Serial cytoreductive surgery and survival outcomes in recurrent adult-type ovarian granulosa cell tumors.

BACKGROUND: Few studies have evaluated the role of cytoreductive surgery in patients with recurrent adult granulosa cell tumors of the ovary. Despite a multitude of treatment modalities in the recurrent setting, the optimal management strategy is not known. Cytoreductive surgery offers an attractive option for disease confined to the abdomen/pelvis. However, few studies have evaluated the role of surgery compared with systemic therapy alone following the first recurrence and subsequent disease progressions. OBJECTIVE: This study aimed to determine the impact of secondary, tertiary, and quaternary cytoreductive surgery on survival outcomes in recurrent adult granulosa cell tumors of the ovary. STUDY DESIGN: This is a multicenter, retrospective cohort study evaluating patients with recurrent adult granulosa cell tumors of the ovary enrolled in the MD Anderson Rare Gynecologic Malignancy Registry from 1970 to 2022. Study inclusion criteria consisted of histology-proven recurrent disease, at least 1 documented recurrence, and treatment/treatment planning at the MD Anderson Cancer Center or Lyndon B. Johnson General Hospital. The primary exposure was cytoreductive surgery, and the outcomes of interest were progression-free survival and overall survival. Survival analyses were restricted to eligible patients with resectable disease without medical barriers to surgery at each progression episode. Demographic and clinicopathologic characteristics were summarized using descriptive statistics. Progression-free survival (after first, second, and third progression) and overall survival were estimated with methods of Kaplan and Meier, and were modeled via Cox proportional hazards regression. Multivariable analyses were performed for progression-free survival after first progression and overall survival. RESULTS: Among the 369 patients with adult granulosa cell tumors of the ovary in the registry, 149 patients met the study inclusion criteria. Secondary cytoreductive surgery was associated with a significant improvement in progression-free survival on univariable (hazard ratio, 0.37; 95% confidence interval, 0.17-0.81, P=.01) and multivariable analyses (hazard ratio, 0.42; 95% confidence interval, 0.19-0.92; P=.03). Those who underwent secondary cytoreductive surgery had a significantly improved median overall survival compared with those who did not undergo cytoreductive surgery (181.92 vs 61.56 months, respectively; P=.002). Overall survival benefit remained statistically significant on multivariable analysis (hazard ratio, 0.28; 95% confidence interval, 0.11-0.67; P=.004). Tertiary cytoreductive surgery was similarly associated with a significant improvement in progression-free survival (hazard ratio, 0.43; 95% confidence interval, 0.26-0.70; P=.001). Despite a similar trend, quaternary cytoreductive surgery was not associated with a significant improvement in progression-free survival (hazard ratio, 0.74; 95% confidence interval, 0.42-1.26; P=.27). CONCLUSION: Among those with resectable disease and no medical contraindications to surgery, cytoreductive surgery may have a beneficial impact on progression-free survival and overall survival in patients with recurrent adult granulosa cell tumors of the ovary.

Final survival analysis of topotecan and paclitaxel for first-line treatment of advanced cervical cancer: An NRG oncology randomized study.

OBJECTIVE: To determine whether a non­platinum chemotherapy doublet improves overall survival (OS) among patients with recurrent/metastatic cervical carcinoma. METHODS: Gynecologic Oncology Group protocol 240 is a phase 3, randomized, open-label, clinical trial that studied the efficacy of paclitaxel 175 mg/m2 plus topotecan 0.75 mg/m2 days 1-3 (n = 223) vs cisplatin 50 mg/m2 plus paclitaxel 135 or 175 mg/m2 (n = 229), in 452 patients with recurrent/metastatic cervical cancer. Each chemotherapy doublet was also studied with and without bevacizumab (15 mg/kg). Cycles were repeated every 21 days until progression, unacceptable toxicity, or complete response. The primary endpoints were OS and the frequency and severity of adverse effects. We report the final analysis of OS. RESULTS: At the protocol-specified final analysis, median OS was 16.3 (cisplatin-paclitaxel backbone) and 13.8 months (topotecan-paclitaxel backbone) (HR 1.12; 95% CI, 0.91-1.38; p = 0.28). Median OS for cisplatin-paclitaxel and topotecan-paclitaxel was 15 vs 12 months, respectively (HR 1.10; 95% CI,0.82-1.48; p = 0.52), and for cisplatin-paclitaxel-bevacizumab and topotecan-paclitaxel-bevacizumab was 17.5 vs 16.2 months, respectively (HR 1.16; 95% CI, 0.86-1.56; p = 0.34). Among the 75% of patients in the study population previously exposed to platinum, median OS was 14.6 (cisplatin-paclitaxel backbone) vs 12.9 months (topotecan-paclitaxel backbone), respectively (HR 1.09; 95% CI, 0.86-1.38;p = 0.48). Post-progression survival was 7.9 (cisplatin-paclitaxel backbone) vs 8.1 months (topotecan-paclitaxel backbone) (HR 0.95; 95% CI, 0.75-1.19). Grade 4 hematologic toxicity was similar between chemotherapy backbones. CONCLUSIONS: Topotecan plus paclitaxel does not confer a survival benefit to women with recurrent/metastatic cervical cancer, even among platinum-exposed patients. Topotecan-paclitaxel should not be routinely recommended in this population. NCT00803062.

