Intraperitoneal and Hyperthermic Intraperitoneal Chemotherapy for the Treatment of Ovarian Cancer.

OPINION STATEMENT: In our clinical practice, we have shifted away from the use of adjuvant normothermic intraperitoneal (IP) chemotherapy, particularly following the publication of GOG 252. Our decision is rooted in the accumulating evidence indicating a lack of demonstrable superiority, alongside the recognized toxicities and logistical challenges associated with its administration. This strategic departure is also influenced by the rising utilization of maintenance therapies such as bevacizumab and PARP inhibitors, which present viable alternatives for improving patient outcomes. Our utilization of hyperthermic IP chemotherapy (HIPEC) is currently reserved for a specific cohort of patients, mirroring the patient population studied in the OVHIPEC-1 trial. Specifically, our HIPEC protocol applies to patients presenting with newly diagnosed stage IIIC high-grade epithelial ovarian cancer who are deemed ineligible for primary debulking surgery. Patients must exhibit at least stable disease with neoadjuvant platinum-based chemotherapy, maintain a favorable performance status (ECOG score 0-1), possess good nutritional reserves (with no evidence of protein-calorie malnutrition and an albumin level exceeding 3.5), and not have chronic kidney disease. When HIPEC is planned, it is administered at the time of interval debulking surgery, contingent upon the attainment of optimal surgical outcomes (< 1 cm of residual disease). Our HIPEC protocol adheres to the original OVHIPEC-1 trial guidelines, employing cisplatin at a dosage of 100 mg/m2. We administer at least two antiemetics, antihistamines, and sodium thiosulfate to mitigate known side effects. Postoperatively, patients are admitted to the general surgical floor, reserving the intensive care unit for those in critical condition. We follow Enhanced Recovery After Surgery principles, incorporating early ambulation and feeding into our postoperative care strategy. We have encountered encouraging results with this approach, with most patients having largely uncomplicated postoperative courses and resuming adjuvant chemotherapy within 3 to 4 weeks of surgery.

Timing and duration of bevacizumab treatment and survival in patients with recurrent ovarian, fallopian tube, and peritoneal cancer: a multi-institution study.

Bevacizumab has demonstrated significant benefit in recurrent ovarian, fallopian tube and peritoneal cancer (OC), but its optimal position within the sequence of systemic therapies remains controversial. Since rebound progression after bevacizumab has been observed in other cancers, and because bevacizumab is incorporated in several regimens used in the recurrent setting, the duration of treatment may impact survival. We sought to identify whether earlier bevacizumab exposure is associated with prolonged bevacizumab therapy and survival by conducting a multi-institution retrospective study of recurrent OC patients treated with bevacizumab from 2004-2014. Multivariate logistic regression identified factors associated with receiving more than six bevacizumab cycles. Overall survival by duration and ordinal sequence of bevacizumab therapy were evaluated using logrank testing and Cox regression. In total, 318 patients were identified. 89.1% had stage III or IV disease; 36% had primary platinum resistance; 40.5% received two or fewer prior chemotherapy regimens. Multivariate logistic regression demonstrated that primary platinum sensitivity (Odds Ratio (OR) 2.34, p = 0.001) or initiating bevacizumab at the first or second recurrence (OR 2.73, p < 0.001) were independently associated with receiving more than six cycles of bevacizumab. Receiving more cycles of bevacizumab was associated with improved overall survival whether measured from time of diagnosis (logrank p < 0.001), bevacizumab initiation (logrank p < 0.001), or bevacizumab discontinuation (logrank p = 0.017). Waiting one additional recurrence to initiate bevacizumab resulted in a 27% increased hazard of death (Hazard Ratio (HR) 1.27, p < 0.001) by multivariate analysis. In conclusion, patients with primary platinum sensitive disease who received fewer prior lines of chemotherapy were able to receive more cycles of bevacizumab, which was associated with improved overall survival. Survival worsened when bevacizumab was initiated later in the ordinal sequence of therapies.

Endometrial cancer: A society of gynecologic oncology evidence-based review and recommendations.

