Publications by authors named "Robert M Wenham"

86 Publications

IgA transcytosis and antigen recognition govern ovarian cancer immunity.

Nature 2021 Feb 3. Epub 2021 Feb 3.

Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Most ovarian cancers are infiltrated by prognostically relevant activated T cells, yet exhibit low response rates to immune checkpoint inhibitors. Memory B cell and plasma cell infiltrates have previously been associated with better outcomes in ovarian cancer, but the nature and functional relevance of these responses are controversial. Here, using 3 independent cohorts that in total comprise 534 patients with high-grade serous ovarian cancer, we show that robust, protective humoral responses are dominated by the production of polyclonal IgA, which binds to polymeric IgA receptors that are universally expressed on ovarian cancer cells. Notably, tumour B-cell-derived IgA redirects myeloid cells against extracellular oncogenic drivers, which causes tumour cell death. In addition, IgA transcytosis through malignant epithelial cells elicits transcriptional changes that antagonize the RAS pathway and sensitize tumour cells to cytolytic killing by T cells, which also contributes to hindering malignant progression. Thus, tumour-antigen-specific and -antigen-independent IgA responses antagonize the growth of ovarian cancer by governing coordinated tumour cell, T cell and B cell responses. These findings provide a platform for identifying targets that are spontaneously recognized by intratumoural B-cell-derived antibodies, and suggest that immunotherapies that augment B cell responses may be more effective than approaches that focus on T cells, particularly for malignancies that are resistant to checkpoint inhibitors.
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http://dx.doi.org/10.1038/s41586-020-03144-0DOI Listing
February 2021

Comparison of Definitive Cervical Cancer Management With Chemotherapy and Radiation Between Two Centers With Variable Resources and Opportunities for Improved Treatment.

JCO Glob Oncol 2020 10;6:1510-1518

Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.

Purpose: Cervical cancer remains a major health challenge in low- to middle-income countries. We present the experiences of two centers practicing in variable resource environments to determine predictors of improved radiochemotherapy treatment.

Methods And Materials: This comparative review describes cervical cancer presentation and treatment with concurrent chemoradiotherapy with high-dose-rate brachytherapy between 2014 and 2017 at the National Radiotherapy Oncology and Nuclear Medicine Center (NRONMC) in Korle-Bu Teaching Hospital, Accra, Ghana, and Moffitt Cancer Center (MCC), Tampa, FL.

Results: Median follow-up for this study was 16.9 months. NRONMC patients presented with predominantly stage III disease (42% 16%; = .002). MCC patients received para-aortic node irradiation (16%) and interstitial brachytherapy implants (19%). Median treatment duration was longer for NRONMC patients compared with MCC patients (59 52 days; < .0001), and treatment duration ≥ 55 days predicted worse survival on multivariable analysis (MVA; = .02). Stage ≥ III disease predicted poorer local control on MVA. There was a difference in local control among patients with stage III disease (58% 91%; = .03) but not in survival between MCC and NRONMC. No significant difference in local control was observed for stage IB, IIA, and IIB disease.

Conclusion: Although there were significant differences in disease presentation between the two centers, treatment outcomes were similar for patients with early-stage disease. Longer treatment duration and stage ≥ III disease predicted poor outcomes.
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http://dx.doi.org/10.1200/GO.20.00303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605379PMC
October 2020

"I think that a brief conversation from their provider can go a very long way": Patient and provider perspectives on barriers and facilitators of genetic testing after ovarian cancer.

Support Care Cancer 2020 Sep 25. Epub 2020 Sep 25.

Department of Health Outcomes & Behavior, Moffitt Cancer Center, 12902 Magnolia Drive, MRC-COEE, Tampa, FL, 33612, USA.

Objective: Identify predisposing, enabling, and reinforcing factors impacting genetic counseling/testing among ovarian cancer patients guided by Green and Kreuter's PRECEDE-PROCEED model.

Methods: Gynecologic oncology providers (N = 4), genetic counselors (N = 4), and ovarian cancer patients (N = 9) completed semi-structured qualitative interviews exploring participants' knowledge of and experiences with genetic counseling/testing. Interviews were audio recorded, transcribed verbatim, and analyzed using inductive content analysis by two independent raters.

Results: Thematic analysis identified predisposing, enabling, and reinforcing factors impacting referral for and uptake of genetic counseling/testing. Predisposing factors included participant's knowledge, beliefs, and attitudes related to genetic counseling/testing. Both patients and providers also cited that insurance coverage and out-of-pocket cost are major concerns for ovarian cancer patients considering genetic testing. Finally, both patients and providers emphasized that genetic counseling/testing would provide additional information to an ovarian cancer patient. While providers emphasized that genetic testing results were useful for informing a patient's personal treatment plan, patients emphasized that this knowledge would be beneficial for their family members.

Conclusion: Barriers to genetic testing for ovarian cancer patients exist at multiple levels, including the patient (e.g., knowledge, attitudes), the provider (e.g., workload, availability of services), the institution (e.g., difficulty with referrals/scheduling), and the healthcare system (e.g., insurance/cost). Interventions aiming to increase genetic testing among ovarian cancer patients will likely need to target multiple levels of influence. Future quantitative studies are needed to replicate these results. This line of work will inform specific multilevel intervention strategies that are adaptable to different practice settings, ultimately improving guideline concordant care.
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http://dx.doi.org/10.1007/s00520-020-05779-1DOI Listing
September 2020

A Biomarker-enriched, Randomized Phase II Trial of Adavosertib (AZD1775) Plus Paclitaxel and Carboplatin for Women with Platinum-sensitive -mutant Ovarian Cancer.

Clin Cancer Res 2020 Sep 1;26(18):4767-4776. Epub 2020 Jul 1.

Stephenson Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.

Purpose: Preclinical studies show that adavosertib, a WEE1 kinase inhibitor, sensitizes -mutant cells to chemotherapy. We hypothesized that adavosertib, plus chemotherapy, would enhance efficacy versus placebo in -mutated ovarian cancer.

Patients And Methods: Following safety run-in, this double-blind phase II trial (NCT01357161) randomized women with -mutated, platinum-sensitive ovarian cancer to oral adavosertib (225 mg twice daily for 2.5 days/21-day cycle) or placebo, plus carboplatin (AUC5) and paclitaxel (175 mg/m), until disease progression or for six cycles. The primary endpoints were progression-free survival (PFS) by enhanced RECIST v1.1 [ePFS (volumetric)] and safety. Secondary/exploratory objectives included PFS by RECIST v1.1 (single dimension), objective response rate, overall survival, and analysis of tumor gene profile versus sensitivity to adavosertib.

Results: A total of 121 patients were randomized to adavosertib (A+C; = 59) and placebo (P+C; = 62) plus chemotherapy. Adding adavosertib to chemotherapy improved ePFS [median, 7.9 (95% confidence interval (CI), 6.9-9.9) vs. 7.3 months (5.6-8.2); HR 0.63 (95% CI, 0.38-1.06); two-sided = 0.080], meeting the predefined significance threshold ( < 0.2). Clinical benefit was observed following A+C for patients with different mutation subtypes, identifying possible response biomarkers. An increase in adverse events was seen with A+C versus P+C: greatest for diarrhea (adavosertib 75%; placebo 37%), vomiting (63%; 27%), anemia (53%; 32%), and all grade ≥3 adverse events (78%; 65%).

