Anna V. Hoekstra

The impact of robotics on practice management of endometrial cancer: transitioning from traditional surgery

Evaluation of the impact of a new robotic surgery programme on perioperative outcomes for endometrial cancer

Robotic surgery in gynecologic oncology: Impact on fellowship training

OBJECTIVES To report the impact of a new robotic surgery program on the surgical training of gynecologic oncology fellows over a 12 month period of time. METHODS A robotic surgery program was introduced into the gynecologic oncology fellowship program at Northwestern University Feinberg School of Medicine in June 2007. A database of patients undergoing surgical management of endometrial and cervical cancer between July 2007 and July 2008 was collected and analyzed. Changes in fellow surgical training were measured and analyzed. RESULTS Fellow surgical training for endometrial and cervical cancer underwent a dramatic transition in 12 months. The proportion of patients undergoing minimally invasive surgery increased from 3.3% (4/110 patients) to 43.5% (47/108 patients). Fellow training transitioned from primarily an open approach (94.4%) to a minimally invasive approach (11% laparoscopic, 49% robotic, 40% open) for endometrial cancer stagings, and from an open approach (100%) to an open (50%) and robotic (50%) approach for radical hysterectomies. Fellow participation in robotic procedures increased from 45% in the first 3 months to 72% within 6 months, and 92% by 12 months. The role of the fellow in robotic cases transitioned from bedside assistant to console operator within 3 months. CONCLUSIONS Fellow surgical training underwent a dramatic change with the introduction of a robotic surgery program. The management of endometrial and cervical cancer was impacted the most by robotics. Robotic surgery broadened fellowship surgical training, but balanced surgical training and standardized fellow training modules remain challenges for fellowship programs.

Treatment of nonmetastatic and metastatic low-risk gestational trophoblastic neoplasia: Factors associated with resistance to single-agent methotrexate chemotherapy

OBJECTIVE To determine factors associated with resistance to methotrexate treatment of low-risk gestational trophoblastic neoplasia (GTN). METHODS We reviewed the records of 358 patients with low-risk GTN (FIGO stage I and stages II-III, score<7) treated initially with methotrexate 0.4 mg/kg (max 25mg) IV push daily × 5 days every 14 days between 1979 and 2009. Actinomycin D 0.5mg IV push daily × 5 days every 14 days was used in 64 patients who developed resistance or toxicity to initial methotrexate chemotherapy, and combination drug regimens were used in 20 patients who failed single-agent chemotherapy. Adjuvant surgery was used in 34 selected patients. Clinical response and survival as well as factors affecting outcomes were analyzed retrospectively. RESULTS The complete response rate to initial methotrexate chemotherapy was 81% (290/358) and the complete response rate to actinomycin D as secondary therapy was 75% (48/64), for an overall complete response rate to sequential single-agent chemotherapy of 94% (338/358). The remaining 20 patients (6%) were all placed into permanent remission with the use of multiagent chemotherapy with or without surgery. Resistance to initial methotrexate chemotherapy was associated with increasing FIGO score (p<.0001), clinicopathologic diagnosis of choriocarcinoma (p=.028), higher pretreatment hCG (p=0.001) and presence of metastatic, disease (p=.018). CONCLUSIONS Sequential single-agent chemotherapy with methotrexate (0.4 mg/kg-max 25mg) followed by actinomycin D (0.5mg) each given IV push for 5 consecutive days every other week for treatment of low-risk GTN resulted in only 6% of patients requiring multiagent chemotherapy and a 100% survival rate.

