Trends in the use of neoadjuvant chemotherapy for low-grade serous ovarian cancer in the United States.

OBJECTIVE: To describe trends in neoadjuvant chemotherapy (NACT) use for low-grade serous ovarian carcinoma (LGSOC) and to quantify associations between NACT and extent of cytoreductive surgery. METHODS: We identified women treated for stage III or IV serous ovarian cancer in a Commission on Cancer accredited program between January 2004-December 2020. Regression models were developed to evaluate trends in NACT use for LGSOC, to identify factors associated with receipt of NACT, and to quantify associations between NACT and bowel or urinary resection at the time of surgery. Demographic and clinical factors were used for confounder control. RESULTS: We observed 3350 patients who received treatment for LGSOC during the study period. The proportion of patients who received NACT increased from 9.5% in 2004 to 25.9% in 2020, corresponding to an annual percent change of 7.2% (95% CI 5.6-8.9). Increasing age (rate ratio (RR) 1.15; 95% CI 1.07-1.24), and stage IV disease (RR 2.66; 95% CI 2.31-3.07) were associated with a higher likelihood of receiving NACT. For patients with high-grade disease, NACT was associated with a decrease in likelihood of bowel or urinary surgery (35.3% versus 23.9%; RR 0.68, 95% CI 0.65-0.71). For LGSOC, NACT was associated with a higher likelihood of these procedures (26.6% versus 32.2%; RR 1.24, 95% CI 1.08-1.42). CONCLUSION: NACT use among patients with LGSOC has increased from 2004 to 2020. While NACT was associated with a lower rate of gastrointestinal and urinary surgery among patients with high-grade disease, patients with LGSOC receiving NACT were more likely to undergo these procedures.

Trastuzumab with carboplatin/paclitaxel for treatment of advanced stage and recurrent uterine papillary serous carcinoma: A cost-effectiveness analysis.

OBJECTIVE: Uterine papillary serous carcinoma (UPSC) is a variant of endometrial cancer that is aggressive and associated with poor outcomes. We sought to evaluate the cost effectiveness of carboplatin/paclitaxel alone versus carboplatin/paclitaxel with trastuzumab among patients with Her2/neu-positive advanced or recurrent UPSC. METHODS: We designed a Markov model in TreeAge Pro 2019 software to simulate management of a theoretical cohort of 4000 patients with Her2/neu-positive advanced or recurrent uterine papillary serous carcinoma (UPSC) followed for four years. In the carboplatin/paclitaxel with trastuzumab strategy, we included the cost of testing for Her2/neu status. We obtained all model inputs from the literature and a societal perspective was assumed. Outcomes included progression-free survival, progression, UPSC-specific mortality, cost, and quality-adjusted life years (QALYs). The intervention was considered cost effective if the incremental cost-effectiveness ratio (ICER) was below the willingness-to-pay threshold of $100,000 per QALY. Sensitivity analyses were used to determine the robustness of the results. RESULTS: In our theoretical cohort of 4000 women, treatment with the addition of trastuzumab resulted in 637 fewer deaths and 627 fewer cases of progression compared with treatment with carboplatin/paclitaxel alone. Treatment with trastuzumab was associated with an additional cost of $144,335,895, but was associated with an increase of 2065 QALYs. The ICER was $69,903 per QALY, which was below our willingness-to-pay threshold. Sensitivity analysis demonstrated that this treatment strategy was cost-effective until the cost of 6 months of treatment surpassed $38,505 (baseline input: $27,562). CONCLUSION: We found that the addition of trastuzumab to carboplatin/paclitaxel was a cost-effective treatment strategy for patients with advanced/recurrent Her2/neu-positive UPSC.

Clinical calculator predictive of chemotherapy benefit in stage 1A uterine papillary serous cancers.

