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4 Diagnosis and Treatment
Pages 147-212

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From page 147...
... This chapter discusses the diagnosis and therapeutic management of women with newly diagnosed and recurrent ovarian cancer, discusses new therapies on the horizon, and gives an overview of the cancer clinical trials landscape. As noted in Chapter 1, these discussions focus primarily on the treatment of women diagnosed with high-grade serous carcinomas (HGSCs)
From page 148...
... Diagnosis Several bodies have established guidelines for the initial assessment and treatment of women with suspected ovarian cancer. The Society for Gynecologic Oncologists (SGO)
From page 149...
... . Another evaluation of nearly 500 pathology reports for advanced ovarian, fallopian tube, and primary peritoneal cancers found that although most specimens were microscopically described (92.3 percent of reports)
From page 150...
...  xtension to other pelvic intraperitoneal (IP) tissues E Stage III: Tumor involves one or both ovaries or fallopian tubes, or primary peritoneal cancer, with cytologically and histologically confirmed spread to the peritoneum outside the pelvis and/or metastasis to the retroperitoneal lymph nodes
From page 151...
... Given the necessity for a sophisticated diagnostic and initial surgical approach, evidence shows that the surgical treatment for ovarian cancers is best performed by those with expertise in managing this disease specifically (e.g., gynecologic oncologists) (Giede et al., 2005; Hacker, 2011; Vernooij et al., 2007)
From page 152...
... . However, these findings were met with skepticism from several groups in the gynecologic oncology community who criticized various elements of the trial design (Dai-yuan et al., 2013; du Bois et al., 2012; Gasparri et al., 2015; Hacker, 2013; Kehoe and Nankivell, 2015; Scaletta et al., 2015; Vergote et al., 2013)
From page 153...
... . Later trials found little difference in clinical efficacy between the two-drug combination of cisplatin and cyclophosphamide and multidrug combinations including anthracyclines, so the combination of cisplatin and cyclophosphamide became standard chemotherapy for the first-line treatment of advanced ovarian cancer (Bertelsen et al., 1987; Omura et al., 1989)
From page 154...
... chemotherapy has proven to be one of the more effective treatment strategies. Intraperitoneal Chemotherapy For both primary and metastatic ovarian cancers, the peritoneal cavity is the principal site of disease upon diagnosis (Lengyel, 2010)
From page 155...
... . The seminal results from the 2006 GOG-172 clinical trial showed that treatment with IP chemotherapy resulted in a 5-month improvement in median PFS and a 16-month improvement in median overall survival over IV chemotherapy (Armstrong et al., 2006)
From page 156...
... Maintenance Therapy Maintenance therapies may be beneficial for women with advanced ovarian cancers, especially given the high rates of recurrence with standard therapies. Several trials have tested a variety of agents for use in maintenance therapy, including hormones, radiation, chemotherapy, immunotherapy, biological therapy, and complementary medicines.
From page 157...
... Patients with recurrent ovarian cancers have traditionally been categorized as either platinum sensitive (if recurrence is diagnosed more than 6 months after prior therapy) or platinum resistant (if recurrence is diagnosed less than 6 months after prior therapy)
From page 158...
... cytoreduction is generally reserved for patients with isolated, resectable, platinum-sensitive disease. Validated scoring systems can be used to predict which women with recurrent ovarian cancers undergoing secondary cytoreduction are most likely to achieve complete resection of all visible disease (Harter et al., 2011, 2014; Nick et al., 2015; Tian et al., 2012; Wimberger et al., 2007)
From page 159...
... . Clinical trials in cancer care tend to have lower levels of enrollment among older adults and racial and ethnic minorities (Lewis et al., 2003; Murthy et al., 2004; Stewart et al., 2007; Talarico et al., 2004)
From page 160...
... is beyond the scope of this report, but the following sections highlight the overarching findings in the research of cancer care delivery and discuss the specific evidence related to the delivery of care for women with ovarian cancer. Standard-of-Care Guidelines According to the 2013 IOM report, "clinical research leads to improvements in the quality of care only if these research results are translated into clinical practice" (IOM, 2013, p.
