Prognostic impact of clinical tumor size on overall survival for subclassifying stages I and II vaginal cancer: A SEER analysis.

PURPOSE: This study accessed the Surveillance, Epidemiology and End Results (SEER) database to determine if tumor size is an independent predictor of overall survival (OS) for patients with stages I and II vaginal cancer (VC). MATERIALS AND METHODS: We identified in the SEER database, patients with available tumor size having stage I or II squamous cell histology from January 2004 through December 2012 with minimum follow-up of six months. Univariate analyses (UA) and multivariable analyses (MVA) evaluated the effect of several prognostic factors, including tumor size, regarding OS. RESULTS: 529 SEER patients were found with recorded tumor sizes, of which 293 (55.4%) were stage I and 236 (44.6%) stage II. UA found the following significant prognostic factors of worse OS: tumor size >2cm (HR=1.80, p=0.02) and older age at diagnosis (p<0.001) in stage I; and tumor size >2cm (HR=2.13, p=0.04) and older age at diagnosis (p<0.001) in stage II. Estimates of 5-year OS in patients with tumor size ≤2cm vs. >2cm were 79.2% vs. 66.1% in stage I (p=0.0187) and 80.9% vs. 51.2% in stage II (p=0.0369). MVA confirmed about double risk of death for patients with tumor size >2cm (HRs: 1.88 in stage I and 2.06 in stage II). CONCLUSIONS: Tumor size seems to predict OS outcome in patients with stages I/II VC. Further confirmatory investigations are recommended to firmly establish its incorporation into currently accepted staging criteria for these patients.

Teleoncology for gynecologic cancers.

Teleoncology describes cancer care provided remotely to improve access to care in rural or underserved areas. In the United States, 14.8 million women live more than 50 miles away from the closest gynecologic oncologist; 4.3 million women live more than 100 miles distant. Teleoncology may therefore partially relieve the geographic barriers to high-quality gynecologic cancer care these women experience. Little has been published on the feasibility of remote provision of high-quality care for gynecologic cancers, perhaps owing to the particular difficulties inherent in remote management of patients who may require both medical and surgical intervention. In this article, we review the data supporting the use of telemedicine in the treatment of cancer patients with a specific focus on applicability to management of gynecologic malignancies. We further add our group's experience with the treatment of rural, underserved gynecologic cancer patients. We believe that development of teleoncologic systems is critical to ensure that all women have access to high-quality gynecologic cancer care, regardless of where they reside.

Society of Gynecologic Oncology recommendations for the prevention of ovarian cancer.

Mortality from ovarian cancer may be dramatically reduced with the implementation of attainable prevention strategies. The new understanding of the cells of origin and the molecular etiology of ovarian cancer warrants a strong recommendation to the public and health care providers. This document discusses potential prevention strategies, which include 1) oral contraceptive use, 2) tubal sterilization, 3) risk-reducing salpingo-oophorectomy in women at high hereditary risk of breast and ovarian cancer, 4) genetic counseling and testing for women with ovarian cancer and other high-risk families, and 5) salpingectomy after childbearing is complete (at the time of elective pelvic surgeries, at the time of hysterectomy, and as an alternative to tubal ligation). The Society of Gynecologic Oncology has determined that recent scientific breakthroughs warrant a new summary of the progress toward the prevention of ovarian cancer. This review is intended to emphasize the importance of the fallopian tubes as a potential source of high-grade serous cancer in women with and without known genetic mutations in addition to the use of oral contraceptive pills to reduce the risk of ovarian cancer.

The impact of liquid-based cytology in decreasing the incidence of cervical cancer.

Major advances in screening have lowered the death rate from cervical cancer in the United States. One of the first major advances in cervical cancer screening was the Papanicolaou (Pap) test. The second major advance was liquid-based cytology (LBC). This review presents a wide range of data, discusses the strengths and weaknesses of the available information regarding Pap technologies, and reviews the meta-analyses, which have examined the differences in clinical performance. The review concludes with information on new and future developments to further decrease cervical cancer deaths.

Ovarian cancer patient surveillance after curative-intent initial treatment.

