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The NCCN Guidelines for Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer provide multidisciplinary diagnostic workup, staging, and treatment recommendations for this disease. These NCCN Guidelines Insights detail how the evolution of the use of PARP inhibitors as maintenance and single-agent regimens for the treatment of ovarian cancer informed panel recommendations in the guidelines.

Vulvar cancer is annually diagnosed in an estimated 6,470 individuals and the vast majority are histologically squamous cell carcinomas. Vulvar cancer accounts for 5% to 8% of gynecologic malignancies. Known risk factors for vulvar cancer include increasing age, infection with human papillomavirus, cigarette smoking, inflammatory conditions affecting the vulva, and immunodeficiency. Most vulvar neoplasias are diagnosed at early stages. Rarer histologies exist and include melanoma, extramammary Paget's disease, Bartholin gland adenocarcinoma, verrucous carcinoma, basal cell carcinoma, and sarcoma. This manuscript discusses recommendations outlined in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for treatments, surveillance, systemic therapy options, and gynecologic survivorship.

The NCCN Guidelines for Cervical Cancer provide recommendations for all aspects of management for cervical cancer, including the diagnostic workup, staging, pathology, and treatment. The guidelines also include details on histopathologic classification of cervical cancer regarding diagnostic features, molecular profiles, and clinical outcomes. The treatment landscape of advanced cervical cancer is evolving constantly. These NCCN Guidelines Insights provide a summary of recent updates regarding the systemic therapy recommendations for recurrent or metastatic disease.

Objective: Controversy exists regarding optimal management of high risk localized endometrial cancer. Given that vaginal brachytherapy (VB) alone is used routinely at our institution, we retrospectively reviewed our outcomes among high risk patients defined according to the PORTEC, GOG 99, and/or Aalders randomized trials of pelvic radiation versus observation to determine if acceptable rates of locoregional control could be achieved with vaginal brachytherapy alone in this highest risk patient population., Methods: The Roswell Park Cancer Institute hospital tumor registry was used to identify all patients with Stage I or IIA endometrial cancer treated between January 1992 and June 2006. A total of 464 patients were identified. Of 261 patients who received post-operative RT, 225 received VB alone. Of those 225, 87 met the high risk criteria as designated by PORTEC (at least 2 of the following high risk features: age>60, Grade 3, and/or myometrial invasion >or=Occurrences of the mathematical operator' (='were changed to 'OE'. Please check.-->50%), GOG 99 (any age with 3 high risk features: Grade 2-3, >66% myometrial invasion, and/or LVSI; age >or=50 with 2 high risk features; or age >or=70 with 1 high risk feature), and/or Aalders (Stage IC, Grade 3). Descriptive recurrence statistics are provided., Results: Among 87 high risk patients treated with VB alone, 36, 77, and 14 were high risk per PORTEC, GOG 99, and Aalders respectively. Forty (46%) underwent pelvic lymph node dissection. With a median follow-up of 52 months, 3 (3.4%) pelvic recurrences were observed including 1 vaginal recurrence, 1 pelvic recurrence, and 1 local recurrence involving both the vagina and pelvis. All 3 local recurrences were successfully salvaged with pelvic RT+/-surgery., Conclusions: This represents one of the largest known series of high risk localized endometrial cancer treated with VB alone. The observed 3.4% locoregional recurrence compares favorably with the 5% locoregional recurrence noted among the highest risk patients receiving pelvic RT in the PORTEC, GOG 99, and Aalders randomized trials. In this single institution experience, the 3 local recurrences were salvaged. Based on these findings, we will continue to use VB alone in the adjuvant setting for patients with high risk localized endometrial cancer.