OBJECTIVE: Determine the utility of a clinical calculator to predict the benefit of chemotherapy in stage IA uterine papillary serous cancer (UPSC). PATIENTS AND METHODS: Data were collected from NCDB from years 2010-2014. Based on demographic and surgical characteristics, a clinical score was developed using the random survival forest machine learning algorithm. RESULTS: Of 1,751 patients with stage IA UPSC, 1,012 (58%) received chemotherapy and 739 (42%) did not. Older age (HR 1.06), comorbidities (HR 1.31), larger tumor size (HR 1.27), lymphovascular invasion (HR 1.86), positive peritoneal cytology (HR 2.62), no pelvic lymph node dissection (HR 1.51), and no chemotherapy (HR 2.16) were associated with poorer prognosis. Compared to no chemotherapy, patients who underwent chemotherapy had a 5-year overall survival of 80% vs. 67%. To better delineate those who may derive more benefit from chemotherapy, we designed a clinical calculator capable of dividing patients into low, moderate, and high-risk groups with associated 5-year OS of 86%, 73%, and 53%, respectively. Using the calculator to assess the relative benefit of chemotherapy in each risk group, chemotherapy improved the 5-year OS in the high (42% to 64%; p < 0.001) and moderate risk group (66% to 79%; p < 0.001) but did not benefit the low risk group (84% to 87%; p = 0.29). CONCLUSION: Our results suggest a clinical calculator is useful for counseling and personalizing chemotherapy for stage IA UPSC.

Sperm associated antigen 9 (SPAG9) a promising therapeutic target of ovarian carcinoma.

SPAG9 is a novel tumor associated antigen, expressed in variety of malignancies. However, its role in ovarian cancer remains unexplored. SPAG9 expression was validated in ovarian cancer cells by real time PCR and Western blot. SPAG9 involvement in cell cycle, DNA damage, apoptosis, paclitaxel sensitivity and epithelial- mesenchymal transition (EMT) was investigated employing RNA interference approach. Combinatorial effect of SPAG9 ablation and paclitaxel treatment was evaluated in in vitro. Quantitative PCR and Western blot analysis revealed SPAG9 expression in A10, SKOV-3 and Caov3 compared to normal ovarian epithelial cells. SPAG9 ablation resulted in reduced cellular proliferation, colony forming ability and enhanced cytotoxicity of chemotherapeutic agent paclitaxel. Effect of ablation of SPAG9 on cell cycle revealed S phase arrest and showed decreased expression of CDK1, CDK2, CDK4, CDK6, cyclin B1, cyclin D1, cyclin E and increased expression of tumor suppressor p21. Ablation of SPAG9 also resulted in increased apoptosis with increased expression of various pro- apoptotic molecules including BAD, BID, PUMA, caspase 3, caspase 7, caspase 8 and cytochrome C. Decreased expression of mesenchymal markers and increased expression of epithelial markers was found in SPAG9 ablated cells. Combinatorial effect of SPAG9 ablation and paclitaxel treatment was evaluated in in vitro assays which showed that ablation of SPAG9 resulted in increased paclitaxel sensitivity and caused enhanced cell death. In vivo ovarian cancer xenograft studies showed that ablation of SPAG9 resulted in significant reduction in tumor growth. Present study revealed therapeutic potential of SPAG9 in ovarian cancer.

Melatonin Reduces Angiogenesis in Serous Papillary Ovarian Carcinoma of Ethanol-Preferring Rats.

Angiogenesis is a hallmark of ovarian cancer (OC); the ingrowth of blood vessels promotes rapid cell growth and the associated metastasis. Melatonin is a well-characterized indoleamine that possesses important anti-angiogenic properties in a set of aggressive solid tumors. Herein, we evaluated the role of melatonin therapy on the angiogenic signaling pathway in OC of an ethanol-preferring rat model that mimics the same pathophysiological conditions occurring in women. OC was chemically induced with a single injection of 7,12-dimethylbenz(a)anthracene (DMBA) under the ovarian bursa. After the rats developed serous papillary OC, half of the animals received intraperitoneal injections of melatonin (200 µg/100 g body weight/day) for 60 days. Melatonin-treated animals showed a significant reduction in OC size and microvessel density. Serum levels of melatonin were higher following therapy, and the expression of its receptor MT1 was significantly increased in OC-bearing rats, regardless of ethanol intake. TGFß1, a transforming growth factor-beta1, was reduced only after melatonin treatment. Importantly, vascular endothelial growth factor (VEGF) was severely reduced after melatonin therapy in animals given or not given ethanol. Conversely, the levels of VEGF receptor 1 (VEGFR1) was diminished after ethanol consumption, regardless of melatonin therapy, and VEGFR2 was only reduced following melatonin. Hypoxia-inducible factor (HIF)-1α was augmented with ethanol consumption, and, notably, melatonin significantly reduced their levels. Collectively, our results suggest that melatonin attenuates angiogenesis in OC in an animal model of ethanol consumption; this provides a possible complementary therapeutic opportunity for concurrent OC chemotherapy.

