GOG 244 - The Lymphedema and Gynecologic cancer (LeG) study: The impact of lower-extremity lymphedema on quality of life, psychological adjustment, physical disability, and function.

OBJECTIVE: To assess quality of life (QOL) in patients who developed lower-extremity lymphedema (LLE) after radical gynecologic cancer surgery on prospective clinical trial GOG 244. METHODS: The prospective, national, cooperative group trial GOG-0244 determined the incidence of LLE and risk factors for LLE development, as well as associated impacts on QOL, in newly diagnosed patients undergoing surgery for endometrial, cervical, or vulvar cancer from 6/4/2012-11/17/2014. Patient-reported outcome (PRO) measures of QOL (by the Functional Assessment of Cancer Therapy [FACT]), body image, sexual and vaginal function, limb function, and cancer distress were recorded at baseline (within 14 days before surgery), and at 6, 12, 18, and 24 months after surgery. Assessments of LLE symptoms and disability were completed at the time of lower limb volume measurement. A linear mixed model was applied to examine the association of PROs/QOL with a Gynecologic Cancer Lymphedema Questionnaire (GCLQ) total score incremental change ≥4 (indicative of increased LLE symptoms) from baseline, a formal diagnosis of LLE (per the GCLQ), and limb volume change (LVC) ≥10%. RESULTS: In 768 evaluable patients, those with a GCLQ score change ≥4 from baseline had significantly worse QOL (p < 0.001), body image (p < 0.001), sexual and vaginal function (p < 0.001), limb function (p < 0.001), and cancer distress (p < 0.001). There were no significant differences in sexual activity rates between those with and without LLE symptoms. CONCLUSIONS: LLE is significantly detrimental to QOL, daily function, and body image. Clinical intervention trials to prevent and manage this chronic condition after gynecologic cancer surgery are needed.

GOG 244-The lymphedema and gynecologic cancer (LEG) study: Incidence and risk factors in newly diagnosed patients.

OBJECTIVES: To evaluate the incidence and risk factors for lymphedema associated with surgery for gynecologic malignancies on GOG study 244. METHODS: Women undergoing a lymph node dissection for endometrial, cervical, or vulvar cancer were eligible for enrollment. Leg volume was calculated from measurements at 10-cm intervals starting 10 cm above the bottom of the heel to the inguinal crease. Measurements were obtained preoperatively and postoperatively at 4-6 weeks, and at 3-, 6-, 9-, 12-, 18-, and 24- months. Lymphedema was defined as a limb volume change (LVC) ≥10% from baseline and categorized as mild: 10-19% LVC; moderate: 20-40% LVC; or severe: >40% LVC. Risk factors associated with lymphedema were also analyzed. RESULTS: Of 1054 women enrolled on study, 140 were inevaluable due to inadequate measurements or eligibility criteria. This left 734 endometrial, 138 cervical, and 42 vulvar patients evaluable for LVC assessment. Median age was 61 years (range, 28-91) in the endometrial, 44 years (range, 25-83) in the cervical, and 58 years (range, 35-88) in the vulvar group. The incidence of LVC ≥10% was 34% (n = 247), 35% (n = 48), and 43% (n = 18), respectively. The peak incidence of lymphedema was at the 4-6 week assessment. Logistic regression analysis showed a decreased risk with advanced age (p = 0.0467). An exploratory analysis in the endometrial cohort showed an increased risk with a node count >8 (p = 0.033). CONCLUSIONS: For a gynecologic cancer, LVC decreased with age greater than 65, but increased with a lymph node count greater than 8 in the endometrial cohort. There was no association with radiation or other risk factors.

GOG 244 - The LymphEdema and Gynecologic cancer (LEG) study: The association between the gynecologic cancer lymphedema questionnaire (GCLQ) and lymphedema of the lower extremity (LLE).

