Clinicopathologic characteristics associated with long-term survival in advanced epithelial ovarian cancer: an NRG Oncology/Gynecologic Oncology Group ancillary data study.

OBJECTIVE: To identify clinicopathologic factors associated with 10-year overall survival in epithelial ovarian cancer (EOC) and primary peritoneal cancer (PPC), and to develop a predictive model identifying long-term survivors. METHODS: Demographic, surgical, and clinicopathologic data were abstracted from GOG 182 records. The association between clinical variables and long-term survival (LTS) (>10years) was assessed using multivariable regression analysis. Bootstrap methods were used to develop predictive models from known prognostic clinical factors and predictive accuracy was quantified using optimism-adjusted area under the receiver operating characteristic curve (AUC). RESULTS: The analysis dataset included 3010 evaluable patients, of whom 195 survived greater than ten years. These patients were more likely to have better performance status, endometrioid histology, stage III (rather than stage IV) disease, absence of ascites, less extensive preoperative disease distribution, microscopic disease residual following cyoreduction (R0), and decreased complexity of surgery (p<0.01). Multivariable regression analysis revealed that lower CA-125 levels, absence of ascites, stage, and R0 were significant independent predictors of LTS. A predictive model created using these variables had an AUC=0.729, which outperformed any of the individual predictors. CONCLUSIONS: The absence of ascites, a low CA-125, stage, and R0 at the time of cytoreduction are factors associated with LTS when controlling for other confounders. An extensively annotated clinicopathologic prediction model for LTS fell short of clinical utility suggesting that prognostic molecular profiles are needed to better predict which patients are likely to be long-term survivors.

Evaluation of a chemoresponse assay as a predictive marker in the treatment of recurrent ovarian cancer: further analysis of a prospective study.

BACKGROUND: Recently, a prospective study reported improved clinical outcomes for recurrent ovarian cancer patients treated with chemotherapies indicated to be sensitive by a chemoresponse assay, compared with those patients treated with non-sensitive therapies, thereby demonstrating the assay's prognostic properties. Due to cross-drug response over different treatments and possible association of in vitro chemosensitivity of a tumour with its inherent biology, further analysis is required to ascertain whether the assay performs as a predictive marker as well. METHODS: Women with persistent or recurrent epithelial ovarian cancer (n=262) were empirically treated with one of 15 therapies, blinded to assay results. Each patient's tumour was assayed for responsiveness to the 15 therapies. The assay's ability to predict progression-free survival (PFS) was assessed by comparing the association when the assayed therapy matches the administered therapy (match) with the association when the assayed therapy is randomly selected, not necessarily matching the administered therapy (mismatch). RESULTS: Patients treated with assay-sensitive therapies had improved PFS vs patients treated with non-sensitive therapies, with the assay result for match significantly associated with PFS (hazard ratio (HR)=0.67, 95% confidence interval (CI)=0.50-0.91, P=0.009). On the basis of 3000 simulations, the mean HR for mismatch was 0.81 (95% range=0.66-0.99), with 3.4% of HRs less than 0.67, indicating that HR for match is lower than for mismatch. While 47% of tumours were non-sensitive to all assayed therapies and 9% were sensitive to all, 44% displayed heterogeneity in assay results. Improved outcome was associated with the administration of an assay-sensitive therapy, regardless of homogeneous or heterogeneous assay responses across all of the assayed therapies. CONCLUSIONS: These analyses provide supportive evidence that this chemoresponse assay is a predictive marker, demonstrating its ability to discern specific therapies that are likely to be more effective among multiple alternatives.

BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel: a Gynecologic Oncology Group Study.

