Vulvar cancer survival by primary treatment modality: A retrospective cohort study.

OBJECTIVE: To compare survival and complications for women with vulvar cancer treated with primary radiation vs surgery. METHODS: Retrospective cohort study of Kaiser Permanente members diagnosed with vulvar squamous cell carcinoma (SCC) between 2008 and 2018 and treated with primary surgery (PS only), surgery with adjuvant radiation (PS + RT), or primary radiation (PRT). Primary outcomes were 1- and 3-year overall (OS) and progression-free (PFS) survival. Multivariable regression adjusted for age, stage, comorbidities, and smoking. RESULTS: We included 201 women: 114 PS only (56.7%), 36 PS + RT (17.9%), and 51 PRT (25.4%). PS only patients had less advanced disease. Crude 1- and 3-year OS were 96.5% and 82.6% for PS only compared to 72.2% and 48.3% for PS + RT and 72.6% and 53.9% for PRT (p < 0.001). There were no statistical differences in hazard of death when controlling for stage and other covariates (PRT vs PS only: aHR 1.35, 95% CI 0.61-2.99; PS + RT vs PS only: aHR 1.28, 95% CI 0.60-2.75; PS + RT vs PRT: aHR 0.95, CI 0.48-1.90). Older age and stage III disease were poor prognostic factors. Risk of lymphedema was elevated with PS + RT (36.1% vs 20.2% for PS only and 9.8% for PRT, p = 0.011). Wound infection was more likely in surgical groups, whereas hospital readmission and blood transfusion were more common with PRT. CONCLUSIONS: Vulvar cancer survival was not statistically different among women treated with primary radiation compared to primary surgery when controlling for stage. Surgery followed by adjuvant radiation demonstrated elevated rates of lymphedema. Primary radiation therapy may be an acceptable alternative to primary surgery in women who are likely to need adjuvant therapy.

Cost effectiveness of neoadjuvant chemotherapy followed by interval cytoreductive surgery versus primary cytoreductive surgery for patients with advanced stage ovarian cancer during the initial treatment phase.

OBJECTIVE: Advanced stage epithelial ovarian cancer (AEOC) can be treated with either neoadjuvant chemotherapy (NACT) or primary cytoreductive surgery (PCS). Although randomized controlled trials show that NACT is non-inferior in overall survival compared to PCS, there may be improvement in short-term morbidity. We sought to investigate the cost-effectiveness of NACT relative to PCS for AEOC from the US Medicare perspective. METHODS: A cost-effectiveness analysis using a Markov model with a 7-month time horizon comparing (1) 3cycles of NACT with carboplatin and paclitaxel (CT), followed by interval cytoreductive surgery, then 3 additional cycles of CT, or (2) PCS followed by 6cycles of CT. Input parameters included probability of chemotherapy complications, surgical complications, treatment completion, treatment costs, and utilities. Model outcomes included costs, life-years gained, quality-adjusted life-years (QALYs) gained, and incremental cost-effectiveness ratios (ICER), in terms of cost per life-year gained and cost per QALY gained. We accounted for differences in surgical complexity by incorporating the cost of additional procedures and the probability of undergoing those procedures. Probabilistic sensitivity analysis (PSA) was performed via Monte Carlo simulations. RESULTS: NACT resulted in a savings of $7034 per patient with a 0.035 QALY increase compared to PCS; therefore, NACT dominated PCS in the base case analysis. With PSA, NACT was the dominant strategy more than 99% of the time. CONCLUSIONS: In the short-term, NACT is a cost-effective alternative compared to PCS in women with AEOC. These results may translate to longer term cost-effectiveness; however, data from randomized control trials continues to mature.

Economic Analysis of Neoadjuvant Chemotherapy Versus Primary Debulking Surgery for Advanced Epithelial Ovarian Cancer Using an Aggressive Surgical Paradigm.