Utility of radiation therapy for early-stage uterine papillary serous carcinoma.

OBJECTIVE: Early-stage uterine papillary serous carcinoma (UPSC) has a poor prognosis and high recurrence rate. While adjuvant chemotherapy is generally recommended, the role of radiation is uncertain. We examined the association between vaginal brachytherapy and whole pelvic radiation and survival in women treated with and without adjuvant chemotherapy. METHODS: The National Cancer Data Base was used to identify women with stage I-II UPSC treated between 1998 and 2012. Trends in use of chemotherapy, brachytherapy, and external beam radiation over time were examined. The association between these treatments and mortality were examined using multivariable Cox proportional hazards models. RESULTS: A total of 7325 patients were identified. Overall, 2779 (37.9%) received chemotherapy. The use of vaginal brachytherapy increased from 7.2% in 1998 to 29.1% in 2012 (P<0.0001), while use of external beam radiation decreased from 18.2% to 11.7% over the same period (P<0.0001). Use of chemotherapy was associated with a 22% reduction in mortality (HR=0.78; 95% CI, 0.69-0.88). While brachytherapy was associated with decreased mortality (HR=0.67; 95% CI, 0.57-0.78), use of external beam radiation was not associated with survival (HR=1.03; 95% CI, 0.92-1.17). Stratified by stage, use of chemotherapy was associated with decreased mortality for women with stage IB and II tumors, but not for stage IA neoplasms. Vaginal brachytherapy was associated with reduced mortality for stage IA and II neoplasms. CONCLUSION: For women with early-stage UPSC, chemotherapy is associated with improved survival. Vaginal brachytherapy was also associated with improved survival, however, there was little benefit to use of external beam radiation.

Levatorplasty for Symptomatic Posterior Prolapse due to Recurrent Malignant Ascites.

BACKGROUND: Although infrequently described, massive ascites due to malignancy contributes to symptomatic pelvic organ prolapse. CASE: A 73-year-old woman with recurrent ovarian cancer and massive ascites underwent a levatorplasty for repair of posterior prolapse after failing conservative management. CONCLUSIONS: Management of patient with cancer with prolapse is complex. Patients with cancer with ascites also have pelvic organ prolapse, in addition to other, better described sequelae of increased intra-abdominal pressure. These patients should be treated specifically for prolapse, with therapy, including type of surgery, chosen with special consideration of their underlying disease.

Impact of adjuvant chemotherapy and pelvic radiation on pattern of recurrence and outcome in stage I non-invasive uterine papillary serous carcinoma. A multi-institution study.

OBJECTIVES: To determine the impact of adjuvant chemotherapy or pelvic radiation on risk of recurrence and outcome in stage IA non-invasive uterine papillary serous carcinoma (UPSC). METHODS: This is a multi-institutional retrospective study for 115 patients with stage IA non-invasive UPSC (confined to endometrium) treated between 2000 and 2012. Kaplan-Meier and multivariable Cox proportional hazards regression modeling were used. RESULTS: Staging lymphadenectomy and omentectomy were performed in 84% and 57% respectively. Recurrence was seen in 26% (30/115). Sites of recurrences were vaginal in 7.8% (9/115), pelvic in 3.5% (4/115) and extra-pelvic in 14.7% (17/115). Adjuvant chemotherapy did not impact risk of recurrence (25.5% vs. 26.9%, p=0.85) even in subset of patients who underwent lymphadenectomy (20% vs. 23.5%, p=0.80). These findings were consistent for pattern of recurrence. Among those who underwent lymphadenectomy, adjuvant chemotherapy did not impact progression-free survival (p=0.34) and overall survival (p=0.12). However among patients who did not have lymphadenectomy, adjuvant chemotherapy or pelvic radiation was associated with longer progression-free survival (p=0.04) and overall survival (p=0.025). In multivariable analysis, only staging lymphadenectomy was associated with improved progression-free survival (HR 0.34, 95% CI 0.12-0.95, p=0.04) and overall survival (HR 0.35, 95% CI 0.12-1.0, p=0.05). Neither adjuvant chemotherapy nor pelvic radiation were predictors of progression-free or overall survivals. CONCLUSION: In stage IA non-invasive UPSC, staging lymphadenectomy was significantly associated with recurrence and outcome and therefore, should be performed in all patients. Adjuvant chemotherapy or pelvic radiation had no impact on outcome in surgically staged patients but was associated with improved outcome in unstaged patients.

