Two staged phase II clinical trial of Eribulin monotherapy in advanced or recurrent cervical cancer.

BACKGROUND: Eribulin a microtubule targeting agent and analog of Halichondrin B, a natural product isolated from marine sponge H. okadai, has proven clinical efficacy in metastatic pretreated breast cancer and liposarcoma. We conducted a 2-stage Phase II study of eribulin in patients with advanced/recurrent cervical cancer to examine its clinical activity and evaluate biomarkers for predictors of response. METHODS: Women with advanced/recurrent cervical cancer after ≤1 prior chemotherapy regimen, measurable disease and ECOG performance status ≤2 were treated with eribulin (1.4 mg/m2 IV day 1 and 8, every 21 days) with tumor assessments every 2 cycles. Primary endpoint was 6-month progression-free survival (PFS6); secondary were best overall response (RECISTv1.1), toxicity (CTCAEv4.03) and overall survival (OS). Exploratory endpoints were associations of biomarkers with clinical activity. Immunohistochemistry was performed on archival tumor samples. Overexpression was defined when both intensity and distribution scores were ≥ 2. RESULTS: 32 patients enrolled from 11/2012-5/2017. 29/32 patients had prior chemotherapy with cisplatin/paclitaxel/bevacizumab (n = 12) or cisplatin/gemcitabine (n = 12) as the most common regimens. 14 patients received prior paclitaxel. 1 (3%) had a complete response, 5 (16%) had a partial response and 13 (41%) had stable disease for ORR of 19% (95% CI 8, 37). Those who are paclitaxel naïve experienced the greatest benefit with a 29% ORR (95% CI 12, 54). Patients who received prior paclitaxel responded less favorably than those who did not (p = .002) and had a shorter PFS and OS. Grade 3/4 adverse events occurring in >10% of patients were anemia (n = 12, 38%), neutropenia (n = 7, 22%) and leukopenia (n = 6, 19%). Analysis of correlative predictors of response revealed that patients who did not overexpress ßII and BAX were significantly more likely to respond to e`ribulin. PFS was significantly shorter in patients with ßII and BAX overexpression, OS was significantly shorter in those with ßIII and BAX overexpression. These associations remained after multivariate analysis. CONCLUSIONS: Eribulin shows modest activity in patients with recurrent/advanced cervical cancer with a favorable toxicity profile. Prior paclitaxel exposure is associated with decreased eribulin response. ßII, ßIII tubulin subtypes and BAX are predictors of response and survival. Eribulin may be an option for women with paclitaxel-naïve recurrent/advanced cervical cancer.

Secondary ovarian cancer after external beam radiotherapy for nonovarian pelvic malignancy.

OBJECTIVE: To examine characteristics and survival of patients who developed secondary ovarian cancer after external beam radiotherapy (EBRT) for a prior nonovarian pelvic malignancy. METHODS: This is a population-based retrospective cohort study, querying the Surveillance, Epidemiology, and End Result program from 1975 to 2016. 167,269 women who received EBRT for 7 malignancies (anus, rectum, bladder, cervix, uterus, vulva, or vagina) were examined to identify subsequent secondary ovarian cancer diagnosis after EBRT. Then, within the ovarian cancer cohort (n = 147,618), characteristics and survival of patients with secondary ovarian cancer after EBRT were compared to those with ovarian cancer who did not receive prior EBRT. RESULTS: Following EBRT for a pelvic malignancy, 215 (1.3 per 1000) patients developed secondary ovarian cancer. Among those, the most frequent prior malignancy was cervical cancer (45.6%), followed by rectal cancer (20.9%). The median time from prior EBRT to secondary ovarian cancer was 8.8 years (interquartile range, 2.8-14.5). In multivariable analysis, patients with secondary ovarian cancer after EBRT were more likely to be older, and have a recent year of diagnosis, but less likely to have early-disease compared to ovarian cancer patients without prior EBRT (all, P < 0.05). In weighted model, patients with secondary ovarian cancer after EBRT had decreased overall survival compared to those with ovarian cancer without prior EBRT (5-year rates, 19.6% versus 39.9%, hazard ratio 1.62, 95% confidence interval 1.43-1.85). Similar association was observed in ages <70, ≥70, White, non-White, early-disease, and advanced-disease in sensitivity analyses. CONCLUSION: Radiotherapy-related secondary ovarian cancer may be associated with decreased overall survival.

