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Purpose: The Sedlis criteria define risk factors for recurrence warranting post-hysterectomy radiation for early-stage cervical cancer; however, these factors were defined for squamous cell carcinoma (SCC) at an estimated recurrence risk of ≥30%. Our study evaluates and compares risk factors for recurrence for cervical SCC compared with adenocarcinoma (AC) and develops histology-specific nomograms to estimate risk of recurrence and guide adjuvant treatment., Methods: We performed an ancillary analysis of GOG 49, 92, and 141, and included stage I patients who were surgically managed and received no neoadjuvant/adjuvant therapy. Multivariable Cox proportional hazards models were used to evaluate independent risk factors for recurrence by histology and to generate prognostic histology-specific nomograms for 3-year recurrence risk., Results: We identified 715 patients with SCC and 105 with AC; 20% with SCC and 17% with AC recurred. For SCC, lymphvascular space invasion (LVSI: HR 1.58, CI 1.12-2.22), tumor size (TS ≥4 cm: HR 2.67, CI 1.67-4.29), and depth of invasion (DOI; middle 1/3, HR 4.31, CI 1.81-10.26; deep 1/3, HR 7.05, CI 2.99-16.64) were associated with recurrence. For AC, only TS ≥4 cm, was associated with recurrence (HR 4.69, CI 1.25-17.63). For both histologies, there was an interaction effect between TS and LVSI. For those with SCC, DOI was most associated with recurrence (16% risk); for AC, TS conferred a 15% risk with negative LVSI versus a 25% risk with positive LVSI., Conclusions: Current treatment standards are based on the Sedlis criteria, specifically derived from data on SCC. However, risk factors for recurrence differ for squamous cell and adenocarcinoma of the cervix. Histology-specific nomograms accurately and linearly represent risk of recurrence for both SCC and AC tumors and may provide a more contemporary and tailored tool for clinicians to base adjuvant treatment recommendations to their patients with cervical cancer., Competing Interests: Declaration of Competing Interest Dr. Van Le reports royalties from Wolters Kluwer (as an editor of TeLinde's textbook). Dr. Huh reports money paid to him from consultancy with DYSIS. Dr. Miller reports money paid to him from consultancy with Tesaro, Eisai, Incyte, Karyopharm, and Genentech as well as money paid to his institution from Merck. He also reports money paid to his institution from grants or grants pending with nVision Medical, Advenchen, Forty Seven, Merck, Syros, and US BIOTEST. Dr. Ragab reports money paid to him from Consultancy with Regeneron. Dr. Viswanathan reports employment with money paid to her from Elsevier as the Ediotr in Chief for Seminars in Radiation Oncology. She also has an R01 NIH grant with money to her institution, and she received textbook royalties from Springer. Dr. Tewari has received money paid to him from consultancy with Clovis, Merck, Abbvie, Amgen, GSK, and Astra-Zenega, as well as payment for lectures from Clovis, Merck, Abbvie, Amgen, GSK, Astra-Zenega. Drs. Levinson, Fader, Beavis, Wolfson, Waggoner, Guntupalli, Lee, Kelly, McNally, Casablanca, Rositch, Spirtos, Wilkinson, Holman and Chris Purdy have no financial disclosures., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To analyze clinical prognostic factors for survival after recurrence of high-grade, advanced-stage ovarian-peritoneal-tubal carcinoma and to develop a nomogram to predict individual survival after recurrence., Methods: We retrospectively analyzed patients treated in multicenter Gynecologic Oncology Group protocols for stage III and IV ovarian-peritoneal-tubal carcinoma who underwent primary debulking surgery, received chemotherapy with paclitaxel and a platinum compound, and subsequently developed recurrence. Prognostic factors affecting survival were identified and used to develop a nomogram, which was both internally and externally validated., Results: There were 4,739 patients included in this analysis, of whom, 84% had stage III and 16% had stage IV ovarian carcinoma. At a median follow-up of 88.8 months (95% CI 86.2-92.0 months), the vast majority of patients (89.4%) had died. The median survival after recurrence was 21.4 months (95% CI 20.5-21.9 months). Time to recurrence after initial chemotherapy, clear cell or mucinous histology, performance status, stage IV disease, and age were significant variables used to develop a nomogram for survival after recurrence, which had a concordance index of 0.67. The time to recurrence alone accounted for 85% of the prognostic information. Similar results were found for patients who underwent second look laparotomy and had a complete pathologic response or received intraperitoneal chemotherapy., Conclusion: For individuals with advanced-stage ovarian carcinoma who recur after standard first-line therapy, estimated survivals after recurrence are closely related to the time to recurrence after chemotherapy and prognostic variables can be used to predict subsequent survival., Clinical Trial Registration: ClinialTrials.gov, NCT00002568, NCT00837993, NCT00002717, NCT01074398, and NCT00011986.