BACKGROUND: Breast cancer 1, early onset (BRCA1) is a tumour-suppressor gene associated with familial epithelial ovarian cancer (EOC). Reduced BRCA1 expression is associated with enhanced sensitivity to platinum-based chemotherapy. We sought to examine the prognostic relevance of BRCA1 expression in EOC patients treated with intraperitoneal platinum/taxane. METHODS: The GOG-172 was a phase III, multi-institutional randomised trial of intravenous paclitaxel and cisplatin (IV therapy) vs intravenous paclitaxel, intraperitoneal cisplatin plus paclitaxel (IP therapy) in patients with optimally resected stage III EOC. The BRCA1 expression was assessed with immunohistochemistry (IHC) staining blinded to clinical outcome in archival tumour specimens. Slides with 10% staining were defined as aberrant and >10% as normal. Correlations between BRCA1 expression and progression-free survival (PFS) and overall survival (OS) were analysed using Kaplan-Meier method and Cox regression analysis. RESULTS: Of the 393 patients, 189 tumours had aberrant expression, and 204 had normal BRCA1 expression. There was an interaction between BRCA1 expression and route of administration on OS (P=0.014) but not PFS (P=0.054). In tumours with normal BRCA1 expression, the median OS was 58 months for IP group vs 50 months for IV group (P=0.818). In tumours with aberrant BRCA1 expression, the median OS was 84 vs 47 months in the IP vs IV group, respectively (P=0.0002). Aberrant BRCA1 expression was an independent prognostic factor for better survival in women randomised to IP therapy (hazard ratio (HR)=0.67, 95% confidence interval (CI)=0.47-0.97, P=0.032). Similar survival was observed in the IV and IP patients with normal BRCA1 expression. Multivariate but not univariate modelling demonstrated that IV patients with aberrant vs normal BRCA1 expression had worse survival. CONCLUSION: Decreased BRCA1 expression is associated with a 36-month survival improvement in patients with EOC treated with IP chemotherapy. Although these results merit validation in future studies, the results suggest that decreased BRCA1 expression predicts for improved response to cisplatin-based IP chemotherapy with cisplatin and paclitaxel.

Palliative care education in gynecologic oncology: a survey of the fellows.

INTRODUCTION: Gynecologic oncologists regularly care for patients at the end of life, yet little is known about their training or preparedness to deal with issues of palliative care. We sought to examine the training provided to gynecologic oncology fellows as well as their perceived preparedness to provide palliative care. METHODS: A self-administered survey was distributed to all fellows enrolled in all gynecologic oncology fellowships during the 2009 academic year. The instrument assessed attitudes, training, experience, and preparedness regarding caring for patients at the end of life. Descriptive, bivariate and multivariable analyses were performed. RESULTS: Sixty-one percent (103/168) of fellows completed the survey. Most (89%) feel that palliative care is integral to their training, but few (11%) have had any palliative care training, including either a rotation or fellowship. Using a scale of 1-10, fellows rated teaching quality on two common training opportunities, specifically managing postoperative complications (7.8) and endometrial cancer patients (8.7), as significantly higher than teaching on managing patients at the end of life (5.5; p<0.001). Fellows rated the quality of end of life teaching as significantly lower than overall teaching (55% vs. 92%; p=0.001). Their self-assessment regarding overall preparedness to deal with end of life issues was associated with higher end of life teaching quality and experience caring for more than 10 dying patients. CONCLUSIONS: The quantity and quality of training in palliative care are lower compared to other common procedural and oncological issues. Gynecologic oncology fellowship programs need to incorporate a palliative care training curriculum.

Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer.

BACKGROUND: Defects in BRCA1, BRCA2, and other members of the homologous recombination pathway have potential therapeutic relevance when used to support agents that introduce or exploit double-stranded DNA breaks. This study examines the association between homologous recombination defects and genomic patterns of loss of heterozygosity (LOH). METHODS: Ovarian tumours from two independent data sets were characterised for defects in BRCA1, BRCA2, and RAD51C, and LOH profiles were generated. Publically available data were downloaded for a third independent data set. The same analyses were performed on 57 cancer cell lines. RESULTS: Loss of heterozygosity regions of intermediate size were observed more frequently in tumours with defective BRCA1 or BRCA2 (P=10(-11)). The homologous recombination deficiency (HRD) score was defined as the number of these regions observed in a tumour sample. The association between HRD score and BRCA deficiency was validated in two independent ovarian cancer data sets (P=10(-5) and 10(-29)), and identified breast and pancreatic cell lines with BRCA defects. CONCLUSION: The HRD score appears capable of detecting homologous recombination defects regardless of aetiology or mechanism. This score could facilitate the use of PARP inhibitors and platinum in breast, ovarian, and other cancers.