Conclusions: Establishing an optimal strategy for managing tolerability and identifying specific patient populations most likely to benefit from treatment may increase clinical benefit. Future studies should consider additional adavosertib doses within the chemotherapy treatment cycle and the potential for maintenance therapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0219DOI Listing
September 2020

A sporadic gastric-type endocervical adenocarcinoma with endometrial involvement and bilateral ovarian metastasis, a case report.

Gynecol Oncol Rep 2020 May 18;32:100572. Epub 2020 Apr 18.

Department of Gynecologic Oncology, MCC, United States.

•Gastric type endocervical adenocarcinoma (GAS) is rare in the United States.•GAS is an aggressive tumor and can metastasize unusual sites including peritoneal surfaces and adnexa.•Metastatic lesions can mimic benign/borderline mucinous tumors of ovaries.•There is no established standard of care for GAS.•Genetic consultation should be included in patient's management.
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http://dx.doi.org/10.1016/j.gore.2020.100572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182719PMC
May 2020

Is hormonal therapy after risk-reducing salpingo-oophorectomy associated with an increased risk of malignancy in pathogenic variant carriers?

Gynecol Oncol 2020 06 3;157(3):706-710. Epub 2020 Mar 3.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University, St. Louis, MO, United States of America.

Objectives: This study aimed to assess the association between hormone replacement therapy and the incidence of subsequent malignancies in patients who underwent risk-reducing salpingo-oophorectomy and had mutations predisposing them to Müllerian cancers.

Methods: This Institutional Review Board-approved retrospective study was performed at five academic institutions. Women were included if they were age 18-51 years, had one or more confirmed germline highly penetrant pathogenic variants, and underwent risk-reducing salpingo-oophorectomy. Patients with a prior malignancy were excluded. Clinicodemographic data were collected by chart review. Patients with no documented contact for one year prior to study termination were called to confirm duration of hormone use and occurrence of secondary outcomes. Hormone replacement therapy included any combination of estrogen or progesterone.

Results: Data were analyzed for 159 women, of which 82 received hormone replacement therapy and 77 did not. In both groups an average of 6 years since risk reduction had passed. The patients treated with hormone replacement therapy did not have a higher risk of subsequent malignancy than those not treated with hormone replacement therapy (6 out of 82 vs. 7 out of 77, P = .68). Patients who received hormone replacement therapy were younger than those who did not receive hormone replacement therapy (39.0 vs. 43.9 years, P < .01) and were more likely to have undergone other risk reductive procedures including mastectomy and/or hysterectomy, though this difference was not statistically significant (69.5% vs. 55.8%, P = .07).

Conclusions: In this multi-institution retrospective study of data from patients with high-risk variant carriers who underwent risk-reducing salpingo-oophorectomy, there was no statistically significant difference in the incidence of malignancy between women who did and did not receive hormone replacement therapy.
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http://dx.doi.org/10.1016/j.ygyno.2020.02.033DOI Listing
June 2020

A randomized, double-blind, placebo-controlled phase 1b/2 study of ralimetinib, a p38 MAPK inhibitor, plus gemcitabine and carboplatin versus gemcitabine and carboplatin for women with recurrent platinum-sensitive ovarian cancer.

Gynecol Oncol 2020 01 29;156(1):23-31. Epub 2019 Nov 29.

Moffitt Cancer Center, Tampa, FL, USA.

Objective: This phase 1b/2 clinical trial (NCT01663857) evaluated the efficacy of ralimetinib in combination with gemcitabine (G) and carboplatin (C), followed by maintenance ralimetinib, for patients with recurrent platinum-sensitive epithelial ovarian cancer.

Methods: Phase 1b was to determine the recommended phase 2 dose (RP2D) of ralimetinib administered Q12H on Days 1-10 (q21d) in combination with G (1000 mg/m, Days 3 and 10) and C (AUC 4, Day 3) for six cycles. In phase 2, patients were randomized double-blind 1:1 to ralimetinib (R)+GC or placebo (P)+GC, for six cycles, followed by ralimetinib 300 mg Q12H or placebo on Days 1-14, q28d.

Results: 118 patients received at least one dose of ralimetinib or placebo; eight in phase 1b and 110 in phase 2 (R+GC, N = 58; P+GC, N = 52). The RP2D for R+GC was 200 mg Q12H. The study met its primary objective of a statistically significant difference in PFS (median: R+GC, 10.3 mo vs. P+GC, 7.9 mo; hazard ratio [HR] = 0.773, P = 0.2464, against a two-sided false positive rate of 0.4). Secondary objectives were not statistically significant for median overall survival (R+GC, 29.2 mo vs. P+GC, 25.1 mo; HR = 0.827, P = 0.4686) or overall response rate (R+GC 46.6% vs. P+GC, 46.2%; P = 0.9667). The safety profile of R+GC therapy was mainly consistent with safety of the chemotherapy backbone alone. Grade 3/4 elevated alanine aminotransferase was more common in the ralimetinib arm.

Conclusions: Addition of ralimetinib to GC resulted in a modest improvement in PFS.
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http://dx.doi.org/10.1016/j.ygyno.2019.11.006DOI Listing
January 2020

High-dose intensity-modulated chemoradiotherapy in vulvar squamous cell carcinoma: Outcome and toxicity.

Gynecol Oncol 2020 02 23;156(2):349-356. Epub 2019 Nov 23.

Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. Electronic address:

Introduction: To evaluate clinical outcomes, pattern of failure, and toxicity after high-dose intensity-modulated radiation therapy (IMRT) for advanced vulvar cancer.

Methods: In this IRB approved retrospective study, the charts of women with histologically confirmed, non-metastatic vulvar cancer consecutively treated at our institution from 2012 to 2018 were reviewed to identify patients that received high-dose IMRT with curative intent. The treatment compliance, toxicities, and patterns of failure were investigated. Actuarial local, regional and distant recurrence and survival were estimated using Kaplan-Meier method and compared using log rank test.

Results: Twenty-six patients were identified, 23 were unresectable, and 3 refused surgery. Fifteen patients (58%) had inguinal node metastases; 10(38%) had pelvic node metastases. Elective surgical staging of groins was performed in 9-patients. Median tumor dose was 65.4Gy. Concurrent platinum-based chemotherapy was administered in 22(84.6%) patients. Complete response (CR) was achieved in 21/26 (80.7%) patients. Five patients had persistent disease following treatment and one sustained recurrence 5-months following radiotherapy. All persistent or recurrent disease occurred inside the irradiated volume. Median follow-up was 19 months (3-52 months). Actuarial 1-year local, regional and distant controls were 72.4%, 85.4%, and 86%, respectively. One and 2-year overall survivals were 91% and 62%, respectively. Complete response at 3-months was a strong predictor for overall survival (1-yr OS 73% vs 27%, HR 7.1 (95% CI 1.2-44); p = 0.01). Lymph node metastases adversely affected overall survival (2-yr OS 49% vs. 83%, p = 0.09). Grade 3-4 late urinary and soft-tissue toxicity was seen in 5 patients. Tumor doses >66 Gy (p = 0.03) and prior pelvic radiotherapy (p = 0.002) predicted grade 3-4 toxicity.

Conclusion: High-dose IMRT for vulvar cancer achieves high rates of local control with acceptable dose dependent long-term toxicity.
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http://dx.doi.org/10.1016/j.ygyno.2019.11.027DOI Listing
February 2020

Prospective follow-up of quality of life for participants undergoing risk-reducing salpingo-oophorectomy or ovarian cancer screening in GOG-0199: An NRG Oncology/GOG study.