From page 161...
... . Some of the areas that have been identified as in need of further research in general for the cancer care of older adults include the efficacy and toxicity of commonly used therapeies in older patients, clinical trials to better understand specific issues for older patients (including consideration of comorbidities)
From page 162...
... Patient Engagement The 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.
From page 163...
... Researchers should consider using endpoints in clinical trials that better reflect the outcomes of greatest importance to women with ovarian cancer (e.g., quality of life versus overall survival)
From page 164...
... or that preclude payment for certain genetic tests. Health Care Workforce The 2013 IOM report Delivering High-Quality Cancer Care noted that "the cancer care team includes those with specialized training in oncology, such as oncologists and oncology nurses, other specialists and primary care clinicians, as well as family caregivers and direct care workers" (IOM, 2013, p.
From page 165...
... . In 2013, the IOM noted that family caregivers are "particularly important in cancer care because of the debilitating effect of the disease; the side effects associated with many of the common cancer treatments; the complexity of the medical decisions; and the ongoing need for medical treatment, home care, and surveillance" (IOM, 2013, p.
From page 166...
... The 2013 IOM report reviewed several challenges to the development of cancer care quality metrics, including the failure to address the entire trajectory of cancer care and the underrepresentation of older adults in quality measurement. In particular, the report found that "there are few or no measures for other rare cancers, such as brain and ovarian cancers" (IOM, 2013, p.
From page 167...
... For example, the Cancer Therapy Evaluation Program (CTEP) 1 of the NCI, which sponsors clinical trials for new anticancer agents, focuses on agents that target pathways involved in apoptosis, survival and proliferation, migration and invasion, angiogenesis, mitosis, protein turnover, immunomodulation, DNA repair and epigenetics, and stem cell signaling (see Appendix C for a list of current ovarian cancer clinical trials compiled from www.ClinicalTrials.gov)
From page 168...
... In particular, anti-angiogenic therapies (e.g., bevacizumab) have been shown to be effective in treating recurrent ovarian cancer both when used as a single agent and in combination with chemotherapy or other targeted agents (Liu et al., 2014a)
From page 169...
... . Studies have indeed shown that PARP inhibitors, alone or in combination with chemotherapy, are effective in women with recurrent ovarian cancer, particularly those with a BRCA1 or BRCA2 mutation.
From page 170...
... . Additional evidence suggests that the addition of olaparib to chemotherapy improves PFS in platinum-sensitive recurrent ovarian cancer (Oza et al., 2015)
From page 171...
... . A clinical trial is currently under way to investigate the use of a p53-reactivating compound APR-246 in ovarian cancer (Aprea, 2014)
From page 172...
... . Another anti-CA-125 antibody, abagovomab, failed to demonstrate significant prolongation of PFS or overall survival in ovarian cancer patients in first remission (Sabbatini et al., 2013)
From page 173...
... Immune Modulation Immune modulation acts to reinstate an existing anticancer immune response or to elicit novel responses as a result of antigen spreading. Studies of immune modulation have been carried out in a variety of solid tumors, but there has been more limited research with ovarian cancers.
From page 174...
... . CLINICAL TRIALS FOR OVARIAN CANCER Clinical researchers are regularly developing new trial designs in order to accommodate new approaches to the development of anticancer agents, to make the trial designs more efficient, and to study types of therapies that have not been evaluated before.
From page 175...
... . Greater incentives and resources for the creation of such models could benefit ovarian cancer drug development programs and, if the models are successful, could increase the number of promising drugs for human clinical trials.
From page 176...
... Phase IV • The main goal is to acquire more real-world experience for a new agent following marketing authorization in order to gain information in a broader patient population that encompasses a variety of disease severities and comorbid conditions, with the goal of better understanding the agent's effectiveness and to identify rare or late-appearing adverse effects. • Phase IV studies may include studies that collect extended follow-up data on patients who have completed Phase III trials, noninterventional observa tional studies, large simple trials, and post-marketing surveillance studies.