INTRODUCTION: In 2014, the Society of Gynecologic Oncology's Clinical Practice Committee published a clinical update reviewing the treatment of women with endometrial cancer. At that time, there had been significant advances in the diagnosis, work-up, surgical management, and available treatment options allowing for more optimal care of affected women. Despite these advances, the incidence of endometrial cancer as well as the deaths attributable to the disease have continued to rise; from 1987 to 2014 there has been a 75% increase in cases and almost 300% increase in endometrial cancer deaths. Fortunately, since then, there has been progress in the treatment of patients with endometrial cancer with increased utilization of molecular pathology, greater understanding of genetic predisposition, enhanced methods for lymph node assessment, a broader understanding of the efficacy of radiation and chemotherapy, and a more efficient approach to survivorship and surveillance. The purpose of this document is to present a comprehensive review of this progress. MANUSCRIPT DEVELOPMENT PROCESS: The authors reviewed the available evidence, contributed to the development of this manuscript, provided critical review of the guidelines, and finalized the manuscript recommendations. The review was also presented to and approved by the Society of Gynecologic Oncology (SGO) Clinical Practice Committee, SGO Publications Committee, and the SGO board members prior to submission for publication. The recommendations for this manuscript were developed by a panel of gynecologic oncologists who were members of the SGO Clinical Practice and Education Committees. Panelists reviewed and considered evidence from current uterine cancer literature. The terminology used in these guidelines was adopted from the ASCCP management guidelines [1] using a two-part rating system to grade the strength of recommendation and quality of evidence (Table 1). The rating for each recommendation is given in parentheses.

Endometrial cancer: A society of gynecologic oncology evidence-based review and recommendations, part II.

In 2014, the Society of Gynecologic Oncology's Clinical Practice Committee published a clinical update reviewing the treatment of women with endometrial cancer. At that time, there had been significant advances in the diagnosis, work-up, surgical management, and available treatment options allowing for more optimal care of affected women. This manuscript, Part II in a two-part series, includes specific recommendations on treatment of recurrent disease, post treatment surveillance and survivorship, considerations for younger women, and special situations. Part I covered histopathology and molecular pathology, risk factors, presentation and diagnostic approach, surgical approach and adjuvant therapy.

Intraperitoneal ports placed at the time of bowel resection for treatment of ovarian cancer: Complications and surgical outcomes.

OBJECTIVES: To determine if intraperitoneal (IP) ports placed concurrently with bowel resection during surgical treatment of ovarian cancer is associated with more complications than those ports placed without concurrent bowel resection. METHODS: The medical records of all patients who had an IP port placed at our institution between 2005 and 2016 were reviewed. Two groups were analyzed: IP ports placed with bowel resection (IP-BR) and those without (IP). RESULTS: Of 306 patient charts reviewed, 31% had a surgery with IP port placement and concurrent bowel resection (IP-BR). Demographics were similar except for mean BMI (25.6 IP-BR vs 27.4 IP, p = 0.007). More IP-BR patients had stage IIIC disease (83.3% IP-BR vs 56.9% IP, p ≤0.01). Patients were cytoreduced to R0 in 48.7% IP-BR vs 56.4% IP (p = 0.253). For adjuvant treatment, IV chemotherapy was administered before IP chemotherapy in 90.4% IP-BR (median 2 cycles), and 50.3% IP, (median 2 cycles, p < 0.01). Ultimately 80.2% IP-BR (median 4 cycles) and 77.8% IP (median 5 cycles) received IP chemotherapy (p = 0.65). Rates of total IP port complications were similar (19.2% IP-BR vs 23.2% IP, p = 0.397), including IP port infections (0% IP-BR vs 0.7% IP, p = 0.5). Eleven percent of IP-BR patients had a bowel complication (e.g. obstruction or perforation) while IP port was in situ vs 2.7% IP (p = 0.01). Only 2.7% IP-BR and 6% IP discontinued IP chemotherapy due to IP port complication (p = 0.3). CONCLUSIONS: Patients who have IP ports placed concurrently with a bowel resection do not appear to have more complications, nor lower rates of IP chemotherapy administration.

