C. David Wrede

Quality of life after total laparoscopic hysterectomy versus total abdominal hysterectomy for stage I endometrial cancer (LACE): a randomised trial

BACKGROUND This two-stage randomised controlled trial, comparing total laparoscopic hysterectomy (TLH) with total abdominal hysterectomy (TAH) for stage I endometrial cancer (LACE), began in 2005. The primary objective of stage 1 was to assess whether TLH results in equivalent or improved quality of life (QoL) up to 6 months after surgery compared with TAH. The primary objective of stage 2 was to test the hypothesis that disease-free survival at 4.5 years is equivalent for TLH and TAH. Here, we present the results of stage 1. METHODS Between Oct 7, 2005, and April 16, 2008, 361 participants were enrolled in the QoL substudy at 19 centres across Australia, New Zealand, and Hong Kong; 332 completed the QoL analysis. Randomisation was done centrally and independently from other study procedures via a computer-generated, web-based system (providing concealment of the next assigned treatment), using stratified permuted blocks of three and six patients. Patients with histologically confirmed stage I endometrioid adenocarcinoma and Eastern Cooperative Oncology Group performance status less than 2 were randomly assigned to TLH (n=190) or TAH (n=142), stratified by histological grade and study centre. Patients and study personnel were not masked to treatment assignment. QoL was measured at baseline, 1 and 4 weeks (early), and 3 and 6 months (late) after surgery, using the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire. The primary endpoint was the difference between groups in QoL change from baseline at early and late timepoints (a 5% difference was considered clinically significant). Analysis was done according to the intention-to-treat principle. Patients for both stages of the trial have now been recruited and are being followed up for disease-specific outcomes. The LACE trial is registered with ClinicalTrials.gov, number NCT00096408. FINDINGS Eight of 332 patients (2.4%) had treatment conversion-seven from TLH to TAH and one from TAH to TLH (patient preference). In the early phase of recovery, patients who had TLH reported significantly greater improvement in QoL from baseline compared with those who had TAH, in all subscales apart from emotional and social wellbeing. Improvements in QoL up to 6 months after surgery continued to favour TLH, except in the emotional and social wellbeing measures of FACT and the visual analogue scale of the EuroQoL five dimensions (EuroQoL-VAS). Operating time was significantly longer in the TLH group (138 min [SD 43]) than in the TAH group (109 min [34]; p=0.001). Although the proportion of intraoperative adverse events was similar between groups (TAH eight of 142 [5.6%] vs TLH 14 of 190 [7.4%]; p=0.53); postoperatively, twice as many patients in the TAH group experienced adverse events of grade 3 or higher (33 of 142 [23.2%] vs 22 of 190 [11.6%] in the TLH group; p=0.004). Postoperative serious adverse events occurred more in the TAH group (27 of 142 [19.0%]) than in the TLH group (16 of 190 [7.9%]; p=0.002). INTERPRETATION QoL improvements from baseline during early and later phases of recovery, and the adverse event profile, favour TLH compared with TAH for treatment of stage I endometrial cancer. FUNDING Cancer Council Queensland, Cancer Council New South Wales, Cancer Council Victoria, Cancer Council Western Australia; NHMRC project grant 456110; Cancer Australia project grant 631523; The Women and Infants Research Foundation, Western Australia; Royal Brisbane and Womens Hospital Foundation; Wesley Research Institute; Gallipoli Research Foundation; Gynetech; TYCO Healthcare, Australia; Johnson and Johnson Medical, Australia; Hunter New England Centre for Gynaecological Cancer; Genesis Oncology Trust; and Smart Health Research Grant QLD Health.