[ULTRASOUND CRITERIA OR THE OPERABILITY AND EFFICACY OF THE TREATMENT OF THE MALIGNANT EPITHELIAL OVARIAN TUMOURS].

In order to isolate the main sonographic criteria of ovarian cancer operability the dynamical U.S. examination was performed on 65 women with epithelial tumors of II-III stages before and during 5 years after treatment beginning, which included (in different combinations) cytoreductive surgery and neoadjuvant chemotherapy. Only total 14 (21.5%) relapses were revealed. The U.S. prognostic criteria of the ovarian cancer treatment efficacy with and without neoadjuvant chemotherapy were defined.

Follicle-stimulating hormone induced epithelial-mesenchymal transition of epithelial ovarian cancer cells through follicle-stimulating hormone receptor PI3K/Akt-Snail signaling pathway.

PURPOSE: It has previously been shown that follicle-stimulating hormone (FSH) and its receptor contribute to epithelial ovarian cancer (EOC) development. Epithelial-mesenchymal transition (EMT) is the early event of metastasis in cancer. Therefore, the aim of this study was to investigate the roles of FSH and the FSH receptor (FSHR) in EMT of EOC. METHODS: Ovarian cancer cells treated with various doses of FSH were used to investigate the effect of FSH on EMT. Small interfering RNA-mediated FSHR depletion or reexpression of FSHR by acute transfecting pcDNA-hFSHR plasmid was performed to determine the role of FSHR in FSH-induced EMT. Moreover, LY294002, a potent and specific cell-permeable inhibitor of phosphatidylinositol 3-kinases (PI3K), was selected to pretreat ovarian cancer cells to confirm whether PI3K/Akt signaling is involved in this event. RESULTS: In the current study, FSH was found to induce the phenotypes of EMT including migration and invasion in EOC cells. Elevated FSHR levels promoted EMT, migration, and invasion, whereas small interfering RNA-mediated FSHR knockdown inhibited these processes. Moreover, the inhibition of FSH-induced PI3K/Akt signaling pathway attenuated Snail expression and the EMT process. CONCLUSIONS: Collectively, the findings of the current study indicate that FSH induced the EMT of ovarian cancer cells through the FSHR-PI3K/Akt-Snail signaling pathway.

Collision of three histologically distinct endometrial cancers of the uterus.

A collision tumor is defined by the presence of two separate masses in one organ, which are pathologically distinct. We described a 70-yr-old patient who complained of abnormal vaginal bleeding with a collision tumor of the uterine corpus. The patient received total hysterectomy, bilateral salphingo-oophorectomy, bilateral pelvic-paraaortic lymphadenectomy, omentectomy, and intraperitoneal chemotherapy. The uterine corpus revealed three separate masses, which were located at the fundus, anterior and posterior wall. Each tumor revealed three pathologically different components, which were malignant mixed müllerian tumor, papillary serous carcinoma, and endometrioid adenocarcinoma. Among these components, only the papillary serous carcinoma component invaded the underlying myometrium and metastasized to the regional lymph node. Adjuvant chemotherapy and radiation therapy were performed. The patient is still alive and has been healthy for the last 8 yr. We have reviewed previously reported cases of collision tumors which have occurred in the uterine corpus.

Role of adjuvant chemotherapy in patients with early stage uterine papillary serous cancer.