Clinical outcomes of leuprolide acetate in the treatment of recurrent ovarian granulosa cell tumors.

BACKGROUND: The optimal treatment of recurrent ovarian granulosa cell tumors is not known. Preclinical studies and small case series have suggested direct antitumor activity of gonadotropin-releasing hormone agonists in the treatment of this disease, but little is known about the efficacy and safety of this approach. OBJECTIVE: This study aimed to describe patterns of use and clinical outcomes of leuprolide acetate in a cohort of patients with recurrent granulosa cell tumors. STUDY DESIGN: This was a retrospective cohort study of patients enrolled in the Rare Gynecologic Malignancy Registry at a large cancer referral center and affiliated county hospital. Patients meeting inclusion criteria had a diagnosis of recurrent granulosa cell tumor and received either leuprolide acetate or traditional chemotherapy as cancer treatment. Outcomes were separately examined for leuprolide acetate used as adjuvant treatment, maintenance therapy, and the treatment of gross disease. Demographic and clinical data were summarized using descriptive statistics. Progression-free survival was calculated from the initiation of treatment to the date of disease progression or death, and compared between groups with the log-rank test. The 6-month clinical benefit rate was defined as the percentage of patients without disease progression 6 months after starting therapy. RESULTS: Sixty-two patients received a total of 78 leuprolide acetate-containing therapy courses, owing to 16 instances of retreatment. Of these 78 courses, 57 (73%) were for treatment of gross disease, 10 (13%) were adjuvant to tumor reductive surgery, and 11 (14%) were for maintenance therapy. Patients had received a median of 2 (interquartile range, 1-3) systemic therapy regimens before their first leuprolide acetate treatment. Tumor reductive surgery (100% [62/62]) and platinum-based chemotherapy (81% [50/62]) were common before first leuprolide acetate exposure. The median duration of leuprolide acetate therapy was 9.6 months (interquartile range, 4.8-16.5). Nearly half of the therapy courses were single-agent leuprolide acetate (49% [38/78]). Combination regimens most often included an aromatase inhibitor (23% [18/78]). Disease progression was the most common cause of discontinuation (77% [60/78]); only 1 patient (1%) discontinued leuprolide acetate because of adverse events. In the treatment of gross disease, the 6-month clinical benefit rate for first use of leuprolide acetate was 66% (95% confidence interval, 54-82). Median progression-free survival was not statistically different compared with that which followed chemotherapy (10.3 months [95% confidence interval, 8.0-16.0] vs 8.0 months [95% confidence interval, 5.0-15.3]; P=.3). CONCLUSION: In a large cohort of patients with recurrent granulosa cell tumors, the 6-month clinical benefit rate of first-time leuprolide acetate treatment of gross disease was 66% and progression-free survival was comparable to patients treated with chemotherapy. Leuprolide acetate regimens were heterogeneous, but significant toxicity was rare. These results support leuprolide acetate as safe and effective for the treatment of relapsed adult granulosa cell tumors in the second line and beyond.

The clinical efficacy and safety of single-agent pembrolizumab in patients with recurrent granulosa cell tumors of the ovary: a case series from a phase II basket trial.

Background Treatment of recurrent, unresectable granulosa cell tumor (GCT) of the ovary can be challenging. Given the rarity of the tumor, alternative therapies have been difficult to evaluate in large prospective clinical trials. Currently, to our knowledge, there are no reports of the use of immune checkpoint inhibitors in GCT patients. Here, we present a case series of GCT patients treated with pembrolizumab who were enrolled in a phase II basket trial in advanced, rare solid tumors (ClinicalTrials.gov: NCT02721732). Cases We identified 5 patients with recurrent GCT (4 adult and 1 juvenile type); they had an extensive history of systemic therapy at study enrollment (range, 3-10), with most regimens resulting in less than 12 months of disease control. Pembrolizumab was administered in these patients, as per trial protocol. Although there were no objective responses according to the irRECIST guidelines, 2 patients with adult-type GCT experienced disease control for ≥ 12 months (565 and 453 days). In one, pembrolizumab represented the longest duration of disease control compared to prior lines of systemic therapy (565 days vs. 13 months). In the other, pembrolizumab was the second longest systemic therapy associated with disease control (453 days vs. 22 months) compared to prior lines of therapy. In this patient, pembrolizumab was discontinued following withdrawal of consent. PD-L1 expression was not observed in any baseline tumor samples. Pembrolizumab was well tolerated, with no grade 3 or 4 treatment-related adverse events. Conclusions Although our results do not support the routine use of pembrolizumab monotherapy in unselected GCT patients, some patients with adult-type GCT may derive a clinical benefit, with a low risk of toxicity. Future studies should investigate the role of immunotherapy and predictors of clinical benefit in this patient population.

Toxicity and efficacy of the combination of pembrolizumab with recommended or reduced starting doses of lenvatinib for treatment of recurrent endometrial cancer.