Gynecol Oncol 2020 01 21;156(1):131-139. Epub 2019 Nov 21.

Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, 10065, USA. Electronic address:

Background: Risk-reducing salpingo-oophorectomy (RRSO) and ovarian cancer screening (OCS) are management options for women at increased risk of ovarian cancer. Long-term effects of these interventions on quality of life (QOL) are not well understood.

Methods: GOG-0199 is a prospective cohort study of women at increased ovarian cancer risk who chose either RRSO or OCS as their risk management intervention. At study entry, 6, 12, 24 and 60 months of follow-up, participants completed the QOL questionnaire, which included the Medical Outcome Study Short Form-36, the Impact of Events Scales, the Center for Epidemiological Studies Depression Scale, the State-Trait Anxiety Inventory, the Functional Assessment of Cancer Therapy - Endocrine Subscale, and the Sexual Activity Questionnaire. QOL measures were compared between the RRSO and OCS cohort at baseline and over time.

Results: Five-hundred-sixty-two participants in the RRSO cohort and 1,010 in the OCS completed the baseline and at least one follow-up questionnaire. At baseline, participants selecting RRSO reported lower health-related QOL (HRQOL), greater ovarian cancer-related stress, greater anxiety, and more depressive symptomatology, which improved during follow-up, especially for ovarian cancer-related stress. Screening was not found to adversely impact HRQOL. Hormone-related menopausal symptoms worsened and sexual functioning declined during follow-up in both cohorts, but more so among participants who underwent RRSO.

Conclusions: HRQOL improved after surgery among women who chose RRSO and remained stable among participants undergoing screening. The adverse effects of RRSO and screening on short-term and long-term sexual activity and sexual functioning warrant consideration in the decision-making process for high-risk women.
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http://dx.doi.org/10.1016/j.ygyno.2019.10.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980744PMC
January 2020

Using the Radiosensitivity Index (RSI) to Predict Pelvic Failure in Endometrial Cancer Treated With Adjuvant Radiation Therapy.

Int J Radiat Oncol Biol Phys 2020 03 20;106(3):496-502. Epub 2019 Nov 20.

Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. Electronic address:

Purpose: Variability exists in the adjuvant treatment for endometrial cancer (EC) based on surgical pathology and institutional preference. The radiosensitivity index (RSI) is a previously validated multigene expression index that estimates tumor radiosensitivity. We evaluate RSI as a genomic predictor for pelvic failure (PF) in EC patients treated with adjuvant radiation therapy (RT).

Methods And Materials: Using our institutional tissue biorepository, we identified EC patients treated between January 1999 and April 2011 with primarily endometrioid histology (n = 176; 86%) who received various adjuvant therapies. The RSI 10-gene signature was calculated for each sample using the previously published algorithm. Radiophenotype was determined using the previously identified cutpoint where RSI ≥ 0.375 denotes radioresistance (RR) and RSI < 0.375 describes radiosensitivity.

Results: A total of 204 patients were identified, of which 83 (41%) were treated with adjuvant RT. Median follow-up was 38.5 months. All patients underwent hysterectomy with bilateral salpingo-oophorectomy with the majority undergoing lymph node dissection (n = 181; 88%). In patients treated with radiation, RR tumors were more likely to experience PF (3-year pelvic control 84% vs 100%; P = .02) with worse PF-free survival (PFFS) (3-year PFFS 65% vs 89%; P = .04). Furthermore, in the patients who did not receive RT, there was no difference in PF (P = .87) or PFFS (P = .57) between the RR/radiosensitive tumors. On multivariable analysis, factors that continued to predict for PF included the RR phenotype (hazard ratio [HR], 12.2; P = .003), lymph node involvement (HR, 4.4; P = .02), and serosal or adnexal involvement (HR, 5.3; P = .01).

Conclusions: On multivariable analysis, RSI was found to be a significant predictor of PF in patients treated with adjuvant RT. We propose using RSI to predict which patients are at higher risk for failing in the pelvis and may be candidates for treatment escalation in the adjuvant setting.
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http://dx.doi.org/10.1016/j.ijrobp.2019.11.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050205PMC
March 2020

Patterns and predictors of genetic referral among ovarian cancer patients at a National Cancer Institute-Comprehensive Cancer Center.

Clin Genet 2020 02 24;97(2):370-375. Epub 2019 Nov 24.

Department of Health Outcomes and Behavior, Moffitt Cancer Center, Tampa, Florida.

Germline mutations (eg, BRCA1/2) have prognostic and treatment implications for ovarian cancer (OVCA) patients. Thus, national guidelines recommend genetic testing for OVCA patients. The present study examines patterns and predictors of genetics referral in OVCA patients. Electronic medical record data were abstracted retrospectively from 557 OVCA patients treated from 1 January 2001 to 31 December 2015. Logistic regression models identified sociodemographic characteristics, disease/treatment characteristics, family history data, provider characteristics, and survival data that predicted genetics referral. Overall, 27.5% of patients received referral. Eleven variables predicting referral were selected during stepwise regression: younger age, White race, not having private insurance, professional school education, year of OVCA diagnosis, platinum sensitivity, female gynecologic oncologist, chemotherapy administered by a gynecologic oncologist, clinical trial enrollment, longer overall survival, and family history of OVCA. Genetics referral among OVCA patients was similar to rates reported nationwide. Unique predictive factors will contribute to quality improvement and should be validated at a multi-institutional level to ensure guideline concordant care is provided to all OVCA patients. Future research should identify both patient-level and provider-level factors associated with genetics referral.
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http://dx.doi.org/10.1111/cge.13654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322721PMC
February 2020

Twenty-year surgical trends in a gynecologic oncology fellowship training program: Implications for practice.

Gynecol Oncol 2019 11 28;155(2):359-364. Epub 2019 Sep 28.

Department of Gynecologic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; The University of South Florida Morsani College of Medicine, Tampa, FL, USA.

Objective: To assess whether there were any significant changes in surgical training volume over the past 20 years that might have ramifications toward preparedness for practice.

Methods: We used deidentified annual summaries of fellow case numbers for the academic years 1999 through 2018. Unpaired t-tests with Welch's correction were performed on all surgical categories for 10-year and 5-year periods.

Results: The total number of hysterectomies performed each year did not change significantly. The percent of hysterectomies performed by minimally invasive surgery increased significantly starting in 2008. There was a significant decline in the number of radical hysterectomies conducted starting after 2004, which then remained stable. There was also a significant decline in the number of bowel resections/anastomoses performed by fellows on the gynecologic oncology services that occurred and stabilized during the same time frame. There were other significant trends associated with the introduction of minimally invasive techniques.

Conclusion: The results of this study suggest the need to reevaluate fellowship training and/or the scope of surgical practice in gynecologic oncology.
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http://dx.doi.org/10.1016/j.ygyno.2019.09.013DOI Listing
November 2019

Niraparib Maintenance Treatment Improves Time Without Symptoms or Toxicity (TWiST) Versus Routine Surveillance in Recurrent Ovarian Cancer: A TWiST Analysis of the ENGOT-OV16/NOVA Trial.

J Clin Oncol 2019 12 16;37(34):3183-3191. Epub 2019 Sep 16.