Assessing genital human papillomavirus genoprevalence in young Australian women following the introduction of a national vaccination program

OBJECTIVES Following the implementation of Australias National HPV Vaccination Program in April 2007, this study evaluated the prevalence of vaccine-targeted human papillomavirus (HPV) genotypes (HPV 6, 11, 16, 18) amongst vaccine-eligible young women. METHODS Between September 2011 and August 2013, women from Victoria, Australia aged 18-25 were recruited through targeted advertising on the social networking website Facebook. Participants completed an online questionnaire, and sexually active women were asked to provide a self-collected vaginal swab for HPV deoxyribonucleic acid (DNA) detection and genotyping. Samples positive for HPV were genotyped using the Linear Array HPV genotyping test (Roche Diagnostics). Self-reported HPV vaccination details were verified with the National HPV Vaccination Program Register (NHVPR). RESULTS Of 431 vaginal swabs, 24.8% were positive for HPV DNA. Vaccine-targeted HPV genotypes were detected in only seven (1.6%) samples; all HPV 16 (of the six HPV 16 positive vaccinated women, all had received the vaccine after sexual debut). There were no cases of HPV 6, 11 or 18 identified. HPV types 51, 59, 73, 84, and 89 were the most prevalent genotypes. Vaccination rates were high, with 77.3% of participants having received all three doses of the vaccine, and there was an 89.8% concordance between self-reported and registry-reported HPV vaccination status. Strong associations were observed between vaccination status, age, language spoken at home and country of birth, as well as between HPV detection and the number of male sexual partners. CONCLUSION Preliminary data from this study demonstrate a very low prevalence of vaccine-related HPV genotypes amongst vaccine-eligible women from Victoria, Australia. We were able to use Facebook to effectively reach and recruit young women to participate in the assessment of the impact of Australias HPV vaccination program.

Effect of total laparoscopic hysterectomy vs total abdominal hysterectomy on disease-free survival among women with stage I endometrial cancer. A randomized clinical trial

Importance Standard treatment for endometrial cancer involves removal of the uterus, tubes, ovaries, and lymph nodes. Few randomized trials have compared disease-free survival outcomes for surgical approaches. Objective To investigate whether total laparoscopic hysterectomy (TLH) is equivalent to total abdominal hysterectomy (TAH) in women with treatment-naive endometrial cancer. Design, Setting, and Participants The Laparoscopic Approach to Cancer of the Endometrium (LACE) trial was a multinational, randomized equivalence trial conducted between October 7, 2005, and June 30, 2010, in which 27 surgeons from 20 tertiary gynecological cancer centers in Australia, New Zealand, and Hong Kong randomized 760 women with stage I endometrioid endometrial cancer to either TLH or TAH. Follow-up ended on March 3, 2016. Interventions Patients were randomly assigned to undergo TAH (n = 353) or TLH (n = 407). Main Outcomes and Measures The primary outcome was disease-free survival, which was measured as the interval between surgery and the date of first recurrence, including disease progression or the development of a new primary cancer or death assessed at 4.5 years after randomization. The prespecified equivalence margin was 7% or less. Secondary outcomes included recurrence of endometrial cancer and overall survival. Results Patients were followed up for a median of 4.5 years. Of 760 patients who were randomized (mean age, 63 years), 679 (89%) completed the trial. At 4.5 years of follow-up, disease-free survival was 81.3% in the TAH group and 81.6% in the TLH group. The disease-free survival rate difference was 0.3% (favoring TLH; 95% CI, −5.5% to 6.1%; P = .007), meeting criteria for equivalence. There was no statistically significant between-group difference in recurrence of endometrial cancer (28/353 in TAH group [7.9%] vs 33/407 in TLH group [8.1%]; risk difference, 0.2% [95% CI, −3.7% to 4.0%]; P = .93) or in overall survival (24/353 in TAH group [6.8%] vs 30/407 in TLH group [7.4%]; risk difference, 0.6% [95% CI, −3.0% to 4.2%]; P = .76). Conclusions and Relevance Among women with stage I endometrial cancer, the use of total abdominal hysterectomy compared with total laparoscopic hysterectomy resulted in equivalent disease-free survival at 4.5 years and no difference in overall survival. These findings support the use of laparoscopic hysterectomy for women with stage I endometrial cancer. Trial Registration clinicaltrials.gov Identifier: NCT00096408; Australian New Zealand Clinical Trials Registry: CTRN12606000261516

Mainstreaming cancer genetics: A model integrating germline BRCA testing into routine ovarian cancer clinics