OBJECTIVES: Neoadjuvant chemotherapy (NACT) versus primary debulking surgery (PDS) for advanced epithelial ovarian cancer (AEOC) remains controversial in the United States. Generalizability of existing trial results has been criticized because of less aggressive debulking procedures than commonly used in the United States. As a result, economic evaluations using input data from these trials may not accurately reflect costs and outcomes associated with more aggressive primary surgery. Using data from an ongoing trial performing aggressive debulking, we investigated the cost-effectiveness and cost-utility of NACT versus PDS for AEOC. METHODS: A decision tree model was constructed to estimate differences in short-term outcomes and costs for a hypothetical cohort of 15,000 AEOC patients (US annual incidence of AEOC) treated with NACT versus PDS over a 1-year time horizon from a Medicare payer perspective. Outcomes included costs per cancer-related death averted, life-years and quality-adjusted life-years (QALYs) gained. Base-case probabilities, costs, and utilities were based on the Surgical Complications Related to Primary or Interval Debulking in Ovarian Neoplasms trial. Base-case analyses assumed equivalent survival; threshold analysis estimated the maximum survival difference that would result in NACT being cost-effective at $50,000/QALY and $100,000/QALY willingness-to-pay thresholds. Probabilistic sensitivity analysis was used to characterize model uncertainty. RESULTS: Compared with PDS, NACT was associated with $142 million in cost savings, 1098 fewer cancer-related deaths, and 1355 life-years and 1715 QALYs gained, making it the dominant treatment strategy for all outcomes. In sensitivity analysis, NACT remained dominant in 99.3% of simulations. Neoadjuvant chemotherapy remained cost-effective at $50,000/QALY and $100,000/QALY willingness-to-pay thresholds if survival differences were less than 2.7 and 1.4 months, respectively. CONCLUSIONS: In the short term, NACT is cost-saving with improved outcomes. However, if PDS provides a longer-term survival advantage, it may be cost-effective. Research is needed on the role of patient preferences in tradeoffs between survival and quality of life.

Impact of Trainee Involvement in Cervical Excision Procedures: Does Trainee Involvement Impact Quality?

OBJECTIVE: Cervical excision procedures are essential to the care of cervical dysplasia and malignancy. We sought to determine whether learner involvement in cervical excision procedures affects the quality of excision specimen. MATERIALS AND METHODS: A retrospective cohort study of cervical cancer patients diagnosed from July 1, 2000, to July 1, 2015, was performed. We included patients who had (1) a cervical excision procedure, either loop electrosurgical excision procedure or cold knife cone, and (2) pathologic information available. Primary outcome was the margin status of the specimen; secondary outcome was the size of the excision specimen including both width and depth. The exposure of interest was trainee participation, defined as resident physicians under the supervision of either a gynecologist or gynecologic oncologist. Descriptive statistics and general linear models were used for analysis. RESULTS: Ninety-four patients were identified. Overall, 58% (n = 54) of procedures were performed with trainee involvement. There was no difference in age, body mass index, or specimen width between trainee-performed and nontrainee-performed excisions. There was no significant difference in the status of margins with or without a trainee [44/57 (77%) and 29/37 (78%), respectively, p = .89]. There was a statistically significant difference in median specimen depth between trainee-performed and nontrainee-performed cases (15.4 mm vs 12 mm, p < .02). When adjusting for age, body mass index, excision type, indication, presence of trainee, and type of supervising physician, only the indication and type of excision were associated with greater depth of excision, (p < .01). CONCLUSIONS: Trainee involvement in cervical excision procedures does not alter the quality of excision specimen.

Association between timing of cervical excision procedure to minimally invasive hysterectomy and surgical complications.