Recurrent metastatic vulvar carcinoma treated with cisplatin plus cetuximab.

Recurrent vulvar carcinoma with metastasis has few effective treatment options, which are mainly directed toward palliation of symptoms. A 70-year-old woman was originally treated in 1999 for vulvar squamous cell carcinoma (SCC) with radical vulvectomy and bilateral inguinofemoral groin dissection. She represented in 2005 with a new lesion distinct from the margin of her first disease occurrence. Although treatment of this area included surgical resection and chemoradiation, she recurred 3 months later. Despite radical surgical resection with an anal perineal resection, she presented 2 months later with widely metastatic disease. Epidermal growth factor receptor (EGFR) staining of the tumor cells showed 3+ staining in 100% of the cells. She was treated with palliative radiation therapy (RT) and a cetuximab plus cisplatin chemotherapy protocol. A partial response was obtained for 5 months with palliation of symptoms. Few treatment options exist for recurrent metastatic vulvar carcinoma. The combination of the EGFR antagonist cetuximab with cisplatin has shown modest success in other metastatic SCCs. The partial response experienced in our patient suggests its potential use in women with recurrent or metastatic vulvar carcinoma.

Abnormal fragile histidine triad (FHIT) expression in advanced cervical carcinoma: a poor prognostic factor.

The FHIT gene is a candidate tumor suppressor gene that has been implicated in the development of cervical carcinoma. We hypothesized that abnormal Fhit expression might be a poor prognostic factor for patients with cervical cancer. The tumors from 59 high-risk patients (stage II-III) were evaluated for abnormal Fhit expression by immunohistochemical staining. Abnormal Fhit expression (absent or reduced) was noted in 66% of the specimens. There was no statistical difference with respect to stage, performance status, para-aortic node metastasis, completion of therapy, grade, race, age, and HIV status between the normal and abnormal Fhit expression groups. The 3-year survival for patients whose tumors displayed normal Fhit expression versus abnormal Fhit expression was 74% versus 37%, respectively. Univariate analysis demonstrated a difference in survival that was statistically significant for age <55 years versus > or =55 years (P = 0.015), normal Fhit expression versus abnormal Fhit expression (P = 0.015), and stage II versus stage III (P = 0.033). Multivariate analysis showed that abnormal Fhit expression was a poor prognostic factor (P = 0.015).

Cervical adenocarcinoma in situ: a systematic review of therapeutic options and predictors of persistent or recurrent disease.

The incidence of cervical adenocarcinoma in situ is increasing in frequency, and our limited knowledge about this lesion presents the physician with a therapeutic dilemma. Treatment for this lesion has included conservative therapy, large loop excision or cold-knife cone biopsy, or definitive therapy consisting of hysterectomy. But, rates of residual adenocarcinoma in situ after cone biopsy with negative margins vary from 0% to 40%, and residual disease rates as high as 80% have been noted when the margins are positive. Despite these recent data on follow-up after conservative therapy such as cone biopsy, it seems that this method is safe and gaining acceptance by many physicians and patients. However, the short follow-up duration and small number of patients limit the conclusions of many studies. The relative infrequency of this diagnosis has precluded extensive clinical experience with the natural history of this lesion.

Kielland vs. nonrotational forceps for the second stage of labor.