Nordic Society of Gynaecological Oncology and Copenhagen University Hospital, Copenhagen, Denmark.

Purpose: This study estimated time without symptoms or toxicity (TWiST) with niraparib compared with routine surveillance (RS) in the maintenance treatment of patients with recurrent ovarian cancer.

Patients And Methods: Mean progression-free survival (PFS) was estimated for niraparib and RS by fitting parametric survival distributions to Kaplan-Meier data for 553 patients with recurrent ovarian cancer who were enrolled in the phase III ENGOT-OV16/NOVA trial. Patients were categorized according to the presence or absence of a germline mutation-gmut and non-gmut cohorts. Mean time with toxicity was estimated based on the area under the Kaplan-Meier curve for symptomatic grade 2 or greater fatigue, nausea, and vomiting adverse events (AEs). Time with toxicity was the number of days a patient experienced an AE post-random assignment and before disease progression. TWiST was estimated as the difference between mean PFS and time with toxicity. Uncertainty was explored using alternative PFS estimates and considering all symptomatic grade 2 or greater AEs.

Results: In the gmut and non-gmut cohorts, niraparib treatment resulted in a mean PFS benefit of 3.23 years and 1.44 years, respectively, and a mean time with toxicity of 0.28 years and 0.10 years, respectively, compared with RS. Hence, niraparib treatment resulted in a mean TWiST benefit of 2.95 years and 1.34 years, respectively, compared with RS, which is equivalent to more than four-fold and two-fold increases in mean TWiST between niraparib and RS in the gmut and non-gmut cohorts, respectively. This TWiST benefit was consistent across all sensitivity analyses, including modeling PFS over 5-, 10-, and 15-year time horizons.

Conclusion: Patients who were treated with niraparib compared with RS experienced increased mean TWiST. Thus, patients who were treated with niraparib in the ENGOT-OV16/NOVA trial experienced more time without symptoms or symptomatic toxicities compared with control.
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http://dx.doi.org/10.1200/JCO.19.00917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881097PMC
December 2019

A phase II, multicenter, open-label trial of OTL38 injection for the intra-operative imaging of folate receptor-alpha positive ovarian cancer.

Gynecol Oncol 2019 10 27;155(1):63-68. Epub 2019 Jul 27.

University of Pennsylvania Health System, Philadelphia, PA, United States of America.

Purpose: OTL38 is a folate-indole-cyanine green-like conjugate to folate receptor alpha (FRa). The objectives of this prospective trial were to assess the safety and efficacy (sensitivity and positive predictive value (PPV)) of OTL38 for intraoperative imaging during epithelial ovarian cancer surgery.

Methods: Patients with suspected ovarian cancer planned for cytoreductive surgery were eligible to receive OTL38. Near-infrared (NIR) imaging was used to visualize target lesions that were evaluated by two blinded pathologists. A modified intent to treat (mITT) population of lesions from all patients who received OTL38-NIR imaging, underwent surgery, and had at least one FRa + target lesion was used to determine sensitivity and PPV. Two generalized linear models, with and without random effects, were employed to estimate sensitivity and PPV.

Results: Forty-four patients were evaluated for safety, and 225 lesions from 29 patients (the mITT population) were evaluated for efficacy. When assuming no correlation of interlesional results within a patient, sensitivity was estimated at 85.93% (95% lower boundary CI = 81.19) and PPV at 88.14% (95% lower boundary CI = 83.59). When controlling for actual correlation of detection among multiple lesions within a single patient (a random effect), sensitivity was estimated at 97.97% (95% lower boundary CI = 87.75) and PPV at 94.93% (95% lower boundary CI = 86.13). A total of 48.3% [14/29, (95% CI 0.29-0.67)] of patients had at least one additional lesion detected by OTL38 alone. Eight patients had mild drug-related adverse events including infusion reaction, nausea, vomiting, and abdominal pain.

Conclusions: OTL38-NIR was safe and efficacious in this phase II study regardless of folate expression levels and merits phase III evaluation.
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http://dx.doi.org/10.1016/j.ygyno.2019.07.010DOI Listing
October 2019

Niraparib Maintenance Therapy in Patients With Recurrent Ovarian Cancer After a Partial Response to the Last Platinum-Based Chemotherapy in the ENGOT-OV16/NOVA Trial.

J Clin Oncol 2019 11 7;37(32):2968-2973. Epub 2019 Jun 7.

NSGO and Rigshospitalet-Copenhagen University Hospital, Copenhagen, Denmark.

Purpose: In the ENGOT-OV16/NOVA trial (ClinicalTrials.gov identifier: NCT01847274), maintenance therapy with niraparib, a poly(ADP-ribose) polymerase inhibitor, prolonged progression-free survival in patients with platinum-sensitive, recurrent ovarian cancer who had a response to their last platinum-based chemotherapy. The objective of the study was to assess the clinical benefit and patient-reported outcomes in patients who had a partial response (PR) and complete response (CR) to their last platinum-based therapy.

Patients And Methods: A total of 553 patients were enrolled in the trial. Of 203 patients with a germline mutation (gmut), 99 had a PR and 104 had a CR to their last platinum-based therapy; of 350 patients without a confirmed gmut (non-gmut), 173 had a PR and 177 had a CR. Post hoc analyses were carried out to evaluate safety and the risk of progression in these patients according to gmut status and response to their last platinum-based therapy. Ovarian cancer-specific symptoms and quality of life were assessed using the Functional Assessment of Cancer Therapy-Ovarian Symptom Index.

Results: Progression-free survival was improved in patients treated with niraparib compared with placebo in both the gmut cohort (PR: hazard ratio [HR], 0.24; 95% CI, 0.131 to 0.441; < .0001; CR: HR, 0.30; 95% CI, 0.160 to 0.546; < .0001) and the non-gmut cohort (PR: HR, 0.35; 95% CI, 0.230 to 0.532; < .0001; CR: HR, 0.58; 95% CI, 0.383 to 0.868; = .0082). The incidence of any-grade and grade 3 or greater adverse events was manageable. No meaningful differences were observed between niraparib and placebo in PR and CR subgroups with respect to patient-reported outcomes.

Conclusion: Patients achieved clinical benefit from maintenance treatment with niraparib regardless of response to the last platinum-based therapy.
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http://dx.doi.org/10.1200/JCO.18.02238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839909PMC
November 2019

Illuminating the Numbers: Integrating Mathematical Models to Optimize Photomedicine Dosimetry and Combination Therapies.

Front Phys 2019 Apr 2;7. Epub 2019 Apr 2.

Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States.

Cancer photomedicine offers unique mechanisms for inducing local tumor damage with the potential to stimulate local and systemic anti-tumor immunity. Optically-active nanomedicine offers these features as well as spatiotemporal control of tumor-focused drug release to realize synergistic combination therapies. Achieving quantitative dosimetry is a major challenge, and dosimetry is fundamental to photomedicine for personalizing and tailoring therapeutic regimens to specific patients and anatomical locations. The challenge of dosimetry is perhaps greater for photomedicine than many standard therapies given the complexity of light delivery and light-tissue interactions as well as the resulting photochemistry responsible for tumor damage and drug-release, in addition to the usual intricacies of therapeutic agent delivery. An emerging multidisciplinary approach in oncology utilizes mathematical and computational models to iteratively and quantitively analyze complex dosimetry, and biological response parameters. These models are parameterized by preclinical and clinical observations and then tested against previously unseen data. Such calibrated and validated models can be deployed to simulate treatment doses, protocols, and combinations that have not yet been experimentally or clinically evaluated and can provide testable optimal treatment outcomes in a practical workflow. Here, we foresee the utility of these computational approaches to guide adaptive therapy, and how mathematical models might be further developed and integrated as a novel methodology to guide precision photomedicine.
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http://dx.doi.org/10.3389/fphy.2019.00046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529192PMC
April 2019

Trebananib or placebo plus carboplatin and paclitaxel as first-line treatment for advanced ovarian cancer (TRINOVA-3/ENGOT-ov2/GOG-3001): a randomised, double-blind, phase 3 trial.