OBJECTIVE Owing to the rapid increase in clinical need, we aimed to implement and review the performance of a mainstreaming model of germline BRCA1/2 genetic testing in eligible women with high grade non-mucinous epithelial ovarian cancer via a Genetic Counselor embedded in the gynecology oncology clinic. METHODS The model implemented involved a specialized referral form, weekly genetics-lead multidisciplinary review of referrals, and pre- and post-test genetic counseling provided by an embedded genetic counselor during chemotherapy chair time. Performance and outcomes were retrospectively audited over the following two consecutive one year periods, including survey data on medical specialist comfort with mainstreaming and the model. RESULTS Sixty-four women underwent mainstreamed BRCA1/2 testing over the two year post-implementation period with a rate of detection of BRCA1/2 pathogenic variants of 17%. The referral rate for eligible women significantly increased to over 90% (p<0.001). The median time from referral to delivery of genetic testing results was less than five months, with >90% of patients receiving results during first line chemotherapy. Genetic counseling time decreased from 120 to 54min. Cancer specialists were comfortable with the model. CONCLUSIONS The mainstreaming model proved effective, increasing uptake of genetic testing in eligible patients to over 90%; it was efficient for patients, genetic counselors and cancer specialists and acceptable to cancer specialists. It facilitated co-location of genetic and oncology service delivery but separation of clinical responsibility for genetic testing to a specialist genetics service, ensuring accurate and robust patient-centred care.

Home‐based HPV self‐sampling improves participation by never‐screened and under‐screened women: Results from a large randomized trial (iPap) in Australia

We conducted a randomized controlled trial to determine whether HPV self‐sampling increases participation in cervical screening by never‐ and under‐screened (not screened in past 5 years) women when compared with a reminder letter for a Pap test. Never‐ or under‐screened Victorian women aged 30–69 years, not pregnant and with no prior hysterectomy were eligible. Within each stratum (never‐screened and under‐screened), we randomly allocated 7,140 women to self‐sampling and 1,020 to Pap test reminders. The self‐sampling kit comprised a nylon tipped flocked swab enclosed in a dry plastic tube. The primary outcome was participation, as indicated by returning a swab or undergoing a Pap test; the secondary outcome, for women in the self‐sampling arm with a positive HPV test, was undergoing appropriate clinical investigation. The Roche Cobas® 4800 test was used to measure presence of HPV DNA. Participation was higher for the self‐sampling arm: 20.3 versus 6.0% for never‐screened women (absolute difference 14.4%, 95% CI: 12.6–16.1%, p < 0.001) and 11.5 versus 6.4% for under‐screened women (difference 5.1%, 95% CI: 3.4–6.8%, p < 0.001). Of the 1,649 women who returned a swab, 45 (2.7%) were positive for HPV16/18 and 95 (5.8%) were positive for other high‐risk HPV types. Within 6 months, 28 (62.2%) women positive for HPV16/18 had colposcopy as recommended and nine (20%) had cytology only. Of women positive for other high‐risk HPV types, 78 (82.1%) had a Pap test as recommended. HPV self‐sampling improves participation in cervical screening for never‐ and under‐screened women and most women with HPV detected have appropriate clinical investigation.

Measuring effectiveness of the cervical cancer vaccine in an Australian setting (the VACCINE study)