OBJECTIVE: To explore whether patient-reported lymphedema-related symptoms, as measured by the Gynecologic Cancer Lymphedema Questionnaire (GCLQ), are associated with a patient-reported diagnosis of lymphedema of the lower extremity (LLE) and limb volume change (LVC) in patients who have undergone radical surgery, including lymphadenectomy, for endometrial, cervical, or vulvar cancer on Gynecologic Oncology Group (GOG) study 244. METHODS: Patients completed the baseline and at least one post-surgery GCLQ and LVC assessment. The 20-item GCLQ measures seven symptom clusters-aching, heaviness, infection-related, numbness, physical functioning, general swelling, and limb swelling. LLE was defined as a patient self-reported LLE diagnosis on the GCLQ. LVC was measured by volume calculations based on circumferential measurements. A linear mixed model was fitted for change in symptom cluster scores and GCLQ total score and adjusted for disease sites and assessment time. RESULTS: Of 987 eligible patients, 894 were evaluable (endometrial, 719; cervical, 136; vulvar, 39). Of these, 14% reported an LLE diagnosis (endometrial, 11%; cervical, 18%; vulvar, 38%). Significantly more patients diagnosed versus not diagnosed with LLE reported ≥4-point increase from baseline on the GCLQ total score (p < 0.001). Changes from baseline were significantly larger on all GCLQ symptom cluster scores in patients with LLE compared to those without LLE. An LVC increment of >10% was significantly associated with reported general swelling (p < 0.001), heaviness (p = 0.005), infection-related symptoms (p = 0.002), and physical function (p = 0.006). CONCLUSIONS: Patient-reported symptoms, as measured by the GCLQ, discerned those with and without a patient-reported LLE diagnosis and demonstrated predictive value. The GCLQ combined with LVC may enhance our ability to identify LLE.

Phase II Trial of Chemopreventive Effects of Levonorgestrel on Ovarian and Fallopian Tube Epithelium in Women at High Risk for Ovarian Cancer: An NRG Oncology Group/GOG Study.

A large body of epidemiologic evidence has shown that use of progestin-containing preparations lowers ovarian cancer risk. The purpose of the current study was to gather further preclinical evidence supporting progestins as cancer chemopreventives by demonstrating progestin-activation of surrogate endpoint biomarkers pertinent to cancer prevention in the genital tract of women at increased risk of ovarian cancer. There were 64 women enrolled in a multi-institutional randomized trial who chose to undergo risk-reducing bilateral salpingo-oophorectomy (BSO) and to receive the progestin levonorgestrel or placebo for 4 to 6 weeks prior to undergoing BSO. The ovarian and fallopian tube epithelia (FTE) were compared immunohistochemically for effects of levonorgestrel on apoptosis (primary endpoint). Secondary endpoints included TGFß isoform expression, proliferation, and karyometric features of nuclear abnormality. In both the ovary and fallopian tube, levonorgestrel did not confer significant changes in apoptosis or expression of the TGFß1, 2, or 3 isoforms. In the ovarian epithelium, treatment with levonorgestrel significantly decreased the proliferation index. The mean ovarian Ki-67 value in the placebo arm was 2.027 per 100 cells versus 0.775 per 100 cells in the levonorgestrel arm (two-sided P value via Mann-Whitney U test = 0.0114). The karyometric signature of nuclei in both the ovarian and FTE deviated significantly from normal controls (women at average risk of ovarian cancer), but was significantly less abnormal in women treated with levonorgestrel. These karyometric data further support the idea that progestins may clear genetically abnormal cells and act as chemopreventive agents against ovarian and fallopian tube cancer.

A phase II evaluation of elesclomol sodium and weekly paclitaxel in the treatment of recurrent or persistent platinum-resistant ovarian, fallopian tube or primary peritoneal cancer: An NRG oncology/gynecologic oncology group study.

OBJECTIVE: Preclinical data suggest elesclomol increases oxidative stress and enhances sensitivity to cytotoxic agents. The objective of this prospective multicenter phase 2 trial was to estimate the activity of IV elesclomol plus weekly paclitaxel in patients with platinum-resistant recurrent ovarian, tubal or peritoneal cancer through the frequency of objective tumor responses (ORR). METHODS: Patients with measurable disease, acceptable organ function, performance status ≤ 2, and one prior platinum containing regimen were eligible. A two-stage design was utilized with a target sample size of 22 and 30 subjects, respectively. Prior Gynecologic Oncology Group studies within the same population involving single agent taxanes showed an ORR of approximately (20%) and served as a historical control for direct comparison. The present study was designed to determine if the regimen had an ORR of ≥40% with 90% power. RESULTS: Fifty-eight patients were enrolled, of whom 2 received no study treatment and were inevaluable. The median number of cycles was 3 (268 total cycles, range 1-18). The number of patients responding was 11 (19.6%; 90% CI 11.4% to 30.4%) with one complete response. The median progression-free survival and overall survival was 3.6 months and 13.3 months, respectively. The median ORR duration was 9.2 months. Percentages of subjects with grade 3 toxicity included: Neutropenia 9%; anemia 5%; metabolic 5%; nausea 4%; infection 4%; neurologic (mostly neuropathy) 4%; and vascular (mostly thromboembolism) 4%. There were no grade 4 toxicities reported. CONCLUSIONS: This combination was well tolerated but is unworthy of further investigation based on the proportion responding [ClinicalTrials.gov Identifier: NCT00888615].