OBJECTIVE: To examine and compare maternal and neonatal morbidity after use of two types of obstetric forceps used in the management of the second stage of labor. STUDY DESIGN: This retrospective investigation was conducted from January 1993 to December 1995 and included 55 infants delivered with Kielland forceps as compared to 213 infants delivered with nonrotational forceps. The maternal and neonatal charts were reviewed for data collection. Maternal complications compared included blood loss, vaginal lacerations, postpartum hemorrhage, and third- and fourth-degree perineal lacerations. Infant data collected compared fetal lacerations, nerve palsies, shoulder dystocias, blood gas values and admissions to the neonatal intensive care unit. Statistical analysis was performed by Fisher's exact, chi 2 and Student's t test. RESULTS: Women in both groups were similar with respect to age, gravidity, parity and estimated gestational age at delivery. Infants were similar in both groups with respect to fetal weight, admissions to the neonatal intensive care unit, nerve compromise, scalp lacerations and facial bruising. The Kielland group had statistically significantly longer labor, 671 +/- 285.8 vs. 614 +/- 226.5 minutes (P < .05) and longer second stage of labor 184 +/- 74.71 vs. 161 +/- 65.79 minutes (P < .05). The Kielland group also had a statistically higher percentage of one-minute Apgar scores < 6, 18.2% vs. 4.7% (P < .05), and meconium present at delivery, 14.5% vs. 5.6% (P < .05). CONCLUSION: Management of the second stage of labor can be accomplished safely with Kielland forceps and rotation of the fetal head. Supervision by an experienced operator will allow residents to be trained with respect to appropriate patient selection and application of these forceps.

Conservative management of isolated posthysterectomy fever.

OBJECTIVE: To demonstrate that an isolated fever in the absence of other signs or symptoms of infection following hysterectomy does not require empiric antibiotics and laboratory tests. METHODS: Retrospective analysis of all the charts of patients who had a hysterectomy from July 1995 to December 1996 at our institution. Patients with a postoperative temperature > 38 degrees C had a physical examination. If the examination was normal, no studies were ordered, and antibiotic therapy was not initiated. If a patient was febrile after 72 hours postoperatively, laboratory studies and radiographic tests were ordered. If the results were negative, the patient did not appear septic, and physical examination was normal, no antibiotics were given. Outcomes were measured by comparing patients with postoperative infections and fever to those without infections. RESULTS: Of 132 patients, 112 were included in the study. Seventy-two hysterectomies were abdominal and 40 vaginal. Postoperative fever during the first 72 hours following hysterectomy occurred in 51/112 (46%) patients. Clinically significant infection was documented in seven patients, all of whom manifested signs and symptoms of infection > 72 hours postoperatively. CONCLUSION: Postoperative fever in the first 72 hours after hysterectomy is common and nonspecific. If a febrile patient does not show any other signs or symptoms of infection, it is safe to forego routine laboratory and imaging studies as well as therapeutic antibiotics.

Three-dimensional high dose rate intracavitary image-guided brachytherapy for the treatment of cervical cancer using a hybrid magnetic resonance imaging/computed tomography approach: feasibility and early results.

AIMS: To evaluate the feasibility and outcome of image-guided brachytherapy (IGBT) for treating cervical cancer using magnetic resonance imaging (MRI)-based planning for the first fraction followed by computed tomography (CT)-based planning for subsequent fractions. MATERIALS AND METHODS: Forty-four patients with cervical cancer were treated with three-dimensional high dose rate IGBT. The brachytherapy dose was 5.0-6.0 Gy × five fractions. All but five patients received concurrent weekly cisplatinum at 40 mg/m(2). All patients received external beam radiotherapy (EBRT) with a median dose of 45Gy over 25 fractions. Total doses for the high-risk clinical target volume (HRCTV) and organs at risk, including the rectum, bladder and sigmoid, from EBRT and brachytherapy were summated and normalised to a biologically equivalent dose of 2Gy per fraction (EQD(2)). At 3 months after therapy, any early response was assessed with positron emission tomography (PET)/CT imaging. RESULTS: The mean D(90) for the HRCTV was 83.3 (3.0) Gy. The mean 2 cm (3) dose to the bladder, rectum and sigmoid colon organs was 79.7 (5.1), 57.5 (4.4) and 66.8 (5.7) Gy, respectively. All but one (2.3%) patient had a complete response. Follow-up PET/CT was carried out in 41 (93.0%) patients, of whom 38 (92.5%) had a complete response. Of the 38 patients with a complete response on PET/CT, two had local recurrences at 6 and 8 months, respectively. Actuarial 2 year local control, disease-specific and overall survival rates were 88, 85 and 86%, respectively. CONCLUSION: This is the first report of three-dimensional high dose rate IGBT for the treatment of cervical cancer using a hybrid MRI/CT approach. Early results have shown the feasibility of this approach with excellent local control. Additional studies are needed to assess long-term outcomes of local control and associated morbidities.