Several studies have investigated the associations between diet and endometrial cancer, but few have focused specifically on coffee and tea. In a hospital-based case-control study, we examined the associations between endometrial cancer risk and usual consumption of coffee, decaffeinated coffee, and black tea among 541 women with endometrial cancer and 541 women with an intact uterus but without a cancer diagnosis seen at Roswell Park Cancer Institute (Buffalo, New York) between 1982 and 1998. Daily frequency of consumption of coffee, decaffeinated coffee, and black tea in the few years prior to diagnosis in cases and questionnaire completion in controls was assessed with a self-administered epidemiologic questionnaire and categorized as none, 0.5 cups/d, 1-2 cups/d and >2 cups/d. Odds ratios (OR) and 95% confidence intervals (CI) for each category referent to nondrinkers were estimated with unconditional logistic regression adjusting for age, endometrial cancer risk factors and each beverage mutually adjusted for other beverages. Compared to nondrinkers, we observed a nonsignificant negative association with endometrial cancer risk among women who reported >2 cups/d regular coffee (OR 0.71, 95% CI 0.49-1.03), a significant inverse association with >2 cups/d black tea (OR 0.56, 95% CI 0.35-0.90) and a significant inverse association with >4 cups/d combined coffee and tea consumption (OR 0.47, 95% CI 0.28-0.80). These findings suggest coffee and tea may be important in reducing endometrial cancer risk.

We conducted a prospective study where 4 pathologists examined patients' problematic cases of cervical curetting for adenocarcinoma to determine whether it is of endocervical or endometrial origin based on 3 parameters: age, morphology, and immunohistochemistry (IHC) panel. Our aims were to evaluate the intraobserver and interobserver variability and to compare the results using those parameters to the final hysterectomy specimens. The value of morphology, morphology+age, and the combined parameters (morphology+age+IHC) in predicting the correct origin of the tumor was evaluated. The intraobserver agreements ranged from fair to almost perfect for each of morphology, morphology+age, and the combined parameters. The interobserver agreements were fair in the first review and ranged from slight to fair in the second review. The agreements between the diagnosis based on morphology, morphology+age, and the combined parameters compared with the final diagnosis on the hysterectomy specimen were slight (kappa=0.137), fair (kappa=0.290), and moderate (kappa=0.497), respectively. We concluded that (i) discriminating between endocervical and endometrial carcinoma is highly subject to intraobserver and interobserver variability. (ii) Surprisingly, this variability is not affected by pathologists' experience. (iii) An IHC panel adds a useful piece of information to predict the tumor origin. Lastly, even though the combination of morphology, age, and IHC is far from perfect in predicting the correct origin of the tumor, it is still the best available method.

We report 2 cases of desmoplastic small round cell tumor (DSRCT) involving the ovaries in young women. The first patient presented with symptoms of acute appendicitis and the second patient presented with a mass in the lower abdomen and slightly elevated CA-125 level. In both patients, the tumor was widely metastatic at presentation. The ovarian involvement was unilateral in the first patient and bilateral in the second with tumor size ranging from 9 to 11 cm. Morphology, immunohistochemistry, and molecular cytogenetics were consistent with DSRCT. Despite tumor debulking and multiple chemotherapy regimens, the first patient died at 20 months after initial diagnosis and the second is still undergoing chemotherapy at 7 months after initial presentation. To gain additional insight on DSRCT with ovarian involvement, the literature was reviewed and summarized.

NY-ESO-1 is a "cancer-testis" antigen expressed in epithelial ovarian cancer (EOC) and is among the most immunogenic tumor antigens defined to date. The NY-ESO-1 peptide epitope, ESO(157-170), is recognized by HLA-DP4-restricted CD4+ T cells and HLA-A2- and A24-restricted CD8+ T cells. To test whether providing cognate helper CD4+ T cells would enhance the antitumor immune response, we conducted a phase I clinical trial of immunization with ESO(157-170) mixed with incomplete Freund's adjuvant (Montanide ISA51) in 18 HLA-DP4+ EOC patients with minimal disease burden. NY-ESO-1-specific Ab responses and/or specific HLA-A2-restricted CD8+ and HLA-DP4-restricted CD4+ T cell responses were induced by a course of at least five vaccinations at three weekly intervals in a high proportion of patients. There were no serious vaccine-related adverse events. Vaccine-induced CD8+ and CD4+ T cell clones were shown to recognize NY-ESO-1-expressing tumor targets. T cell receptor analysis indicated that tumor-recognizing CD4+ T cell clones were structurally distinct from non-tumor-recognizing clones. Long-lived and functional vaccine-elicited CD8+ and CD4+ T cells were detectable in some patients up to 12 months after immunization. These results confirm the paradigm that the provision of cognate CD4+ T cell help is important for cancer vaccine design and provides the rationale for a phase II study design using ESO(157-170) epitope or the full-length NY-ESO-1 protein for immunotherapy in patients with EOC.