Post-diagnosis use of antihypertensive medications and the risk of death from ovarian cancer.

OBJECTIVE: To examine associations between post-diagnosis use of antihypertensive (AH) medications including thiazide diuretics (TDs), angiotensin converting enzyme inhibitors (ACEIs), beta blockers (BBs) [both non-selective (NSBBs) and selective (SBBs)] and calcium channel blockers (CCBs) and ovarian cancer-specific survival. METHODS: This cohort study used SEER-Medicare data on 2195 women 66+ years of age who were diagnosed with ovarian cancer during 2007-2012 and who survived for at least 12 months. Use of an AH class was defined as two or more fills during the year after diagnosis. Ovarian cancer-specific death was assessed starting one year after diagnosis and continued through the end of 2013. Associations between AH use and ovarian cancer-specific mortality were assessed using Cox proportional hazard models, comparing users of a given class of AH to non-AH users. RESULTS: Overall, 718 (33%), 690 (31%), 521 (24%), 154 (7%) of women used a TD, ACEI, BB, or CCB, respectively, with some women (48%) using more than one class of drug. Ovarian cancer-specific mortality was found to be lower among women who used an ACEI (adjusted hazard ratio [aHR] 0.76, 95% confidence interval [CI] 0.63-0.92), a TD (aHR 0.82, 95%CI 0.68-0.99), or a NSBB (aHR 0.60, 95%CI 0.43-0.83), but no such association was seen in women who took a SBB or CCB. CONCLUSION: We observed that women who took certain forms of an AH medication during the year following a diagnosis of ovarian cancer were thereafter at a relatively reduced risk of dying from their disease. However, the potential for residual confounding by disease severity argues for a cautious interpretation.

Revisiting Minimally Invasive Surgery in the Management of Early-Stage Cervical Cancer.

Minimally invasive surgery (MIS) was previously considered an acceptable alternative to open radical hysterectomy in the management of early-stage cervical cancer (ESCC), but adequately powered, high-quality prospective trials evaluating survival outcomes were lacking. Recently, a large randomized phase III trial, the Laparoscopic Approach to Cervical Cancer (LACC) trial, showed that MIS for ESCC is associated with a higher risk of recurrence and death compared with open surgery. We review the LACC trial findings in depth, as well as a recent National Cancer Database analysis using propensity score weighting that supports the LACC trial findings. Additional studies are needed to better understand the mechanisms explaining the worse survival associated with MIS for ESCC. This review discusses considerations for integrating the findings of the LACC trial into clinical practice. Based on the high-quality evidence now available, open radical hysterectomy should be offered as standard of care for stage IA2-IB1 cervical cancer and patients should be guided appropriately to make informed shared decision-making if they still desire MIS.

The end of life costs for Medicare patients with advanced ovarian cancer.

OBJECTIVE: To describe the Medicare payments at the end of life for patients with advanced ovarian cancer, and assess factors responsible for payment variation METHODS: Using the linked Surveillance, Epidemiology and End Results (SEER)-Medicare database, we identified a cohort of women with stage III/IV epithelial ovarian cancer diagnosed between 1995 and 2007. We defined the end of life as the last 90days prior to death. Total medical costs were estimated from overall Medicare payments, and adjusted for geography and for inflation to the 2009 U.S. dollar. A generalized linear regression was performed to assess factors associated with variability in cost. RESULTS: Of 5509 patients, 78.9% died from ovarian cancer. In the 90days prior to death, 65.2% of patients had an inpatient admission, 53.7% received chemotherapy, 19.3% had a palliative procedure, and 62.5% had hospice services. The mean total payment per patient in the last 90days of life was $24,073 (range 0-$484,119) over the study time period. The mean cost of inpatient admissions was $14,529 (range 0-$483,932). On a multivariate analysis, costs at the end of life did not vary based on length of patient survival (p=0.77). Factors associated with significantly increased costs in the last 90days of life were medical comorbidity, chemotherapy, time spent as an inpatient, and admissions associated with emergency room visits. CONCLUSIONS: Reducing the prescription of chemotherapy and increasing the use of hospice services for ovarian cancer patients at the end of life will aid in lowering costs.