Importance: Ovarian cancer is the leading cause of gynecologic cancer deaths in the United States. Pazopanib is an oral, multitarget kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptors α and β; and proto-oncogene receptor tyrosine kinase (c-KIT)., Objective: To estimate the progression-free survival (PFS) hazard ratio (HR) of weekly paclitaxel and pazopanib compared with weekly paclitaxel and placebo in women with recurrent ovarian cancer. Secondary objectives included frequency and severity of adverse events, proportion responding, and overall survival (OS) in each arm. Translational research objectives included exploring the association between possible biomarkers and single-nucleotide polymorphisms in vascular endothelial growth factor A, interleukin 8, and hypoxia-inducible factor 1α; and PFS, OS, and proportion responding., Design, Setting, and Participants: A randomized, placebo-controlled, double-blind phase 2 study was conducted at 26 participating institutions. Patients were enrolled between December 12, 2011, and April 22, 2013. Data were frozen on August 11, 2014. Participants were patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma with 1 to 3 prior regimens and performance status of 0 to 2. One hundred six patients enrolled; 100 were evaluable for toxic effects., Interventions: All patients received paclitaxel 80 mg/m2 intravenously on days 1, 8, and 15 every 28 days and were randomized 1:1 to pazopanib 800 mg orally daily or placebo., Main Outcomes and Measures: The primary end point was PFS. The study was designed to detect a 37.5% reduction in the hazard with 80% power (α = 10%)., Results: A total of 106 women (median age [range], 61 [35-87] years; 88 [83%] white) were enrolled. Study arms were well balanced for age, performance status, measurable disease, and prior bevacizumab. Proportion responding was 14 of 44 (31.8%) vs 10 of 44 (22.7%) for pazopanib plus paclitaxel vs paclitaxel alone. Median PFS was 7.5 vs 6.2 months for pazopanib plus paclitaxel vs paclitaxel alone, respectively (HR, 0.84; 90% CI, 0.57-1.22; P = .20). Median OS was 20.7 vs 23.3 months for pazopanib plus paclitaxel vs paclitaxel alone (HR, 1.04; 90% CI, 0.60-1.79; P = .90). Severe hypertension was more common on the pazopanib plus paclitaxel arm (relative risk, 12.0; 95% CI, 1.62-88.84). More patients discontinued treatment on the paclitaxel arm for disease progression (34 of 52 [65.4%] vs 17 of 54 [31.5%]), and more on the pazopanib plus paclitaxel arm for adverse events (20 of 54 [37%] vs 5 of 52 [9.6%]). No association was found between single-nucleotide polymorphisms (interleukin 8 and hypoxia-inducible factor 1α) and OS and proportion responding. Patients with VEGFA CC genotype may be more resistant to weekly paclitaxel than those with the AC or AA genotype, with 1 of 14 (7%), 3 of 15 (20%), and 4 of 8 (50%) responding, respectively., Conclusions and Relevance: The combination of pazopanib plus paclitaxel is not superior to paclitaxel in women with recurrent ovarian cancer., Trial Registration: clinicaltrials.gov Identifier: NCT01468909.