Population-level uptake of neoadjuvant chemotherapy for stage IVB endometrial cancer.

OBJECTIVE: To examine population-level trends, characteristics, and outcomes of patients with stage IVB endometrial cancer who received neoadjuvant chemotherapy (NACT) prior to surgery. METHODS: The National Cancer Institute's Surveillance, Epidemiology, and End Results Program was retrospectively queried by examining 5505 patients with stage IVB endometrial cancer from 2010 to 2018. Exposure allocation was per treatment: primary surgery followed by chemotherapy (n = 3052, 55.4%), NACT followed by surgery (n = 930, 16.9%), and chemotherapy alone (n = 1523, 27.7%). Main outcomes measured were (i) the trend of utilization of NACT and patient characteristics related to NACT assessed with multinomial regression analysis and (ii) overall survival (OS) assessed with multivariable Cox proportional hazards regression model. RESULTS: The number of patients receiving NACT prior to surgery increased from 11.6% to 21.7% whereas those undergoing primary surgery followed by chemotherapy decreased from 62.7% to 48.3% (P < 0.001). Increasing utilization of NACT remained independent in multivariable analysis (adjusted-odds ratio per one-year increments 1.11, 95% confidence interval [CI] 1.08-1.15). Increasing utilization of NACT was observed in several sub-cohorts including patients aged <65 years, ≥65 years, White, non-White, endometrioid, non-endometrioid, and cases with non-distant organ metastasis (P < 0.05). In a multivariable analysis, NACT followed by surgery and primary surgery followed by chemotherapy had comparable OS (median 25 versus 26 months, adjusted-hazard ratio [HR] 1.03, 95%CI 0.93-1.15). When examined for metastatic extent, NACT followed by surgery was associated with decreased OS compared to primary surgery followed by chemotherapy in the non-distant organ metastasis group (adjusted-HR 1.20, 95%CI 1.05-1.36) whereas it was associated with improved OS in the distant organ metastasis group (adjusted-HR 0.79, 95%CI 0.66-0.95). CONCLUSION: The treatment of stage IVB endometrial cancer is shifting from primary surgery to NACT in the United States.

Side-to-end reanastomosis after low-anterior resection (STELAR): Outcomes, feasibility, and description of procedure performed by a gynecologic oncology service.

BACKGROUND AND OBJECTIVES: Low anterior rectosigmoid resection for a gynecologic disease is usually performed in concert with other procedures and can result in significant morbidity should anastomotic complication occur. This study examined surgical outcomes of side-to-end reanastomosis after low anterior resection (STELAR) performed by gynecologic oncology service. METHODS: This is a case series examining consecutive patients who underwent STELAR for gynecologic indications by a single gynecologic oncology group from 2009 to 2018. Prospectively collected institutional surgical database was searched for STELAR, and standard descriptive statistics were used to describe intraoperative and postoperative complications specific to reanastomosis. RESULTS: A total of 69 women underwent STELAR, with median age and body mass index of 54 years and 24 kg/m2 , respectively. 63.8% of patients had ovarian cancer and 84.4% had stage III-IV disease. The median estimated blood loss was 875 ml. Four (5.8%) women underwent protective loop colostomy at the time of STELAR. Postoperatively, there was 1 (1.4%) case of abscess formation within 30 days and 1 (1.4%) case of anastomotic leak 5 weeks after STELAR that required reoperation and diversion. No cases of fistula were clinically identified. CONCLUSION: Side-to-end reanastomosis may be a safe and feasible procedure to accomplish low rectosigmoid anastomosis in women with gynecologic disease.

Incorporation of sentinel lymph node biopsy in cervical cancer surgery: Recent U.S. trends.