Lancet Oncol 2019 06 7;20(6):862-876. Epub 2019 May 7.

Gynecologic Oncology Group, Arizona Oncology (US Oncology Network), University of Arizona, Phoenix, AZ, USA; Creighton University, Phoenix, AZ, USA.

Background: Angiopoietin 1 and 2 regulate angiogenesis and vascular remodelling by interacting with the tyrosine kinase receptor Tie2, and inhibition of angiogenesis has shown promise in the treatment of ovarian cancer. We aimed to assess whether trebananib, a peptibody that inhibits binding of angiopoietin 1 and 2 to Tie2, improved progression-free survival when added to carboplatin and paclitaxel as first-line therapy in advanced epithelial ovarian, primary fallopian tube, or peritoneal cancer in a phase 3 clinical trial.

Methods: TRINOVA-3, a multicentre, multinational, phase 3, double-blind study, was done at 206 investigational sites (hospitals and cancer centres) in 14 countries. Eligible patients were aged 18 years or older with biopsy-confirmed International Federation of Gynecology and Obstetrics (FIGO) stage III to IV epithelial ovarian, primary peritoneal, or fallopian tube cancers, and an ECOG performance status of 0 or 1. Eligible patients were randomly assigned (2:1) using a permuted block method (block size of six patients) to receive six cycles of paclitaxel (175 mg/m) and carboplatin (area under the serum concentration-time curve 5 or 6) every 3 weeks, plus weekly intravenous trebananib 15 mg/kg or placebo. Maintenance therapy with trebananib or placebo continued for up to 18 additional months. The primary endpoint was progression-free survival, as assessed by the investigators, in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01493505, and is complete.

Findings: Between Jan 30, 2012, and Feb 25, 2014, 1164 patients were screened and 1015 eligible patients were randomly allocated to treatment (678 to trebananib and 337 to placebo). After a median follow-up of 27·4 months (IQR 17·7-34·2), 626 patients had progression-free survival events (405 [60%] of 678 in the trebananib group and 221 [66%] of 337 in the placebo group). Median progression-free survival did not differ between the trebananib group (15·9 months [15·0-17·6]) and the placebo group (15·0 months [12·6-16·1]) groups (hazard ratio 0·93 [95% CI 0·79-1·09]; p=0·36). 512 (76%) of 675 patients in the trebananib group and 237 (71%) of 336 in the placebo group had grade 3 or worse treatment-emergent adverse events; of which the most common events were neutropenia (trebananib 238 [35%] vs placebo 126 [38%]) anaemia (76 [11%] vs 40 [12%]), and leucopenia (81 [12%] vs 35 [10%]). 269 (40%) patients in the trebananib group and 104 (31%) in the placebo group had serious adverse events. Two fatal adverse events in the trebananib group were considered related to trebananib, paclitaxel, and carboplatin (lung infection and neutropenic colitis); two were considered to be related to paclitaxel and carboplatin (general physical health deterioration and platelet count decreased). No treatment-related fatal adverse events occurred in the placebo group.

Interpretation: Trebananib plus carboplatin and paclitaxel did not improve progression-free survival as first-line treatment for advanced ovarian cancer. The combination of trebananib plus carboplatin and paclitaxel did not produce new safety signals. These results show that trebananib in combination with carboplatin and paclitaxel is minimally effective in this patient population.

Funding: Amgen.
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http://dx.doi.org/10.1016/S1470-2045(19)30178-0DOI Listing
June 2019

Efficacy and safety of niraparib as maintenance treatment in older patients (≥ 70 years) with recurrent ovarian cancer: Results from the ENGOT-OV16/NOVA trial.

Gynecol Oncol 2019 03 9;152(3):560-567. Epub 2019 Jan 9.

Dana-Farber Cancer Institute, Boston, MA, USA.

Objective: To analyze the safety and efficacy of niraparib in patients aged ≥70 years with recurrent ovarian cancer in the ENGOT-OV16/NOVA trial.

Methods: The trial enrolled 2 independent cohorts with histologically diagnosed recurrent ovarian, fallopian tube, or peritoneal cancer who responded to platinum rechallenge, on the basis of germline breast cancer susceptibility gene mutation (gBRCAmut) status. Patients were randomized 2:1 to receive niraparib (300 mg) or placebo once daily until disease progression. The primary endpoint was progression-free survival (PFS) by blinded independent central review. Adverse events (AEs) of special interest were based on the known safety profile of poly(ADP-ribose) polymerase inhibitors.

Results: Patients aged ≥70 years in the gBRCAmut cohort receiving niraparib (n = 14) had not yet reached a median PFS compared with a median PFS of 3.7 months for the same age group in the placebo arm (hazard ratio [HR], 0.09 [95% confidence interval (CI), 0.01 to 0.73]). Non-gBRCAmut patients aged ≥70 years receiving niraparib (n = 47) had a median PFS of 11.3 months compared with 3.8 months in the placebo arm (HR, 0.35 [95% CI, 0.18 to 0.71]). Median duration of follow-up in the niraparib arm was 17.3 months in patients ≥70 years and 17.2 months in patients <70 years. Frequency, severity of AEs, and dose reductions in the niraparib arm were similar in patients aged <70 and ≥ 70 years population. The most common grade ≥ 3 AEs in patients ≥70 years were hematologic: thrombocytopenia event (34.4%), anemia event (13.1%), and neutropenia event (16.4%).

Conclusions: For patients ≥70 years of age receiving niraparib as maintenance treatment in the ENGOT-OV16/NOVA trial, PFS benefits and incidence of any grade or serious treatment-emergent AEs were comparable to results in the younger population. Use of niraparib should be considered in this population.
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http://dx.doi.org/10.1016/j.ygyno.2018.12.009DOI Listing
March 2019

Nomogram for Predicting Individual Survival After Recurrence of Advanced-Stage, High-Grade Ovarian Carcinoma.

Obstet Gynecol 2019 02;133(2):245-254

Cleveland Clinic Foundation and Case Western Reserve University, Cleveland, Ohio; NRG Oncology Statistics and Data Management Center, Roswell Park Cancer Institute, Buffalo, New York; The Ohio State University, Columbus, Ohio; the University of Minnesota, Minneapolis, Minnesota; Duke University Hospital; Durham, North Carolina; the University of California at Irvine, Orange, California; the University of Iowa Hospital, Iowa City, Iowa; Washington University in St. Louis School of Medicine, St. Louis, Missouri; ANZGOG, Australia-New Zealand Gynaecological Oncology Group, Sydney, Australia; the University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Community Health Network and Indiana University School of Medicine, Indianapolis, Indiana; Walter Reed Army Medical Center; Bethesda, Maryland; Tacoma General Hospital, Tacoma, Washington; Moffitt Cancer Center, Tampa, Florida; the University of Colorado School of Medicine at Denver, Aurora, Colorado; Cancer Treatment Centers of America, Philadelphia Pennsylvania; NYU Clinical Cancer Center, New York, New York; Johns Hopkins University/Sidney Kimmel Cancer Center, Baltimore, Maryland; US Oncology Research, Arizona Oncology, Tucson, Arizona; the University of Pennsylvania Medical Center, Philadelphia, Pennsylvania; and The Ohio State University Medical Center, Columbus, Ohio.