Correlation between Surgeon's assessment and radiographic evaluation of residual disease in women with advanced stage ovarian cancer reported to have undergone optimal surgical cytoreduction: An NRG Oncology/Gynecologic Oncology Group study.

PURPOSE: We sought to determine the level of concordance among surgeons' assessment of residual disease (RD) and pre-treatment computed tomography (CT) findings among women who underwent optimal surgical cytoreduction for advanced stage ovarian cancer. METHODS: This is a post-trial ad hoc analysis of a phase 3 randomized clinical trial evaluating the impact of bevacizumab in primary and maintenance therapy for patients with advanced stage ovarian cancer following surgical cytoreduction. All subjects underwent imaging of the chest/abdomen/pelvis to establish a post-surgical baseline prior to the initiation of chemotherapy. Information collected on trial was utilized to compare surgeon's operative assessment of RD, to pre-treatment imaging. RESULTS: Of 1873 enrolled patients, surgical outcome was described as optimal (RD≤1cm) in 639 subjects. Twelve patients were excluded as they did not have a baseline, pretreatment imaging, leaving 627 participants for analysis. The average interval from surgery to baseline scan was 26days (range: 1-109). In 251 cases (40%), the post-operative scan was discordant with surgeon assessment, demonstrating RD>1cm in size. RD>1cm was most commonly identified in the right upper quadrant (28.4%), retroperitoneal para-aortic lymph nodes (RD>1.5cm; 28.2%) and the left upper quadrant (10.7%). Patients with RD>1cm on pre-treatment CT (discordant) exhibited a significantly greater risk of disease progression (HR 1.30; 95% CI 1.08-1.56; p=0.0059). CONCLUSIONS: Among patients reported to have undergone optimal cytoreduction, 40% were found to have lesions >1cm on postoperative, pretreatment imaging. Although inflammatory changes and/or rapid tumor regrowth could account for the discordance, the impact on PFS and distribution of RD may suggest underestimation by the operating surgeon.

Bone loss after oophorectomy among high-risk women: an NRG oncology/gynecologic oncology group study.

OBJECTIVE: Women undergoing premenopausal oophorectomy for a variety of reasons, including to reduce ovarian or breast cancer risk were evaluated for accelerated bone loss. METHODS: The Gynecologic Oncology Group (GOG)-0215 randomized phase-II trial of zoledronic acid was initiated to determine if postoophorectomy bisphosphonate therapy could prevent this bone loss. The study was closed after slow accrual prevented evaluation of the primary study endpoint. We analyzed changes in bone mineral density (BMD) among the 80 women randomized to the observation arm of this study, as measured 3, 9, and 18 months postenrollment. RESULTS: The mean change in BMD from baseline to 18 months was -0.09 (95% CI, -0.12 to -0.07), -0.05 (95% CI, -0.07 to -0.03), and -0.06 (95% CI, -0.07 to -0.05) g/cm across the lumbar spine, right hip, and left hip, respectively. This represents a BMD decrease of -8.5% for the lumbar spine and -5.7% for both the right and left hips from baseline to 18 months' observation. CONCLUSIONS: These results demonstrate that premenopausal women undergoing oophorectomy clearly experience bone loss, an adverse effect of oophorectomy, which requires attention and active management. BMD should be monitored postoophorectomy, and treated per standard practice guidelines. Future studies will be required to determine if early treatment can mitigate fracture risk, and to test promising therapeutic interventions and novel prevention strategies, such as increased physical activity or alternative medications, in randomized trials.

Patient and physician factors associated with participation in cervical and uterine cancer trials: an NRG/GOG247 study.