OBJECTIVE: We reviewed our institutional data to evaluate toxicity and efficacy outcomes of pembrolizumab/lenvatinib in recurrent endometrial cancer in a "real-world" clinical setting and to compare the impact of reduced lenvatinib starting dose on outcomes. METHODS: Retrospectively, we reviewed toxicity, treatment responses, and survival outcomes of patients with recurrent endometrial cancer who received ≥1 cycle of pembrolizumab/lenvatinib. We compared subgroups based on lenvatinib starting dose (recommended [20 mg] vs reduced [<20 mg]) and histologic type. RESULTS: We analyzed 70 patients (recommended dose cohort, n = 16; reduced dose cohort, n = 54). The most common starting dose was 14 mg daily. Compared to the reduced dose cohort, the recommended dose cohort had a significantly higher mean number of lenvatinib dose reductions due to side effects (1.1 vs. 0.4; p = 0.003) and significantly shorter median time to treatment toxicity (1.3 vs. 3.7 days; p = 0.0001). Response rates did not differ significantly between the recommended and reduced dose cohorts (28.6% vs. 38.3%, respectively; p = 0.752). Two patients, both in the reduced dose cohort, had complete responses. Patients with carcinosarcoma histology had response and clinical benefit rates of 25% (3 of 12) and 58.3% (7 of 12), respectively. There were no differences between the 2 dose cohorts with respect to progression-free (p = 0.245) or overall survival (p = 0.858). CONCLUSION: In clinical practice, a lower starting dose of lenvatinib (14 mg daily) in combination with pembrolizumab was safe and efficacious in recurrent endometrial cancer. The combination produced responses in endometrial carcinosarcomas. Larger studies are required to validate these findings.

Prospective phase II trial of levonorgestrel intrauterine device: nonsurgical approach for complex atypical hyperplasia and early-stage endometrial cancer.

BACKGROUND: The incidence of complex atypical hyperplasia and early-stage endometrioid endometrial cancer is increasing, in part owing to the epidemic of obesity, which is a risk factor tightly linked to the development of endometrial hyperplasia and cancer. The standard upfront treatment for complex atypical hyperplasia and early-stage endometrial cancer is hysterectomy. However, nonsurgical treatment of early-stage endometrial neoplasia may be necessary owing to medical comorbidities precluding surgery or desired future fertility. OBJECTIVE: This study aimed to evaluate the efficacy of the levonorgestrel intrauterine device to treat complex atypical hyperplasia and grade 1 endometrioid endometrial carcinoma. STUDY DESIGN: A single-institution, single-arm, phase II study of the levonorgestrel intrauterine device (52 mg levonorgestrel, Mirena) was conducted in patients with complex atypical hyperplasia or grade 1 endometrioid endometrial cancer. The primary endpoint was pathologic response rate at 12 months, including complete or partial response. Quality of life and toxicity were assessed. Molecular analyses for proliferation markers, hormone-regulated genes, and wingless-related integration site pathway activation were performed at baseline and 3 months. RESULTS: A total of 57 patients were treated (21 endometrial cancer, 36 complex atypical hyperplasia). The median age was 48.0 years, and the median body mass index was 45.5 kg/m2. Of the 47 evaluable patients, 12-month response rate was 83% (90% credible interval, 72.7-90.3)-37 were complete responders (8 endometrial cancer; 29 complex atypical hyperplasia), 2 were partial responders (2 endometrial cancer), 3 had stable disease (2 endometrial cancer; 1 complex atypical hyperplasia), and 5 had progressive disease (3 endometrial cancer; 2 complex atypical hyperplasia). After stratification for histology, the response rate was 90.6% for complex atypical hyperplasia and 66.7% for grade 1 endometrioid endometrial cancer. Notably, 4 patients (9.5%) experienced relapse after the initial response. Adverse events were mild, primarily irregular bleeding and cramping. Quality of life was not negatively affected. At 3 months, exogenous progesterone effect was present in 96.9% of responders (31 of 32) vs 25% of nonresponders (2 of 8) (P=.001). Nonresponders had higher baseline proliferation (Ki67) and lower dickkopf homolog 3 gene expression than responders (P=.023 and P=.030). Nonresponders had significantly different changes in secreted frizzled-related protein 1, frizzled class receptor 8, and retinaldehyde dehydrogenase 2 compared with responders. CONCLUSION: The levonorgestrel intrauterine device has a substantial activity in complex atypical hyperplasia and grade 1 endometrioid endometrial cancer, with a modest proportion demonstrating upfront progesterone resistance. Potential biomarkers were identified that may correlate with resistance to therapy; further exploration is warranted.

A phase III study of transdermal granisetron versus oral ondansetron for women with gynecologic cancers receiving pelvic chemoradiation.