Combined symptom index and second-generation multivariate biomarker test for prediction of ovarian cancer in patients with an adnexal mass.

OBJECTIVE: To assess the performance of a symptom index (SI) and multivariate biomarker panel in the identification of ovarian cancer in women presenting for surgery with an adnexal mass. STUDY DESIGN: Prospective study of patients seen at a tertiary medical center. Following consent, patients completed an SI and preoperative serum was collected for individual markers (CA 125) and a second-generation FDA-cleared biomarker test (MIA2G). Results for the SI and MIA2G were correlated with operative findings and surgical pathology. Logistic regression modeling was performed to assess the interaction of the SI with MIA2G to determine the risk of malignancy (ROM). RESULTS: Of the 218 patients enrolled, the mean age was 53.6 years (range 18-86). One-hundred and forty-seven patients (67.4%) were postmenopausal. Sixty-four patients (29.4%) had epithelial ovarian cancer or fallopian tube cancer (EOC/FTC) and 17 (7.8%) had borderline ovarian tumors. A positive SI or MIA2G correctly identified 96.1% of patients with EOC/FTC. Using logistic regression, we found that both SI and MIA2G score were significantly associated with ROM (p < 0.001). In a simulation with disease prevalence set at 5%, patients with a negative SI and a MIA2G score of 6 had a ROM of 1.8% whereas patients with the same MIA2G and positive SI had a 10.5% ROM, nearly a 6-fold higher risk. CONCLUSIONS: The combination of a patient-reported symptom index and refined biomarker panel allows for improved accuracy in the assessment for ovarian cancer in patients with an adnexal mass. This strategy could offer a personalized approach to addressing ROM to triage patients with an adnexal mass to appropriate care.

Opioid use in gynecologic oncology in the age of the opioid epidemic: Part I - Effective opioid use across clinical settings, a society of gynecologic oncology evidence-based review.

As the only oncologists that provide both medical and surgical oncologic care, gynecologic oncologists encounter an exceptionally broad range of indications for prescribing opioids, from management of acute post-operative pain to chronic cancer-related pain to end-of-life care. If we are to balance opioid efficacy, safety and accessibility for our patients, we must be intimately familiar with appropriate clinical use of opioids in a range of settings, and engage in the national conversation around opioid misuse and how associated regulations and legislation may impact us and our patients. This article examines the appropriate use of opioids across the range of clinical settings encountered in gynecologic oncology.

Opioid use in gynecologic oncology in the age of the opioid epidemic: Part II - Balancing safety & accessibility.

As the only oncologists that provide both medical and surgical care, gynecologic oncologists encounter an exceptionally broad range of indications for prescribing opioids in clinical situations ranging from management of acute post-operative pain to chronic cancer-related pain to end-of-life care. While opioids are essential to the practice of gynecologic oncology, they can also have significant side effects and can be misused. Due to the explosive growth of opioid prescriptions and opioid-related overdoses and deaths during the first decade of the 21st century, there has been a recent concerted public health effort to prevent and treat opioid misuse through both legislation and education [1]. The first article in this two part series focused on appropriate use of opioids across clinical settings. This article addresses both the clinical and regulatory aspects of balancing opioid safety and accessibility for patients with gynecologic cancer.

Robotic, Laparoscopic, or Open Hysterectomy: Surgical Outcomes by Approach in Endometrial Cancer.

