Sean C. Dowdy

Prospective assessment of lymphatic dissemination in endometrial cancer: a paradigm shift in surgical staging.

OBJECTIVE To prospectively assess pelvic and para-aortic lymph node metastases in endometrial cancer with lymphatic dissemination, emphasizing the examination of para-aortic metastases relative to the inferior mesenteric artery (IMA). METHODS Over 36 months, 422 consecutive patients were managed by predefined surgical guidelines differentiating low-risk patients from patients at risk for dissemination requiring systematic lymphadenectomy. Low risk was defined as grade 1 or 2 endometrioid type with myometrial invasion (MI) < or = 50% and primary tumor diameter (PTD) < or = 2 cm. Pelvic and para-aortic lymph nodes were submitted separately, with nodes identified from all 8 pelvic and 4 para-aortic node-bearing basins. Surgical quality assessments examined median node counts (primary surrogate for quality) and nodes harvested above and below the IMA and excised gonadal veins (secondary surrogates). RESULTS Lymphadenectomy was not required in 27% of patients (all low risk) and in 33% (n=112) of endometrioid cases. However, 22 patients (20%) of this latter cohort had lymphadenectomy and all lymph nodes were negative. Sixty-three (22%) of 281 patients undergoing lymphadenectomy had lymph node metastases: both pelvic and para-aortic in 51%, only pelvic in 33%, and isolated to the para-aortic area in 16%. Therefore, 67% of patients with lymphatic dissemination had para-aortic lymph node metastases. Furthermore, 77% of patients with para-aortic node involvement had metastases above the IMA, whereas nodes in the ipsilateral para-aortic area below the IMA and ipsilateral common iliac basin were declared negative in 60% and 71%, respectively. Gonadal veins were excised in 25 patients with para-aortic node metastases; 7 patients (28%) had documented metastatic involvement of gonadal veins or surrounding soft tissue. CONCLUSIONS The high rate of lymphatic metastasis above the IMA indicates the need for systematic pelvic and para-aortic lymphadenectomy (vs sampling) up to the renal vessels. The latter should include consideration of excision of the gonadal veins. Conversely, lymphadenectomy does not benefit patients with grade 1 and 2 endometrioid lesions with MI < or = 50% and PTD < or = 2 cm.

Aggressive surgical effort and improved survival in advanced-stage ovarian cancer

OBJECTIVE: Residual disease after initial surgery for ovarian cancer is the strongest prognostic factor for survival. However, the extent of surgical resection required to achieve optimal cytoreduction is controversial. Our goal was to estimate the effect of aggressive surgical resection on ovarian cancer patient survival. METHODS: A retrospective cohort study of consecutive patients with International Federation of Gynecology and Obstetrics stage IIIC ovarian cancer undergoing primary surgery was conducted between January 1, 1994, and December 31, 1998. The main outcome measures were residual disease after cytoreduction, frequency of radical surgical resection, and 5-year disease-specific survival. RESULTS: The study comprised 194 patients, including 144 with carcinomatosis. The mean patient age and follow-up time were 64.4 and 3.5 years, respectively. After surgery, 131 (67.5%) of the 194 patients had less than 1 cm of residual disease (definition of optimal cytoreduction). Considering all patients, residual disease was the only independent predictor of survival; the need to perform radical procedures to achieve optimal cytoreduction was not associated with a decrease in survival. For the subgroup of patients with carcinomatosis, residual disease and the performance of radical surgical procedures were the only independent predictors. Disease-specific survival was markedly improved for patients with carcinomatosis operated on by surgeons who most frequently used radical procedures compared with those least likely to use radical procedures (44% versus 17%, P < .001). CONCLUSION: Overall, residual disease was the only independent predictor of survival. Minimizing residual disease through aggressive surgical resection was beneficial, especially in patients with carcinomatosis. LEVEL OF EVIDENCE: II-2

Phase I Trial of Intraperitoneal Administration of an Oncolytic Measles Virus Strain Engineered to Express Carcinoembryonic Antigen for Recurrent Ovarian Cancer