Purpose: This open-label study assessed the safety and immunogenicity of two doses and two routes of the anti-idiotypic monoclonal antibody abagovomab (formerly ACA125) in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer., Experimental Design: Eligible patients from the three participating institutions were any stage at diagnosis, had relapsed, and had complete or partial response to additional chemotherapy. Patients were randomized to receive abagovomab at 2.0 versus 0.2 mg and i.m. versus s.c. for four immunizations every 2 weeks and then monthly for two additional immunizations. Planned evaluation included interval physical examinations and laboratory assessments with immune assessment, including HLA typing, human anti-mouse antibody, ELISA, and enzyme-linked immunospot. Patients were required to remain on study until week 10 (the first post-baseline Ab3 determination) to be considered for immunologic assessment. The primary end points were safety and immunogenicity primarily determined by Ab3 response., Results: Forty-two patients received at least one vaccination and were eligible for safety analysis. Thirty-three patients were available for Ab3 analysis (removed for progression of disease, 6; withdrawal of consent, 2; unrelated adverse event, 1). The most common adverse events were self-limited pain at injection site, myalgia, and fever. No hematologic or nonhematologic toxicity grade>2 related to immunization was seen. Ab3 was detectable in all patients (median, 236,794 ng/mL); none of route of administration (P=0.6268), dose (P=0.4602), or cohort (P=0.4944) was statistically significant in terms of effect on maximum post-baseline Ab3 titer. Human anti-mouse antibody was not detectable at baseline but was present in all patients at week 16 (range, 488-45,000 ng/mL)., Conclusions: Immunization with abagovomab is well tolerated and induced robust Ab3 responses at the two doses and routes tested. A phase III randomized study with abagovomab (2.0 mg s.c.) is warranted.

Background: Current surgical recommendations for ovarian cancer prophylaxis in women at high risk of developing ovarian cancer include bilateral salpingo-oophorectomy (risk-reducing salpingo-oophorectomy (RRSO)). The role of hysterectomy is unclear. We sought to determine outcomes following prophylactic surgery in high-risk women., Methods: We surveyed unaffected members of the Gilda Radner Familial Ovarian Cancer Registry who had undergone oophorectomy from 1981 to 2002. Data were collected and analyzed for statistical significance by the Fisher's Exact Test., Results: Two hundred eighty women were surveyed, and 154 (55%) responded; 97% were Caucasian and 14% reported being Jewish. The median age of the respondents was 51 years (range 29-79); median age at oophorectomy was 41 years (range 15-68). Fifty-eight patients (38%) reported a laparoscopic procedure. One hundred five patients (68%) had a simultaneous hysterectomy, and 4 (3%) had a prior hysterectomy. Forty-four patients (29%) underwent BSO only. Of these 44 patients, 40 (91%) did not require a subsequent hysterectomy. Of the 4 who did, 2 were for leiomyomas, one for menorrhagia and the other was unknown. While not statistically significant, of the 3 patients who developed a subsequent gynecologic malignancy, all had undergone a hysterectomy. There was a statistically significant difference in whether or not the uterus was removed as part of the procedure by time period, whereby women treated prior to 1990 had a higher likelihood of having a hysterectomy (P = 0.03)., Conclusion: The women in our study did not require hysterectomy for prevention of malignancy. We conclude that one should screen for benign gynecological indications for hysterectomy when planning a prophylactic BSO for prevention of ovarian cancer. Other potential risk factors for endometrial cancer, including the role of UPSC in HBOC, remain to be elucidated.