Objective: To analyze clinical prognostic factors for survival after recurrence of high-grade, advanced-stage ovarian-peritoneal-tubal carcinoma and to develop a nomogram to predict individual survival after recurrence.

Methods: We retrospectively analyzed patients treated in multicenter Gynecologic Oncology Group protocols for stage III and IV ovarian-peritoneal-tubal carcinoma who underwent primary debulking surgery, received chemotherapy with paclitaxel and a platinum compound, and subsequently developed recurrence. Prognostic factors affecting survival were identified and used to develop a nomogram, which was both internally and externally validated.

Results: There were 4,739 patients included in this analysis, of whom, 84% had stage III and 16% had stage IV ovarian carcinoma. At a median follow-up of 88.8 months (95% CI 86.2-92.0 months), the vast majority of patients (89.4%) had died. The median survival after recurrence was 21.4 months (95% CI 20.5-21.9 months). Time to recurrence after initial chemotherapy, clear cell or mucinous histology, performance status, stage IV disease, and age were significant variables used to develop a nomogram for survival after recurrence, which had a concordance index of 0.67. The time to recurrence alone accounted for 85% of the prognostic information. Similar results were found for patients who underwent second look laparotomy and had a complete pathologic response or received intraperitoneal chemotherapy.

Conclusion: For individuals with advanced-stage ovarian carcinoma who recur after standard first-line therapy, estimated survivals after recurrence are closely related to the time to recurrence after chemotherapy and prognostic variables can be used to predict subsequent survival.

Clinical Trial Registration: ClinialTrials.gov, NCT00002568, NCT00837993, NCT00002717, NCT01074398, and NCT00011986.
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http://dx.doi.org/10.1097/AOG.0000000000003086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551603PMC
February 2019

The role of menopausal hormone therapy in women with or at risk of ovarian and breast cancers: Misconceptions and current directions.

Cancer 2019 02 20;125(4):499-514. Epub 2018 Dec 20.

Department of Gynecologic Oncology, Moffitt Cancer Center, Tampa, Florida.

For women who are candidates for menopausal hormone therapy (MHT), estrogen can provide relief from symptomatic menopause, decrease rates of chronic illnesses, and improve health-related quality of life. However, confusion surrounds the evidence regarding the impact of exogenous estrogen and progesterone on the breast and ovary. Available data regarding the risks of MHT (estrogen and/or progestin) related to the development of breast and ovarian cancer are often inconsistent or incomplete. Modern molecular and genetic techniques have improved our understanding of the heterogeneity of breast and ovarian cancer. This enhanced understanding of the disease has impacted our understanding of carcinogenesis. Treatment options have evolved to be more targeted toward hormonal therapy for certain subtypes of disease, whereas cytotoxic chemotherapy remains the standard for other histological and molecular subtypes. The role of MHT in the breast and ovarian cancer survivor, as well as women who are at high risk for the development of hereditary breast and ovarian cancer, remains controversial despite evidence that this treatment can improve quality of life and survival outcomes. Through this article, we examine the evidence for and against the use of MHT with a focus on women who have or are at high risk for breast and ovarian cancer.
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http://dx.doi.org/10.1002/cncr.31911DOI Listing
February 2019

Does adjuvant chemotherapy dose modification have an impact on the outcome of patients diagnosed with advanced stage ovarian cancer? An NRG Oncology/Gynecologic Oncology Group study.

Gynecol Oncol 2018 10 19;151(1):18-23. Epub 2018 Aug 19.

The Permanente Medical Group, Inc. 2350 Geary Blvd, Room 115 San Francisco, CA 94115, United States of America. Electronic address:

Purpose: To determine the relationship between chemotherapy dose modification (dose adjustment or treatment delay), overall survival (OS) and progression-free survival (PFS) for women with advanced-stage epithelial ovarian carcinoma (EOC) and primary peritoneal carcinoma (PPC) who receive carboplatin and paclitaxel.

Methods: Women with stages III and IV EOC and PPC treated on the Gynecologic Oncology Group phase III trial, protocol 182, who completed eight cycles of carboplatin with paclitaxel were evaluated in this study. The patients were grouped per dose modification and use of granulocyte colony stimulating factor (G-CSF). The primary end point was OS; Hazard ratios (HR) for PFS and OS were calculated for patients who completed eight cycles of chemotherapy. Patients without dose modification were the referent group. All statistical analyses were performed using the R programming language and environment.

Results: A total of 738 patients were included in this study; 229 (31%) required dose modification, 509 did not. The two groups were well-balanced for demographic and prognostic factors. The adjusted hazard ratios (HR) for disease progression and death among dose-modified patients were: 1.43 (95% CI, 1.19-1.72, P < 0.001) and 1.26 (95% CI, 1.04-1.54, P = 0.021), respectively. Use of G-CSF was more frequent in dose-modified patients with an odds ratio (OR) of 3.63 (95% CI: 2.51-5.26, P < 0.001) compared to dose-unmodified patients.

Conclusion: Dose-modified patients were at a higher risk of disease progression and death. The need for chemotherapy dose modification may identify patients at greater risk for adverse outcomes in advanced stage EOC and PPC.
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http://dx.doi.org/10.1016/j.ygyno.2018.07.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6151871PMC
October 2018

Surgical prevention strategies in ovarian cancer.

Gynecol Oncol 2018 10 4;151(1):166-175. Epub 2018 Aug 4.

Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, United States of America; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States of America. Electronic address:

Given the current lack of effective screening for ovarian cancer, surgical removal of at-risk tissue is the most successful strategy to decrease risk of cancer development. However, the optimal timing of surgery and tissues to remove, as well as the appropriate patients to undergo preventive procedures are poorly understood. In this review, we first discuss the origin and precursors of ovarian epithelial carcinomas, focusing on high-grade serous carcinomas and endometriosis-associated carcinomas, which cause the majority of the mortality and incidence of ovarian cancer. In addition, we summarize the implications of current understanding of specific pathogenic origins for surgical prevention and remaining gaps in knowledge. Secondly, we review evidence from the epidemiologic literature on the associations of various surgical prevention strategies, including endometriosis excision, tubal procedures, and bilateral salpingo-oophorectomy, with risk of future ovarian cancer development, as well as the short- and long-term consequences of these strategies on women's health and quality and life. We conclude with recommendations for surgical prevention in women with high-risk genetic mutations and average-risk women, and a brief discussion of ongoing research that will help clarify optimal surgical approaches that balance risk-reduction with maintenance of women's quality of life.
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http://dx.doi.org/10.1016/j.ygyno.2018.08.005DOI Listing
October 2018

Quality of life after pelvic exenteration for gynecologic cancer: Findings from a qualitative study.

Psychooncology 2018 10 18;27(10):2357-2362. Epub 2018 Jul 18.

Department of Health Outcomes and Behavior, Moffitt Cancer Center, Tampa, FL, USA.

