Christopher Giede

Clinical Performance of the PreTect HPV-Proofer E6/E7 mRNA Assay in Comparison with That of the Hybrid Capture 2 Test for Identification of Women at Risk of Cervical Cancer

ABSTRACT Human papillomavirus (HPV) DNA testing has a higher clinical sensitivity than cytology for the detection of high-grade cervical intraepithelial neoplasia or worse (CIN 2+). However, an improvement in specificity would be desirable. As malignant transformation is induced by HPV E6/E7 oncogenes, detection of E6/E7 oncogene activity may improve specificity and be more predictive of cervical cancer risk. The PreTect HPV-Proofer assay (Proofer; Norchip) detects E6/E7 mRNA transcripts from HPV types 16, 18, 31, 33, and 45 with simultaneous genotype-specific identification. The clinical performance of this assay was assessed in a cross-sectional study of women referred for colposcopy in comparison with the Hybrid Capture 2 (HC2; Qiagen) test, which detects DNA of 13 high-risk oncogenic HPV types collectively. Cervical specimens were collected in PreservCyt, and cytology was performed using the ThinPrep method (Hologic). The samples were processed for HPV detection with Proofer and HC2 and genotyping with the Linear Array method (Roche Molecular Systems). Histology-confirmed CIN 2+ served as the disease endpoint to assess the clinical performance of the tests. A total of 1,551 women were studied, and of these, 402 (25.9%) were diagnosed with CIN 2+ on histology. The Proofer assay showed a sensitivity of 78.1% (95% confidence interval [CI], 74.1 to 82.1) versus 95.8% (95% CI, 93.8 to 97.8) for HC2 (P < 0.05) and a specificity of 75.5% (95% CI, 73.0 to 78.0) versus 39.6% (95% CI, 36.8 to 42.4), respectively (P < 0.05). The lower sensitivity and higher specificity of Proofer for detection of CIN 2+ can be attributed to the fact that this test detects the expression of E6/E7 genes beyond a threshold from a limited number of oncogenic HPV types. In conclusion, Proofer is more specific than HC2 in identifying women with CIN 2+ but has a lower sensitivity.

Sentinel lymph node procedure in endometrial cancer: A systematic review and proposal for standardization of future research.

OBJECTIVES Sentinel lymph node (SLN) procedure could be an attractive solution to the debate on lymphadenectomy in endometrial cancer; however challenges to interpreting the literature include marked heterogeneity across studies, a wide variety of injection techniques and a lack of uniformly accepted definitions for important outcomes. We aim to critically appraise the published literature and streamline terminology and methodology for future studies in this field. METHODS We conducted a PubMed search and included all original research of endometrial cancer patients having undergone SLN procedure with an n>30. Data collected included injection technique, unilateral, bilateral, and para-aortic detection rates, and ultrastaging results. When different definitions were used for reporting outcomes, we recalculated the original study results according to our proposed definitions. Data was analyzed using descriptive statistics. RESULTS Seventeen studies met our inclusion criteria. Injection sites were categorized into cervical versus corporeal. Overall detection rates ranged from 60 to 100%; studies with n>100 all had overall detection rates of >80%. Bilateral detection rates were higher with a combination of two injection agents. Para-aortic mapping was most frequent after corporeal injection techniques (39%), and was higher after deep vs. standard cervical injection (17% vs. 2%). The proportion of metastatic lymph nodes diagnosed through ultrastaging was high (around 40%) and ultrastaging of SLN upstaged approximately 5% of patients. Retrospectively applying a surgical algorithm revealed a sensitivity of 95%, a negative predictive value of 99%, and a false negative rate of 5% (with only 9 false negative cases remaining in total). CONCLUSION Results of SLN research for endometrial cancer are promising. We believe that in future studies, uniform reporting is needed to improve our understanding of the safety and feasibility of SLN in EC. We propose 2 strategies: a checklist of elements to include in future reports and the standardization of key definitions.

Initial Evaluation and Referral Guidelines for Management of Pelvic/Ovarian Masses

OBJECTIVES To optimize the management of adnexal masses and to assist primary care physicians and gynaecologists determine which patients presenting with an ovarian mass with a significant risk of malignancy should be considered for gynaecologic oncology referral and management. OPTIONS Laparoscopic evaluation, comprehensive surgical staging for early ovarian cancer, or tumour debulking for advanced stage ovarian cancer. OUTCOMES To optimize conservative versus operative management of women with possible ovarian malignancy and to optimize the involvement of gynaecologic oncologists in planning and delivery of treatment. EVIDENCE Published literature was retrieved through searches of PubMed or MEDLINE, CINAHL, and the Cochrane Library, using appropriate controlled vocabulary and key words. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Grey (unpublished) literature was identified by searching the web sites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. RECOMMENDATIONS 1. Primary care physicians and gynaecologists should always consider the possibility of an underlying ovarian cancer in patients in any age group who present with an adnexal or ovarian mass. (II-2B) 2. Appropriate workup of a perimenopausal or postmenopausal woman presenting with an adnexal mass should include evaluation of symptoms and signs suggestive of malignancy, such as persistent pelvic/abdominal pain, urinary urgency/frequency, increased abdominal size/bloating, and difficulty eating. In addition, CA125 measurement should be considered. (II-2B) 3. Transvaginal or transabdominal ultrasound examination is recommended as part of the initial workup of a complex adnexal/ovarian mass. (II-2B) 4. Ultrasound reports should be standardized to include size and unilateral/bilateral location of the adnexal mass and its possible origin, thickness of septations, presence of excrescences and internal solid components, vascular flow distribution pattern, and presence or absence of ascites. This information is essential for calculating the risk of malignancy index II score to identify pelvic mass with high malignant potential. (IIIC) 5. Patients deemed to have a high risk of an underlying malignancy should be reviewed in consultation with a gynaecologic oncologist for assessment and optimal surgical management. (II-2B).