PURPOSE: To compare rates of complete response (no emesis, retching, or rescue antiemetics) in the late phase (days 4-7 post-chemotherapy) of cycle 1 between transdermal granisetron and oral ondansetron in cervical, endometrial, or vaginal cancer survivors undergoing chemoradiation at The University of Texas MD Anderson Cancer Center and LBJ Hospital in Houston, TX. METHODS: In this non-blinded parallel design trial, eligible patients received a granisetron patch replaced every 7 days or 8 mg of ondansetron thrice daily continued for 72 h after chemotherapy completion. Data were collected on medication compliance, episodes of chemotherapy-induced nausea and vomiting (CINV), use of rescue antiemetics, and effects of CINV on quality of life. RESULTS: Seventy-five survivors receiving chemoradiation for cervical (n = 61), endometrial (n = 12), or vaginal (n = 2) cancer were electronically randomized to transdermal granisetron (n = 41) or oral ondansetron (n = 34). In the late phase of cycle 1, the rate of complete response was 49.8% (95% CI, 35.2-64.3%) for transdermal granisetron and 39.7% (95% CI, 24.4-56.1%) for oral ondansetron. The posterior probability that transdermal granisetron achieved a higher success rate in controlling late-onset CINV compared with oral ondansetron was 82%. During the acute phase (day 1 post-chemotherapy) of cycles 2 and 3, transdermal granisetron patients used more rescue antiemetics than oral ondansetron patients (p = 0.006 and p = 0.003, respectively). Otherwise, no between-group differences in CINV events were observed. Medication compliance and the effect of CINV on quality of life were similar between groups. CONCLUSION: Transdermal granisetron was 82% more like to control CINV than oral ondansetron in the late phase of cycle 1 and performed similarly to oral ondansetron in all other cycles. Transdermal granisetron should be considered an option as prophylactic antiemetic therapy for gynecologic cancer survivors undergoing chemoradiation.

ConCerv: a prospective trial of conservative surgery for low-risk early-stage cervical cancer.

OBJECTIVE: The objective of the ConCerv Trial was to prospectively evaluate the feasibility of conservative surgery in women with early-stage, low-risk cervical cancer. METHODS: From April 2010 to March 2019, a prospective, single-arm, multicenter study evaluated conservative surgery in participants from 16 sites in nine countries. Eligibility criteria included: (1) FIGO 2009 stage IA2-IB1 cervical carcinoma; (2) squamous cell (any grade) or adenocarcinoma (grade 1 or 2 only) histology; (3) tumor size <2 cm; (4) no lymphovascular space invasion; (5) depth of invasion <10 mm; (6) negative imaging for metastatic disease; and (7) negative conization margins. Cervical conization was performed to determine eligibility, with one repeat cone permitted. Eligible women desiring fertility preservation underwent a second surgery with pelvic lymph node assessment, consisting of sentinel lymph node biopsy and/or full pelvic lymph node dissection. Those not desiring fertility preservation underwent simple hysterectomy with lymph node assessment. Women who had undergone an 'inadvertent' simple hysterectomy with an unexpected post-operative diagnosis of cancer were also eligible if they met the above inclusion criteria and underwent a second surgery with pelvic lymph node dissection only. RESULTS: 100 evaluable patients were enrolled. Median age at surgery was 38 years (range 23-67). Stage was IA2 (33%) and IB1 (67%). Surgery included conization followed by lymph node assessment in 44 women, conization followed by simple hysterectomy with lymph node assessment in 40 women, and inadvertent simple hysterectomy followed by lymph node dissection in 16 women. Positive lymph nodes were noted in 5 patients (5%). Residual disease in the post-conization hysterectomy specimen was noted in 1/40 patients-that is, an immediate failure rate of 2.5%. Median follow-up was 36.3 months (range 0.0-68.3). Three patients developed recurrent disease within 2 years of surgery-that is, a cumulative incidence of 3.5% (95% CI 0.9% to 9.0%). DISCUSSION: Our prospective data show that select patients with early-stage, low-risk cervical carcinoma may be offered conservative surgery.

Knowledge matters and empowers: HPV vaccine advocacy among HPV-related cancer survivors.

PURPOSE: To describe knowledge about human papillomavirus (HPV), HPV-related care behavior, and advocacy intent (e.g., vaccine recommendation and willingness to become an advocate for vaccination) and to investigate associations between knowledge, HPV-related care behavior, and advocacy intent among HPV-related cancer survivors. METHODS: A cross-sectional online survey was offered through Qualtrics to HPV-related cancer survivors who were either volunteers at a cancer center or patients of survivorship clinics. RESULTS: A total of 200 survivors responded. Only 33.2% of respondents reported knowing their cancer was HPV-related and 56.8% reported HPV vaccine is safe. Participants who knew that their cancer was caused by HPV were more likely to have vaccinated their children (p < .001). Also, participants who knew that the vaccine is safe were more willing to recommend the vaccine (p < .001), to be a peer mentor for others with HPV-related cancers (43.2% vs. 14.0%, p < .001), and to act as an advocate for increasing vaccination rates (44.1% vs. 24.4%, p = 0.01). Finally, survivors who were aware of the vaccine's effectiveness in decreasing precancerous lesions were more likely to recommend the vaccine (45.7% vs. 12.0%, p = .002). CONCLUSIONS: Raising survivor awareness of the link between HPV and cancer and HPV vaccine safety may increase their willingness to serve as powerful opinion leaders and peer mentors to promote HPV vaccination. Providers may take the simple step of informing patients that their cancer is HPV-related and HPV vaccine is safe to increase the number of informed and empowered survivors.

Disseminating universal genetic testing to a diverse, indigent patient population at a county hospital gynecologic oncology clinic.