OBJECTIVE: To examine the trends, characteristics, and outcomes related to sentinel lymph node (SLN) biopsy for cervical cancer surgery. METHODS: This retrospective cohort study queried the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. Study population included patients with invasive cervical cancer (squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinoma) who underwent both hysterectomy and lymphadenectomy for T1 classification from 2003 to 2018. Exposure allocation was per surgical nodal evaluation type (SLN biopsy or lymphadenectomy). Main outcome measures were (i) trend of utilization and patient characteristics related to SLN biopsy assessed with multivariable analysis and (ii) overall survival associated with SLN biopsy assessed with propensity score inverse probability of treatment weighting. Sensitivity cohorts included uterine-preserving conservative surgeries. RESULTS: A total of 12,966 patients met the inclusion criteria. Of those, 430 (3.3%) patients underwent SLN biopsy. The utilization of SLN biopsy increased significantly from 0.8% to 15.2% during the study period (P < 0.001). This association remained independent in multivariable analysis: 2011-2014 versus 2003-2010 adjusted-odds ratio 4.87, 95% confidence interval (CI) 3.29-7.23, and 2015-2018 versus 2003-2010 adjusted-odds ratio 20.6, 95%CI 14.6-29.2. In a propensity score weighted model, patients who had SLN biopsy had similar overall survival compared to those without SLN biopsy (3-year rates, 94.8% versus 94.2%, hazard ratio 0.95, 95%CI 0.64-1.41, P = 0.799). In sensitivity analysis, the increase in SLN biopsy was also observed in uterine-preserving surgeries (3.5% to 9.6% for trachelectomy, P = 0.043; and 2.5% to 19.5% in cervical excision, P < 0.001). CONCLUSION: Landscape of surgical nodal evaluation is gradually shifting from lymphadenectomy to SLN biopsy in cervical cancer surgery.

Rhabdomyolysis following single administration of pembrolizumab: Is severe immune-reaction a marker for durable treatment response?

•Immune checkpoint inhibitors are approved for all mismatch repair deficient tumors.•Although rare, autoimmune myositis complicating pembrolizumab therapy may be fatal.•In this case, pembrolizumab caused rhabdomyolysis but also a durable response.•Severe autoimmune reaction may be associated with durable treatment response.

Inhibition of poly(ADP-ribose) polymerase induces synthetic lethality in BRIP1 deficient ovarian epithelial cells.

OBJECTIVE: Pathogenic variations in the homologous recombination (HR) gene, BRCA1 interacting protein C-terminal helicase 1 (BRIP1) increase the risk for ovarian cancer. PARP inhibitors (PARPi) exert a synthetic lethal effect in BRCA-mutated ovarian cancers. Effective HR requires cooperation between BRCA1 and BRIP1; therefore, BRIP1-incompetancy may predict vulnerability to synthetic lethality. Here we investigated the response of ovarian epithelial cells with defective BRIP1 function to PARPi, and compared these cells to those lacking BRCA1 activity. METHODS: We engineered Chinese Hamster ovarian (CHO) epithelial cells to express deficient BRIP1 or BRCA1, and exposed them to olaparib with or without carboplatin or cisplatin. We assessed cellular proliferation and survival; we calculated inhibitory concentrations and combination and reduction drug indices. RESULTS: BRIP1 and BRCA1 inactivation impedes HR activity, decreases cellular proliferation and compromises DNA damage recovery. Platinum agent exposure impairs cellular survival. Olaparib exposure alone decreases cell viability in BRCA1-deficient cells, although has no effect on BRIP1-deficient cells. Combining carboplatin or cisplatin with olaparib synergistically attenuates cellular survival, consistent with synthetic lethality. CONCLUSIONS: BRIP1-deficient ovarian epithelial cells exhibit defective HR, resulting in synthetic lethality when exposed to a platinum agent/PARPi combination. PARPi alone had no effect; this lack of effect may result from distinguishing molecular properties of BRIP1and/or consequences of genomic background. Our study identifies altered BRIP1 as a target for precision medicine-based therapies for ovarian cancers. This investigation supports consideration of the use of a platinum agent/PARPi combination in ovarian cancers depending upon genetic profile and genomic background.