Edmonston vaccine strains of measles virus (MV) have shown significant antitumor activity in preclinical models of ovarian cancer. We engineered MV to express the marker peptide carcinoembryonic antigen (MV-CEA virus) to also permit real-time monitoring of viral gene expression in tumors in the clinical setting. Patients with Taxol and platinum-refractory recurrent ovarian cancer and normal CEA levels were eligible for this phase I trial. Twenty-one patients were treated with MV-CEA i.p. every 4 weeks for up to 6 cycles at seven different dose levels (10(3)-10(9) TCID(50)). We observed no dose-limiting toxicity, treatment-induced immunosuppression, development of anti-CEA antibodies, increase in anti-MV antibody titers, or virus shedding in urine or saliva. Dose-dependent CEA elevation in peritoneal fluid and serum was observed. Immunohistochemical analysis of patient tumor specimens revealed overexpression of measles receptor CD46 in 13 of 15 patients. Best objective response was dose-dependent disease stabilization in 14 of 21 patients with a median duration of 92.5 days (range, 54-277 days). Five patients had significant decreases in CA-125 levels. Median survival of patients on study was 12.15 months (range, 1.3-38.4 months), comparing favorably to an expected median survival of 6 months in this patient population. Our findings indicate that i.p. administration of MV-CEA is well tolerated and results in dose-dependent biological activity in a cohort of heavily pretreated recurrent ovarian cancer patients.

Multi-Institutional Reciprocal Validation Study of Computed Tomography Predictors of Suboptimal Primary Cytoreduction in Patients With Advanced Ovarian Cancer

PURPOSE Identify features on preoperative computed tomography (CT) scans to predict suboptimal primary cytoreduction in patients treated for advanced ovarian cancer in institution A. Reciprocally cross validate the predictors identified with those from two previously published cohorts from institutions B and C. PATIENTS AND METHODS Preoperative CT scans from patients with stage III/IV epithelial ovarian cancer who underwent primary cytoreduction in institution A between 1999 and 2005 were retrospectively reviewed by radiologists blinded to surgical outcome. Fourteen criteria were assessed. Crossvalidation was performed by applying predictive model A to the patients from cohorts B and C, and reciprocally applying predictive models B and C to cohort A. RESULTS Sixty-five patients from institution A were included. The rate of optimal cytoreduction ( 1 cm residual disease) was 78%. Diaphragm disease and large bowel mesentery implants were the only CT predictors of suboptimal cytoreduction on univariate (P < .02) and multivariate analysis (P < .02). In combination (model A), these predictors had a sensitivity of 79%, a specificity of 75%, and an accuracy of 77% for suboptimal cytoreduction. When model A was applied to cohorts B and C, accuracy rates dropped to 34% and 64%, respectively. Reciprocally, models B and C had accuracy rates of 93% and 79% in their original cohorts, which fell to 74% and 48% in cohort A. CONCLUSION The high accuracy rates of CT predictors of suboptimal cytoreduction in the original cohorts could not be confirmed in the cross validation. Preoperative CT predictors should be used with caution when deciding between surgical cytoreduction and neoadjuvant chemotherapy.

Nonhistone protein acetylation as cancer therapy targets

Acetylation and deacetylation are counteracting, post-translational modifications that affect a large number of histone and nonhistone proteins. The significance of histone acetylation in the modification of chromatin structure and dynamics, and thereby gene transcription regulation, has been well recognized. A steadily growing number of nonhistone proteins have been identified as acetylation targets and reversible lysine acetylation in these proteins plays an important role(s) in the regulation of mRNA stability, protein localization and degradation, and protein–protein and protein–DNA interactions. The recruitment of histone acetyltransferases (HATs) and histone deacetylases (HDACs) to the transcriptional machinery is a key element in the dynamic regulation of genes controlling cellular proliferation, differentiation and apoptosis. Many nonhistone proteins targeted by acetylation are the products of oncogenes or tumor-suppressor genes and are directly involved in tumorigenesis, tumor progression and metastasis. Aberrant activity of HDACs has been documented in several types of cancers and HDAC inhibitors (HDACi) have been employed for therapeutic purposes. Here we review the published literature in this field and provide updated information on the regulation and function of nonhistone protein acetylation. While concentrating on the molecular mechanism and pathways involved in the addition and removal of the acetyl moiety, therapeutic modalities of HDACi are also discussed.

Current issues in the management of endometrial cancer.