Background: The Gynecologic Oncology Group conducted this phase 2 trial to estimate the antitumor activity of bevacizumab and to determine the nature and degree of toxicity in patients with recurrent sex cord-stromal tumors of the ovary., Methods: A prospective, multi-institutional cooperative group trial was performed in women with recurrent, measurable ovarian stromal tumors. Patients were allowed to have unlimited prior therapy, excluding bevacizumab. Bevacizumab 15 mg/kg was administered intravenously on day 1 of every 21-day cycle until patients developed disease progression or adverse effects that prohibited further treatment. The primary endpoint was the response rate (RR). Inhibin A and B levels were measured before each cycle, and the values were examined in relation to response and progression., Results: Thirty-six patients were enrolled, and all were eligible and evaluable. Patients received a median of 9 cycles of treatment (range, 2-37 cycles). Six patients (16.7%) had partial responses (90% confidence interval, 7.5%-30.3%), 28 patients (77.8%) had stable disease, and 2 patients (5.6%) had progressive disease. This met the criterion for declaring the regimen active. The median progression-free survival was 9.3 months, and the median overall survival was not reached in during reporting period. Two grade 4 toxicities occurred, including hypertension and proteinuria; and the most common grade 3 toxicities were hypertension (n = 5) and pain (n = 5). Inhibin A and B values were lower in patients who responded to treatment., Conclusions: Bevacizumab has activity in the treatment of recurrent sex cord-stromal tumors of the ovary, and its toxicity is acceptable. Further investigation is warranted., (© 2013 American Cancer Society.)

Purpose: The Gynecologic Oncology Group (GOG) conducted a phase II trial to assess the efficacy and tolerability of the anti-EGFR antibody cetuximab, in persistent or recurrent carcinoma of the cervix., Patients and Methods: Eligible patients had cervical cancer, measurable disease, and GOG performance status ≤2. Treatment consisted of cetuximab 400 mg/m(2) initial dose followed by 250 mg/m(2) weekly until disease progression or prohibitive toxicity. The primary endpoints were progression-free survival (PFS) at 6 months and response. The study used a 2-stage group sequential design., Results: Thirty-eight patients were entered with 3 exclusions, leaving 35 evaluable for analysis. Thirty-one patients (88.6%) received prior radiation as well as either 1 (n=25, 71.4%) or 2 (n=10) prior cytotoxic regimens. Twenty-four patients (68.6%) had a squamous cell carcinoma. Grade 3 adverse events possibly related to cetuximab included dermatologic (n=5), GI (n=4), anemia (n=2), constitutional (n=3), infection (n=2), vascular (n=2), pain (n=2), and pulmonary, neurological, vomiting and metabolic (n=1 each). No clinical responses were detected. Five patients (14.3%; two-sided 90% CI, 5.8% to 30%) survived without progression for at least 6 months. The median PFS and overall survival (OS) times were 1.97 and 6.7 months, respectively. In this study, all patients with PFS at 6 months harbored tumors with squamous cell histology., Conclusion: Cetuximab is well tolerated but has limited activity in this population. Cetuximab activity may be limited to patients with squamous cell histology., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: The objective of this study was to estimate antitumor activity and toxicity of weekly docetaxel and gemcitabine as second-line chemotherapy for patients with recurrent uterine carcinosarcoma., Methods: Patients with recurrent carcinosarcoma of the uterus who had failed one regimen of chemotherapy, had a Gynecologic Oncology Group (GOG) performance status of 0-2 and had measurable disease were included. Treatment consisted of gemcitabine 600 mg/m(2) and docetaxel 35 mg/m(2) intravenously on days 1, 8 and 15 of a 28-day cycle until disease progression or intolerable adverse effects. This study employed an optimal but flexible two-stage design with an early stopping rule. If more than 3 out of 22-24 or more than 4 out of 25-29 patients responded, accrual to the second stage was to be initiated., Results: Twenty-eight patients were enlisted. Three patients were not eligible after pathology review. One patient was never treated. Twenty-four patients were evaluable. Nine patients had previous radiation therapy. There were no complete responses. Partial responses were seen in two patients (8.3%), stable disease in eight (33.3%) and progressive disease in 12 patients (50%). Two patients were not evaluable (8.3%). The median progression-free survival was 1.8 months. The median survival was 4.9 months. The treatment caused myelosuppression, mainly neutropenia, but also thrombocytopenia and anemia. Dose modifications became necessary in the majority of patients. In five patients, treatment was discontinued due to toxicity., Conclusions: This regimen of docetaxel and gemcitabine is not active in patients with recurrent carcinosarcoma of the uterus as second-line chemotherapy., (Copyright (c) 2010. Published by Elsevier Inc.)