OBJECTIVE: The universal genetic testing initiative (UGTI) is a quality improvement effort to increase rates of guideline-based genetic counseling (GC) and genetic testing (GT) of patients with potentially hereditary cancers. The UGTI was disseminated to a county hospital gynecologic oncology clinic that serves a diverse, indigent patient population. METHODS: Using the Model for Improvement quality improvement framework, interventions including integrated GC, clinic tracking, assisted GC referrals, and provider education were tested over 26 months. A retrospective data review included patients with high-grade, non-mucinous epithelial ovarian, fallopian tube, and primary peritoneal cancers (HGOC) and endometrial cancers (EC) diagnosed between 9/1/12-8/31/16. Statistical analyses were performed to describe the population and to evaluate rates of recommendation and use of immunohistochemistry tumor testing (IHC), GC, and GT. RESULTS: A cohort of 241 patients (57 HGOC, 184 EC) were included. At the conclusion of the study 84.2% of HGOC patients were referred for GC, 89.6% (43/48) completed GC, and 90.7% (39/43) completed GT. Of EC patients, 81.0% were recommended to have IHC and 62.4% (93/149) completed IHC. Patients with HGOC diagnosed during dissemination of UGTI were significantly more likely to receive a recommendation for GC (p = 0.02) and to complete GT (p = 0.03) than those diagnosed before UGTI. Patients with EC were significantly more likely to complete IHC if diagnosed after UGTI than those diagnosed prior to dissemination (p < 0.001). CONCLUSIONS: The UGTI can be adapted to increase use of guideline-based cancer genetics services in a diverse, indigent, gynecologic cancer patient population.

Prognostic factors impacting survival in early stage uterine carcinosarcoma.

OBJECTIVE: Evaluate the impact of clinicopathologic characteristics and adjuvant treatment on survival outcomes in early stage uterine carcinosarcoma patients. METHODS: We performed a retrospective cohort study of women with stage I or II uterine carcinosarcoma at our institution between March 1990 and June 2016. All pathology had been reviewed and confirmed by gynecologic pathologists. Data were extracted from the electronic medical record. Descriptive and comparative statistics were used to compare clinicopathologic characteristics. Univariable and multivariable analyses were performed for survival outcomes. RESULTS: 140 patients were identified. Median age was 67 years (range: 36-91). Median follow-up was 39.1 months (2.9-297.4). The majority of patients had stage IA (67%) versus stage IB (21%) or stage II (11%) disease. The majority of patients (63%) received adjuvant treatment: vaginal brachytherapy only (14%); whole pelvic radiation therapy only (16%); chemotherapy only (n = 13, 9%); combination chemotherapy and vaginal brachytherapy (15%); combination chemotherapy and whole pelvic radiation (9%). 52 patients (37%) received no adjuvant therapy. Median overall survival (OS) was 48.0 months (95% CI 32.7-80.9). On multivariable analysis for OS, advancing age (HR 1.05, 95% CI 1.03-1.08, p < 0.001), higher stage (stage IB: HR 1.64, 95% CI 0.91-2.95, p = 0.10; stage II: HR 3.04, 95% CI 1.51-6.13, p = 0.002), and the presence of a rhabdomyosarcoma component (HR 1.66, 95% CI 1.02-2.70, p = 0.04) were significantly associated with worse OS. CONCLUSIONS: Advancing age, stage, and the presence of a rhabdomyosarcoma component were all associated with worse OS in patients with early stage uterine carcinosarcoma. New treatment algorithms should incorporate factors aside from stage alone.

How we use hospice: Hospice enrollment patterns and costs in elderly ovarian cancer patients.

OBJECTIVE: To describe disparities in patterns of hospice use and end-of-life costs among ovarian cancer patients. METHODS: Using Texas Cancer Registry-Medicare data, ovarian cancer patients deceased 2005-2012 with >12 months of continuous Medicare coverage before death were included. Descriptive statistics and multivariable logistic regressions were used to evaluate patterns of hospice use. Cost and resource utilization was obtained from Medicare claims and analyzed using a non-parametric Mann-Whitney test. RESULTS: 2331 patients were assessed: 1788 (77%) white, 359 (15%) Hispanic, 158 (7%) black and 26 (1%) other. 1756 (75%) enrolled in hospice prior to death but only 1580 (68%) died with hospice. 176 (10%) of 1756 patients unenrolled and died without hospice. 346 (20%) unenrolled from hospice multiple times. From 2008 to 2012, patients were less likely to unenroll from hospice prior to death. Black patients were more likely to unenroll from hospice prior to death (OR 2.07 [1.15-3.73]; p = 0.02) compared to white patients. The median amount paid by Medicare during the last six months of life was $38,530 for those in hospice compared to $49,942 if never enrolled in hospice (p < 0.0001) and was higher for black and Hispanic patients compared to white patients. 30% hospice unenrolled patients and 40% multiply enrolled hospice patients received at least one life extending or invasive care procedure following unenrollment from hospice. CONCLUSION: Recently, more patients remain enrolled in hospice, but black patients have a higher risk of unenrollment. Hospice enrollment was associated with lower costs as long as a patient did not unenroll from hospice.

Prospective pilot trial with combination of propranolol with chemotherapy in patients with epithelial ovarian cancer and evaluation on circulating immune cell gene expression.