Molecular Pathways and Targeted Therapies for Malignant Ovarian Germ Cell Tumors and Sex Cord-Stromal Tumors: A Contemporary Review.

Non-epithelial ovarian tumors are heterogeneous and account for approximately 10% of ovarian malignancies. The most common subtypes of non-epithelial ovarian tumors arise from germ cells or sex cord and stromal cells of the gonads. These tumors are usually detected at an early stage, and management includes surgical staging and debulking. When indicated for advanced disease, most respond to chemotherapy; however, options for patients with refractory disease are limited, and regimens can be associated with significant toxicities, including permanent organ dysfunction, secondary malignancies, and death. Targeted therapies that potentially decrease chemotherapy-related adverse effects and improve outcomes for patients with chemotherapy-refractory disease are needed. Here, we review the molecular landscape of non-epithelial ovarian tumors for the purpose of informing rational clinical trial design. Recent genomic discoveries have uncovered recurring somatic alterations and germline mutations in subtypes of non-epithelial ovarian tumors. Though there is a paucity of efficacy data on targeted therapies, such as kinase inhibitors, antibody-drug conjugates, immunotherapy, and hormonal therapy, exceptional responses to some compounds have been reported. The rarity and complexity of non-epithelial ovarian tumors warrant collaboration and efficient clinical trial design, including high-quality molecular characterization, to guide future efforts.

Progestin therapy for obese women with complex atypical hyperplasia: levonorgestrel-releasing intrauterine device vs systemic therapy.

BACKGROUND: Though hysterectomy remains the standard treatment for complex atypical hyperplasia, patients who desire fertility or who are poor surgical candidates may opt for progestin therapy. However, the effectiveness of the levonorgestrel-releasing intrauterine device compared to systemic therapy in the treatment of complex atypical hyperplasia has not been well studied. OBJECTIVE: We sought to examine differences in treatment response between local progestin therapy with the levonorgestrel-releasing intrauterine device and systemic progestin therapy in women with complex atypical hyperplasia. METHODS: This single-institution retrospective study examined women with complex atypical hyperplasia who received progestin therapy between 2003 and 2018. Treatment response was assessed by histopathology on subsequent biopsies. Time-dependent analyses of complete response and progression to cancer were performed comparing the levonorgestrel-releasing intrauterine device and systemic therapy. A propensity score inverse probability of treatment weighting model was used to create a weighted cohort that differed based on treatment type but was similar with respect to other characteristics. An interaction-term analysis was performed to examine the impact of body habitus on treatment response, and an interrupted time-series analysis was employed to assess if changes in treatment patterns correlated with outcomes over time. RESULTS: A total of 245 women with complex atypical hyperplasia received progestin therapy (levonorgestrel-releasing intrauterine device n = 69 and systemic therapy n = 176). The mean age and body mass index were 36.9 years and 40.0 kg/m2, respectively. In the patient-level analysis, women who received the levonorgestrel-releasing intrauterine device had higher rates of complete response (78.7% vs 46.7%; adjusted hazard ratio, 3.32; 95% confidence interval, 2.39-4.62) and a lower likelihood of progression to cancer (4.5% vs 15.7%; adjusted hazard ratio, 0.28; 95% confidence interval, 0.11-0.73) compared to those who received systemic therapy. In particular, women with class III obesity derived a higher relative benefit from levonorgestrel-releasing intrauterine device therapy in achieving complete response compared to systemic therapy: class III obesity, adjusted hazard ratio 4.72, 95% confidence interval 2.83-7.89; class I-II obesity, adjusted hazard ratio 1.83, 95% confidence interval 1.09-3.09; and nonobese, adjusted hazard ratio 1.26, 95% confidence interval 0.40-3.95. In the cohort-level analysis, the obesity rate increased during the study period (77.8% to 88.2%, 13.4% relative increase, P = .033) and levonorgestrel-releasing intrauterine device use significantly increased after 2007 (6.3% to 82.7%, 13.2-fold increase, P < .001), both concomitant with a higher proportion of women achieving complete response (32.9% to 81.4%, 2.5-fold increase, P = .005). CONCLUSION: Our study suggests that local therapy with the levonorgestrel-releasing intrauterine device may be more effective than systemic therapy for women with complex atypical hyperplasia who opt for nonsurgical treatment, particularly in morbidly obese women. Shifts in treatment paradigm during the study period toward increased levonorgestrel-releasing intrauterine device use also led to improved complete response rates despite increasing rates of obesity.