From page 177...
... In both cases, tissue samples are collected both at the time of the laparoscopy and at the time of surgery, which allows researchers to examine the in vivo effects of the novel agents and may provide valuable insights into the mechanism of action or resistance for those agents. Phase I Clinical Trials Phase I studies attempt to find a dose that provides an acceptable balance between killing tumor cells and patient toxicity by delivering increasing doses of the experimental agent to successive patients while they are FIGURE 4-1  Novel clinical trial design using the Anderson algorithm.
From page 178...
... Phase II Clinical Trials Randomized Phase II trials allow for a preliminary assessment of the clinical benefits of an experimental therapy relative to other therapies, but they also require larger sample sizes. Single-arm trials with a tumor-­ response endpoint have been a mainstay of oncology Phase II trials, but newer anticancer agents often do not fit into the traditional paradigm of cytotoxic chemotherapies.
From page 179...
... . Phase III Clinical Trials Phase III clinical trials are intended to provide definitive evidence about whether an experimental therapy has clinical efficacy when compared to a standard treatment or no treatment.
From page 180...
... . Multiarm Phase II and III Clinical Trial Designs Extending the conventional single- and two-arm clinical trial designs to three or more arms is relatively straightforward and can offer substantial advantages.
From page 181...
... Post-marketing studies are rare, but they may be particularly valuable for use with ovarian cancer treatments due to the cancer's rarity, the relatively small size of ovarian cancer trials, their typically long clinical trajectory, and the substantial potential for late adverse effects associated with many commonly used treatments for ovarian cancer. One post-marketing study that is currently being set up will evaluate the safety and efficacy of bevacizumad in routine clinical practice in patients with advanced ovarian carcinoma, fallopian tube cancer, or primary peritoneal cancer (Hoffmann-La Roche, 2015)
From page 182...
... Furthermore, if an experimental agent is not expected to shrink tumors, then PFS or overall survival is a more informative endpoint than tumor response. A white paper from the SGO discusses the advantages and disadvantages of a variety of endpoints used in ovarian cancer clinical trials.
From page 183...
... DIAGNOSIS AND TREATMENT 183 TABLE 4-2 Comparison of Potential Endpoints for Ovarian Cancer Trials Endpoint Definition Advantages Disadvantages Response Assessed by the Objective Difficult to measure rate RECIST criteria Quantifiable accurately and on the basis of Results quickly available reproducibly in ovarian imaging studies, Tumor shrinkage cancer GCIG has Appealing to patient and Not considered sufficient defined changes physician as a primary endpoint for in CA-125 as a Phase III trials response criterion Not necessarily a clinically relevant benefit for the patient Patient- Symptom-based Direct clinical benefit as Need randomized blinded recorded parameters perceived and quantified studies outcomes by patient Subjective and dependent on limited validation instruments Progression- Time from entry Provides answer sooner Does not include deaths free survival into trial to Avoids the impact progression of of post-progression disease, death, or therapy lost to follow-up Preferred to time to progression by regulatory agencies Time to Time from entry Similar to progression- Does not include deaths progression into trial to free survival progression of disease Overall Time from entry Clear-cut endpoint of Longer time to answer survival into trial to death Impacted by post death or lost to Indisputably indicative of progression therapy follow-up clinical benefit Time to Uses prescribed Novel metric Not validated in ovarian tumor longitudinal tumor In some models is best cancer growth models predictor of OS Subjectivity in assessment Reduces time and cost NOTE: GCIG = Gynecologic Cancer Intergroup; OS = overall survival; RECIST = Response Evaluation Critera in Solid Tumors. SOURCE: Herzog et al., 2014.
From page 184...