STUDY OBJECTIVES: To compare patient outcomes by surgical approach in the management of endometrial cancer (EC) in Washington State from 2008 to 2013. DESIGN: Population-based retrospective cohort study (Canadian Task Force classification II-2). SETTING: Washington State. PATIENTS: EC patients treated with robotic-assisted surgery (RAS), laparoscopy (LS), or laparotomy (XLAP). INTERVENTIONS: Comprehensive Hospital Abstract Reporting System to identify patients and assess the association of surgical approach with length of stay, readmissions, and perioperative complications. MEASUREMENTS AND RESULTS: We identified 3712 cases of EC managed with either RAS, LS, or XLAP. Mean length of stay was not clinically different for RAS (1.5 days) and LS (1.6 days) but was 2.31 days longer for XLAP compared with LS (p < .001). Odds of any readmission did not differ for either RAS or XLAP compared with LS; however, early readmissions were half as likely for RAS compared with LS (p = .014). Complications were more than 2.5 times as likely for XLAP versus LS (p < .001), whereas complications did not differ for RAS versus LS (p = .931). CONCLUSIONS: RAS is as an alternative to LS in the treatment of EC and is preferable to XLAP. The use of RAS resulted in fewer early readmissions compared with LS and resulted in an increased proportion of cases via minimally invasive surgery.

Physicians' Perspectives and Practice Patterns Toward Opportunistic Salpingectomy in High- and Low-Risk Women.

BACKGROUND: Opportunistic bilateral salpingectomy (OBS) has been proposed as an ovarian cancer risk-reducing strategy. METHODS: A survey was emailed to 300 members of the American College of Obstetricians and Gynecologists. RESULTS: 125 (42%) surveys were returned: 60% female, 88% generalists, 67% private practice. Only 36% correctly identified the lifetime risk of ovarian cancer, only 23% understood the risk-reducing benefit of bilateral salpingo-oophorectomy. 75% perform salpingectomy during hysterectomy, 26-53% use for sterilization depending on approach. Concerns were increased operative time and complications. For BRCA mutations, 64% recommend BSO, 12% recommend a two-step risk-reducing strategy, and 14% refer to gynecologic oncology. CONCLUSIONS: We identified broad support and factors limiting willingness to perform OBS.

Combining a symptom index, CA125 and HE4 (triple screen) to detect ovarian cancer in women with a pelvic mass.

OBJECTIVES: To assess a simple algorithm of CA125, HE4 and Symptom Index to predict ovarian cancer in women with a pelvic mass. METHODS: This was a prospective study of women referred to a gynecologic oncology clinic for surgical evaluation of a pelvic mass. Preoperatively, women completed a SI and had serum markers drawn. Results were correlated with pathology. A triple screen was considered positive if at least 2 of the 3 markers were abnormal (positive SI, CA125≥35U/mL, HE4≥140pmol/L). RESULTS: 218 patients enrolled in the study. 66 patients (30%) had ovarian or fallopian tube cancer (97% epithelial), 124 (57%) had benign masses, 17 (8%) had borderline tumors, and 11 (5%) had metastatic disease. The SI, CA125 and HE4 were positive in 87.9%, 74.2% and 60.6% of ovarian cancer patients, respectively. Of the 112 women with a positive SI 58 (52%) had ovarian cancer and 75 (67%) had non-benign masses. Excluding borderline and metastatic cancers the sensitivity of the triple screen was 79%; specificity 91%, PPV 83% and NPV 89%. CA125 alone had a sensitivity, specificity, PPV and NPV of 79%, 76%, 63% and 87% respectively. Requiring only one of the three tests to be abnormal resulted in a sensitivity of 97% but specificity dropped to 50%. CONCLUSIONS: An algorithm using SI, CA125 and HE4 has good performance statistics for predicting cancer in women with pelvic masses. The triple screen has higher specificity and PPV than CA125 alone but similar sensitivity and NPV for predicting ovarian cancer.

Evaluation of a Validated Biomarker Test in Combination With a Symptom Index to Predict Ovarian Malignancy.