PURPOSE: The aim of this study was to identify patient and physician factors related to enrollment onto Gynecologic Oncology Group (GOG) trials. METHODS: Prospective study of women with primary or recurrent cancer of the uterus or cervix treated at a GOG institution from July 2010 to January 2012. Logistic regression examined probability of availability, eligibility and enrollment in a GOG trial. Odds ratios (OR) and 95% confidence intervals (CI) for significant (p<0.05) results reported. RESULTS: Sixty institutions, 781 patients, and 150 physicians participated, 300/780 (38%) had a trial available, 290/300 had known participation status. Of these, 150 women enrolled (59.5%), 102 eligible did not enroll (35%), 38 (13%) were ineligible. Ethnicity and specialty of physician, practice type, data management availability, and patient age were significantly associated with trial availability. Patients with >4 comorbidities (OR 4.5; CI 1.7-11.8) had higher odds of trial ineligibility. Non-White patients (OR 7.9; CI 1.3-46.2) and patients of Black physicians had greater odds of enrolling (OR 56.5; CI 1.1-999.9) in a therapeutic trial. Significant patient therapeutic trial enrollment factors: belief trial may help (OR 76.9; CI 4.9->1000), concern about care if not on trial (OR12.1; CI 2.1-71.4), pressure to enroll (OR .27; CI 0.12-.64), caregiving without pay (OR 0.13; CI .02-.84). Significant physician beliefs were: patients would not do well on standard therapy (OR 3.6; CI 1.6-8.4), and trial would not be time consuming (OR 3.3; CI 1.3-8.1). CONCLUSIONS: Trial availability, patient and physician beliefs were factors identified that if modified could improve enrollment in cancer cooperative group clinical trials.

Factors associated with grade 3 or 4 treatment-related toxicity in women with advanced or recurrent cervical cancer: an exploratory analysis of NRG Oncology/Gynecologic Oncology Group trials 179 and 204.

OBJECTIVE: This study aimed to describe pretreatment patient characteristics and baseline quality-of-life scores as they relate to the development of grade 3 or 4 toxicity in patients receiving chemotherapy for advanced/recurrent cervical cancer. METHODS: The study sample was drawn from Gynecologic Oncology Group protocols 179 and 204. Grade 3 or 4 toxicities were considered in 4 specified categories as follows: peripheral neuropathy, fatigue, hematological, and gastrointestinal (GI). The data variables explored included age, stage, pretreatment radiation, performance status (PS) at treatment initiation, and baseline Functional Assessment of Cancer Therapy-Cervix (FACT-Cx) score. A logistic regression model was developed with various adverse events as binary (0/1) outcomes. RESULTS: Six hundred seventy-three patient-reported questionnaires were used in the analyses. At baseline, pain was the most severe patient-reported symptom. Baseline line-item patient concerns did demonstrate specific correlations with the development of individual toxicities. In 401 patients who were enrolled on Gynecologic Oncology Group 204 (fatigue not measured on 179), a worse PS predicted the development of grade 3 or 4 fatigue (odds ratio, 2.78; 95% confidence interval, 1.66-4.68). Exposure to previous radiation, treatment regimen, and a worse FACT-Cx score were associated with the reporting of both grade 3 or 4 leukopenia (P < 0.05) and anemia (P < 0.0005). Performance status and treatment regimen (P < 0.05) were associated with the development of grade 3 or 4 thrombocytopenia. Age and treatment regimen (P < 0.05) were associated with the development of grade 3 or 4 neutropenia. The FACT-Cx score (P = 0.0016) predicted grade 3 or 4 GI toxicity. CONCLUSIONS: The development of fatigue, hematological, and GI toxicity might be predictable based on factors other than treatment assignment such as age, PS, and patient-reported quality-of-life measurement.

A fast Monte Carlo EM algorithm for estimation in latent class model analysis with an application to assess diagnostic accuracy for cervical neoplasia in women with AGC.

In this article we use a latent class model (LCM) with prevalence modeled as a function of covariates to assess diagnostic test accuracy in situations where the true disease status is not observed, but observations on three or more conditionally independent diagnostic tests are available. A fast Monte Carlo EM (MCEM) algorithm with binary (disease) diagnostic data is implemented to estimate parameters of interest; namely, sensitivity, specificity, and prevalence of the disease as a function of covariates. To obtain standard errors for confidence interval construction of estimated parameters, the missing information principle is applied to adjust information matrix estimates. We compare the adjusted information matrix based standard error estimates with the bootstrap standard error estimates both obtained using the fast MCEM algorithm through an extensive Monte Carlo study. Simulation demonstrates that the adjusted information matrix approach estimates the standard error similarly with the bootstrap methods under certain scenarios. The bootstrap percentile intervals have satisfactory coverage probabilities. We then apply the LCM analysis to a real data set of 122 subjects from a Gynecologic Oncology Group (GOG) study of significant cervical lesion (S-CL) diagnosis in women with atypical glandular cells of undetermined significance (AGC) to compare the diagnostic accuracy of a histology-based evaluation, a CA-IX biomarker-based test and a human papillomavirus (HPV) DNA test.

A modified Latent Class Model assessment of human papillomavirus-based screening tests for cervical lesions in women with atypical glandular cells: a Gynecologic Oncology Group study.

