Michael K. Cheung

Uterine papillary serous and clear cell carcinomas predict for poorer survival compared to grade 3 endometrioid corpus cancers

To compare the survival of women with uterine papillary serous carcinoma (UPSC) and clear cell carcinoma (CC) to those with grade 3 endometrioid uterine carcinoma (G3EC). Demographic, pathologic, treatment, and survival information were obtained from the Surveillance, Epidemiology, and End Results Program from 1988 to 2001. Data were analysed using Kaplan–Meier and Cox proportional hazards regression methods. Of 4180 women, 1473 had UPSC, 391 had CC, and 2316 had G3EC cancers. Uterine papillary serous carcinoma and CC patients were older (median age: 70 years and 68 vs 66 years, respectively; P<0.0001) and more likely to be black compared to G3EC (15 and 12% vs 7%; P<0.0001). A higher proportion of UPSC and CC patients had stage III–IV disease compared to G3EC patients (52 and 36% vs 29%; P<0.0001). Uterine papillary serous carcinoma, CC and G3EC patients represent 10, 3, and 15% of endometrial cancers but account for 39, 8, and 27% of cancer deaths, respectively. The 5-year disease-specific survivals for women with UPSC, CC and G3EC were 55, 68, and 77%, respectively (P<0.0001). The survival differences between UPSC, CC and G3EC persist after controlling for stage I–II (74, 82, and 86%; P<0.0001) and stage III–IV disease (33, 40, and 54; P<0.0001). On multivariate analysis, more favourable histology (G3EC), younger age, and earlier stage were independent predictors of improved survival. Women with UPSC and CC of the uterus have a significantly poorer prognosis compared to those with G3EC. These findings should be considered in the counselling, treating and designing of future trials for these high-risk patients.

Therapeutic role of lymph node resection in endometrioid corpus cancer: a study of 12,333 patients.

The purpose of the current study was to determine the potential therapeutic role of lymphadenectomy in women with endometrioid corpus cancer.

Trends in demographic and clinical characteristics in women diagnosed with corpus cancer and their potential impact on the increasing number of deaths.

OBJECTIVE The purpose of this study was to determine factors responsible for the increasing number of deaths from corpus cancer over three time periods. STUDY DESIGN Data were collected from the Surveillance, Epidemiology and End Results database from 1988-2001. Kaplan-Meier and Cox proportional hazards regression analyses were performed. RESULTS Of 48,510 women with corpus cancer, there was an increase in the proportion of patients dying from advanced cancers (52.1% to 56.0% to 68.8%; P < .001), grade 3 disease (47.5% to 53.3% to 60.6%; P < .001), serous tumors (14.3% to 18.4% to 16.6%; P < .001), and sarcomas (19.1% to 20.4% to 27.2%; P < .001) over time. On multivariate analysis, older age, African American race, lack of primary staging procedures, advanced-stage, high-grade, and non-endometrioid histology were independent prognostic factors for worse survival. CONCLUSION Our data suggest that the increase in mortality in women with corpus cancer over the last 14 years may be related to an increased rate of advanced-stage cancers and high-risk histologies.

Association of lymphadenectomy and survival in stage I ovarian cancer patients.

OBJECTIVE: To estimate the survival impact of lymphadenectomy in women diagnosed with clinical stage I ovarian cancer. METHODS: Demographic and clinicopathologic information were obtained from the Surveillance, Epidemiology and End Results Program between 1988 and 2001. Data were analyzed using Kaplan-Meier methods and Cox proportional hazards regression. RESULTS: A total of 6,686 women had clinical stage I ovarian cancer (median age 54 years, range 1–99). Of this total, 75.9% of patients were Caucasian, 8.3% were Hispanic, 5.8% were African American, and 7.3% were Asian. Epithelial tumors were present in 85.8% of the women, and 2,862 (42.8%) patients underwent lymphadenectomy. Patients aged 50 years or more were less likely to undergo lymphadenectomy compared with their younger cohorts (39.8% compared with 60.2%, P<.001). Only 32.7% of African-American women had lymphadenectomy compared with 42.7% of Caucasian women, 47.2% of Hispanics, and 48.8% of Asians (P<.001). Lymphadenectomy was associated with improved 5-year disease-specific survival of all patients from 87.0% to 92.6% (P<.001). More specifically, lymphadenectomy improved the survival in those with non–clear cell epithelial ovarian cancer (85.9% to 93.3%, P<.001) but not in those with clear cell carcinoma, germ cell tumors, sex cord stromal tumors, and sarcomas. Moreover, the extent of lymphadenectomy (0 nodes, less than 10 nodes, and 10 or more nodes) increased the survival rates from 87.0% to 91.9% to 93.8%, respectively (P<.001). On multivariable analysis, the extent of lymphadenectomy was a significant prognostic factor for improved survival, independently of other factors such as age, stage, histology, and grade of disease. CONCLUSION: Our data suggest that women with stage I non–clear cell ovarian cancers who underwent lymphadenectomy had a significant improvement in survival. LEVEL OF EVIDENCE: II