Introduction: Primary fallopian tube carcinoma is a rare tumor. The aim of this study was to evaluate clinical characteristics and management of fallopian tube malignancies at a large tertiary care cancer institute., Methods: A retrospective review of the Tumor Registry was conducted to identify all primary fallopian tube carcinomas between 1980 and 2001. Medical charts were retrospectively reviewed. Primary endpoints were overall survival and disease recurrence., Results: Thirty-five patients had histology consistent with fallopian tube carcinoma. The median age at diagnosis was 56 years. The most common signs or symptoms were abnormal vaginal bleeding (29%) and abdominal/pelvic mass (26%). The most common histology was adenocarcinoma in 16 (46%) patients. Five patients (14%) were Stage I, seven patients (20%) Stage II, 17 patients (49%) Stage III and six patients (17%) Stage IV. Thirty-two (91%) patients received adjuvant chemotherapy and 77% received platinum-based chemotherapy. Twenty-seven (77%) patients underwent second-look surgery, of which 17 patients (63%) were positive for disease. The 5-year survival rate was 64% for Stage I, 42% for Stage II, 32% for Stage III, and 17% for Stage IV., Conclusions: Fallopian tube malignancies are rare and carry a poor prognosis. More extensive research needs to be performed to have definitive etiologic, diagnostic and treatment guidelines.

Objectives: Cancer-testis (CT) antigens are expressed in tumors but not normal tissues except the testis and could be targets for vaccine therapy in epithelial ovarian cancer (EOC). A-kinase anchoring protein 3 (AKAP-3) is a novel member of the CT antigen family. The aim of this study was to examine the expression of AKAP-3 in EOC and correlate with clinico-pathologic characteristics., Methods: One step RT-PCR was performed with RNA from normal and ovarian cancer cell lines and 74 epithelial ovarian tumor tissues. AKAP-3-specific PCR product was amplified. The distribution of AKAP-3 expression and clinico-pathologic variables was analyzed. Survival distributions were estimated, and multivariate analyses were performed., Results: AKAP-3 mRNA expression was demonstrated in 43/74 (58%) of the ovarian cancer specimens. AKAP-3 was expressed in normal testis, but not in other normal tissues. AKAP-3 expression significantly correlated with increased likelihood of residual tumor (P = 0.005), but no increase in the likelihood of recurrence or persistent disease (P = 0.06). Patients with AKAP-3 mRNA expression were found to have a significantly poorer overall survival (median 50 months) compared with patients without AKAP-3 expression (median not reached) (P = 0.007). Multivariate analysis of AKAP-3 expression, residual disease, and response to frontline chemotherapy found response to be the strongest predictor of overall survival (P = 0.012)., Conclusions: Our data demonstrate that AKAP-3 is expressed at high frequency in patients with EOC. Since AKAP-3 demonstrates tumor-restricted expression and appears to be associated with worse overall survival, it could represent an attractive target for antigen-specific immunotherapy in EOC.

Objective: It has been postulated that gemcitabine inhibits DNA repair, and platinum resistance is due to increased DNA repair activity. The addition of gemcitabine to platinum-based agents may have synergistic tumoricidal activity., Methods: Retrospective chart review of all patients with recurrent, persistent, or progressive fallopian tube or ovarian carcinoma treated with a platinum-based compound and gemcitabine from 2001 to present was performed., Results: Twenty-nine patients on second to eight line chemotherapy met inclusion criteria. The median age was 53 years. Twenty-two patients received cisplatin and gemcitabine, and 7 patients received carboplatin and gemcitabine based on results of chemoresistance assays or prior chemorelated toxicities. The intent to treat was with six cycles of gemcitabine (1000 mg/m(2)) and either cisplatin (75 mg/m(2)) or carboplatin (AUC 5) day 1 and gemcitabine only on day 8 of a 21-day cycle. The median number of cycles administered was six. There were 20 grade 3 and 4 toxicities and 63% of patients by cycle 6 needed erythropoietin marrow support and 19% needed GCSF support by cycle 4. Twenty-one patients required discontinuation of day 8 that most commonly occurred at cycle 4. Eleven (38%) had CR, 5 (17%) had PR, 6 (21%) had SD, and 7 (24%) had PD, which is a 55% overall response. Nineteen of 29 patients (66%) showed platinum resistance to initial therapy. Of those, four (21%) had CR, four (21%) had PR, six (32%) had SD, and five (26%) with PD, which demonstrates a 42% overall response rate for this particular subset of patients., Conclusions: Adjuvant combination platinum-based agent with gemcitabine is a very effective and well-tolerated treatment for recurrent fallopian tube or ovarian carcinoma; even in those who exhibit initial platinum resistance.