Emerging serine-threonine kinase inhibitors for treating ovarian cancer.

Introduction: Ovarian cancer is the leading cause of gynecologic cancer death, owing to high rates of incurable, recurrent disease after initial treatment. Serine threonine kinases (STKs) have been proposed as potential therapeutic targets in ovarian cancer because of their role in the initiation and progression of cancers. Experience in non-ovarian cancers suggests that STK inhibitors are active against tumors with specific molecular alterations.Areas covered: This review discusses STK inhibitors in active development in phase II/III clinical trials for ovarian cancer. PubMed and ClinicalTrials.gov were systematically searched to identify STK inhibitor trials for ovarian cancer; active development was confirmed via Pharmaprojects. Available data regarding the efficacy and safety of these compounds are explored.Expert opinion: STK inhibitors currently in development have modest activity as single agents and are unlikely to achieve approval as monotherapy for unselected ovarian cancer patients. Combination trials of STK inhibitors with chemotherapy and/or targeted therapies have suggested an acceptable efficacy/toxicity ratio for certain combinations but confirmatory studies are needed. Carefully designed trials, especially those including somatic molecular analysis, may help identify the subsets of patients most likely to benefit from these therapeutic strategies and determine the role of STK inhibitors in the evolving landscape of precision oncology.

Effectiveness of progestin-based therapy for morbidly obese women with complex atypical hyperplasia.

OBJECTIVE: While progestins can effectively treat women with complex atypical hyperplasia (CAH), the impact of body habitus on treatment outcome is not well studied. We examine the association between body mass index (BMI) and progestin treatment outcomes. METHODS: We conducted a retrospective cohort study of patients diagnosed with hyperplasia between 2003 and 2011. Demographics, past medical history, BMI, hormonal therapy, and histologic treatment response were abstracted. Patients with CAH who received progestin therapy were examined, and rates of regression were assessed. RESULTS: Of 623 patients identified, 117 had CAH and satisfied the inclusion criteria. Median age was 34, and nearly, two-thirds (64%) were nulliparous. Mean BMI was 40.2, and 81% were obese (BMI 30-39.9: 36%, BMI ≥ 40: 45%). 103 patients (88%) received systemic progestin therapy and 14 patients (12%) received levonorgestrel-releasing intrauterine devices (LNG-IUS). 47 patients (40%) had a complete response to progestin-based therapy. BMI had no effect on the rate of complete response. The proportions of CAH patients with complete regression after hormonal therapy were BMI < 30: 39%, 30-39.9: 40%, and ≥ 40: 36% (P = 0.73). Women treated with LNG-IUS displayed higher rates of complete regression than those receiving systemic therapy (62% versus 38%, P = 0.096), and those with class III obesity were more likely than non-obese patients to receive LNG-IUS although neither reached statistical significance (< 40: 6.7% versus ≥ 40: 17%, P = 0.09). CONCLUSION: In this morbidly obese population, response to progestin therapy was generally low; body habitus did not impact treatment outcome for CAH, but local therapy may be more effective than systemic therapy.

Nivolumab use for BRCA gene mutation carriers with recurrent epithelial ovarian cancer: A case series.