OBJECTIVE: To determine if the time interval between excision procedure and definitive minimally invasive surgery (MIS) for cervical cancer impacts 30-day postoperative complications. METHODS: A retrospective cohort of patients diagnosed with cervical cancer from January 2000 to July 2015 was evaluated. Patients who underwent a cervical excision procedure followed by definitive MIS within 90days were included. Early definitive surgery was defined as ≤6 weeks following excision procedure, while delayed was defined as 6weeks to 3months. The primary outcome was 30-day complications. Statistical analysis included descriptive statistics and modified Poission regression. RESULTS: Overall, 138 patients met inclusion criteria. Of these, 33% (n=46) had early definitive surgery and 67% (n=92) had delayed definitive surgery. Median age was 42years (range 23-72years) and median BMI was 28kg/m2 (range 16-50kg/m2). Within demographic and surgical factors collected, only smoking status differed between groups with those in the delayed surgery group more likely to be non-smokers than those in the early surgery group (p=0.04). When adjusting for relevant demographic and surgical factors, patients in the early group were twice as likely to have 30-day complication (aRR 2.6, 95%CI 1.14-5.76, p=0.02). Evaluating only women who underwent a radical procedure, 30-day complications remained higher in the early surgery group (RR 2.56; 95%CI 1.22-5.38, p=0.01). CONCLUSIONS: Performing definitive MIS for cervical cancer within 6weeks after cervical excision is associated with increased risk for 30-day complications. Providers should consider delaying definitive surgical procedures for at least 6weeks following excision to reduce surgical complications.

Robotic Radical Parametrectomy With Upper Vaginectomy and Pelvic Lymphadenectomy in Patients With Occult Cervical Carcinoma After Extrafascial Hysterectomy.

STUDY OBJECTIVE: To confirm the safety and feasibility outcomes of robotic radical parametrectomy and pelvic lymphadenectomy and compare the clinicopathological features of women requiring adjuvant treatment with the historical literature. DESIGN: Retrospective cohort study and review of literature (Canadian Task Force classification II-2). SETTING: Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill. PATIENTS: All patients who underwent robotic radical parametrectomy with upper vaginectomy (RRPV), and pelvic lymphadenectomy for occult cervical cancer discovered after an extrafascial hysterectomy at our institution between January 2007 and December 2015. INTERVENTIONS: RRPV and pelvic lymphadenectomy for occult cervical cancer discovered after an extrafascial hysterectomy. We also performed a literature review of the literature on radical parametrectomy after occult cervical carcinoma. MEASUREMENTS AND MAIN RESULTS: Seventeen patients with invasive carcinoma of the cervix discovered after extrafascial hysterectomy underwent RRPV with bilateral pelvic lymphadenectomy. There were 2 intraoperative complications, including 1 bowel injury and 1 bladder injury. One patient required a blood transfusion of 2 units. Three patients underwent adjuvant treatment with chemoradiation with radiation-sensitizing cisplatin. One of these patients had residual carcinoma on the upper vagina, 1 patient had positive parametria and pelvic nodes, and 1 patient had positive pelvic lymph nodes. No patients experienced recurrence, and 1 patient died from unknown causes at 59.4 months after surgery. We analyzed 15 studies reported in the literature and found 238 women who underwent radical parametrectomy; however, no specific preoperative pathological features predicted outcomes, the need for adjuvant treatment, or parametrial involvement. CONCLUSION: RRPV is a feasible and safe treatment option. As reflected in the literature, RRPV can help avoid empiric adjuvant chemoradiation; however, no pathological features predict the need for adjuvant treatment after surgery.

Impact of obesity on secondary cytoreductive surgery and overall survival in women with recurrent ovarian cancer.

OBJECTIVES: Obesity may negatively influence tumor biology in women with epithelial ovarian cancers. To date, only body mass indices (BMI) determined at the time of diagnosis have correlated with clinical outcome. We hypothesized that obesity negatively affects survival throughout the disease course, and sought to determine the prognostic role of BMI at the time of secondary cytoreductive surgery (SCS) for recurrent ovarian cancer. METHODS: We performed a review of patients undergoing SCS for recurrent epithelial ovarian or peritoneal cancer between 1997 and 2012. We retrospectively reviewed data which were analyzed using Fisher's exact test, Kaplan-Meier survival, and Cox regression analysis. BMI was defined according to the National Institutes of Health's categorizations. RESULTS: We identified 104 patients; 2 were underweight, 46 were of ideal body weight, 32 were overweight, and 24 were obese. Overall, 90 patients underwent optimal resection and BMI did not correlate with ability to perform optimal SCS (p=0.25). When examining BMI strata (underweight, ideal, overweight, and obese), we observed a statistical trend between increasing BMI and poor outcome; median survival was undetermined (greater than 50 months), 46 months, 38 months, and 34 months, respectively (p=0.04). In a multivariate analysis, BMI was an independent predictor of survival (p=0.02). CONCLUSIONS: In this cohort of women undergoing SCS for recurrent ovarian cancer, BMI significantly and independently correlated with overall survival. This observation suggests an effect of excess weight on tumor biology and/or response to treatment that is prevalent throughout the disease course.