OBJECTIVE: To determine the feasibility of pharmacologic beta-adrenergic blockade in women with newly diagnosed stage II-IV epithelial ovarian cancer (EOC) throughout primary treatment. METHODS: Patients initiated propranolol prior to beginning chemotherapy or surgery. Feasibility was assessed as proportion able to complete 6 chemotherapy cycles while on adrenergic suppression. Descriptive statistics summarized surveys, and paired changes were analyzed using signed rank tests. Random-intercept Tobit models examined immune response. RESULTS: Median age was 59.9; 88.5% were stage IIIC/IV; and 38.5% underwent primary debulking. Thirty-two patients were enrolled; 3 excluded because they never took propranolol; an additional 3 didn't meet inclusion criteria, leaving 26 evaluable. Eighteen of 26 (69%), 90% credible interval (CI) of 53-81%, completed 6 chemotherapy cycles plus propranolol (an 82% posterior probability that the true proportion of success is ≥60%). Among the 23 patients with baseline and six month follow up data, overall QOL, anxiety, and depression improved (P < 0.05) and leukocyte expression of pro-inflammatory genes declined (P = 0.03) after completion of therapy. Decrease from baseline of serum IL-6 and IL-8 preceded response to chemotherapy (P < 0.0014). Change from baseline IL-10 preceded complete response. CONCLUSION: Use of propranolol during primary treatment of EOC is feasible and treatment resulted in decrease in markers of adrenergic stress response. In combination with chemotherapy, propranolol potentially results in improved QOL over baseline.

Accuracy of Intraoperative Frozen Section Diagnosis of Borderline Ovarian Tumors by Hospital Type.

STUDY OBJECTIVE: To compare the accuracy of frozen section diagnosis of borderline ovarian tumors among 3 distinct types of hospital-academic hospital with gynecologic pathologists, academic hospital with nongynecologic pathologists, and community hospital with nongynecologic pathologists-and to determine if surgical staging alters patient care or outcomes for women with a frozen section diagnosis of borderline ovarian tumor. DESIGN: Retrospective study (Canadian Task Force classification II-1). SETTING: Tertiary care, academic, and community hospitals. PATIENTS: Women with an intraoperative frozen section diagnosis of borderline ovarian tumor at 1 of 3 types of hospital from April 1998 through June 2016. INTERVENTIONS: Comparison of final pathology with intraoperative frozen section diagnosis. MEASUREMENTS AND MAIN RESULTS: Two hundred twelve women met the inclusion criteria. The frozen section diagnosis of borderline ovarian tumor correlated with the final pathologic diagnosis in 192 of 212 cases (90.6%), and the rate of correlation did not differ among the 3 hospital types (p = .82). Seven tumors (3.3%) were downgraded to benign on final pathologic analysis and 13 (6.1%) upgraded to invasive carcinoma. The 3 hospital types did not differ with respect to the proportion of tumors upgraded to invasive carcinoma (p = .62). Mucinous (odds ratio, 7.1; 95% confidence interval, 2.1-23.7; p = .002) and endometrioid borderline ovarian tumors (odds ratio, 32.4; 95% confidence interval, 1.8-595.5; p = .02) were more likely than serous ovarian tumors to be upgraded to carcinoma. Only 88 patients (41.5%) underwent lymphadenectomy, and only 1 (1.1%) had invasive carcinoma in a lymph node. CONCLUSIONS: A frozen section diagnosis of borderline ovarian tumor correlates with the final pathologic diagnosis in a variety of hospital types.

Cervical, Vaginal, and Vulvar Cancer Costs Incurred by the Medicaid Program in Publicly Insured Patients in Texas.

OBJECTIVES: To determine from the perspective of the State of Texas, the direct medical care costs associated with cervical, vaginal, and vulvar cancers in Texas Medicaid enrollees. MATERIALS AND METHODS: We conducted a case-control study and searched Texas Medicaid databases between 2008 and 2012 for eligible cancer patients. A comparison group was selected for each cancer site using a 2-step 1:1 propensity score matching method. Patients were followed for 2 years after cancer diagnosis to estimate monthly and yearly direct medical costs. For each cancer site, the differential cost between patients and the matched comparison individuals was the estimated cost associated with cancer. RESULTS: The study included 583 cervical, 62 vaginal, and 137 vulvar cancer patients and equal numbers of cancer-free comparison individuals. Among the cases, 322 cervical cancer patients, 46 vaginal cancer patients, and 102 vulvar cancer patients were Medicaid-Medicare dual eligible enrollees. For Medicaid-only enrollees, the adjusted first- and second-year mean total differential costs were US $19,859 and $3,110 for cervical cancer, US $19,627 and $4,582 for vaginal cancer, and US $7,631 and $777 for vulvar cancer patients, respectively. For Medicaid-Medicare dual eligible enrollees, adjusted first- and second-year mean total differential costs incurred by Medicaid were US $2,565 and $792 for cervical cancer, US $1,293 and $181 for vaginal cancer, and US $1,774 and $1,049 for vulvar cancer patients, respectively. CONCLUSIONS: The direct medical costs associated with cervical, vaginal, and vulvar cancers in Texas Medicaid were substantial in the first 2 years after cancer diagnosis, but dual eligibility for Medicare coverage attenuated Medicaid costs.

Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240).

BACKGROUND: On Aug 14, 2014, the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial. In this study, we report the prespecified final analysis of the primary objectives, OS and adverse events. METHODS: In this randomised, controlled, open-label, phase 3 trial, we recruited patients with metastatic, persistent, or recurrent cervical carcinoma from 81 centres in the USA, Canada, and Spain. Inclusion criteria included a GOG performance status score of 0 or 1; adequate renal, hepatic, and bone marrow function; adequately anticoagulated thromboembolism; a urine protein to creatinine ratio of less than 1; and measurable disease. Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible. We randomly allocated patients 1:1:1:1 (blocking used; block size of four) to intravenous chemotherapy of either cisplatin (50 mg/m2 on day 1 or 2) plus paclitaxel (135 mg/m2 or 175 mg/m2 on day 1) or topotecan (0·75 mg/m2 on days 1-3) plus paclitaxel (175 mg/m2 on day 1) with or without intravenous bevacizumab (15 mg/kg on day 1) in 21 day cycles until disease progression, unacceptable toxic effects, voluntary withdrawal by the patient, or complete response. We stratified randomisation by GOG performance status (0 vs 1), previous radiosensitising platinum-based chemotherapy, and disease status (recurrent or persistent vs metastatic). We gave treatment open label. Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information), assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board. The cutoff for final analysis was 450 patients with 346 deaths. This trial is registered with ClinicalTrials.gov, number NCT00803062. FINDINGS: Between April 6, 2009, and Jan 3, 2012, we enrolled 452 patients (225 [50%] in the two chemotherapy-alone groups and 227 [50%] in the two chemotherapy plus bevacizumab groups). By March 7, 2014, 348 deaths had occurred, meeting the prespecified cutoff for final analysis. The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups: 16·8 months in the chemotherapy plus bevacizumab groups versus 13·3 months in the chemotherapy-alone groups (hazard ratio 0·77 [95% CI 0·62-0·95]; p=0·007). Final OS among patients not receiving previous pelvic radiotherapy was 24·5 months versus 16·8 months (0·64 [0·37-1·10]; p=0·11). Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8·4 months) and chemotherapy-alone groups (7·1 months; 0·83 [0·66-1·05]; p=0·06). Fistula (any grade) occurred in 32 (15%) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1%) of 220 in the chemotherapy-alone groups (all previously irradiated). Grade 3 fistula developed in 13 (6%) versus one (<1%). No fistulas resulted in surgical emergencies, sepsis, or death. INTERPRETATION: The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated. After progression while receiving bevacizumab, we did not observe a negative rebound effect (ie, shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped). These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer. FUNDING: National Cancer Institute.

Complete Resection Is Essential in the Surgical Treatment of Gestational Trophoblastic Neoplasia.

OBJECTIVE: The aim of this study was to determine the utility of surgery in patients with gestational trophoblastic neoplasia (GTN). MATERIALS AND METHODS: We performed a retrospective institutional review board-approved analysis of all patients with GTN at a single institution from 1985 to 2015 and compared all patients who underwent surgery as definitive management for their disease to a matched cohort of those who did not. Kaplan-Meier curves were used to estimate progression-free survival (PFS) and overall survival (OS). RESULTS: Sixty-nine patients underwent a total of 94 surgeries as definitive treatment for GTN. Nineteen patients had multiple surgeries. Progression-free survival and OS were improved in patients with complete macroscopic surgical resection (n = 61) compared with patients with gross residual disease (n = 33) (median PFS 91.2 months vs 3.3 months, and median OS not reached at 108.8 months vs 66.3 months, respectively; P < 0.05). The nature of the surgery (emergent vs planned) and site of metastatic disease did not influence PFS or OS. Of the 61 patients with no visible residual disease, 17 received adjuvant chemotherapy and 44 did not; there were no observed differences in PFS or OS. Patients who underwent surgery as part of definitive treatment (n = 69 patients) were compared with patients with GTN over the same period who received chemotherapy alone (n = 33 patients). Median PFS was improved in the surgical group (5.9 vs 5.1 months, P < 0.01), but OS was not significantly different (P = 0.37). CONCLUSIONS: Complete resection results in improved outcomes in patients who undergo surgery for GTN, whether emergent or planned, independent of disease site, and should be considered as an important component of treatment in some situations.

Role of Radiation Therapy in the Multidisciplinary Management of Uterine Carcinosarcoma.