OBJECTIVE: This study aimed to evaluate the predictive ability of a multivariate biomarker test in combination with a symptom index (SI) to identify ovarian cancer in a cohort of women planning to undergo surgery for a pelvic mass. METHODS: This was a prospective study of patients seen at a tertiary care medical center. Following consent, patients completed an SI and preoperative serum was collected for a Food and Drug Administration-cleared multivariate biomarker test [multivariate index assay (MIA)]. Results for the SI and MIA were correlated with operative findings and surgical pathology. RESULTS: Of 218 patients enrolled, 124 (56.9%) had benign disease and 94 (43.1%) had borderline tumors or carcinomas. Sixty-six patients had a primary ovarian or fallopian tube cancer. The median age of patients enrolled in this study was 54 years (interquartile range, 44-63 years), of whom 148 (67.9%) were postmenopausal. More than a third (36.3%) of patients with benign masses was accurately identified as low risk by MIA and SI. The sensitivity and negative predictive value (NPV) of the SI relative to primary ovarian cancer was 87.9% (95% CI, 77.9%-93.7%) and 91.6% (95% CI, 84.3%-95.7%), respectively. The sensitivity and NPV of CA125 was 75.4% (95% CI, 63.7%-84.2%) and 86.4% (95% CI, 79.1%-91.5%), respectively, and the sensitivity and NPV of the MIA were 93.9% (95% CI, 85.4%-97.6%) and 94.5% (95% CI, 94.5%-100%), respectively. The overall sensitivity for the combination of MIA plus SI was 100% (66/66; 95% CI, 94.5%-100%), and specificity was 36.3% (45/124; 95% CI, 28.4%-45.0%), with an NPV of 100% (95% CI, 92.1%-100%). CONCLUSIONS: The addition of a patient-reported SI, which captures subjective symptoms in an objective manner, improved the sensitivity of MIA across all stages and subtypes of ovarian cancer.

Gynecologic Oncologist Views Influencing Referral to Outpatient Specialty Palliative Care.

OBJECTIVE: Early specialty palliative care is underused for patients with advanced gynecologic malignancies. We sought to understand how gynecologic oncologists' views influence outpatient specialty palliative care referral to help inform strategies for improvement. METHODS/MATERIALS: We conducted a qualitative interview study at 6 National Cancer Institute-designated cancer centers with well-established outpatient palliative care services. Between September 2015 and March 2016, 34 gynecologic oncologists participated in semistructured telephone interviews focused on attitudes, experiences, and preferences related to outpatient specialty palliative care. A multidisciplinary team analyzed transcripts using constant comparative methods to inductively develop a coding framework. Through an iterative, analytic process, codes were classified, grouped, and refined into themes. RESULTS: Mean (SD) participant age was 47 (10) years. Mean (SD) interview length was 25 (7) minutes. Three main themes emerged regarding how gynecologic oncologists view outpatient specialty palliative care: (1) long-term relationships with patients is a unique and defining aspect of gynecologic oncology that influences referral, (2) gynecologic oncologists value palliative care clinicians' communication skills and third-party perspective to increase prognostic awareness and help negotiate differences between patient preferences and physician recommendation, and (3) gynecologic oncologists prefer specialty palliative care services embedded within gynecologic oncology clinics. CONCLUSIONS: Gynecologic oncologists value longitudinal relationships with patients and use specialty palliative care to negotiate conflict surrounding prognostic awareness or the treatment plan. Embedding specialty palliative care within gynecologic oncology clinics may promote communication between clinicians and facilitate gynecologic oncologist involvement throughout the illness course.

Preoperative hyponatremia in women with ovarian cancer: An additional cause for concern?

OBJECTIVE: To determine if preoperative hyponatremia in women with ovarian, fallopian tube (FT), and primary peritoneal cancers (PPC) is associated with postoperative complications. METHODS: We performed a retrospective population-based cohort study of women with a postoperative diagnosis of ovarian, FT, or PPC who had a cytoreductive procedure in the National Surgical Quality Improvement Program (NSQIP) database from 2005 to 2013. The primary exposure, preoperative sodium, was classified as normal (135mEq/L-142mEq/L) or hyponatremic (≤134mEq/L). Where appropriate, preoperative characteristics were compared with Chi-squared or Fisher's exact tests. Multivariate logistic regression was used to determine adjusted odds ratios (aOR) with 95% confidence intervals (CI). RESULTS: 4009 subjects met inclusion criteria. Thirty day mortality was higher in the hyponatremic group compared to the normal serum sodium group (3.56% vs 1.18%). When patients of any age were noted to have at least two pertinent preoperative lab abnormalities, including hyponatremia, there was an increased risk of postoperative complications for patients over the age of 65 (Table 3). After adjusting for serum albumin and other confounders, preoperative hyponatremia was associated with an increased risk of hospital stay of >14days (aOR 1.69; 95% CI 1.11-2.57) and 30day postoperative mortality (aOR 2.37; 95% CI 1.13-4.98). CONCLUSIONS: Hyponatremia is associated with postoperative 30day mortality and morbidity in women with ovarian, FT, and PPC. Serum sodium in conjunction with other markers may have the potential to identify candidates for neoadjuvant chemotherapy. Additional work is needed to determine if correction of hyponatremia in the preoperative period alters outcomes.