Thrombocytosis at secondary cytoreduction for recurrent ovarian cancer predicts suboptimal resection and poor survival.

OBJECTIVES: A growing body of evidence supports a role for thrombocytosis in the promotion of epithelial ovarian cancer biology. However, studies have only linked preoperative platelet count at time of initial cytoreductive surgery to clinical outcome. Here, we sought to determine the impact of elevated platelet count at time of secondary cytoreductive surgery (SCS) for recurrent disease. METHODS: Under an IRB-approved protocol, we identified 107 women with invasive epithelial ovarian cancer who underwent SCS between January 1997 and June 2012. We reviewed clinical, laboratory, and pathologic records from this retrospective cohort. The data was analyzed using the chi-squared, Fisher's exact, Cox proportional hazards, and Kaplan-Meier tests. We defined thrombocytosis as a platelet count ≥ 350 × 10(9)/L and optimal resection at SCS as microscopic residual disease. RESULTS: Thirteen of 107 women (12%) with recurrent ovarian cancer had thrombocytosis prior to SCS. Preoperative thrombocytosis at SCS was associated with failure to undergo optimal resection (p=0.0001). Women with preoperative thrombocytosis at time of SCS demonstrated shorter overall survival (33 months) compared to those with normal platelet counts (46 months, p=0.004). On multivariate analysis, only preoperative platelet count retained significance as an independent prognostic factor (p=0.025) after controlling for age at SCS (p=0.90), disease free interval from primary treatment (0.06), and initial stage of disease (0.66). CONCLUSIONS: Elevated platelet count at time of SCS is associated with suboptimal resection and shortened overall survival. These data provide further evidence supporting a plausible role for thrombocytosis in aggressive ovarian tumor biology.

Asparagus officinalis Exhibits Anti-Tumorigenic and Anti-Metastatic Effects in Ovarian Cancer.

Ovarian cancer is one of the leading causes of female cancer death. Emerging evidence suggests that many dietary natural products have anti-tumorigenic activity, including that of asparagus officinalis. The current study aimed to assess the anti-tumorigenic and anti-metastatic effects of asparagus officinalis on serous ovarian cancer cell lines and a transgenic mouse model of high grade serous ovarian cancer. Asparagus officinalis decreased cellular viability, caused cell cycle G1 phase arrest and induced apoptosis in the OVCAR5 and SKOV3 cells. Induction of apoptosis and inhibition of cell proliferation was rescued by the pan-caspase inhibitor, Z-VAD-FMK, implying that its cytotoxic effects were mainly dependent on caspase pathways. Asparagus officinalis increased levels of ROS and decreased mitochondrial membrane potential with corresponding increases in PERK, Bip, Calnexin PDI and ATF4 in both cell lines. Treatment with asparagus officinalis also reduced ability of adhesion and invasion through epithelial-mesenchymal transition and reduction of VEGF expression. The combination of Asparagus officinalis with paclitaxel had synergistic anti-proliferative activity. Furthermore, Asparagus officinalis significantly inhibited tumor growth and reduced serum VEGF in a genetically engineered mouse model of ovarian cancer under obese and lean conditions, accompanied with a decrease in the expression of Ki67, VEGF and phosphorylated S6, and in an increase in phosphorylation of AMPK in the ovarian tumor tissues. Overall, our data provide a pre-clinical rationale for asparagus officinalis in the prevention and treatment of ovarian cancer as a novel natural product.

Treatment of invasive Paget's disease of the vulva in pregnancy: A case report.