Patterns and Progress in Ovarian Cancer Over 14 Years

OBJECTIVE: To estimate the change in survival rates of women with ovarian cancer during the past 14 years. METHODS: Women diagnosed with epithelial, germ cell, sarcomas, and sex-cord stromal ovarian tumors were identified from the Surveillance Epidemiology and End Results Database. Demographic and clinicopathologic factors, and survival information were extracted and tested using &khgr;2 and Kaplan-Meier and Cox regression analyses. RESULTS: A total of 30,246 women were diagnosed with ovarian cancer, including 26,753 non–clear cell epithelial, 1,411 clear cell, 818 sarcoma, 778 germ cell, and 486 sex-cord stromal tumors. The 5-year disease-specific survival rate across 1988–1992 and 1993–1997 improved from 45.4% to 48.6% (P<.001). The corresponding estimates show increases for non–clear cell epithelial carcinoma from 42.5% to 45.8% (P<.001), and for sarcomas from 33.5% to 38.8% (P=.07). However, improvements were not observed in those with clear cell, 64.3% to 63.9% (P=.82), and sex-cord stromal, 89.7% to 85.7% (P=.18), tumors of the ovary. In multivariable analyses, younger age, early stage, favorable histologic cell types, low-grade tumors, standard surgery, and recent time interval from 1993–1997 were independent prognostic factors for improved survival. CONCLUSION: In this large population-based study, there has been some improvement in the overall survival of women with ovarian cancers during a 14-year period. However, new treatment strategies are warranted for those with epithelial cancer and sarcomas of the ovary, given their overall poor prognosis. These results from our updated analyses might help to counsel women diagnosed with ovarian cancers. LEVEL OF EVIDENCE: II-2

Enhanced Killing of Primary Ovarian Cancer by Retargeting Autologous Cytokine-Induced Killer Cells with Bispecific Antibodies: A Preclinical Study

Cytokine-induced killer (CIK) cells are ex vivo activated and expanded CD8+ natural killer T cells that have been shown to have antitumor activity. This is the first study exploring cell killing of primary ovarian carcinoma cells with and without bispecific antibodies. Primary cancer cells and autologous CIK cells were collected from women with epithelial ovarian cancer. Bispecific antibodies against cancer antigen-125 (BSAbxCA125) and Her2 (BSAbxHer2) were developed using chemical heteroconjugation. On fluorescence-activated cell sorting analysis, the expansion of CIK cells resulted in a significant increase of CD3+CD8+ and CD3+CD56+ T cells. With enhancement by bispecific antibodies, the mean percent lysis in a 51Cr release assay of fresh ovarian cancer cells exposed to autologous CIK cells increased from 21.7 ± 0.3% to 89.4 ± 2.1% at an E:T ratio of 100:1 (P < 0.001). Anti-NKG2D antibodies attenuated the CIK activity by 56.8% on primary cells (P < 0.001). In a xenograft severe combined immunodeficient mouse model, real-time tumor regression and progression was visualized using a noninvasive in vivo bioluminescence imaging system. Four hours after CIK cell injection, we were able to visualize CD8+NKG2D+ CIK cells infiltrating Her2-expressing cancer cells on fluorescence microscopy. Mice that underwent adoptive transfer of CIK cells redirected with BSAbxCA125 and BSAbxHer2 had significant reduction in tumor burden (P < 0.001 and P < 0.001) and improvement in survival (P = 0.05 and P = 0.006) versus those treated with CIK cells alone. Bispecific antibodies significantly enhanced the cytotoxicity of CIK cells in primary ovarian cancer cells and in our in vivo mouse model. The mechanism of cytolysis seems to be mediated in part by the NKG2D receptor.

