and their families would benefit from transitioning to end-of-life care.

The committee recognizes that many of the supportive care needs of women with ovarian cancer are similar to those of women with other cancers. The committee therefore endorses the following goals and recommendations from previous IOM reports that are relevant to supportive care for women with ovarian cancer:

  • Organizations sponsoring research in oncology should include research on the development of reliable, valid, and efficient tools and strategies for use by clinical practices to ensure that all patients with cancer receive care that meets the standard of psychosocial care, including
    • Approaches for improving patient–provider communication and providing decision support to patients;
    • Screening instruments to identify individuals experiencing psychosocial problems;
Suggested Citation:"6 Recommendations." National Academies of Sciences, Engineering, and Medicine. 2016. Ovarian Cancers: Evolving Paradigms in Research and Care. Washington, DC: The National Academies Press. doi: 10.17226/21841.
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    • Needs assessment instruments for psychosocial care planning; and
    • Illness and wellness management interventions (IOM, 2008).
  • The cancer care team should provide patients and their families with understandable information on cancer prognosis, treatment benefits and harms, palliative care, psychosocial support, and estimates of total and out-of-pocket costs of cancer care (IOM, 2013).
  • To expand the depth of data available for assessing interventions, stakeholders should build on ongoing efforts to develop a common set of data elements that capture patient-reported outcomes, relevant patient characteristics, and health behaviors that researchers should collect from clinical trials and other studies (IOM, 2013).
  • In the setting of advanced cancer, the cancer care team should provide patients with end-of-life care consistent with their needs, values, and preferences. The cancer care team should place a primary emphasis on providing cancer patients with palliative care, psychosocial support, and timely referral to hospice care for end-of-life care (IOM, 2013).
  • Stakeholders should provide fact-based information about care of people with advanced serious illness to encourage advance care planning and informed choice based on the needs and values of individuals (IOM, 2015).

DISSEMINATION AND IMPLEMENTATION

Amassing evidence on risk factors, treatments, and preventive strategies is not sufficient to ensure that this knowledge will be acquired and utilized 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.

A review and discussion on the evidence base of dissemination and implementation science, as well as a discussion of potential avenues for dissemination and implementation of specific messages for women diagnosed with or at risk for ovarian cancer, is presented in the following chapter.

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Suggested Citation:"6 Recommendations." National Academies of Sciences, Engineering, and Medicine. 2016. Ovarian Cancers: Evolving Paradigms in Research and Care. Washington, DC: The National Academies Press. doi: 10.17226/21841.
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Suggested Citation:"6 Recommendations." National Academies of Sciences, Engineering, and Medicine. 2016. Ovarian Cancers: Evolving Paradigms in Research and Care. Washington, DC: The National Academies Press. doi: 10.17226/21841.
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In an era of promising advances in cancer research, there are considerable and even alarming gaps in the fundamental knowledge and understanding of ovarian cancer. Researchers now know that ovarian cancer is not a single disease--several distinct subtypes exist with different origins, risk factors, genetic mutations, biological behaviors, and prognoses. However, persistent questions have impeded progress toward improving the prevention, early detection, treatment, and management of ovarian cancers. Failure to significantly improve morbidity and mortality during the past several decades is likely due to several factors, including the lack of research being performed by specific disease subtype, lack of definitive knowledge of the cell of origin and disease progression, and incomplete understanding of genetic and non-genetic risk factors.

Ovarian Cancers examines the state of the science in ovarian cancer research, identifies key gaps in the evidence base and the challenges to addressing those gaps, considers opportunities for advancing ovarian cancer research, and examines avenues for translation and dissemination of new findings and communication of new information to patients and others. This study makes recommendations for public- and private-sector efforts that could facilitate progress in reducing the incidence of morbidity and mortality from ovarian cancers.

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