Hematologic changes after splenectomy for cytoreduction: implications for predicting infection and effects on chemotherapy.

Postsplenectomy leukocytosis and thrombocytosis are common findings in trauma patients. The intent of this study is to describe postsplenectomy hematologic changes in gynecological oncology surgery and subsequent chemotherapy. We performed a retrospective record review of gynecological oncology patients at our institutions. Postsurgical hematologic changes, infectious morbidity, and pre- and post-chemotherapy hematologic changes were noted. Data were analyzed using repeated measures analysis of variance. We identified 27 patients who underwent cytoreductive surgery with splenectomy. Thirteen patients with splenectomy had postoperative chemotherapy data available, and we matched these patients with 13 control patients who underwent cytoreduction surgery without splenectomy and postoperative chemotherapy. Nine of the 27 splenectomy patients had documented infectious morbidity. There was a significant difference in postoperative platelet counts between the infected and the noninfected splenectomy patients (P= 0.037), and a significant difference between splenectomy and control patients for white blood cell (WBC) counts (P = 0.007). Patients with splenectomy had higher precycle WBC, absolute neutrophil count (ANC), platelet counts, and higher postcycle nadir levels in all cycles compared to control patients. There was a significant overall difference between splenectomy patients and controls with regard to WBC (P = 0.001), ANC (P = 0.005), and platelet counts (P = 0.016) during chemotherapy cycles. Median postchemotherapy nadir WBC was 4.4 (range: 3.4-4.8) for the splenectomy group versus 2.8 (range: 2.5-3.0) for the control group. Median postchemotherapy nadir ANC was 1800 (range: 1320-2450) for the splenectomy group and 1001 (range: 864-1064) for the control group. Median postchemotherapy nadir platelet count was 222 (range: 181-277) for the splenectomy patients and 169 (range 164-215) for the control patients. In conclusion, the patients who undergo splenectomy as part of cytoreductive surgeries have a statistically significant leukocytosis and insignificant thrombocytosis relative to the control patients. Leukocytosis alone is not an accurate indicator of infection. Splenectomy is not associated with an increased risk of chemotherapy-related neutropenia and thrombocytopenia.

Recurrent invasive adenocarcinoma after hysterectomy for cervical adenocarcinoma in situ.

BACKGROUND: Unlike its squamous counterpart, therapy for cervical adenocarcinoma in situ with positive endocervical cone margin remains controversial. CASE: A 52-year-old gravida 2, para 1,0,1,1, presented with vaginal bleeding. Gynecologic history was significant for cervical cold knife conization with a positive endocervical margin and endocervical curettage with atypical endocervical cells. Repeat cone biopsy was considered unsafe given the large initial cone specimen. An extrafascial hysterectomy was performed 5 weeks later and pathology confirmed a disease-free cervix. Pap smear performed 1 year later was interpreted as recurrent adenocarcinoma but later downgraded to inflammation. Inspection and random biopsies of the vaginal cuff revealed only inflammation. Two subsequent Pap smears also returned inflammation. Seventeen months after the hysterectomy physical examination revealed a 2 x 3-cm smooth mass at the vaginal cuff. Biopsy revealed invasive adenocarcinoma. The patient underwent an upper vaginectomy followed by postoperative pelvic radiation. CONCLUSION: This case suggests that despite extrafascial hysterectomy for presumed adenocarcinoma in situ of the cervix, a residual focus could remain and present later as invasive adenocarcinoma.

Large cell neuroendocrine cervical carcinoma: a report of two cases and review of the literature.

BACKGROUND: Large cell neuroendocrine cervical carcinoma is a rare malignancy. These tumors appear to mimic the aggressive behavior of small cell neuroendocrine tumors. Metastasis and recurrent disease are common. Due to the low incidence of these tumors, optimal therapy has not been delineated. CASES: Two patients presented with large cell neuroendocrine cervical carcinoma, stage IB1 and IIA, at our institution from 1997 to 1999. We describe the clinical course for these two patients and review the relevant literature for the management of large cell cervical carcinoma. CONCLUSION: Unlike squamous cell carcinoma, early-stage large cell neuroendocrine tumors of the cervix are aggressive. Disease recurrences are frequent and distant metastasis is common. Multimodal therapy should be considered at the time of initial diagnosis.