Epidemiology and investigations for suspected endometrial cancer.

OBJECTIVE To review the evidence relating to the epidemiology of endometrial cancer and its diagnostic workups. OPTIONS Women with possible endometrial cancer can undergo an endometrial evaluation by office biopsy, hysteroscopy, or dilatation and curettage. To assist in treatment planning, pelvic ultrasound, CT scan, or MRI may be considered. OUTCOMES The identification of optimal diagnostic tests to evaluate patients with possible endometrial cancer. EVIDENCE Published literature was retrieved through searches of PubMed, CINAHL, and The Cochrane Library, using appropriate controlled vocabulary (e.g., endometrial neoplasms) and key words (e.g., endometrium cancer, endometrial carcinoma). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to December 31, 2011. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, national and international medical specialty societies, and recent conference abstracts. VALUES The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table). BENEFITS, HARMS, AND COSTS This document is intended to guide the development of a standardized cost-effective investigation of patients with suspected endometrial cancer. VALIDATION The guideline was reviewed for accuracy by experts in pathology, radiation oncology, and medical oncology. Guideline content was also compared with relevant documents from the American Congress of Obstetricians and Gynecologists.

The role of surgery in endometrial cancer.

OBJECTIVE To review current practice and make recommendations for the management and treatment of endometrial cancer. OUTCOMES This guideline makes recommendations with respect to extended surgical staging, which provides important prognostic information and aids in determining the need for adjuvant treatments. EVIDENCE Published literature was retrieved through searches of PubMed, CINAHL, and The Cochrane Library, using appropriate controlled vocabulary (e.g., endometrial neoplasms) and key words (e.g., endometrium cancer, endometrial carcinoma). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to December 31, 2011. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, national and international medical specialty societies, and recent conference abstracts BENEFITS, HARMS, AND COSTS This guideline reviews the benefit of extended surgical staging compared with the potential harm of a limited surgery in grade 2 and 3 disease. VALUES The quality of evidence is rated and recommendations are made using the criteria described by the Canadian Task Force on Preventive Health Care (Table).

The Role of Adjuvant Therapy in Endometrial Cancer

OBJECTIVE To review the evidence relating to the use of adjuvant therapy after surgical treatment for endometrial cancer. OPTIONS Women with endometrial cancer can be given the option of receiving adjuvant radiotherapy and/or chemotherapy according to pathologic findings at time of surgery. OUTCOMES The outcomes measured are postoperative progression-free and overall survival in endometrial cancer patients. EVIDENCE Published literature was retrieved through searches of PubMed, CINAHL, and The Cochrane Library, using appropriate controlled vocabulary (e.g., endometrial neoplasms) and key words (e.g., endometrium cancer, endometrial carcinoma). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to December 31, 2011. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, national and international medical specialty societies, and recent conference abstracts. VALUES The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table). BENEFITS, HARMS, AND COSTS This guideline is intended to help standardize postoperative treatment of endometrial cancer and minimize undertreatment and overtreatment. VALIDATION The guideline was reviewed for accuracy by content experts in pathology, radiation oncology, and medical oncology. Guideline content was also compared with relevant documents from the American Congress of Obstetricians and Gynecologists.

Prospective cohort study comparing quality of life and sexual health outcomes between women undergoing robotic, laparoscopic and open surgery for endometrial cancer

OBJECTIVE To evaluate patient-reported outcomes (PROs) between women treated by laparoscopic, robotic and open approaches for endometrial cancer. METHODS Prospective cohort study comparing PRO at baseline, short- (1 and 3 weeks) and long-term (12 and 24 weeks) follow-up postoperatively. Quality of life (QOL) measures were the Functional Assessment of Cancer Therapy (FACT-G), EuroQol Five Dimensions (EQ-5D), and Brief Pain Inventory (BPI). Sexual health measures were the Female Sexual Function Index (FSFI) and the Sexual Adjustment and Body Image Scale for Gynecologic Cancer (SABIS-G). RESULTS 468 eligible patients (laparotomy = 92, laparoscopy = 152, robotic = 224) were recruited. There were no significant differences between the laparoscopy and robotic groups for any PRO (P > 0.05). At short-term follow-up, patients who underwent minimally invasive surgery (robotic or laparoscopy) had significantly higher FACT-G (P < 0.0001) and EQ-5D (P < 0.0001) scores, with less pain (P = 0.02) and improved pain interference (P = 0.0008), than patients undergoing laparotomy. At long-term follow-up, there were sustained improvements in the FACT-G (P = 0.035) and the health state EQ-5D visual analogue scale (P = 0.022). Surgical approach had no impact on sexual health (P > 0.05); however the mean FSFI score for the entire cohort met clinical cut-offs for sexual dysfunction. CONCLUSION Minimally invasive approaches result in improved QOL beyond the short-term postoperative period, with benefits noted up to 12 weeks after surgery. This prolonged QOL advantage provides further evidence that MIS should be the standard surgical approach for women with early stage endometrial cancer.