OBJECTIVE: Patient surveillance after potentially curative treatment of ovarian carcinoma has important clinical and financial implications for patients and society. The optimal intensity of surveillance for these patients is unknown. We aimed to document the current follow-up practice patterns of gynecologic oncologists. METHODS: We created four idealized vignettes describing patients with stages I-III ovarian cancer. We mailed a custom-designed survey instrument based on the vignettes to the members of the Society of Gynecologic Oncologists (SGO). SGO members were asked, via this instrument, how often they requested 11 discrete follow-up evaluations for their patients for the first 10 postoperative years after treatment with curative intent. RESULTS: We received 283 evaluable responses (30%) from the 943 SGO members and candidate members. The most frequently performed items for each year were office visit, pelvic examination, and serum CA-125 level. Imaging studies such as chest X-ray, abdominal-pelvic CT, chest CT, abdominal-pelvic MRI, and transvaginal ultrasound were rarely recommended. There was marked variation in the frequency of use of most tests. There was a decrease in the frequency of testing over time for all modalities. CONCLUSION: This dataset provides detailed documentation of the self-reported surveillance practices of highly credentialed experts who manage patients with ovarian cancer in the 21st century. The optimal follow-up strategy remains unknown and controversial. Our survey showed marked variation in surveillance intensity. Identifying the sources of this variation warrants further research.

ATR mutation in endometrioid endometrial cancer is associated with poor clinical outcomes.

PURPOSE Mutations in the DNA damage response gene ATR (exon 10 A10 mononucleotide repeat) have been previously described in endometrial and other cancers with defective DNA mismatch repair. In vitro studies showed that endometrial cancer cell lines with A10 repeat tract truncating mutations have a failure in the ATR-dependent DNA damage response. Cell lines carrying A10 mutations fail to trigger Chk1 activation in response to ionizing radiation and topoisomerase inhibitors. We sought to determine the frequency and clinicopathologic significance of ATR mutations in patients with endometrioid endometrial cancer. PATIENTS AND METHODS The ATR exon 10 A10 repeat was analyzed by direct sequencing in 141 tumors with microsatellite instability (MSI-positive) and 107 microsatellite stable (MSI-negative) tumors. The relationships between mutations and clinicopathologic variables, including overall and disease-free survival, were assessed using contingency table tests and Cox proportional hazard models. Results ATR mutations were identified in 12 cases (4.8%; three cases with insertions and nine cases with deletions). Mutations occurred exclusively in MSI-positive tumors (P = .02), with an overall mutation rate of 8.5%. Mutation was not associated with age, race, surgical stage, International Federation of Gynecology and Obstetrics grade, or adjuvant treatment. Multivariate analyses revealed a significant association with reduced overall survival (hazard ratio [HR] = 3.88; 95% CI, 1.64 to 9.18; P = .002) and disease-free survival (HR = 4.29; 95% CI, 1.48 to 12.45; P = .007). CONCLUSION Truncating ATR mutations in endometrial cancers are associated with biologic aggressiveness as evidenced by reduced disease-free and overall survival. Knowledge of ATR mutation status may hold promise for individualized treatment and targeted therapies in patients with endometrial cancer.

Phase II evaluation of topotecan and navelbine in patients with recurrent ovarian, fallopian tube or primary peritoneal cancer.

OBJECTIVE: To assess the efficacy and toxicity profile in patients with recurrent ovarian or primary peritoneal cancer treated with topotecan at 2.5 mg/m(2) days 1 and 8 plus vinorelbine at 25 mg/m(2) days 1 and 8 every 3 weeks. MATERIALS AND METHODS: Eligibility criteria included patients with recurrent primary peritoneal or epithelial ovarian cancer with either platinum-resistant or platinum-sensitive disease. Patients were required to have a performance status of

CD83 gene polymorphisms increase susceptibility to human invasive cervical cancer.