PURPOSE: In the absence of gold standard diagnoses, we estimate age-specific false-positive and false-negative prediction rates of HPV-, cytology-, and histology-based tests for significant cervical lesions (SCL) in US women with AGC-NOS Pap smear diagnoses. METHODS: Modified Latent Class Model (LCM) analyses, with prevalence of SCL modeled as a function of age, were applied to GOG-0171 study data (n = 122). The accuracies of several HPV-based tests, including Hybrid Capture II high-risk HPV (HC2 H-HPV); carbonic anhydrase IX (CA-IX); and invasive histological diagnosis, were compared. 1-PPV and 1-NPV were written as functions of sensitivity, specificity, and prevalence to obtain age-specific false-positive and false-negative rates. RESULTS: The histology-based test was nearly perfect (sensitivity = 1.00, CI = 0.98-1.00; specificity = 0.99, CI = 0.96-1.00). Otherwise, HC2 H-HPV performed best (sensitivity = 1.00, CI = 1.00-1.00; specificity = 0.87, CI = 0.79-0.94). The false-positive detection rates (1-PPV) for HC2 H-HPV were high (>17 %) at each age, while those of the histological diagnoses were low (<5 % at ages ≤60 and <17 % overall ages). False-negative prediction rates (1-NPV) for HC2 H-HPV were <0.11 % at each age and were uniformly lower than those of other tests, including the histology-based test (<0.25 %). CA-IX together with HC2 H-HPV did not improve performance. CONCLUSIONS: Women with negative HC2 H-HPV can safely forego invasive treatment (i.e., cone or LEEP biopsy, hysterectomy) in favor of observational follow-up. Additional biomarkers must be found for use in combination with HC2 H-HPV to reduce false-positive rates. This novel application of a modified LCM exemplifies methods for potential use in future cancer screening studies when gold standard diagnoses are not available.

Karyometry in atypical endometrial hyperplasia: a Gynecologic Oncology Group study.

OBJECTIVES: Treatment for atypical endometrial hyperplasia (AEH) is based on pathologic diagnosis. About 40% of AEH is found to be carcinoma at surgery. This study's objective is to derive an objective characterization of nuclei from cases diagnosed as AEH or superficially invasive endometrial cancer (SIEC). METHODS: Cases from GOG study 167A were classified by a central pathology committee as AEH (n=39) or SIEC (n=39). High resolution digitized images of cell nuclei were recorded. Features of the nuclear chromatin pattern were computed. Classification rules were derived by discriminant analysis. RESULTS: Nuclei from cases of AEH and SIEC occupy the same range on a progression curve for endometrial lesions. Cases of AEH and SIEC both comprise nuclei of two phenotypes: hyperplastic characteristics and premalignant/neoplastic characteristics. The principal difference between AEH and SIEC is the percentage of premalignant/neoplastic nuclei. When this percentage approaches 50-60% superficial invasion is likely. SIEC may develop already from lesions at the low end of the progression curve. CONCLUSIONS: AEH comprises cases which may constitute a low risk group involving <40% of AEH cases. These cases hold a percentage of <20% of nuclei of a preneoplastic phenotype. AEH cases from the central and high end of progression have >40% of nuclei of preneoplastic phenotype. Nuclei of the preneoplastic phenotype in AEH lesions are almost indistinguishable from nuclei in SIEC, where this percentage exceeds 60%. The percentage of nuclei of the preneoplastic phenotype in AEH esions might serve as criterion for assessment of risk for the development of invasive disease.

Carbonic anhydrase IX and human papillomavirus as diagnostic biomarkers of cervical dysplasia/neoplasia in women with a cytologic diagnosis of atypical glandular cells: a Gynecologic Oncology Group study in United States.

High-risk human papillomavirus (H-HPV) infection is strongly linked to cervical neoplasia, but its role in detecting glandular lesions (GLs) is unclear. In the cervix, carbonic anhydrase IX (CA-IX) is expressed in cervical neoplasia, but rarely in the benign cervix. The diagnostic utility of these biomarkers was evaluated in women with a cytologic diagnosis of atypical glandular cells (AGC). H-HPV was detected using hybrid capture 2 (HC2) in liquid-based cytology, and CA-IX immunoreactivity was studied on conventional Pap smears. Of 403 patients, 111 (28%) were positive for significant cervical lesions (SCLs) including CIN2, CIN3, adenocarcinoma in situ or invasive carcinoma. CA-IX testing alone (n = 403) had a sensitivity of 75, 95 or 65% for SCLs, significant GLs or squamous lesions (SLs), respectively, with a specificity of 88% and a false negative rate (FNR defined as 1 minus negative predictive value) of 10%. Testing for H-HPV (n = 122) had a sensitivity of 97, 100 or 96% for SCLs, GLs or SLs, respectively, with a specificity of 87% and a FNR of 1%. The combination of CA-IX and H-HPV testing (n = 122), collectively, had the same sensitivity, specificity and FNR for SCLs, GLs or SLs as H-HPV testing alone. The conclusions of our study are that both H-HPV and CA-IX testing are useful diagnostic markers for GLs. However, H-HPV testing is a better diagnostic marker for SLs. The combination of CA-IX with H-HPV testing does not improve the diagnostic accuracy for cervical neoplasia in women with AGC diagnosis over that of H-HPV testing alone.