•Invasive adenocarcinoma of the vulva arising from extramammary Paget's disease is possible in women of child-bearing age.•Radical vulvectomy, sentinel lymph node biopsy, and inguinal lymphadenectomy are safe and feasible during pregnancy.•Chemotherapy may be used as adjuvant therapy for vulvar adenocarcinoma during pregnancy when radiation is contraindicated.•Primary cesarean delivery may be considered for pregnant women with recent vulvar surgery.•Trastuzumab may be considered for maintenance therapy of Her2/Neu positive vulvar cancer in postpartum women.

SPR965, a Dual PI3K/mTOR Inhibitor, as a Targeted Therapy in Ovarian Cancer.

SPR965 is an inhibitor of PI3K and mTOR C1/C2 and has demonstrated anti-tumorigenic activity in a variety of solid tumors. We sought to determine the effects of SPR965 on cell proliferation and tumor growth in human serous ovarian cancer cell lines and a transgenic mouse model of high grade serous ovarian cancer (KpB model) and identify the underlying mechanisms by which SPR965 inhibits cell and tumor growth. SPR965 showed marked anti-proliferative activity by causing cell cycle arrest and inducing cellular stress in ovarian cancer cells. Treatment with SPR965 significantly inhibited tumor growth in KpB mice, accompanied by downregulation of Ki67 and VEGF and upregulation of Bip expression in ovarian tumors. SPR965 also inhibited adhesion and invasion through induction of the epithelial-mesenchymal transition process. As expected, downregulation of phosphorylation of AKT and S6 was observed in SPR965-treated ovarian cancer cells and tumors. Our results suggest that SPR965 has significant anti-tumorigenic effects in serous ovarian cancer in vitro and in vivo. Thus, SPR965 should be evaluated as a promising targeted agent in future clinical trials of ovarian cancer.

Topiramate exhibits anti-tumorigenic and metastatic effects in ovarian cancer cells.

Ovarian cancer is one of the leading causes of cancer related deaths among women worldwide, with an overall 5-year survival of only 30-40%. Carbonic anhydrases are up-regulated in many types of cancer and play an important role in tumor progression and metastasis. Carbonic anhydrase 9 has been implicated as a potential anti-tumorigenic target. Topiramate (TPM) is a potent inhibitor of carbonic anhydrase isozymes, including carbonic anhydrase 9, and has been shown to have anti-tumorigenic activity in several cancer types. Our goal was to evaluate the effect of TPM on cell proliferation and to identify possible mechanisms by which TPM inhibits cell growth in ovarian cancer. TPM significantly inhibited ovarian cancer cell proliferation and induced cell cycle G1 arrest, cellular stress and apoptosis through the AKT/mTOR and MAPK pathways. TPM also exerted anti-metastatic effects by decreasing the adhesion and invasion of ovarian cancer cells and affecting the expression of critical regulators of the epithelial-mesenchymal transition (EMT). Our findings demonstrate that TPM has anti-tumorigenic effects in ovarian cancer and is worthy of further exploration in clinical trials.

Erratum: Atorvastatin exhibits anti-tumorigenic and anti-metastatic effects in ovarian cancer in vitro.

[This corrects the article on p. 2478 in vol. 7, PMID: 29312801.].

ONC201 demonstrates anti-tumorigenic and anti-metastatic activity in uterine serous carcinoma in vitro.

Uterine serous carcinoma (USC) represents an aggressive histologic subtype of endometrial cancer. It is associated with a poor prognosis, and improved therapies for women battling USCs are greatly needed. ONC201 is an orally bioavailable, first-in-class small molecule that induces tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) independent of p53. ONC201 has demonstrated anti-tumorigenic activity in pre-clinical models of solid tumors through induction of apoptosis and inactivation of the AKT/MAPK pathways. Recent phase I and II clinical trials have shown that ONC201 is well tolerated and may have single agent activity in high grade glioma patients among others. We sought to determine the effects of ONC201 on cell proliferation in USC and identify the mechanisms by which ONC201 inhibits cell growth in this disease. ONC201 inhibited cell proliferation in a dose-dependent manner in ARK1, ARK2 and SPEC-2 cell lines. The anti-proliferative activity of ONC201 in ARK1 and SPEC-2 cells was associated with induction apoptosis independent of p53 via both a TRAIL mediated apoptotic pathway and a mitochondrial apoptosis pathway. Treatment with ONC201 resulted in significant reduction in adhesion and invasion as well as inhibition of the AKT and MAPK pathways. In addition, ONC201 markedly potentiated the anti-tumorigenic effects of paclitaxel in USC cells. Our results suggest that ONC201 has significant anti-proliferative and anti-metastatic effects in USC cells through both induction of apoptosis and inhibition of the AKT and MAPK pathways. ONC201 and paclitaxel are a promising therapeutic combination in USC cells. Thus, ONC201 should be evaluated as a single agent and as a therapeutic partner with paclitaxel in future clinical trials of USC.