Objective: We sought to estimate the incidence and clinical significance of a negative therapeutic loop electrosurgical excision procedure (LEEP) and to evaluate patient specimens for limiting histologic features associated with a negative LEEP., Methods: We identified 674 patients with biopsy-confirmed high-grade cervical dysplasia who were treated with LEEP from 1991 through 2001. The results of these LEEP procedures were reviewed for the absence of dysplasia or the presence of cervical intraepithelial neoplasia stages 1-3. Computerized pathology files of patients were then reviewed through July 2002 to determine whether dysplasia recurred. Slides of negative LEEP specimens were reviewed to confirm the absence of dysplasia and to search for histologic features that may have limited our interpretation of the specimen., Results: Ninety-three (14%) of LEEP specimens reviewed were completely negative for dysplasia. Clinical follow-up was available on 75 of the 93 patients, with a median follow-up time of 2 years. Eighteen (24%) patients had subsequent positive follow-up, including carcinoma (n = 2), high-grade squamous intraepithelial lesions (n = 8), low-grade squamous intraepithelial lesion (n = 6), and atypical squamous cells of undetermined significance (n = 2). Patients with negative LEEPs had a recurrence rate similar to patients with positive LEEPs (24% versus 27%). Limiting histologic features were more commonly identified in negative LEEPs as compared with LEEPs containing dysplasia (16% versus 5%, P <.001)., Conclusion: A negative LEEP is not an uncommon finding, occurring in 14% (95% confidence interval 11-17%) of specimens at our institution. Negative LEEPs are more likely to contain histologic features that limit pathology interpretation. A negative LEEP is not a reassuring finding and was associated with a recurrence rate similar to those of a positive LEEP. Both negative and positive populations should be carefully followed.

Management of advanced-stage uterine serous carcinoma (USC) is uncertain, and postsurgical therapeutic options swing between radiation and chemotherapy. The aim of this study is to evaluate the utility of radiotherapy compared to platinum-based chemotherapy in women with advanced-stage USC. We retrospectively identified cases of USC at our institution. Survival distributions were calculated by the Kaplan-Meier method. Two-tailed t-tests were used to compare time to progression and time to death. We identified 24 women diagnosed with either stage III or IV USC. Time to progression for women receiving radiotherapy was 5.3 months as compared with 12.4 months for women receiving chemotherapy (P = 0.01). Mean time to death for the radiotherapy group was 8 months compared to 18 months in the chemotherapy group (P = 0.04). Kaplan-Meier survival curves were significantly different between the two groups (P = 0.01). While radiotherapy appears to control USC recurrences in the pelvis, the disease often recurs distantly. When compared to radiotherapy, platinum-based chemotherapy appears to increase disease-free survival and time to death in women with advanced-stage USC.

Objective: To evaluate whether the surveillance schedule for patients treated with loop excision for high-grade squamous intraepithelial lesions could be improved., Methods: Women treated in our dysplasia clinic for high-grade squamous intraepithelial lesions by loop excision between January 1990 and December 1999 were identified. Demographic information, pathologic diagnosis, and follow-up visits were extracted from medical records. Follow-up data included all Papanicolaou (Pap) tests and/or cervical biopsies performed in our clinic after the initial procedure., Results: Women (n = 705) were treated for biopsy-proven high-grade dysplasia. Of those treated, 526 (74%) had at least 1 follow-up Pap test performed in our clinics within 2 years of their original procedure. During the 2 years of posttreatment surveillance, 70 (13.3%) women demonstrated recurrent cervical intraepithelial neoplasia 2 or 3. Recurrence was highest during the first 6 months and between months 22 and 24 of surveillance. This rate was noted to be dramatically lower during months 7 to 21 of surveillance (P <.001). Increasing age was independently associated with a 1.6-fold per decade (95% confidence interval 1.29, 1.9) increase in risk of recurrence. A negative margin status was independently associated with a 0.29-fold (95% confidence interval 0.17, 0.5) decrease in risk of recurrence. Race was not shown to have an influence on risk of recurrence., Conclusion: A clinically and financially optimal surveillance schedule for women treated for high-grade dysplasia with loop excision would be to obtain Pap tests every 6 months for 1 year and then return to annual screening. Lengthening the surveillance intervals could be beneficial to patients, while decreasing healthcare costs, without compromising the ability to detect and treat recurrent disease., Level of Evidence: II-2