A randomized phase III trial of VH fibrin sealant to reduce lymphedema after inguinal lymph node dissection: a Gynecologic Oncology Group study.

OBJECTIVES: To evaluate VH fibrin sealant's influence on lower extremity lymphedema after inguinal lymphadenectomy in vulvar cancer patients. METHODS: Patients undergoing an inguinal lymphadenectomy during the management of vulvar malignancy were randomized to receive sutured closure (SC) vs VH fibrin sealant sprayed into the groin followed by sutured closure (FS). Leg measurements were taken preoperatively and during postoperative encounters when surgical outcomes were assessed. Grade 2 or 3 lymphedema was defined as circumferential measurement increases of 3-5 cm and >5 cm, respectively. RESULTS: 150 patients were enrolled. 137 patients were evaluable for lymphedema analysis with 67 and 70 patients in the SC arm and FS arm, respectively. The incidence of grade 2 and 3 lymphedema was 67%(45/67) in the SC arm, and 60% (42/70) FS arm (p=0.4779). The incidence of lymphedema was strongly associated with inguinal infection (p=0.0165). Lymphedema was not statistically increased in those who received adjuvant radiation. 139 patients remained evaluable for a descriptive analysis of their surgical complications. The overall incidence of complications was 61%(43/70) and 59% (41/69) for SC and FS arms, respectively. There was no statistically significant difference in duration of drains, drain output or incidence of inguinal infections, wound breakdowns or seromas. There was an increased incidence of vulvar infections in the FS arm (23/69) vs (10/70) (p=0.0098). The utilization of a Blake drain was associated with an increase in vulvar (p=0.0157) and inguinal wound breakdown (p=0.0456). CONCLUSION: VH fibrin sealant in inguinal lymphadenectomies does not reduce leg lymphedema and may increase the risk for complications in the vulvar wound.

Biopsy histomorphometry predicts uterine myoinvasion by endometrial carcinoma: a Gynecologic Oncology Group study.

A barrier to nonsurgical management of premalignant endometrial disease is the need to perform hysterectomy to exclude concurrent myoinvasive endometrioid adenocarcinoma. Occult adenocarcinoma rates for premalignant disease diagnosed by biopsy or curettage are approximately 40%. We applied the histomorphometric 4-class rule ("4C," which measures epithelial abundance, thickness, and nuclear variation) to diagnostic biopsies to predict myoinvasive cancer outcomes at hysterectomy. Women with endometrial biopsies or curettages having a community diagnosis of atypical endometrial hyperplasia were enrolled in a clinical trial in which subsequent hysterectomy was scored for endometrial adenocarcinoma, and 4C rule ability to predict cancer outcomes was measured. Qualifying biopsies were stratified into high- and low-risk histomorphometric subgroups. Two-hundred thirty-three women had biopsies suited to morphometry and scorable hysterectomy outcomes, of which 46% contained adenocarcinoma. Assignment to a high-risk category by the 4C rule was highly sensitive in predicting any (71%) or deeply (92%) myoinvasive adenocarcinoma at hysterectomy, and assignment to a low-risk group had a high negative predictive value for absence of any (90%) or deeply (99%) myoinvasive disease. Volume percentage epithelium was associated with myoinvasive cancer outcomes above a threshold of 50% (P < .001), and a measure of nuclear pleomorphism was significantly increased (P = .004) in deeply myoinvasive cancers. Formal histomorphometry of endometrial biopsies using the 4C rule has been validated as a means to identify a subset of women with premalignant disease who are unlikely to have concurrent myoinvasive adenocarcinoma and who may qualify for alternative nonsurgical therapies.

Concurrent endometrial carcinoma in women with a biopsy diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study.