... This mathematical modeling framework offers the flexibility to adapt many aspects of the trial design. Phase II/III clinical trials, another example of adaptive design, allow for transiting directly from a Phase II to a Phase III trial when an experimental agent demonstrates a positive effect on an intermediate endpoint (Hunsberger et al., 2009; Korn et al., 2012)
From page 185...
... Withouth careful design, adaptive clinical trials are particularly prone to the potential for biased estimates of treatment effects and an increased likelihood of drawing false conclusions (e.g., declaring that a treatment has clinical benefit when it does not) because they are intentionally engineered to repeatedly assess accumulating data in order to alter aspects of the trial.
From page 186...
... . Few of the studies evaluating these chemosensitivity assays have been randomized clinical trials.
From page 187...
... . Advancing Clinical Trials for Ovarian Cancer The clinical trial designs described are broadly applicable to a variety of cancer types.
From page 188...
... Clinical trials that leverage these new biological insights to optimize treatment selection or adapt to data as they accumulate during the course of the trial may also require novel statistical methods for their design and evaluation. KEY FINDINGS AND CONCLUSIONS The committee offers the following findings and conclusions: • PDS is an effective first-line treatment method, yet maximum cy toreduction may be unachievable in women with Stage III or IV ovarian cancer unless NACT is employed.
From page 189...
... • Most ovarian cancers occur in older women, yet little research focuses on how to improve care for older women, especially those with comorbidities, and clinical trials tend to enroll younger patients. • Given that the effectiveness of novel therapeutics may vary within and among subtypes, it will be necessary to evaluate a variety of approaches, including new combinations of existing drugs, new drug formulations, targeted biologics, protein inhibitors, TP53 directed therapies, anti-angiogenics, immunotherapies, and non pharmacologic interventions.
From page 190...
... 2012. Oceans: A randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer.
From page 191...
... 2011. A phase II study of sunitinib in patients with recur rent epithelial ovarian and primary peritoneal carcinoma: An NCIC clinical trials group study.
From page 192...
... 2002. Sur vival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: A meta-analysis.
From page 193...
... 2008. Adaptive clinical trials: Progress and challenges.
From page 194...
... 2011. Phase 1-2 study of docetaxel plus aflibercept in patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer.
From page 195...
... 2009. Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: A combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: By the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR)
From page 196...
... 2014. Incorporation of anti-angiogenesis therapy in the management of advanced ovarian carcinoma -- Mechanistics, review of phase III random ized clinical trials, and regulatory implications.
From page 197...
... 2010. Randomized clinical trials with biomark ers: Design issues.
From page 198...
... 2004. Maintenance treatment with interferon for advanced ovarian cancer: Results of the Northern and Yorkshire gynaecology group randomised phase III study.
From page 199...
... Clinical Trials (London, England)
From page 200...
... in epithelial ovarian can cer. Gynecologic Oncology 101(1)
From page 201...
... 2011. Overall survival as the outcome for ran domized clinical trials with effective subsequent therapies.
From page 202...
... 2003. Participation of patients 65 years of age or older in cancer clinical trials.
From page 203...
... 2001. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: An intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group.
From page 204...
... 2014. Anti-­ ngiopoietin a therapy with trebananib for recurrent ovarian cancer (TRINOVA-1)
From page 205...
... 2003. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: A Gynecologic Oncology Group study.
From page 206...
... 2014. Bevacizumab combined with che motherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial.
From page 207...
... 1993. The use of response-adaptive designs in clinical trials.
From page 208...
... 1997. Accelerated titration designs for phase I clinical trials in oncology.
From page 209...
... consensus statement on clinical trials in ovarian cancer: Report from the fourth Ovarian Cancer Consensus Conference. International Journal of Gynecological Cancer 21(4)
From page 210...
... with PD-L1 positive advanced ovarian cancer: Interim results from a phase Ib study. Journal of Clinical Oncology 33(Suppl)
From page 211...
... An exploratory analysis of a prospectively randomized phase III study of the Arbeitsge meinschaft Gynaekologische Onkologie Ovarian Cancer Study Group (AGO-OVAR)


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