SCP-1 is a novel tumor antigen that belongs to the growing family of cancer/testis (CT) antigens, and it is a potential target for immunotherapy. In an effort to determine the expression of SCP-1 in epithelial ovarian cancer (EOC), one-step RT-PCR was performed with RNA from epithelial ovarian tumor tissues and with two normal ovarian surface epithelial cell lines. We used immunohistochemistry (IHC) to investigate SCP-1 expression in paraffin-fixed EOC samples and ELISA to test sera from a subgroup of patients for SCP-1 antibody. SCP-1 was expressed in 15 out of 100 (15%) primary tumors, as determined by RT-PCR. The normal ovarian surface epithelial cell lines were negative for SCP-1 expression, as were a panel of other normal tissues. None of the patients whose tumors were determined to be SCP-1 positive by RT-PCR expressed the antigen by IHC or demonstrated a humoral immune response by ELISA. Tumors that expressed SCP-1 mRNA tended to have a higher grade than those that did not (P = 0.03). There was a significant decrease in survival time (P = 0.004) for patients with SCP-1 mRNA-positive tumors compared to those with SCP-1 mRNA-negative tumors [median 25 mo, 95% confidence interval (CI) 0-56 mo; and median 97 mo, CI 32-162 mo, respectively]. The present study shows that SCP-1 mRNA expression in patients with EOC is associated with a poorer chance of survival. These findings imply that further evaluation of SCP-1 as a potential target for vaccine therapy in EOC is warranted.

Objectives: The time interval between diagnoses of breast and epithelial ovarian cancer is not well established in women with dual primary tumors of both organ sites. Our goals were to examine the time interval between diagnoses and identify any relationship to clinicopathologic factors., Methods: We identified 49 patients who developed both cancers. These patients were divided into two groups: group 1 patients developed breast cancer first, group 2 patients had ovarian before breast cancer. The risk of a BRCA1 or BRCA2 mutation in our study subjects was estimated using the BRCAPRO. Parameters were compared using either the chi(2) or the Kruskal-Wallace test., Results: There were 26 and 23 patients in groups 1 and 2, respectively. The mean time interval was longer in group 2 (86 vs. 45 months; P = 0.013). Median PFS and OS were longer in group 2 for both cancers [PFS: 161 vs. 61 months for breast (P = 0.85) and 132 vs. 39 months for ovarian (P = 0.019); OS: 250 vs. 115 months for breast (P = 0.77) and 277 vs. 42 months for ovarian (P = 0.0013)]. OS was longer in group 2 for both cancers combined 217 vs. 115 (P = 0.026). The estimated risk of BRCA mutation was at least 20% in the majority of the patents., Conclusions: Our data indicates that the time interval between the diagnosis of breast and ovarian carcinomas is 4 years. In contrast, the time interval between the diagnosis of ovarian and breast carcinomas is 7 years. These results could be useful in counseling women at risk.

Objective: We investigated whether monocyte-derived factors could stimulate the growth of ovarian cancer cells., Study Design: Human peripheral blood monocytes or human monocyte-like cell lines THP-1 and U-937 were cultured with or without macrophage colony-stimulating factor, lipopolysaccharide, or phorbol myristate acetate. Culture supernatants or recombinant cytokines were assayed for growth stimulation of ovarian cancer cell lines by tritium-thymidine incorporation and direct cell counts followed by statistical analysis with Student t test., Results: Conditioned medium from peripheral blood monocytes or from THP-1 or U-937 cells stimulated ovarian cancer cell growth. Interleukin-1 alpha, tumor necrosis factor-alpha, and interleukin-6 also stimulated ovarian cancer cell growth, whereas macrophage, granulocyte, and granulocyte-macrophage colony-stimulating factor did not. Concentrations of tumor necrosis factor, interleukin-1, and interleukin-6 in conditioned medium could not account for all the growth stimulation, and activity remained after neutralization of tumor necrosis factor, interleukin-1, and interleukin-6 with antibodies., Conclusions: Interleukin-1, interleukin-6, tumor necrosis factor, and additional monocyte factor(s) could provide paracrine growth stimulation when monocytes are attracted to ovarian cancers that produce macrophage colony-stimulating factor.