We previously mapped a nonrandom frequent loss of heterozygosity (LOH) region in cervical cancers to 1 Mb of 6p23. Here, we describe the identification of a novel cervical cancer susceptibility gene, CD83. The gene was identified by several complementary approaches, including a family-based association study, comparison of transcript expression in normal and cancerous tissue, and genomic sequencing of candidate. CD83 encodes an inducible glycoprotein in the immunoglobulin superfamily and is a marker for mature dendritic cells. The association study that includes 377 family trios showed that five single nucleotide polymorphisms (SNP) within 8 kb of its 3'-end showed significant allelic association that was strengthened in a subgroup of women with invasive cancers infected by high-risk human papillomavirus type 16 and 18 (rs9296925, P = 0.0193; rs853360, P = 0.0035; rs9230, P = 0.0011; rs9370729, P = 0.0012; rs750749, P = 0.0133). Investigation of CD83 uncovered three alternative transcripts in cervical tissue and cell lines, with variant 3 (lacking exons 3 and 4) being more frequent in cervical cancer than in normal cervical epithelium (P = 0.0181). Genomic sequencing on 36 paired normal and cervical tumors revealed several somatic mutations and novel SNPs in the promoter, exons, and introns of CD83. LOH was confirmed in >90% of cervical cancer specimens. Immunofluorescence colocalized CD83 protein to the Golgi apparatus and cell membrane of cervical cancer cell lines. None of seven nearby genes was differentially expressed in cervical cancer. The importance of CD83 in epithelial versus dendritic cells needs to be determined, as does its role in promoting cervical cancer.

Bevacizumab therapy in patients with recurrent uterine neoplasms.

BACKGROUND: Angiogenesis plays an important role in endometrial carcinogenesis. We reviewed our experience with the anti-VEGF monoclonal antibody bevacizumab for the treatment of recurrent uterine neoplasms. PATIENTS AND METHODS: A retrospective analysis of women with recurrent uterine neoplasms treated with bevacizumab was performed. RESULTS: A total of 11 patients were identified, 9 with epithelial endometrial carcinomas and 2 with leiomyosarcomas. All patients had multi-site disease and were heavily pretreated with a median of 3 prior chemotherapy regimens. All received bevacizumab combination therapy which was well-tolerated. Two patients had partial responses, 3 had stable disease, while 5 patients progressed. One subject was not assessable for response. The median progression-free interval was 5.4 months for the entire cohort and 8.7 months for those who achieved clinical benefit (PR or SD). CONCLUSION: Bevacizumab was well-tolerated and displayed promising anti-neoplastic activity in patients with endometrial cancer and uterine leiomyosarcoma.

Acute toxicity of postoperative IMRT and chemotherapy for endometrial cancer.

PURPOSE: The aim of this study was to determine the acute toxicity of postoperative intensity-modulated radiotherapy (IMRT) with and without chemotherapy in patients with endometrial cancer. MATERIALS AND METHODS: A total of 19 patients with stages IB-IVB endometrial cancer who underwent surgery and postoperative IMRT were reviewed. The treatment planning goal was to cover the tissue at risk and minimize the dose to the bladder, bowel, and bone marrow. Median dose was 50.4 Gy (range 49.6-51.2 Gy). Altogether, 14 patients underwent chemotherapy; most were given carboplatin and paclitaxel. Toxicity was scored according to the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE). RESULTS: The prescribed radiation treatment was completed in all patients. The prescribed cycles of chemotherapy were completed in all 14 patients, except one who received five of six cycles limited by prolonged thrombocytopenia. Chemotherapy was delayed in two patients (14%). Three patients required growth factor support during chemotherapy, and one patient required a blood transfusion. Acute grades 3-4 hematological toxicity occurred in 9 of the 14 patients (64%) who underwent chemotherapy. None experienced acute grade 3 or 4 genitourinary or gastrointestinal toxicity. CONCLUSION: Adjuvant IMRT and chemotherapy following surgery in patients with endometrial cancer is well tolerated and did not lead to treatment modification in most patients.

Novel cytotoxic agents from an unexpected source: bile acids and ovarian tumor apoptosis.