BACKGROUND: Adenocarcinoma of the endometrium is the most common gynecologic malignancy in the United States, accounting for approximately 36,000 diagnoses of invasive carcinoma annually. The most common histologic type, endometrioid adenocarcinoma (EC), accounts for 75-80% of patients. The objective of this work was to estimate the prevalence of concurrent carcinoma in women with a biopsy diagnosis of the precursor lesion, atypical endometrial hyperplasia (AEH). METHODS: This prospective cohort study included women who had a community diagnosis of AEH. Diagnostic biopsy specimens were reviewed independently by three gynecologic pathologists who used International Society of Gynecologic Pathologists/World Health Organization criteria. Study participants underwent hysterectomy within 12 weeks of entry onto protocol without interval treatment. The hysterectomy slides also were reviewed by the study pathologists, and their findings were used in the subsequent analyses. RESULTS: Between November 1998 and June 2003, 306 women were enrolled on the study. Of these, 17 women were not included in the analysis: Two patients had unreadable slides because of poor processing or insufficient tissue, 2 patients had only slides that were not endometrial, the slides for 5 patients were not available for review, and 8 of the hysterectomy specimens were excluded because they showed evidence of interval intervention, either progestin effect or ablation. In total, 289 patients were included in the current analysis. The study panel review of the AEH biopsy specimens was interpreted as follows: 74 of 289 specimens (25.6%) were diagnosed as less than AEH, 115 of 289 specimens (39.8%) were diagnosed as AEH, and 84 of 289 specimens (29.1%) were diagnosed as endometrial carcinoma. In 5.5% (16 of 289 specimens), there was no consensus on the biopsy diagnosis. The rate of concurrent endometrial carcinoma for analyzed specimens was 42.6% (123 of 289 specimens). Of these, 30.9% (38 of 123 specimens) were myoinvasive, and 10.6% (13 of 123 specimens) involved the outer 50% of the myometrium. Among the women who had hysterectomy specimens with carcinoma, 14 of 74 women (18.9%) had a study panel biopsy consensus diagnosis of less than AEH, 45 of 115 women (39.1%) had a study panel biopsy consensus diagnosis of AEH, and 54 of 84 women (64.3%) had a study panel diagnosis of carcinoma. Among women who had no consensus in their biopsy diagnosis, 10 of 16 women (62.5%) had carcinoma in their hysterectomy specimens. CONCLUSIONS: The prevalence of endometrial carcinoma in patients who had a community hospital biopsy diagnosis of AEH was high (42.6%). When considering management strategies for women who have a biopsy diagnosis of AEH, clinicians and patients should take into account the considerable rate of concurrent carcinoma.

Reproducibility of the diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study.

BACKGROUND: Most gynecologists determine therapy based on current International Society of Gynecologic Pathologists (ISGP)/World Health Organization classification of endometrial hyperplasia, the reproducibility of which has been questioned. The Gynecologic Oncology Group (GOG) initiated a protocol to assess the efficacy of hormonal therapy of atypical endometrial hyperplasia (AEH). Primary goals of the first phase (Part A) were to prospectively determine reproducibility of referring institution's pathologist's diagnosis of AEH by a panel of 3 gynecologic pathologists and to determine reproducibility of diagnoses by panel members. METHODS: Three hundred six women were entered on this protocol with a referring institution's pathologist diagnosis of AEH based on biopsy or curettage. Available slides were assessed independently and interpreted by each of a panel of 3 gynecologic pathologists who used International Society of Gynecologic Pathologists (ISGP)/World Health Organization criteria. The majority diagnosis was based on diagnostic concordance by at least 2 of the 3 panelists. RESULTS: The referring institution's pathologist's diagnosis of AEH was supported by the majority of the panel in only 38% of cases. Overall kappa value for the panel diagnosis of AEH was 0.28. The majority diagnosis was adenocarcinoma in 29%, cycling endometrium in 7%, and nonatypical hyperplasia in 18% of cases. Unanimous agreement for any diagnosis was reached among all 3 of the panel in 40% of cases. For the panel, paired kappa values for any diagnosis ranged 0.34-0.43, with an overall kappa value of 0.40. CONCLUSION: Reproducibility of referring institution's pathologists' diagnosis of AEH by a panel of gynecologic pathologists is poor. Both underestimation and overestimation of the severity of the lesion are very common. The level of reproducibility among subspecialist panel members for diagnosis of AEH in these specimens also is poor. Better criteria and better sampling are needed to improve reproducibility of this diagnosis, particularly if it is to be used for clinical decisions.

Adjuvant ifosfamide and cisplatin in patients with completely resected stage I or II carcinosarcomas (mixed mesodermal tumors) of the uterus: a Gynecologic Oncology Group study.