Objective: Pelvic exenteration (PE) in carefully selected gynecologic cancer patients has a 5-year survival rate as high as 60%. Thus, there is a growing number of PE survivors dealing with the effects of this radical surgery. The current study sought to explore women's physical, psychological, and social quality of life (QOL) after PE.

Methods: Fourteen women who had undergone PE for recurrent gynecologic cancer at least 1 year previously completed semistructured qualitative interviews designed to elicit expectations and experiences of QOL following PE. Thematic analysis was used to code transcripts for both a priori and emergent themes.

Results: Themes included PE versus palliative care, preparedness, persistent symptoms, the not so normal new normal, new rules of social engagement, support, emotional diversity, and bouncing back through adaptive coping. Key differences with previous studies include the explicit acknowledgement of the need for palliative care, the chronic nature of multiple, seemingly unaddressed physical symptoms in survivorship, and the predominance of positive psychological symptoms. While a minority expressed emotional distress and regret for undergoing PE, most articulated a sense of resilience gained through a variety of adaptive coping strategies.

Conclusions: Findings underscore the persistent physical, psychological, and social effects of PE on QOL and the need for comprehensive, multidisciplinary patient care before and long after surgery. Findings should promote development of a best practice clinical pathway for the care and education of women who undergo PE with curative intent for gynecologic cancer.
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http://dx.doi.org/10.1002/pon.4832DOI Listing
October 2018

Adherence to practice guidelines is associated with reduced referral times for patients with ovarian cancer.

Am J Obstet Gynecol 2018 04 17;218(4):436.e1-436.e7. Epub 2018 Jan 17.

Department of Gynecologic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL. Electronic address:

Background: Patients with ovarian cancer tend to receive the highest quality of care at high-volume cancer centers with gynecological oncologists. However, the care that they receive prior to gynecological oncology consult has not been examined. We investigated the quantity and quality of care given to patients with ovarian cancer before being seen by a gynecological oncologist.

Objective: We evaluated the variability, quantity, and quality of diagnostic testing and physician-referral patterns prior to consultation with a gynecological oncologist, in women with suspicious pelvic masses seen on imaging.

Study Design: A chart review was performed on patients treated for ovarian cancer at a single institution from 2001 to 2014. We evaluated their workup in 4 categories, drawn from National Comprehensive Care Network guidelines: provider visits, abdominal/pelvic imaging, chest imaging, and tumor markers. Workup was classified as guideline adherent or guideline nonadherent.

Results: We identified 335 cases that met our criteria. In the provider visit category, 83.9% of patients received guideline-adherent workup: 77% in the abdominal/pelvic imaging, 98.2% in the chest imaging, and 95.2% in the tumor marker categories. Each patient's workup was assessed as a compilation of the 4 categories, yielding 65.7% patients as having received an adherent workup and 34.3% of workup as nonadherent to guidelines. The timeframe to see a gynecological oncologist for patients with guideline-adherent workup was significantly shorter than for those whose workup was nonadherant (20 vs 86 days, P < .001). A suspicious pelvic mass was identified by obstetrics-gynecology in only 23.9% of patients; 42.7% of patients did not have tumor marker testing before a gynecological oncologist consult. When an obstetrics-gynecology specialist discovered the suspicious pelvic mass, the remaining workup was more likely to be guideline adherent prior to gynecological oncologist referral than when initial imaging was not ordered by an obstetrics-gynecology specialist (P = .18). Survival was not significantly different (P = .103).

Conclusion: With a guideline-adherent workup, including tumor marker testing, gynecological oncologist referral times can be shortened, minimizing cost inefficiencies and delays that can compromise the effectiveness of downstream care for patients with ovarian cancer. Guidelines should be disseminated beyond the obstetrics-gynecology field.
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http://dx.doi.org/10.1016/j.ajog.2018.01.015DOI Listing
April 2018

New therapies for advanced, recurrent, and metastatic endometrial cancers.

Gynecol Oncol Res Pract 2017 2;4:19. Epub 2017 Dec 2.

Division of Gynecologic Oncology, University of Texas Southwestern Medical Center, Dallas, USA.

Endometrial cancer is the most common gynecologic malignancy in the United States, accounting for 6% of cancers in women. In 2017, an estimated 61,380 women were diagnosed with endometrial cancer, and approximately 11,000 died from this disease. From 1987 to 2008, there was a 50% increase in the incidence of endometrial cancer, with an approximate 300% increase in the number of associated deaths. Although there are many chemotherapeutic and targeted therapy agents approved for ovarian, fallopian tube and primary peritoneal cancers, since the 1971 approval of megestrol acetate for the palliative treatment of advanced endometrial cancer, only pembrolizumab has been Food and Drug Administration (FDA)-approved for high microsatellite instability (MSI-H) or mismatch repair deficient (dMMR) endometrial cancer; this highlights the need for new therapies to treat advanced, recurrent, metastatic endometrial cancer. In this review, we discuss current and emerging treatment options for endometrial cancer, including chemotherapy, targeted therapy, and immunotherapy. The National Cancer Institute (NCI) and others are now focusing their efforts on the design of scientifically rational targeted therapy and immunotherapy trials for specific molecular phenotypes of endometrial cancer. This is essential for the advancement of cancer care for women, which is threatened by a severe enrollment decline of approximately 80% for gynecologic oncology clinical trials.
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http://dx.doi.org/10.1186/s40661-017-0056-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5712183PMC
December 2017

Gene Expression Signature-Based Prediction of Lymph Node Metastasis in Patients With Endometrioid Endometrial Cancer.

Int J Gynecol Cancer 2018 02;28(2):260-266

Objective: This study aimed to develop a prediction model for lymph node metastasis using a gene expression signature in patients with endometrioid-type endometrial cancer.

Methods: Newly diagnosed endometrioid-type endometrial cancer cases in which the patients had undergone lymphadenectomy during a surgical staging procedure were identified from a national dataset (N = 330). Clinical and pathologic data were extracted from patient medical records, and gene expression datasets of their tumors were used to create a 12-gene predictive model for lymph node metastasis. We used principal components analysis on a training set (n = 110) to develop multivariate logistic models to predict low-risk patients having a probability of lymph node metastasis of less than 4%. The model with the highest prediction performance was selected for an evaluation set (n = 112), which, in turn, was validated in an independent validation set (n = 108).

Results: The model applied to the evaluation set showed 100% sensitivity (90% confidence interval [CI], 74%-100%) and 42% specificity (90% CI, 34%-51%), which resulted in 100% negative predictive value (90% CI, 89%-100%). In the validation set, we confirmed that the model consistently showed 100% sensitivity (90% CI, 88%-100%), 42% specificity (90% CI, 32%-50%), and 100% negative predictive value (90% CI, 88%-100%).

Conclusions: Our 12-gene signature model is a useful tool for the identification of patients with endometrioid-type endometrial cancer at low risk of lymph node metastasis, particularly given that it can be used to analyze histologic tissue before surgery and used to tailor surgical options.
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http://dx.doi.org/10.1097/IGC.0000000000001152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5780243PMC
February 2018

Surgical outcomes among elderly women with endometrial cancer treated by laparoscopic hysterectomy: a NRG/Gynecologic Oncology Group study.

Am J Obstet Gynecol 2018 01 14;218(1):109.e1-109.e11. Epub 2017 Oct 14.

Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, University of Oklahoma, Oklahoma City, OK.