OBJECTIVE: Unique biologic activities have been identified for the 4 different bile acids: cholic acid (CA, chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), and ursodeoxycholic acid (UDCA). The aim of this study was to examine and compare the effects of these 4 bile acids on the human ovarian cancer cell lines A2780 and A2780-CP-R(cisplatin-resistant) and to evaluate mechanisms of action. METHODS: Antiproliferative effects were determined by the cytotoxic MTT assay. Cells undergoing apoptosis were identified by morphologic analysis of cells stained using Diff-Quick and nuclear staining with DAPI and by quantitative nucleosome ELISA assay. Cells were lysed in buffer after 24 h of exposure to three different concentrations of bile acid (50 mM, 200 mM, and 400 mM) and protein concentrations were determined. Cell extracts containing 25 mg of protein were assayed for protein kinase C (PKC) enzyme activity. RESULTS: None of the bile acids stimulated proliferation of ovarian cancer cells. CA and UDCA had only minimal cytotoxic effect even at maximum concentrations. In contrast, DCA and CDCA administration resulted in statistically significant dose-dependent cytotoxicity in both platinum sensitive and platinum-resistant cell lines (p<0.05). Cells incubated with DCA and CDCA exhibited morphologic features characteristic of apoptosis. The quantitative nucleosome ELISA assay demonstrated over 10 times increased nucleosome levels after cells were treated for 24 h by DCA and CDCA at 200 mM and 400 mM as compared to CA or UDCA treatment and to untreated controls (p<0.01). All 4 bile acids reduced PKC activity at concentrations of 200 and 400 mM (p<0.01). CONCLUSIONS: CDCA and DCA have significant cytotoxic activity in ovarian cancer cells via induction of apoptosis. The mechanism of apoptosis appears to be mediated by alternative kinases distinct from PKC. CDCA and DCA may have clinical utility in the treatment of ovarian cancer pending in vivo confirmation of activity especially in cisplatin-resistant disease.

Effect of a T0 radical hysterectomy specimen on survival for early stage cervical cancer.

OBJECTIVE: : Radical hysterectomy with regional lymphadenectomy is the surgical procedure of choice for stage IA-IIA cervical carcinoma. The goal of this study was to evaluate the outcome of patients with no residual tumor (T0) in their hysterectomy specimens. METHODS: : An analysis of all women who underwent type II or III hysterectomy for invasive cervical cancer from 1989 to 2005 was performed. The pathologic data and clinical outcome of each patient was documented. T0 subjects were compared to the remainder of the cohort. Survival was evaluated with the Kaplan-Meier method. RESULTS: : A total of 594 patients were identified. No residual tumor was noted in the hysterectomy specimens of 171 (29%). T0 patients had earlier stage tumors than the controls (IA 32%, IB 68%) (p<0.0001). Lymphadenectomy was performed in 89% of the T0 subjects. No T0 patients had lymphatic or parametrial disease. The median node yield was similar between the T0 group and those with residual tumors (24 vs. 25) (p=0.34). Adjuvant therapy was not administered to any of the T0 subjects. There were no recurrences and no cancer-related deaths in the T0 patients. Kaplan-Meier analysis revealed an improved disease free (p<0.0001) and overall survival (p<0.0001) for the T0 subjects compared to women with residual tumors. The results were similar when the analysis was restricted to stage IB1 patients (p=0.0004 and 0.002). CONCLUSIONS: : A T0 radical hysterectomy specimen indicates a curative therapy. This subgroup of patients has a favorable prognosis with minimal risk of recurrence. Patients with T0 tumors may be candidates for less intensive, abbreviated follow-up.

Utility of parametrectomy for early stage cervical cancer treated with radical hysterectomy.

BACKGROUND: Removal of the parametrial soft tissue is recommended for patients with cervical cancer undergoing radical hysterectomy. Parametrectomy results in significant morbidity. The objective of the study was to determine factors predictive of parametrial tumor spread and to define a subset of patients at low risk for parametrial disease. METHODS: Patients with invasive cervical cancer who underwent radical hysterectomy from 1989-2005 were examined. Analysis was performed to determine factors associated with parametrial tumor spread. Survival estimates were determined using the Kaplan-Meier method. RESULTS: A total of 594 patients were identified. Parametrial metastases were documented in 64 (10.8%). Factors associated with parametrial disease were: histology, advanced grade, deep cervical invasion, lymphovascular space invasion (LVSI), large tumor size, advanced stage, uterine or vaginal involvement, and pelvic or para-aortic lymph node metastases (P < .0001 for each). Parametrial metastases were associated with increased risk of recurrence and decreased disease-free and overall survivals (P < .0001). A subgroup analysis was performed to identify patients at low risk for parametrial spread. In pelvic node-negative women parametrial disease was noted in 6.0% (30/498) compared with 47.9% (34 of 71) of those with positive pelvic nodes (P < .0001). If further stratified to women with negative nodes, no LVSI, and tumors < 2 cm, the incidence of parametrial disease was only 0.4%. CONCLUSIONS: Parametrial spread is a strong predictor of recurrence and decreased survival. Parametrial invasion is rare in patients with small tumors, no LVSI, and negative pelvic nodes (no poor prognostic factors). Further study is warranted to determine the feasibility of omitting parametrectomy in these low-risk patients.