Ovarian cancer outcomes: Predictors of early death.

OBJECTIVE: To describe the outcomes and mortality in advanced ovarian cancer patients in a population-based cohort in the 90 days after diagnosis. METHODS: Using the linked Surveillance, Epidemiology and End Results (SEER)-Medicare database, we identified a cohort of women with stage III/IV epithelial ovarian cancer diagnosed between 1995 and 2007. A χ(2) test was used to assess demographic and clinical factors. Kaplan-Meier curves and Cox proportional hazards models were used to assess factors associated with variation in survival. RESULTS: Of the 9491 patients with stage III/IV ovarian cancer identified from the SEER/Medicare system, 4131 (43.6%) patients died in the first year after diagnosis. Of these, 2472 (26.0%) patients died in the first 90 days after diagnosis. Over the study period, the number of patients who died in the first 90 days after diagnosis slightly increased (p=0.053). Older age (>75 years of age), increased comorbidity, stage IV disease, lack of a visit with a gynecologic oncologist, and surgery were associated with an increase in 90-day mortality. Chemotherapy was associated with a reduction in 90-day mortality. CONCLUSIONS: Approximately 25% of patients with advanced ovarian cancer in our study period died within 90 days of diagnosis, and more than 40% died within the first year of diagnosis. In addition, a substantial proportion of patients did not receive any treatment. Further research into the characteristics of these patients should be performed to elucidate clinical areas for intervention to either prevent these poor outcomes or allocate appropriate resources to patients with extremely poor prognoses.

Neoplastic cellularity is associated with clinical and molecular features of high-grade serous ovarian carcinoma.

OBJECTIVE: Most molecular analyses of high-grade serous ovarian, peritoneal and fallopian tube carcinomas (HGSC) require ≥70% tumor (neoplastic) cell nuclei. We characterized the distribution of the percentage of neoplastic nuclei (PNN) in a large cohort of HGSC and correlated PNN with clinical outcomes to determine the fraction of cases outside this range and whether this cut-off introduces selection bias. METHODS: Subjects were prospectively enrolled and normal and neoplastic tissues were snap-frozen. All subjects had grade 2 to 3 HGSC. Subjects that received neoadjuvant chemotherapy were excluded. PNN was determined by estimating the fraction of neoplastic nuclei relative to non-neoplastic nuclei on a representative hematoxylin and eosin stained frozen section from the primary neoplasm. Germline BRCA mutation status was determined with Sanger or BROCA sequencing. RESULTS: PNN was <70% in 101 (33%) of 306 cases. PNN was significantly higher among subjects without optimal cytoreduction (P=0.018). 55 subjects had germline BRCA1/BRCA2 mutations. HGSC associated with BRCA2 but not BRCA1 mutations had significantly lower PNN compared to HGSC in non-carriers (54% vs. 70%, P=0.018). Overall survival was not significantly different between subjects with <70% or ≥70% PNN (median survival 51.8 vs. 46.6months, P=0.858). CONCLUSIONS: One-third of HGSC has PNN <70%. Higher PNN is associated with suboptimal cytoreduction, while lower PNN is associated with inherited BRCA2 mutations. Our findings suggest a nonrandom distribution of PNN that may reflect cancer biology. Further studies exploring the stromal microenvironment are needed. Molecular analyses of HGSC selected for high PNN exclude a significant fraction of patients.