Gestational trophoblastic neoplasia: Treatment outcomes

OBJECTIVE: To report the results of treatment of gestational trophoblastic neoplasia (GTN) at the John I. Brewer Trophoblastic Disease Center over the past 28 years, compare the outcomes to those from the first 16 years, and analyze factors affecting response to treatment and survival. METHODS: We reviewed the records of 408 patients with GTN (excluding placental-site tumors) treated at the Brewer Center from 1979 to 2006. Outcomes and prognostic factors were analyzed and compared with those for the 396 patients treated at the Brewer Center from 1962 to 1978. RESULTS: The overall survival rate in 804 patients with GTN treated from 1962 to 2006 was 93.3% (88.6% from 1962 to 1978 and 97.8% from 1979 to 2006). All 491 patients with nonmetastatic disease treated during both time periods were cured; however, the cure rate for patients with metastatic disease increased from 77.8% (158 of 203) during 1962–1978 to 91.8% (101 of 110) during 1979–2006. Factors determined to significantly influence resistance to initial chemotherapeutic treatment on multivariable analysis from 1979 to 2006 were 1) presence of metastatic compared with nonmetastatic disease (41% compared with 12%; odds ratio [OR] 0.21, 95% confidence interval [CI] 0.13–0.35); 2) metastatic site other than the lung or vagina (76% compared with 31%; OR 0.05, 95% CI 0.02–0.13); 3) prior unsuccessful chemotherapy at another institution compared with primary treatment at our center (63% compared with 17%; OR 0.11, 95% CI 0.05–0.22); and 4) duration of disease greater than 4 months compared with 4 months or less (35% compared with 17%; OR 0.38, 95% CI 0.21–0.66). CONCLUSION: The overall survival rate in patients with GTN treated at the Brewer Center improved from 88.6% in 1962–1978 to 97.8% in 1979–2006. LEVEL OF EVIDENCE: III

Chemosensitization of endometrial cancer cells through AKT inhibition involves FOXO1

OBJECTIVE Endometrial cancer is the most common type of gynecologic cancer in the United States. In this study, we propose that inhibition of the AKT pathway sensitizes cells to chemotherapeutic agents by increasing FOXO1 expression. METHODS Ishikawa and RL95 cells were treated with the AKT inhibitor (API-59CJ-OMe) alone and in combination with carboplatin or paclitaxel. Cells were counted using a hemocytometer and cell cycle analysis done with flow cytometry. Apoptosis was measured with TUNEL and Annexin V/DAPI staining. FOXO1 protein expression and localization was done using immunofluorescent staining of cells. Finally, the adenovirus containing triple mutant FOXO1 was used to overexpress the constitutively active FOXO1 in Ishikawa cells and its effects on cell viability were studied. RESULTS Treatment with 6 microM API-59CJ-OME resulted in preferential cell death in Ishikawa and RL95 cells compared to another endometrial cancer cell line, ECC1 after 48 h of treatment. API-59CJ-OME treatment of Ishikawa cells resulted in cell cycle arrest in the G2/M phase. The addition of API-59CJ-OME to carboplatin resulted in a synergistic increase in cell death by apoptosis compared to the responses to each agent separately. Treatment with API-59CJ-OME, carboplatin, paclitaxel or the combinations for 24 h increased nuclear expression of FOXO1 in Ishikawa cells. Overexpression of FOXO1 caused 37% of the cells to die within 24 h. Addition of carboplatin to the AD-FOXO1 expressing cells further increased cell death to 71%. CONCLUSIONS Inhibition of AKT signaling potentiates cell death in Ishikawa and RL95 cells when combined with carboplatin through mechanisms involving FOXO1 activation.

FIGO stage IIIC endometrial carcinoma: prognostic factors and outcomes.