Microsatellite instability and epigenetic inactivation of MLH1 and outcome of patients with endometrial carcinomas of the endometrioid type.

PURPOSE: Most studies of microsatellite instability (MSI) and outcomes in endometrial cancer patients have included varied histologic subtypes. Nonetheless, MSI occurs almost exclusively in endometrioid tumors. The impact of MSI on outcomes in patients with endometrial cancer is controversial. We sought to determine whether MSI and MLH1 methylation are associated with clinicopathologic variables and survival outcomes in a large series of patients with endometrial carcinomas of the endometrioid type. PATIENTS AND METHODS: Tumor samples, blood, and clinicopathologic data were prospectively collected and analyzed for 446 patients with endometrioid carcinomas. MSI was determined using five National Cancer Institute (NCI) consensus panel markers, and the methylation status of the MLH1 promoter was determined by combined bisulfite restriction analysis (COBRA). Associations with clinicopathologic variables and survival outcomes were evaluated. RESULTS: MSI was identified in 147 cases (33%). MSI was associated with higher International Federation of Gynecology and Obstetrics (FIGO) grade (P < .0001). MSI+ tumors without MLH1 methylation were associated with younger age (P < .001). MSI was not associated with overall survival (OS; hazard ratio [HR], 1.011; 95% CI, 0.688 to 1.484; P = .96) or disease-free survival (DFS; HR 0.951; 95% CI, 0.554 to 1.635; P = .86). The combined MSI/MLH1 methylation status (treating MSI- as the reference) did not predict OS (MSI+/MLH1-U: HR, 0.62; 95% CI, 0.27 to 1.44; P = .26; MSI+/MLH1-M: HR, 0.95; 95% CI, 0.62 to 1.46; P = .82) or DFS (MSI+/MLH1-U: HR, 0.51; 95% CI, 0.22 to 1.19; P = .12; MSI+/MLH1-M: HR, 0.93; 95% CI, 0.62 to 1.40; P = .72). CONCLUSION: MSI is not associated with survival in patients with endometrioid endometrial cancer.

Body mass index: relationship to clinical, pathologic and features of microsatellite instability in endometrial cancer.

OBJECTIVES: There is a well known association between obesity and endometrial cancer. We sought to examine the relationships between body mass index (BMI), as a measure of obesity, and known demographic, clinical, and molecular characteristics of microsatellite instability and MLH1 promoter methylation in a cohort of patients with endometrial cancer. METHODS: Corpus cancer specimens were prospectively obtained from 473 consecutively enrolled patients between 1992 and 2004. Clinical and pathologic data were extracted from review of the medical record. Microsatellite instability (MSI) was evaluated in all tumors, and methylation of the MLH1 promoter was determined for MSI positive tumors. RESULTS: The median (SD) age and BMI were 64.8 years (11.9) and 33.5 (9.4), respectively. Histology included 376 endometrioid (79%), 69 serous/clear cell or mixed (15%), and 28 sarcomas (6%). Median BMI was 32.4 for endometrioid, 31.0 for serous/clear cell or mixed, and 27.8 for sarcomas (p=0.14). BMI was negatively associated with age at surgery (p<0.01). The remainder of analyses excluded sarcoma histology. BMI was associated with stage of disease; patients with stage I/II disease had significantly higher BMI than those with stage III/IV disease (32.6 vs. 30.6; p=0.02). In relation to molecular features of endometrial cancer, BMI was significantly different between MSI positive tumors compared to MSI negative tumors (30.3 vs. 32.7; p=0.02). MSI was also significantly different between tumor histology, occurring with a higher frequency in Type I than Type II tumors (p<0.01). CONCLUSIONS: The majority of endometrial cancer patients are obese. Those with higher BMI are more likely to be younger, present with early stage disease, and have MSI negative tumors.