Objective: Tolerance of and complications caused by minimally invasive hysterectomy and staging in the older endometrial cancer population is largely unknown despite the fact that this is the most rapidly growing age group in the United States. The objective of this retrospective review was to compare operative morbidity by age in patients on the Gynecologic Oncology Group Laparoscopic Surgery or Standard Surgery in Treating Patients With Endometrial Cancer or Cancer of the Uterus (LAP2) trial.

Study Design: This is a retrospective analysis of patients from Gynecologic Oncology Group LAP2, a trial that included clinically early-stage uterine cancer patients randomized to laparotomy vs laparoscopy for surgical staging. Differences in the rates and types of intraoperative and perioperative complications were compared by age. Specifically complications between patients <60 vs ≥60 years old were compared caused by toxicity analysis showing a sharp increase in toxicity starting at age 60 years in the laparotomy group.

Results: LAP2 included 1477 patients ≥60 years old. As expected, with increasing age there was worsening performance status and disease characteristics including higher rates of serous histology, high-stage disease, and lymphovascular space invasion. There was no significant difference in lymph node dissection rate by age for the entire population or within the laparotomy or laparoscopy groups. Toxicity analysis showed a sharp increase in toxicity seen in patients ≥60 years old in the laparotomy group. Further analysis showed that when comparing laparotomy with laparoscopy in patients <60 years old vs ≥60 years old and controlling for race, body mass index, stage, grade, and performance status, patients <60 years old undergoing laparotomy had more hospital stays >2 days (odds ratio, 17.48; 95% confidence interval, 11.71-27.00, P < .001) compared with patients <60 years old undergoing laparoscopy. However, when comparing laparotomy with laparoscopy in patients ≥60 years old, in addition to hospital stay >2 days (odds ratio, 12.77; 95% confidence interval, 8.74-19.32, P < .001), there were higher rates of the following postoperative complications: antibiotic administration (odds ratio, 1.63; 95% confidence interval, 1.24-2.14, P < .001), ileus (odds ratio, 2.16; 95% confidence interval, 1.42-3.31, P <0.001), pneumonias (odds ratio, 2.36; 95% confidence interval, 1.01-5.66, P = .048), deep vein thromboses (odds ratio, 2.87; 95% confidence interval, 1.08-8.03, P = .035), and arrhythmias (odds ratio, 3.21; 95% confidence interval, 1.60-6.65, P = .001) in the laparotomy group.

Conclusion: Laparoscopic staging for uterine cancer is associated with decreased morbidity in the immediate postoperative period in patients ≥60 years old. These results allow for more accurate preoperative counseling. A minimally invasive approach to uterine cancer staging may decrease morbidity that could affect long-term survival.
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http://dx.doi.org/10.1016/j.ajog.2017.09.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5756682PMC
January 2018

Genome-wide association study evaluating single-nucleotide polymorphisms and outcomes in patients with advanced stage serous ovarian or primary peritoneal cancer: An NRG Oncology/Gynecologic Oncology Group study.

Gynecol Oncol 2017 11 19;147(2):396-401. Epub 2017 Sep 19.

Gynecological Oncology, Massachusetts General Hospital, Department of Medicine, Boston, MA, USA. Electronic address:

Objective: This study evaluated single nucleotide polymorphisms (SNPs) associated with progression free (PFS) and overall survival (OS) in patients with advanced stage serous EOC.

Methods: Patients enrolled in GOG-172 and 182 who provided specimens for translational research and consent were included. Germline DNA was evaluated with the Illumina's HumanOMNI1-Quad beadchips and scanned using Illumina's iScan optical imaging system. SNPs with allele frequency>0.05 and genotyping rate>0.98 were included. Analysis of SNPs for PFS and OS was done using Cox regression. Statistical significance was determined using Bonferroni corrected p-values with genomic control adjustment.

Results: The initial GWAS analysis included 1,124,677 markers in 396 patients. To obtain the final data set, quality control checks were performed and limited to serous tumors and self-identified Caucasian race. In total 636,555 SNPs and 289 patients passed all the filters. The pre-specified statistical level of significance was 7.855e. No SNPs met this criteria for PFS or OS, however, two SNPs were close to significance (rs10899426 p-2.144e) (rs6256 p-9.774e) for PFS and 2 different SNPs were identified (rs295315 p-7.536e; rs17693104 p-7.734e) which were close to significance for OS.

Conclusions: Using the pre-specified level of significance of 1×10, we did not identify any SNPs of statistical significance for OS or PFS, however several were close. The SNP's identified in this GWAS study will require validation and these preliminary findings may lead to identification of novel pathways and biomarkers.
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http://dx.doi.org/10.1016/j.ygyno.2017.08.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5706110PMC
November 2017

Phase I study of oral ridaforolimus in combination with paclitaxel and carboplatin in patients with solid tumor cancers.

BMC Cancer 2017 Jun 8;17(1):407. Epub 2017 Jun 8.

Department of Gynecologic Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, 33647, USA.

Background: Ridaforolimus is a mammalian target of rapamycin inhibitor that has activity in solid tumors. Paclitaxel and carboplatin have broad antineoplastic activity in many cancers. This phase I trial was conducted to determine the safety profile, maximal tolerated dose, and recommended phase II dose and schedule of oral ridaforolimus combined with paclitaxel and carboplatin in patients with solid tumor cancers.

Methods: Eligible patients with advanced solid tumor cancers received oral 10 to 30 mg ridaforolimus daily for 5 consecutive days per week combined with intravenous paclitaxel (175 mg/m) and carboplatin (area under the curve [AUC] 5-6 mg/mL/min) in 3-week cycles. A standard 3 + 3 design was used to escalate doses, with predefined changes to an alternate dosing schedule and/or changes in carboplatin AUC doses based on dose-limiting toxicity (DLT). Secondary information was collected regarding response and time to progression. Patients were continued on treatment if therapy was tolerated and if stable disease or better was demonstrated.

Results: Thirty-one patients were consented, 28 patients were screened, and 24 patients met eligibility requirements and received treatment. Two patients were replaced for events unrelated to drug-related toxicity, resulting in 22 DLT-evaluable patients. Two grade 4 DLTs due to neutropenia were observed at dose level 1. The next cohort was changed to a predefined alternate dosing schedule (days 1-5 and 8-12). DLTs were neutropenia, sepsis, mucositis, and thrombocytopenia. The most common adverse events were neutropenia, anemia, thrombocytopenia, fatigue, alopecia, nausea, pain, and leukopenia. Twenty-four patients received a median of 4 cycles (range, 1-12). Evaluable patients for response (n = 18) demonstrated a median tumor measurement decrease of 25%. The best response in these 18 patients included 9 patients with partial response (50%), 6 with stable disease (33%), and 3 with progressive disease (17%). Thirteen of these patients received treatment for 4 or more cycles.

Conclusions: Treatment with ridaforolimus combined with paclitaxel and carboplatin had no unanticipated toxicities and showed antineoplastic activity. The recommended phase II dose and schedule is ridaforolimus 30 mg (days 1-5 and 8-12) plus day 1 paclitaxel (175 mg/m) and carboplatin (AUC 5 mg/mL/min) on a 21-day cycle.

Trial Registration: ClinicalTrials.gov Identifier: NCT01256268 (trial registration date: December 1, 2010).
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http://dx.doi.org/10.1186/s12885-017-3394-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5465458PMC
June 2017