BackgroundThe quadrivalent human papillomavirus vaccine has been provided in Australia through the National Human Papillomavirus Vaccination Program since April 2007. National registry data demonstrates good coverage of the vaccine, with 73% of school-aged girls having received all three doses. To evaluate the effectiveness of the program, we propose a two-pronged approach. In one (sub study A), the prevalence of the vaccine-targeted human papillomavirus genotypes in a population cohort is being estimated, and will be analysed in relation to vaccination status, cervical cytology screening status, demographic, social, behavioural, medical and clinical factors. In sub study B, the distribution of human papillomavirus genotypes detected in high grade cervical intraepithelial neoplastic lesions from vaccine eligible women is being assessed.Methods/DesignSub Study A involves the recruitment of 1569 women aged 18–25, residing in Victoria, Australia, through Facebook advertising. Women who are sexually active are being asked to provide a self-collected vaginal swab, collected at home and posted into the study centre, where human papillomavirus DNA detection and genotyping is performed. Participants also complete an online questionnaire regarding sexual history, experience with, knowledge of, and attitudes towards human papillomavirus, the human papillomavirus vaccine, and cervical screening.Sub Study B will involve the collection of 500 cervical biopsies, positively identified as containing high grade cervical intraepithelial neoplastic lesions and/or adenocarcinoma in situ. Five serial sections are being taken from each case: sections 1 and 5 are being assessed to confirm the presence of the high grade cervical intraepithelial neoplastic lesions or adenocarcinoma in situ; human papillomavirus genotyping is performed on sections 2 and 3; single lesions are excised from section 4 using laser capture microdissection to specifically define causality of a human papillomavirus genotyping of each specific lesion.DiscussionAustralia is well placed to gain a clear and early insight into the effectiveness of the human papillomavirus vaccine in reducing the prevalence of human papillomavirus infection in young women, and any subsequent reduction in the prevalence of pre-cancerous cervical lesions, specifically high grade cervical intraepithelial neoplasia lesions, particularly of vaccine related types. The findings of a successful population based human papillomavirus program will have wide-reaching translational benefits across the globe.

Cervical screening with primary HPV testing or cytology in a population of women in which those aged 33 years or younger had previously been offered HPV vaccination: Results of the Compass pilot randomised trial

Background Using primary human papillomavirus (HPV) testing for cervical screening increases detection of high-grade cervical intraepithelial neoplastic lesions and invasive cancer (cervical intraepithelial neoplasia grade 2+ [CIN2+]) compared to cytology, but no evaluation has been conducted in a population previously offered HPV vaccination. We aimed to assess colposcopy referral and CIN2+ detection rates for HPV-screened versus cytology-screened women in Australia’s HPV-vaccinated population (by 2014, resident women ≤33 years had been age-eligible for HPV vaccination, with 3-dose uptake across age cohorts being about 50%–77%). Methods and findings Compass is an open-label randomised trial of 5-yearly HPV screening versus 2.5-yearly liquid-based cytology (LBC) screening. In the first phase, consenting women aged 25–64 years presenting for routine screening at 47 primary practices in Victoria, Australia, provided a cervical sample and were randomised at a central laboratory at a 1:2:2 allocation to (i) image-read LBC screening with HPV triage of low-grade cytology (‘LBC screening’), (ii) HPV screening with those HPV16/18 positive referred to colposcopy and with LBC triage for other oncogenic (OHR) types (‘HPV+LBC triage’), or (iii) HPV screening with those HPV16/18 positive referred to colposcopy and with dual-stained cytology triage for OHR types (‘HPV+DS triage’). A total of 5,006 eligible women were recruited from 29 October 2013 to 7 November 2014 (recruitment rate 58%); of these, 22% were in the group age-eligible for vaccination. Data on 4,995 participants were analysed after 11 withdrawals; 998 were assigned to, and 995 analysed (99.7%) in, the LBC-screened group; 1,996 assigned to and 1,992 analysed (99.8%) in the HPV+LBC triage group; and 2,012 assigned to and 2,008 analysed (99.8%) in the HPV+DS triage group. No serious trial-related adverse events were reported. The main outcomes were colposcopy referral and detected CIN2+ rates at baseline screening, assessed on an intention-to-treat basis after follow-up of the subgroup of triage-negative women in each arm referred to 12 months of surveillance, and after a further 6 months of follow-up for histological outcomes (dataset closed 31 August 2016). Analysis was adjusted for whether women had been age-eligible for HPV vaccination or not. For the LBC-screened group, the overall referral and detected CIN2+ rates were 27/995 (2.7% [95% CI 1.8%–3.9%]) and 1/995 (0.1% [95% CI 0.0%–0.6%]), respectively; for HPV+LBC triage, these were 75/1,992 (3.8% [95% CI 3.0%–4.7%]) and 20/1,992 (1.0% [95% CI 0.6%–1.5%]); and for HPV+DS triage, these were 79/2,008 (3.9% [95% CI 3.1%–4.9%]) and 24/2,008 (1.2% [95% CI 0.8%–1.6%]) (p = 0.09 for difference in referral rate in LBC versus all HPV-screened women; p = 0.003 for difference in CIN2+ detection rate in LBC versus all HPV-screened women, with p = 0.62 between HPV screening groups). Limitations include that the study population involved a relatively low risk group in a previously well-screened and treated population, that individual women’s vaccination status was unknown, and that long-term follow-up data on disease detection in screen-negative women are not yet available. Conclusions In this study, primary HPV screening was associated with significantly increased detection of high-grade precancerous cervical lesions compared to cytology, in a population where high vaccine uptake was reported in women aged 33 years or younger who were offered vaccination. It had been predicted that increased disease detection might be associated with a transient increase in colposcopy referral rates in the first round of HPV screening, possibly dampened by HPV vaccine effect; in this study, although the point estimates for referral rates in women in each HPV-screened group were 41%–44% higher than in cytology-screened women, the difference in referral rate between cytology- and HPV-screened women was not significant. These findings provide initial support for the implementation of primary HPV screening in vaccinated populations. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12613001207707