Comparison of high-dose-rate and low-dose-rate brachytherapy in the treatment of endometrial carcinoma.

PURPOSE: To compare the outcomes for endometrial carcinoma patients treated with either high-dose-rate (HDR) or low-dose-rate (LDR) brachytherapy. METHODS AND MATERIALS: This study included 1,179 patients divided into LDR (1,004) and HDR groups (175). Patients with International Federation of Gynecology and Obstetrics (FIGO) surgical Stages I-III were included. All patients were treated with postoperative irradiation. In the LDR group, the postoperative dose applied to the vaginal cuff was 60-70 Gy surface doses to the vaginal mucosa. The HDR brachytherapy prescription was 6 fractions of 2 Gy each to a depth of 0.5 cm from the surface of the vaginal mucosa. Overall survival, disease-free survival, local control, and complications were endpoints. RESULTS: For all stages combined, the overall survival, disease-free survival, and local control at 5 years in the LDR group were 70%, 69%, and 81%, respectively. For all stages combined, the overall survival, disease-free survival, and local control at 5 years in the HDR group were 68%, 62%, and 78%, respectively. There were no significant differences in early or late Grade III and IV complications in the HDR or LDR groups. CONCLUSION: Survival outcomes, pelvic tumor control, and Grade III and IV complications were not significantly different in the LDR brachytherapy group compared with the HDR group.

Outcomes in 24 selected patients with stage IVB cervical cancer and excellent performance status treated with radiotherapy and chemotherapy.

PURPOSE: We sought to review outcomes in patients with stage IVB carcinoma of the cervix treated with irradiation in combination with chemotherapy. MATERIALS AND METHODS: We report outcomes of 24 consecutive patients with good performance status treated from 1998 to 2005. Most of these patients underwent concurrent irradiation with platinum-based chemotherapy. Some patients received subsequent systemic chemotherapy. RESULTS: All patients underwent external beam radiotherapy; 7 patients (29%) had additional high-dose-rate and 12 (50%) low-dose-rate brachytherapy. Two patients (8%) received an IMRT boost instead of brachytherapy. The mean dose to point A was variable (73.9 +/- 19.2 Gy). Twenty patients (83%) received radio-sensitizing platinum-based chemotherapy, and the remaining had radiotherapy alone. Seven patients (29%) had further combination chemotherapy. Therapy was well tolerated. The overall survival was 44% at 36 months and 22% at 5 years. CONCLUSION: Patients with stage IVB cervical cancer have mostly been treated with palliative intent. With the advent of concurrent chemoradiation, we have treated many of these cases with aggressive combination therapy. In this series, the use of radiotherapy and multiagent chemotherapy in patients with stage IVB cervical carcinoma and good performance status was well tolerated and resulted in higher survival rates than previously reported.

Colposcopic accuracy of obstetrics and gynecology residents.

OBJECTIVE: The objective of our study was to determine the accuracy of gynecology residents' colposcopic impressions. METHODS: A retrospective review of colposcopic examinations was performed. Colposcopic impressions were compared to cervical biopsy and the results stratified by level of residency training. kappa Statistics were calculated to determine the strength of correlation between impression and biopsy results. RESULTS: Agreement within one-step between cervical histology and the colposcopic impression was found in 351 (77%) of the subjects. Histology impression agreement occurred in 92% of the nurse practitioner procedures, 77% of the second year resident (R2) cases, 75% of R3 colposcopies and 73% of the R4 procedures. The association between cervical biopsy and impression was highly significant (P<0.0001). However, the strength of the correlation was only slight (kappa=0.197). The kappa value was highest for the nurse practitioners (0.376, fair correlation) and lowest for the R3 residents (0.110, slight correlation). The positive predictive value for the association of any colposcopically detected abnormality with any histologic abnormality was 64.1%. The overall PPV was highest for the nurse practitioners (79.3%) and lowest for the R2 residents (58.7%). CONCLUSIONS: While the colposcopic impressions of gynecology residents were accurate, there was little difference in the accuracy of colposcopic assessment based upon the level of resident training.