OBJECTIVES Investigate the clinicopathologic characteristics, nodal distribution, and postoperative treatment of patients with FIGO stage IIIC endometrial carcinoma and determine patterns of recurrence and survival. METHODS A retrospective review of 85 patients who underwent surgical staging with lymph node dissection at a single institution between 1979 and 2005 was performed. Data collected from patient charts included demographics, treatment, recurrence and survival. Variables were compared using the log-rank and X2 tests, and multivariate analysis was performed. RESULTS Of 1487 patients who underwent surgical staging for endometrial cancer, 104 (7.0%) were diagnosed with stage IIIC disease and 85 of these were analyzed. Stage was determined by positive pelvic lymph nodes (PLN) in 54 patients, and positive para-aortic lymph nodes (PaLN)+/-PLN in 31 patients. With a median follow up of 50 months, 5-year overall survival (OS) was 61.3%, recurrence-free survival (RFS) was 58.0%, and disease-specific survival (DSS) was 71.9%. Median OS, RFS and DSS were 131 months, 131 months, and not attained, respectively. Five-year OS and RFS with positive PaLN were 48.8% and 44.4% respectively, compared to 69.7% and 65.6% with positive PLN only. On multivariate analysis, age, non-endometrioid histology, and >50% invasion were significantly associated with OS; age and non-endometrioid histology were associated with RFS. Disease recurred in 21 patients (24.7%): 15 distant, 4 abdominal, 1 para-aortic, and 1 pelvic. Disease recurred outside the field of radiation in all patients. CONCLUSIONS Endometrial cancer patients with FIGO stage IIIC had a 5-year OS of 61.3%, a RFS of 58.0% and a DSS of 71.9% in this series. Because of the high proportion of distant sites of recurrence (71.4%), recurrence outside the radiation field (100%), and mortality after recurrence (86.3%), multimodality therapy should be considered.

Synuclein-γ (SNCG) may be a novel prognostic biomarker in uterine papillary serous carcinoma

OBJECTIVES SNCG in breast cancer is a marker for advanced and aggressive disease thereby correlating with a poor prognosis in patients. We set out to determine if SNCG expression in UPSC correlates with aggressive cellular properties, poor prognosis, and chemoresistance, and if silencing SNCG can reverse these attributes in vitro. METHODS A focused, real time PCR array was performed comparing a papillary serous (SPEC2) and an endometrioid (Ishikawa) endometrial cancer cell line. SNCG was the most differentially expressed gene. SNCG expression was confirmed by real time PCR, Western blot, and immunohistochemistry (IHC) and correlated with outcomes in a pilot set of 20 UPSC patients. A stably transfected SPEC2 cell line was created using shSNCG oligonucleotides. The effect of SNCG knockdown in SPEC2 cells on cell proliferation and sensitivity to paclitaxel-induced apoptosis was measured using a cell viability assay, BrdU incorporation assay, as well as cleaved PARP analyses. RESULTS SNCG mRNA as well as protein was highly expressed in SPEC2 cells while minimally to undetectable in several endometrioid endometrial cancer and normal endometrial cell lines. IHC also confirmed unique SNCG expression in UPSC tumors compared to low grade endometrial cancers. In UPSC patients, SNCG expression by IHC correlated with advanced stage and decreased progression-free survival. Knockdown of SNCG in SPEC2 cells caused a significant decrease in cell proliferation and increased sensitivity to paclitaxel-induced apoptosis. CONCLUSIONS SNCG is a novel biomarker for aggressive disease and chemoresistance in UPSC and merits further investigation both as a prognostic tool and as a therapeutic target.

The combination of monthly carboplatin and weekly paclitaxel is highly active for the treatment of recurrent ovarian cancer

OBJECTIVES To evaluate the response rate and toxicity of a regimen comprised of monthly carboplatin and weekly paclitaxel for recurrent ovarian cancer. METHODS We performed a retrospective chart review of patients with recurrent ovarian cancer treated between 2001 and 2006 at a single institution with carboplatin AUC 5 (day 1), and paclitaxel 80 mg/m(2) (days 1, 8, 15) of a 28-day cycle. Primary endpoints were response rate, progression-free survival and overall survival. RESULTS Twenty patients were treated with this regimen from 2001 to 2006. Stage ranged from stages IC to IV. All received intravenous platinum and taxane as their initial therapy. Histologic subtypes included papillary serous (17), carcinosarcoma (1), and clear cell (2). The median number of prior regimens was 1 (range 1-3). The overall response rate was 85.0% (15 complete responses, 2 partial responses). Patients with tumors categorized as platinum sensitive had a response rate of 93.3% (14/15) and those with tumors deemed platinum resistant had a response rate of 60.0% (3/5). The median survival has not yet been reached after a median follow-up of 28 months. Neutropenia was the only grade 3/4 toxicity, occurring in 7 patients (35.0%). Platinum hypersensitivity reactions occurred in 5 patients (25.0%) who all successfully continued treatment using a carboplatin desensitization protocol. CONCLUSIONS A monthly carboplatin and weekly paclitaxel regimen is highly active for women with recurrent platinum-sensitive and platinum-resistant epithelial ovarian cancer. The regimen is well tolerated. This pilot series demonstrates the potential for this regimen as treatment of choice among doublet first salvage regimens for patients with recurrent epithelial ovarian cancer, thus warranting multi-institutional study.