Ovarian cancer in younger vs older women: a population-based analysis

To compare the clinico-pathologic prognostic factors and survival of younger vs older women diagnosed with epithelial ovarian cancer. Demographic, clinico-pathologic, treatment, and surgery information were obtained from patients with ovarian cancer from the Surveillance, Epidemiology, and End Results Program from 1988 to 2001 and analysed using Kaplan–Meier estimates. Of 28 165 patients, 400 were <30 years (very young), 11 601 were 30–60 (young), and 16 164 were >60 (older) years of age. Of the very young, young, and older patients, 261 (65.3%), 4664 (40.2%), and 3643 (22.5%) had stage I–II disease, respectively (P<0.001). Across all stages, very young women had a significant survival advantage over the young and older groups with 5-year disease-specific survival estimates at 78.8% vs 58.8 and 35.3%, respectively (P<0.001). This survival difference between the age groups persists even after adjusting for race, stage, grade, and surgical treatment. Reproductive age (16–40 years) women with stage I–II epithelial ovarian cancer who received uterine-sparing procedures had similar survivals compared to those who underwent standard surgery (93.3% vs 91.5%, P=0.26). Younger women with epithelial ovarian cancer have a survival advantage compared to older patients.

Lymphadenectomy in endometrioid uterine cancer staging: How many lymph nodes are enough? A study of 11,443 patients

The purpose of the current study was investigate the association between the number of lymph nodes examined and the probability of detecting at least a single lymph node involved by metastatic disease in patients with endometrioid corpus cancer.

Prognostic factors for uterine cancer in reproductive-aged women.

OBJECTIVE: To determine the prognostic factors that influence the survival of younger women diagnosed with uterine cancer. METHODS: Demographic and clinico-pathologic data were collected from the National Cancer Institute database between 1988 and 2001. Data were analyzed with Kaplan-Meier methods and Cox proportional hazards regression. RESULTS: Of the 51,471 women diagnosed with uterine cancer in the study period, 2,076 (4.0%) patients were aged 40 years or younger, and 49,395 (96.0%) were older than 40. The mean age in the younger group was 35.6 years, compared with 65.2 years of the older group. The overall distribution by stage was stage I 75.4%, II 8.1%, III 6.7%, and IV 9.8%. Younger patients were more likely to be nonwhite (42.4% versus 18.3%, P<.001) and have stage I disease (79.2% versus 75.3%, P<.001), grade 1 lesions (47.6% versus 35.6%, P<.001), and sarcomas (15.9% versus 8.2%, P<.001) compared with their older counterparts. The overall 5-year disease-specific survival for younger patients was significantly better than that of older women (93.2% versus 86.4%, P<.001). On multivariable analysis, younger age, earlier stage, lower grade, nonblack race, endometrioid histology, and surgical treatment remained as significant independent prognostic factors for improved survival. CONCLUSION: This large population-based study demonstrates that patients 40 years and younger have an overall survival advantage compared with women older than 40 years, independent of other clinico-pathologic prognosticators. LEVEL OF EVIDENCE: III

The impact of the absolute number and ratio of positive lymph nodes on survival of endometrioid uterine cancer patients

The aim of the study was to determine the impact of the absolute number and ratio of positive lymph nodes on the survival in node-positive endometrioid uterine cancer. Data were obtained from the National Cancer Institute Registry from 1988 to 2001. Analyses were performed using Kaplan–Meier and Cox proportional hazard methods. A total of 1222 women were diagnosed with stage IIIC-IV node-positive endometrioid corpus cancer. The 5-year disease-specific survival of women with 1, 2–5, and >5 positive nodes were 68.1, 55.1, and 46.1%, respectively (P<0.001). Increasing lymph node ratio, expressed as a percentage of positive nodes to total nodes identified (⩽10, >10–⩽50, and >50%), was associated with a decrease in survival from 77.3 to 60.7 to 40.9%, respectively (P<0.001). The absolute number of positive nodes and the lymph node ratio remained significant after adjusting for stage (IIIC vs IV) and the extent of lymphadenectomy (⩽20 vs >20 nodes). On multivariate analysis, the absolute number of positive nodes and lymph node ratio were significant independent prognostic factors for survival. Increasing absolute number of positive nodes and lymph node ratio are associated with a poorer survival in women with node-positive uterine cancers. The stratification of node-positive uterine cancer for prognostic and treatment purposes warrants further investigation.