OBJECTIVES: This study aimed to evaluate the impact of radiation therapy on outcomes for patients with uterine carcinosarcoma (UC). METHODS/MATERIALS: We retrospectively reviewed the records of 155 women with stage I (98), II (11), or III (46) UC who underwent total abdominal hysterectomy/bilateral salpingo-oophorectomy at our institution between 1990 and 2011. Survival rates were assessed using the Kaplan-Meier method and log-rank test. Univariate and multivariate Cox regression analyses were performed. RESULTS: Seventy-six patients (49%) received radiation therapy: 38 (50%) had vaginal cuff brachytherapy (VBT) alone and 38 had external beam radiation therapy (EBRT) ± VBT. Seventy patients (45%) received chemotherapy (12 concurrent, 49 adjuvant, 9 both). The 5-year overall survival rate was 48.6% (stage I, 53.8%; II, 30.0%; and III, 42.5%). The disease-specific survival (DSS) rate was 57.2% (stage I, 60.9%; II, 44.4%; and III, 51.8%). Patients treated with EBRT had a higher 5-year pelvic disease control rate (88.3%) than did patients treated with VBT only (67.4%) or no radiation (71.2%; P = 0.04). In stage III patients, EBRT was associated with higher 5-year pelvic disease control (90.0% vs 55.5%, P = 0.046), DSS (64.6% vs 46.4%, P = 0.13), and overall survival (64.6% vs 34.0%, P = 0.04) rates. For all 155 patients, age at least 65 years, cervical involvement, and lymph vascular space invasion were correlated with lower DSS on univariate and multivariate analyses. In addition, treatment with concurrent chemoradiation therapy was independently associated with a higher DSS rate on multivariate analysis. CONCLUSIONS: Patients with UC have a high rate of relapse in the regional nodes and distant sites. External beam radiation therapy improves locoregional control in all stages and may improve survival in stage III patients who are at the highest risk of pelvic relapse.

Improved survival with bevacizumab in advanced cervical cancer.

BACKGROUND: Vascular endothelial growth factor (VEGF) promotes angiogenesis, a mediator of disease progression in cervical cancer. Bevacizumab, a humanized anti-VEGF monoclonal antibody, has single-agent activity in previously treated, recurrent disease. Most patients in whom recurrent cervical cancer develops have previously received cisplatin with radiation therapy, which reduces the effectiveness of cisplatin at the time of recurrence. We evaluated the effectiveness of bevacizumab and nonplatinum combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer. METHODS: Using a 2-by-2 factorial design, we randomly assigned 452 patients to chemotherapy with or without bevacizumab at a dose of 15 mg per kilogram of body weight. Chemotherapy consisted of cisplatin at a dose of 50 mg per square meter of body-surface area, plus paclitaxel at a dose of 135 or 175 mg per square meter or topotecan at a dose of 0.75 mg per square meter on days 1 to 3, plus paclitaxel at a dose of 175 mg per square meter on day 1. Cycles were repeated every 21 days until disease progression, the development of unacceptable toxic effects, or a complete response was documented. The primary end point was overall survival; a reduction of 30% in the hazard ratio for death was considered clinically important. RESULTS: Groups were well balanced with respect to age, histologic findings, performance status, previous use or nonuse of a radiosensitizing platinum agent, and disease status. Topotecan-paclitaxel was not superior to cisplatin-paclitaxel (hazard ratio for death, 1.20). With the data for the two chemotherapy regimens combined, the addition of bevacizumab to chemotherapy was associated with increased overall survival (17.0 months vs. 13.3 months; hazard ratio for death, 0.71; 98% confidence interval, 0.54 to 0.95; P=0.004 in a one-sided test) and higher response rates (48% vs. 36%, P=0.008). Bevacizumab, as compared with chemotherapy alone, was associated with an increased incidence of hypertension of grade 2 or higher (25% vs. 2%), thromboembolic events of grade 3 or higher (8% vs. 1%), and gastrointestinal fistulas of grade 3 or higher (3% vs. 0%). CONCLUSIONS: The addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer was associated with an improvement of 3.7 months in median overall survival. (Funded by the National Cancer Institute; GOG 240 ClinicalTrials.gov number, NCT00803062.).

Salvage chemotherapy for gestational trophoblastic neoplasia: Utility or futility?

OBJECTIVE: To determine the efficacy of chemotherapy after failed initial treatment in patients with high risk gestational trophoblastic neoplasia (GTN). METHODS: We performed a retrospective IRB-approved chart review of all patients with GTN seen at a single institution from 1985 to 2015, including all patients who failed initial treatment. We summarized clinical characteristics with descriptive statistics and estimated progression-free survival (PFS) and overall survival (OS) with the Kaplan-Meier method. RESULTS: Of 68 identified patients, 38 required >2 chemotherapy regimens. Patients were treated for GTN (n=53), including choriocarcinoma, persistent GTN, and invasive mole; for placental site trophoblastic tumor (PSTT) (n=5); and for intermediate trophoblastic tumor (ITT) (n=10). Patients with GTN had a median of 2 salvage regimens, median PFS of 4.0months, and median OS was not reached at median follow-up of 71.2months. Active regimens included EMACO, MAC, BEP, platinum- and etoposide-based combination therapies, and ICE; 8 of 53 patients died of disease (DOD). Patients with PSTT had a median of 3 salvage regimens, median PFS of 2.8months, and median OS of 38.8months. Active regimens included ICE and EMA-EP; 4 of 5 patients DOD. Patients with ITT had a median of 3 salvage regimens, median PFS of 4.1months, and median OS of 38.2months. Active regimens included liposomal doxorubicin, platinum-containing regimens, EMA-CO, and EMA-EP; 7 of 10 patients DOD. CONCLUSIONS: Several salvage chemotherapy regimens demonstrate activity in high risk GTN. Multiple regimens may be required and cure is not universal.