Clinical Outcomes in International Federation of Gynecology and Obstetrics Stage IA Endometrial Cancer With Myometrial Invasion Treated With or Without Postoperative Vaginal Brachytherapy

PURPOSE To assess the clinical outcomes of patients with Stage IA endometrial cancer with myometrial invasion treated with postoperative vaginal brachytherapy (VBT) with those who received no adjuvant therapy (NAT). METHODS AND MATERIALS All patients treated with hysterectomy for endometrial cancer at Northwestern Memorial Hospital between 1978 and 2005 were identified. Those patients with Stage IA disease with myometrial invasion who were treated with VBT alone or NAT were identified and included in the present analysis. RESULTS Of 252 patients with Stage IA endometrial cancer with superficial (<50%) myometrial invasion who met the inclusion criteria, 169 underwent VBT and 83 received NAT. The median follow-up in the VBT and NAT groups was 103 and 61 months, respectively. In the VBT group, 56.8% had Grade 1, 37.9% had Grade 2, and 5.3% had Grade 3 tumors. In the NAT group, 75.9%, 20.5%, and 3.6% had Grade 1, 2, and 3 tumors, respectively. Lymphatic or vascular space invasion was noted in 12.4% of the VBT patients and 5.6% of the NAT patients. The 5-year overall survival rate was 95.5%. The 5-year recurrence-free survival rate was 92.4% for all patients, 94.4% for the VBT group, and 87.4% for the NAT group (p = NS). Of the 169 VBT patients and 83 NAT patients, 8 (4.7%) and 6 (7.2%) developed recurrent disease. One vaginal recurrence occurred in the VBT group (0.6%) and three in the NAT group (3.8%). Recurrences developed 2-102 months after surgical treatment. Two of the four vaginal recurrences were salvaged. No Grade 3 or higher acute or late radiation toxicity was noted. CONCLUSIONS The use of postoperative VBT in patients with Stage I endometrial cancer with <50% myometrial invasion yielded excellent vaginal disease control and disease-free survival, with minimal toxicity.

Hormonal contraception and false-positive cervical cytology: is there an association?

Objective. The aim of the study was to determine if use of hormonal contraception influences the false-positive rate of cervical cytology when compared with loop electrosurgical excision procedure or cervical biopsy specimens. Materials and Methods. We performed a case-control analysis of 328 women referred for colposcopy after an abnormal Pap test. Patients were divided into cases (true-positive cytology results) and controls (false-positive cytology results). Univariate analysis was performed using the &khgr;2 and Student t test to identify factors associated with false-positive cytology. Multiple logistic regression analysis was used to estimate odds ratios for the independent association of these factors. Results. The false-positive rate for the entire cohort was 44.8%. Cases were more likely to be pregnant and postmenopausal (odds ratio [OR] = 4.98, 95% CI = 2.16-11.47; OR = 5.48, 95% CI = 1.23-24.36, respectively). Use of hormonal contraception was not significantly different between groups (OR = 0.56, 95% CI = 0.29-1.09 for combination oral contraceptive pills; OR = 0.89, 95% CI = 0.35-2.25 for progestin-containing contraception). Low-grade squamous intraepithelial lesion results were more likely to be false positives (51%) than high-grade squamous intraepithelial lesion (27%) (p <.001). Conclusions. There remains a substantial lack of correlation between cervical cytology and histology. Use of hormonal contraception was not shown to increase a patients likelihood of having a false-positive Pap test.