Recent Advances in Endometrial Cancer.

Endometrial cancer is the most common gynecologic malignancy in the United States, with yearly rates continuing to increase. Most women present with early stage disease; however, advanced disease carries a grave prognosis. As a result, novel therapies are currently under investigation for the treatment of endometrial cancer. These advances include a better understanding of the genetic basis surrounding the development of endometrial cancer, novel surgical therapies, and new molecular targets for the treatment of this disease. This review explores the literature regarding these advancements in endometrial cancer.

Atorvastatin exhibits anti-tumorigenic and anti-metastatic effects in ovarian cancer in vitro.

Ovarian cancer is the 8th most common cancer in women, and the 5th leading cause of cancer-related deaths among women in the United States. Statins have been shown to have promising anti-tumorigenic activity in many types of cancers. We sought to determine the effects of atorvastatin (ATO) on cell proliferation in ovarian cancer and identify the mechanisms by which ATO inhibits cell growth in this disease. ATO inhibited cell proliferation of both the Hey and SKOV3 ovarian cancer cells in a dose-dependent manner. The anti-proliferative activity of ATO in the ovarian cancer cell lines was associated with induction of apoptosis, autophagy, cellular stress and cell cycle G1 arrest via inhibition of AKT/mTOR and activation of the MAPK pathways. Moreover, ATO inhibited cell adhesion and invasion as well as decreased expression of VEGF and MMP9. c-Myc was downregulated in ovarian cancer cells exposed to ATO. Inhibition of c-Myc by JQ1 synergistically increased the sensitivity of ovarian cancer cells to ATO. This data suggests that ATO may have a therapeutic role in the treatment of ovarian cancer and warrant further exploration in clinical trials.

Dual inhibition of glycolysis and glutaminolysis as a therapeutic strategy in the treatment of ovarian cancer.

Cancer cell metabolism is required to support the biosynthetic demands of cell growth and cell division, and to maintain reduction oxidaton (redox) homeostasis. This study was designed to test the effects of glucose and glutamine on ovarian cancer cell growth and explore the inter-relationship between glycolysis and glutaminolysis. The SKOV3, IGROV-1 and Hey ovarian cancer cell lines were assayed for glucose, pyruvate and glutamine dependence by analyzing cytotoxicity, cell cycle progression, apoptosis and ATP production. As determined by MTT assay, glucose stimulated cell growth while the combination of glucose, glutamine and pyruvate resulted in the greatest stimulation of cell proliferation. Furthermore, 2-deoxy-glucose (2-DG) and 3-bromopyruvate (3-BP) induced apoptosis, caused G1 phase cell cycle arrest and reduced glycolytic activity. Moreover, 2-DG in combination with a low dose of aminooxyacetate (AOA) synergistically increased the sensitivity to 2-DG in the inhibition of cell growth in the ovarian cancer cell lines. These studies suggest that dual inhibition of glycolysis and glutaminolysis may be a promising therapeutic strategy for the treatment of ovarian cancer.

Sebaceous carcinoma of the vulva: A case report and review of the literature.

•Sebaceous carcinoma (SC) is rare with only nine cases reported in the literature.•Extraocular SC likely has similar prognosis to ocular SC.•Reporting of vulvar SC should include detailed pathologic information so that risk factor associations can be made.