OBJECTIVES: To determine progression-free survival (PFS) and overall survival (OS) in women with completely resected stage I or II carcinosarcoma of the uterus treated with adjuvant ifosfamide and cisplatin, and to assess the toxicity of this regimen. METHODS: Eligible patients had histologically confirmed carcinosarcoma (mixed mesodermal tumor) and no postoperative radiotherapy following complete resection for clinical stage I or II disease. They were to have adequate renal, hepatic, and hematologic functions and performance status of 2 or less. Study entry was to be within 8 weeks of hysterectomy. Patients with previous chemotherapy, or other noncutaneous malignancies, were ineligible. Ifosfamide was administered 1.5 g/m2 intravenously (IV) over 1 h and cisplatin was given 20 mg/m(2) over 15 min followed by mesna 120 mg/m2 IV bolus, then 1.5 g/m2/24 h as a continuous infusion. Initial doses (daily x 5 every 21 days x 3 cycles) were reduced by 20% (to 4 days) for myelotoxicity. RESULTS: Nine of seventy-six patients enrolled were deemed ineligible and another two who did not receive protocol treatment were inevaluable. Of the 65 evaluable patients, median age was 65 years; 50 patients (77%) were stage I and 15 (23%) were stage II. PFS and OS, respectively, were 69% and 82% at 24 months, and 54% and 52% at 84 months. Overall 5-year survival was 62%. Leukopenia was the most commonly reported, but manageable, toxicity. CONCLUSION: Adjuvant ifosfamide and cisplatin after primary surgery for stage I or II carcinosarcoma of the uterus is tolerable. In the absence of concurrent controls, the impact on PFS and OS is unclear. Pelvic relapse remains problematic.

Adjuvant therapy of completely resected dysgerminoma with carboplatin and etoposide: a trial of the Gynecologic Oncology Group.

OBJECTIVE: This study was designed to evaluate the effect of adjuvant chemotherapy with carboplatin and etoposide in patients with completely resected stage IB-III dysgerminoma. METHODS: Eligible patients were treated with three courses of carboplatin 400 mg/m(2) on day 1 plus etoposide 120 mg/m(2) on days 1, 2, and 3 every 4 weeks for three courses. RESULTS: Forty-two patients were entered on this trial, of whom 39 were eligible. No patient suffered a recurrence of dysgerminoma, but one patient ultimately died of lung adenocarcinoma. One patient was excluded on pathology review (elements of endodermal sinus tumor were present) developed recurrent tumor and died despite further therapy. As expected, the regimen was well tolerated. Median follow-up of surviving patients is 7.8 years (range: 2.86 months to 10.92 years). CONCLUSION: The regimen used in this study is an alternative to cisplatin, etoposide, and bleomycin (BEP) for selected patients for whom minimizing toxicity (particularly neuropathy) is critical or for whom reduction in the number of treatment days is important.

An assessment of age and other factors influencing protocol versus alternative treatments for patients with epithelial ovarian cancer referred to member institutions: a Gynecologic Oncology Group study.

OBJECTIVE: To assess the frequency with which patients with epithelial ovarian cancer are enrolled in prospective Gynecologic Oncology Group (GOG) treatment studies and to assess whether enrollment is influenced by patient age or other factors. METHODS: The study was open to patients with primary, previously untreated epithelial ovarian cancer referred to member institutions. Eligible patients provided written informed consent to have demographic and medical records data submitted to the protocol database for analysis. Pathologic diagnosis was confirmed by central review. Demographic and clinical data, including coexisting medical conditions, tumor stage, grade, and histology, surgical procedures, planned postoperative therapy, and reason/s (if applicable) a patient was not treated per GOG protocol, were collected. RESULTS: Nine hundred and forty-eight patients were initially eligible. Subsequently, 137 (15%) patients were excluded based on pathology (low malignant potential tumors), as were 10 whose invasive disease was unstaged. Among 801 eligible patients, 36% were > or =65 years of age, 52% had papillary serous tumors, and 73% had stage III/IV disease. In patients aged <65 years, 67% were stage III/IV compared to 82% of patients > or =65 years of age. The mean age was 5.5 years greater for patients with stage III/IV versus stage I/II disease. Compared to their younger counterparts, older patients with stage III/IV disease were less likely to enter into a GOG treatment protocol. Most common reasons were patient ineligibility (33%), refusal (29%), and investigator decision (20%). CONCLUSION: Age appears to be an important factor influencing treatment selection among patients with stage III/IV ovarian cancer. In addition to reviewing eligibility criteria, practitioners' attitudes should be monitored to assure that elderly patients are not inappropriately denied participation in GOG clinical trials.