Primary appendiceal malignancy mimicking advanced stage ovarian carcinoma: a case series.

BACKGROUND: Primary appendiceal malignancy metastatic to the ovaries is a rare condition that may mimic late stage ovarian cancer. This condition is rarely diagnosed preoperatively. CASES: Three patients referred to our institution from 1994 to 1999 for presumed late stage ovarian cancer were found to have primary appendiceal adenocarcinoma, adenocarcinoid, and mucinous cystadenocarcinoma metastatic to the ovaries at laparotomy. We describe the clinical course of these patients and review the relevant literature. CONCLUSION: It is important for the gynecologic oncologist to be aware of the clinicopathological features and surgical management of these malignancies, as the incidence, prognosis, and recommended treatment vary with histological subtype.

Uterine adenosarcoma with sarcomatous overgrowth versus uterine carcinosarcoma: comparison of treatment and survival.

OBJECTIVE: Uterine adenosarcoma with sarcomatous overgrowth (ASSO) is a rare variant of uterine sarcoma first described in 1989. This clinicopathologic study was undertaken to compare the treatment and survival of uterine adenosarcoma with sarcomatous overgrowth to that of uterine carcinosarcomas. METHODS: A review of uterine sarcomas diagnosed at Washington Hospital Center from January 1988 to December 1998 was performed. Records were reviewed for demographic data, surgical staging, primary and adjuvant therapy, metastatic site, disease recurrence, and survival. All pathology was reviewed and diagnosis confirmed. Statistical analysis included chi(2) test and Student's t test. Kaplan-Meier survival curves were plotted to estimate the median and 5-year survival times. The log-rank test was used to compare survival times. A P value <0.05 was considered significant. RESULTS: Sixty patients were diagnosed with uterine sarcoma at Washington Hospital Center. Of these, 33 (55%) were uterine carcinosarcomas, 11 (18%) ASSOs, 6 (10%) adenosarcomas, and 10 (17%) leiomyosarcomas. Of the patients diagnosed with uterine ASSO, 3 (27%) were stage I, 3 (27%) stage II, 1 (9%) stage III, and 4 (36%) stage IV. All 11 patients with uterine ASSO underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy and tumor debulking. Postoperative adjuvant therapy included chemotherapy (n = 4), radiation (n = 4), combination radiation and chemotherapy (n = 1), and no adjuvant therapy (n = 2). The overall median survival time of patients with uterine ASSO was 13 months. Nine of eleven patients are dead of disease, and two patients (both with stage I) are alive without evidence of disease at 18 and 19 months. Thirty-three patients with carcinosarcoma were identified, with follow-up available on 29 patients. Of these, 10 (34%) were stage I, 6 (22%) stage II, 3 (10%) stage III, and 10 (34%) stage IV. Twenty-seven of the twenty-nine patients diagnosed with carcinosarcoma underwent surgical therapy to include total abdominal hysterectomy, bilateral salpingo-oophorectomy, staging and tumor debulking. Two patients died prior to treatment. Postoperative adjuvant therapy included chemotherapy (n = 9), radiation (n = 13), combination (n = 1), and no further therapy (n = 4). Twenty of the twenty-nine patients are dead of disease; there were nine surviving patients at the time of this report (stage I-5, stage II-3, stage III-1). The median survival of these patients was 31 months, with an overall 5-year survival of 22%. Comparison of the Kaplan-Meier survival curves using the log-rank test suggests a worse prognosis for uterine ASSO. However, this did not reach statistical significance (P = 0.0522). CONCLUSIONS: Patients diagnosed with uterine ASSO have a poor prognosis similar to that of carcinosarcoma. Management should include complete surgical staging. Additional therapy in the form of radiation, chemotherapy, or both has been reported; however, the superiority of one modality could not be determined from our data.