Endometrial cancer (EC) remains the most common gynecologic malignancy in the United States. It is expected to become more common as the prevalence of obesity, one of the most common risk factors for EC, increases worldwide. The 2 main histologic subcategories of EC, endometrioid and nonendometrioid EC, show unique molecular aberrations and are responsible for markedly disparate clinical behaviors. The primary treatment of EC is surgery, ie, hysterectomy, removal of the adnexa, and pelvic and para-aortic lymphadenectomy, either via laparotomy or endoscopic techniques. Adjuvant therapy is necessary for patients at high risk of recurrence and consists of vaginal brachytherapy, teletherapy, systemic chemotherapy, or some combination thereof. Multi-institutional trials are in progress in this country and in Europe to better define optimal adjuvant treatment for subsets of patients, as well as the role of surgical staging in reducing both overuse and underuse of radiation therapy. Hormonal therapy is an option for some young women with EC who wish to preserve fertility. This review summarizes the diagnosis and management of EC and discusses current controversies and upcoming investigations pertaining to EC staging and adjuvant treatment.

Histone deacetylase inhibitors and paclitaxel cause synergistic effects on apoptosis and microtubule stabilization in papillary serous endometrial cancer cells

The use of histone deacetylase (HDAC) inhibitors has shown promise for a variety of malignancies. In this investigation, we define the activity of this class of inhibitors in combination with traditional cytotoxic chemotherapy in endometrial cancer cells. Significant reductions in growth were observed in Ark2 and KLE endometrial cancer cells following treatment with paclitaxel, doxorubicin, carboplatin, or the HDAC inhibitor trichostatin A (TSA). However, only combined treatment with TSA/paclitaxel caused synergistic inhibition of cell growth. This combination also resulted in significant changes in cell morphology. Using cell cycle analysis, nuclear staining, and Western blot analysis for poly(ADP-ribose) polymerase and caspase-9 degradation products, TSA/paclitaxel showed the most dramatic activation of the apoptotic cascade. These effects were also observed when the HDAC inhibitors HDAC inhibitor-1 or oxamflatin were substituted for TSA. The anticancer properties of paclitaxel are known to result in part from inhibition of microtubule depolymerization, which results in apoptosis. We show that TSA administration also stabilizes microtubules via α-tubulin acetylation. Furthermore, using Western blot and immunohistochemical analysis, treatment with TSA/paclitaxel led to a significant increase in acetylated tubulin and microtubule stabilization. These effects were confirmed in a mouse xenograft model. Moreover, TSA/paclitaxel resulted in a 50% reduction in tumor weight compared with either agent alone. This study provides in vivo evidence of nonhistone protein acetylation as one possible mechanism by which HDAC inhibitors reduce cancer growth. The TSA/paclitaxel combination seems to hold promise for the treatment of serous endometrial carcinoma and other malignancies with limited sensitivity to paclitaxel. [Mol Cancer Ther 2006;5(11):2767–76]

Prospective assessment of survival, morbidity, and cost associated with lymphadenectomy in low-risk endometrial cancer.

OBJECTIVE Since 1999, patients with low risk endometrial cancer (EC) as defined by the Mayo criteria have preferably not undergone lymphadenectomy (LND) at our institution. Here we prospectively assess survival, sites of recurrence, morbidity, and cost in this low risk cohort. METHODS Cause-specific survival (CSS) was estimated using the Kaplan-Meier method and compared using the log-rank test. Complications were graded per the Accordion Classification. Thirty-day cost analyses were expressed in 2010 Medicare dollars. RESULTS Among 1393 consecutive surgically managed cases, 385 (27.6%) met inclusion criteria, accounting for 34.1% of type I EC. There were 80 LND and 305 non-LND cases. Complications in the first 30 days were significantly more common in the LND cohort (37.5% vs. 19.3%; P<0.001). The prevalence of lymph node metastasis was 0.3% (1/385). Over a median follow-up of 5.4 years only 5 of 31 deaths were due to disease. The 5-year CSS in LND and non-LND cases was 97.3% and 99.0%, respectively (P=0.32). None of the 11 total recurrences occurred in the pelvic or para-aortic nodal areas. Median 30-day cost of care was

HER2 gene amplification and EGFR expression in a large cohort of surgically staged patients with nonendometrioid (type II) endometrial cancer

15,678 for LND cases compared to

Prognostic and Therapeutic Relevance of Molecular Subtypes in High-Grade Serous Ovarian Cancer

11,028 for non-LND cases (P<0.001). The estimated cost per up-staged low-risk case was