Tumors deficient in DNA mismatch repair are known to display increased susceptibility to immune checkpoint inhibitors due to accumulation of DNA damage and increased neoantigen load. This suggests that deficiency in the BRCA-related DNA repair mechanism may also be a surrogate marker for immunotherapy response. The aim of this study was to examine the efficacy of the immune checkpoint inhibitor, nivolumab, in women with BRCA gene mutations and recurrent müllerian cancer. This retrospective case series followed six BRCA carriers who received nivolumab monotherapy (3.0 mg/kg, intravenous, day 1 and 15, every 4 weeks) as salvage therapy for recurrent epithelial ovarian (n = 5) and fallopian tubal (n = 1) cancers. Toxicity, treatment response, and survival were examined. Median age was 57 (range 51-64). BRCA1 and 2 mutations were equally distributed. All had high-grade serous histology, and all but one had advanced-stage disease at initial diagnosis. The majority had platinum-resistant disease (n = 4). All received salvage therapy prior to nivolumab therapy (median 3 lines), including PARP inhibitors (n = 3). The median number of nivolumab treatment cycles was 9, including 2 women receiving 18 cycles. Three women developed nivolumab-related toxicities, most commonly grade 2 hypothyroidism (n = 2). Median follow-up time was 13.4 months, and there were 3 complete responses, 1 partial response, and 2 patients with progressive disease. Objective response rate was 67% (4 out of 6). In conclusion, our study suggests that nivolumab monotherapy is well-tolerated and may be an effective salvage therapy for BRCA mutation carriers with recurrent epithelial ovarian, fallopian tubal, and primary peritoneal cancers.

Prolonged intubation after robotic-assisted hysterectomy for endometrial cancer: Case reports.

•Experienced prolonged intubation after robotic hysterectomy for endometrial cancer•Risk triad: Trendelenburg position, high pneumo-pressure, and excess hydration•Recognition of the risk triad is key to avoiding airway complications in robotic surgery.•Introduction of a 5-step method to prevent airway complications in robotic surgery.

Successful resuscitation after cardiac arrest secondary to carboplatin infusion: A case report.

•Sudden cardiac arrest can be a form of carboplatin hypersensitivity reaction.•Platinum retreatment and cumulative cycles of ≥ 8 are risk factors.•Awareness of the reaction related to carboplatin infusion is necessary.•Successful resuscitation with high quality CPR is achievable with trained staffs.

Efficacy of Modified Dose-dense Paclitaxel in Recurrent Cervical Cancer.

OBJECTIVE: To examine survival outcomes of women with recurrent cervical cancer who received salvage chemotherapy with modified dose-dense paclitaxel (MDDP) monotherapy (paclitaxel 80 mg/m, administered on day 1, 8, and 15 without day 22). MATERIALS AND METHODS: A retrospective study was conducted to evaluate cause-specific survival after the first recurrence (SAR) of women with recurrent cervical cancer diagnosed between 2006 and 2014. Pooled analyses were performed to examine SAR in women who received MDDP monotherapy (n=17) for any treatment line, compared with those who received salvage chemotherapy with paclitaxel-doublet (n=18) and nonpaclitaxel regimens (n=52). RESULTS: In the whole cohort, median SAR was 13.7 months including 63 (72.4%) events. MDDP monotherapy regimen was most commonly used in the second-line setting (35.3%) followed by the third/fourth lines (both, 23.5%). Among the women who received MDDP regimen, there were 6 (35.3%) women who received ≥6 cycles; there was 1 (5.9%) women who discontinued the regimen due to adverse effects (grade 3 transaminitis); regimen postponement was seen in 2 (1.4%) of 140 total cycles; and the response rate after the sixth cycle of this regimen was 29.4% (1 complete and 4 partial responses). On univariate analysis, MDDP usage had the highest 2-year SAR rate (MDDP 54.1%, paclitaxel-doublet 43.6%, and nonpaclitaxel regimens 28.1%; Ptrend=0.044). On multivariate analysis, MDDP monotherapy remained an independent prognostic factor for improved SAR compared with the nonpaclitaxel regimen (adjusted-hazard ratio, 0.50; 95% confidence interval, 0.26-0.95; P=0.036). CONCLUSION: Our results suggested that MDDP monotherapy is a tolerable and relatively effective regimen for recurrent cervical cancer.