OBJECTIVE: Uterine papillary serous carcinoma (UPSC) is an aggressive subtype of endometrial cancer. We studied survival outcomes in patients with stages I/II UPSC. MATERIALS: A retrospective, multi-institutional study of patients with stages I/II UPSC was conducted. Patients underwent surgical staging followed by observation, adjuvant platinum-based chemotherapy (CT), or radiation therapy (RT). Continuous variables were compared via Wilcoxon rank sum test; Fisher exact test was used for the unordered categorical variables. Kaplan-Meier curves were used to estimate survival. RESULTS: Thirty-nine women were diagnosed with stage I (n = 30) or II (n = 9) UPSC, with a median follow-up of 52 months. Of the 26 patients who did not receive adjuvant CT, 9 developed recurrences and 8 died of their disease. Of the 10 patients with no myometrial invasion who did not receive adjuvant CT, 3 developed recurrences and died. Of the 7 patients who underwent RT, 2 developed distant recurrences and died. Of the 13 patients who underwent CT, 1 developed vaginal recurrence. The 5-year overall (OS) and progression-free survival (PFS) rates for the adjuvant CT group were 100% and 92%, respectively, compared with 69% and 65% for those who did not receive CT (P = 0.002 OS, P = 0.002 PFS). The 5-year OS and PFS rates for RT group were both 71%. CONCLUSIONS: Patients with stages I/II UPSC are at significant risk for distant recurrence and poor survival. Platinum-based adjuvant CT may decrease recurrence rate and improve survival in women with early and well-staged UPSC.

Expression of αV-integrins in uterine serous papillary carcinomas; implications for targeted therapy with intetumumab (CNTO 95), a fully human antagonist anti-αV-integrin antibody.

OBJECTIVE: Uterine serous papillary carcinoma (USPC) is an aggressive variant of endometrial cancer characterized by an innate resistance to chemotherapy and poor prognosis. In this study, we evaluated the expression of αV-integrins in primary USPC cell lines and the in vitro ability of intetumumab (CNTO 95), a fully human monoclonal antibody against αV-integrins, to inhibit USPC cell adhesion and migration. MATERIALS AND METHODS: The surface expression of integrins belonging to the αV-family, including αVß3, αVß5, and αVß6, was evaluated in 6 primary USPC cell lines using flow cytometry analysis. To test the ability of intetumumab to inhibit USPC cell adhesion and migration, adhesion assays in the presence of vitronectin and migration assays through an 8.0-µm pore polycarbonate membrane also were performed. RESULTS: We found high expression of the αV-subunit on the cell surface of all 6 primary USPC cell lines tested (100% positive cells; mean fluorescence intensity range, 13.1-39.5). When the expression of single heterodimeric integrins was evaluated, αVß3, αVß5, and αVß6 were expressed on 37.5%, 32.0%, and 16.3% of cells (mean fluorescence intensity range, 6.5-16.2, 9.2-32.5, and 6.2-11.5, respectively). Importantly, in functional assays, low doses of intetumumab were effective in inhibiting adhesion (0.15 µg/mL, P = 0.003) and migration (1.25 µg/mL P = 0.02) of primary USPC cell lines. CONCLUSIONS: The αV-integrins are overexpressed on the cell surface of primary USPC cell lines. Intetumumab may significantly inhibit USPC cell adhesion and migration pathways and may therefore represent a novel treatment option for patients harboring this rare but highly aggressive variant of endometrial cancer.

Papillary serous adenocarcinoma of the uterine cervix: a case report.

Papillary serous adenocarcinoma of the endocervix (PSAE) is a rarely encountered neoplasm. The literature includes only a limited number of well documented case studies. The present study reports a case of papillary serous adenocarcinoma originating from the endocervix.

Prospective, non-randomized phase 2 clinical trial of carboplatin plus paclitaxel with sequential radical pelvic radiotherapy for uterine papillary serous carcinoma.