From October 1995 to March 1997, a phase II trial of topotecan was carried out in chemotherapy-naive women with advanced, persistent, or recurrent uterine leiomyosarcomas. Thirty-six patients were entered. Median age was 53 years. Performance status was 0 (50%) in 18, 1 (36%) in 13, and 2 (14%) in 5. Most patients, 33 (92%), had undergone prior surgery, and 8 (22%) prior radiation therapy. Topotecan, 1.5 mg/m2. was administered intravenously daily for 5 days, every 3 weeks, until progression of disease or adverse affects prohibited further therapy. Patients received 1 to 13 courses with a median of 3 courses. The most frequent grade 4 adverse effects were neutropenia in 28 (78%), leukopenia in 8 (22%), thrombocytopenia in 3 (8%), and anemia in 3 (8%). Complete response was seen in 1 (3%), partial response in 3 (8%), stable disease in 12 (33%), and increasing tumor in 20 (56%). Thus topotecan at this dose and schedule does not appear to have major activity in uterine leiomyosarcomas.

Background: The aim of this study was to compare the concordance between immunohistochemical (IHC) and biochemical (RIA) methods for determining hormone receptor status in patients with endometrial carcinoma and to determine whether IHC expression of estrogen and progesterone receptors (ER and PR) has prognostic significance., Methods: Paraffin blocks were obtained from patients diagnosed with endometrial carcinoma between 1987 and 1991. IHC analysis for ER and PR expression was performed and scored based on staining intensity and the percentage of tumor cells with nuclear staining. Biochemical assays were performed on frozen tissues. Concordance between the two methods was evaluated and hormone receptor status was correlated with tumor grade, stage, recurrence and survival., Results: ER and PR expression, determined by IHC, correlated well with RIA levels (Spearmans correlation coefficient, P = 0.006 and 0.0005, respectively). Determination of ER and PR expression by both methods was correlated with tumor grade. Hazards ratios revealed that the absence of ER and PR expression, determined by both IHC and RIA, independently correlated with recurrence in early stage disease (P < 0.05)., Conclusions: Historically, receptors have been determined by RIA. In this study, IHC and RIA were equally suitable for determination of ER and PR. This is significant clinically as IHC has several advantages over RIA, including easier processing, lower cost, greater speed, and applicability to fixed tissue samples. In addition, ER negative status was predictive of the recurrence of Stage I tumors independent of tumor grade. ER status may aid the clinician in planning treatment when adjuvant treatment is controversial., (Copyright 1999 American Cancer Society.)

Objective: To determine the impact of margin status on disease recurrence and the incidence of occult cancer in women diagnosed with vulvar intraepithelial neoplasia (VIN) III and treated with surgical excision., Methods: Between 1989 and 1995, 73 women were diagnosed preoperatively with VIN III by vulvar biopsy and were treated with surgical resection. Patients were examined postoperatively, and recurrence was diagnosed when a biopsy of suspicious lesions confirmed VIN III., Results: The mean age was 45 years; 81% of the patients were white, and 18% were black. Eighty-two percent of the women had used tobacco, 56% had prior cervical dysplasia, and 37% had prior genital warts. An underlying squamous vulvar cancer was found in 22% of patients at initial treatment for VIN III. Fifty-nine women had follow-up of at least 7 months. Of these, 66% (39 of 59) had positive surgical margins, 31% (18 of 59) had negative margins and 3% had unknown margins (two of 59). With positive margins, 46% (18 of 39) suffered recurrent disease; with negative margins, only 17% (three of 18) had recurrent disease (P = .03). Multifocal disease and a history of genital warts also correlated with VIN III recurrence (P = .03 for both)., Conclusion: A significant number of women diagnosed initially with VIN III on a vulvar biopsy harbored occult vulvar cancer. Recurrences were almost threefold higher when margins were positive for residual VIN III. We conclude that surgical resection is an appropriate method of treatment of VIN III for both diagnostic and therapeutic purposes.

Objective: Previous studies by the Gynecologic Oncology Group have demonstrated no activity with bolus etoposide in squamous cell carcinoma of the cervix. Prolonged oral etoposide, which exploits the schedule dependency of this agent, has demonstrated activity in non-small cell carcinoma of the lung and has been studied in combination therapy with cisplatin. To evaluate prolonged oral etoposide in previously treated squamous cell carcinoma of the cervix, the current Phase II trial was conducted., Methods: Eligibility included squamous cell cancer of the cervix, measurable disease, allowed no more than one prior chemotherapy regimen which did not include etoposide, WBC >/=3000/microliter, platelet count >/=100, 000/microliter, serum creatinine