OBJECTIVE: Uterine Papillary Serous Carcinoma (UPSC) is uncommon and accounts for less than 5% of all uterine cancers. Therefore the majority of evidence about the benefits of adjuvant treatment comes from retrospective case series. We conducted a prospective multi-centre non-randomized phase 2 clinical trial using four cycles of adjuvant paclitaxel plus carboplatin chemotherapy followed by pelvic radiotherapy, in order to evaluate the tolerability and safety of this approach. METHODS: This trial enrolled patients with newly diagnosed, previously untreated patients with stage 1b-4 (FIGO-1988) UPSC with a papillary serous component of at least 30%. Paclitaxel (175 mg/m(2)) and carboplatin (AUC 6) were administered on day 1 of each 3-week cycle for 4 cycles. Chemotherapy was followed by external beam radiotherapy to the whole pelvis (50.4 Gy over 5.5 weeks). Completion and toxicity of treatment (Common Toxicity Criteria, CTC) and quality of life measures were the primary outcome indicators. RESULTS: Twenty-nine of 31 patients completed treatment as planned. Dose reduction was needed in 9 patients (29%), treatment delay in 7 (23%), and treatment cessation in 2 patients (6.5%). Hematologic toxicity, grade 3 or 4 occurred in 19% (6/31) of patients. Patients' self-reported quality of life remained stable throughout treatment. Thirteen of the 29 patients with stages 1-3 disease (44.8%) recurred (average follow-up 28.1 months, range 8-60 months). CONCLUSION: This multimodal treatment is feasible, safe and tolerated reasonably well and would be suitable for use in multi-institutional prospective randomized clinical trials incorporating novel therapies in patients with UPSC.

Primary serous papillary carcinoma of the peritoneum mimicking pelvic actinomycosis: a case report and brief literature review.

Primary serous papillary carcinoma of the peritoneum is a rare tumor, histologically similar to primary ovarian carcinoma. Pelvic CT and MRI are helpful to diagnose primary carcinoma of the peritoneum. We present a case of primary serous carcinoma of the peritoneum mimicking pelvic actinomycosis in a 59-year-old woman. Pelvic CT and MRI suggested pelvic actinomycosis. Exploratory laparotomy was performed to remove the mass and the diagnosis was confirmed by pathology. A subtotal hysterectomy, left salpingo-oophorectomy and omentectomy were performed. Histopathology examination revealed peritoneal carcinomatosis and primary serous carcinoma of the peritoneum. Pelvic CT and MRI were limited in their ability to differentiate inflammation, such as actinomycosis, from primary carcinoma of the peritoneum.

Differential sensitivity to platinum-based chemotherapy in primary uterine serous papillary carcinoma cell lines with high vs low HER-2/neu expression in vitro.

OBJECTIVE: We sought to identify effective chemotherapy regimens against uterine serous papillary adenocarcinoma (USPC). STUDY DESIGN: Six USPC, half of which overexpress HER-2/neu at 3+ level, were evaluated for growth rate and in vitro sensitivity to 14 single-agent chemotherapies and 5 combinations by ChemoFx (Precision Therapeutics Inc, Pittsburgh, PA). RESULTS: Cell lines overexpressing HER-2/neu showed higher proliferation when compared to low HER-2/neu-expressing cell lines and a lower half maximum inhibitory concentration (IC(50)) when exposed to the majority of single-agent chemotherapies. High HER-2/neu expressors were more sensitive to platinum compounds, manifesting a 5.22-fold decrease in carboplatin-IC(50) (P = .005) and a 5.37-fold decrease in cisplatin-IC(50) (P = .02). When all cell lines were analyzed as a group, chemotherapy agents tested demonstrated lower IC(50) when used in combination than as individual agents. CONCLUSION: USPC overexpressing HER-2/neu display greater in vitro sensitivity to platinum compounds when compared to low HER-2/neu expressors. Higher proliferative capability rather than increased drug resistance may be responsible for the adverse prognosis associated with HER-2/neu overexpression in USPC.

Palliative radiotherapy for the skin metastasis of ovarian cancer: a case report and review of the literature.

Ovarian cancer which is the most common cause of death among all gynecological malignancies tends to metastasize through peritoneal cavity. Skin metastasis, however, is a very rare clinical entity and related with poor prognosis. We report a 43-year-old patient with recurrent ovarian cancer presented with extensive abdominal skin metastasis approximately 6 years after the initial diagnosis. Patient was treated with radiotherapy with electrons to a total dose of 37.5 Gy given in 2.5 Gy per fraction per day. Skin metastasis showed good response to radiotherapy, and the patient has been alive for 7 months after radiotherapy with no recurrences on abdominal skin. Radiotherapy might be considered as an efficient palliative treatment option for the skin metastasis of ovarian cancer.