A pilot study to compare dry cervical sample collection with standard practice of wet cervical samples for human papillomavirus testing

BACKGROUND For human papillomavirus (HPV) DNA detection, specimen collection and transportation using a dry swab without transport medium has advantages, in various situations, over liquid media. OBJECTIVE In this pilot study we evaluated whether a dry cervical sample taken with a flocked swab (dry sample) is a valid alternative for HPV DNA testing compared with the standard practice of a wet sample taken with a cyto-broom placed directly into liquid media (wet sample). STUDY DESIGN Women attending the dysplasia clinic at the Royal Womens Hospital, Melbourne Australia between November 2013 and February 2014 were enrolled. During colposcopic examination, a practitioner collected wet and dry cervical samples, with the order of collection randomised. In the laboratory both samples were left for a week before being tested for 14 high-risk HPV types using the Roche Cobas 4800 test. RESULTS Overall, 209 had valid HPV results from both samples. The observed agreement for HPV detection between wet and dry samples was 92.8% and kappa was 0.85 (95% confidence interval (95% CI): 0.78-0.92). There was no statistical difference in the percent HPV positive for each sample (p = 0.30). HPV testing of the dry sample had an 88.5% (95% CI: 79.9-94.3%) sensitivity for HPV detected using the wet specimen. For the HPV results categorized hierarchically, there was 92.8% overall agreement and a kappa of 0.87 (95% CI = 0.80-0.93) for the paired results. CONCLUSION Using dry flocked swabs to collect cervical cells is a valid alternative to collecting wet samples for HPV DNA testing using a PCR based test.

The urologist's role in multidisciplinary management of placenta percreta.

To evaluate urological interventions in patients with placental adhesive disorders in our collaborative experience at a tertiary referral centre.

Offering HPV vaccination to women treated for high‐grade cervical intra‐epithelial neoplasia: What do you need to know?

Dear Editor, Although Australia has vaccinated a large proportion of its young female population with quadrivalent human papillomavirus (HPV) vaccine, a substantial minority of young women did not receive all three doses of the vaccine course or were not vaccinated. From a public health perspective, ongoing HPV vaccine programs are provided at an age well before the median age of sexual debut (given at age 12–13 in Australia) because HPV vaccines are prophylactic rather than therapeutic. The vaccines induce high levels of antibodies, which prevent a conformational change HPV makes in order to enter basal epithelial cells, thus preventing infection, but have no apparent impact on existing HPV infections. So does this mean that there is no benefit in offering HPV vaccine to women already diagnosed with high-grade cervical disease? A post hoc analysis of the quadrivalent HPV vaccine trials found that the vaccine offered protection against recurrent disease in the group of women diagnosed and treated for cervical or vaginal disease during the trial (caused by any HPV type). Rates of recurrence (CIN1+) for women treated for cervical disease were 4.3 per 100 person-years in vaccinated women compared with 8.4 among unvaccinated women (a reduction of 48.3% (95% CI 19.1 to 67.6)), with even greater reductions for CIN2+ and CIN3+ (CIN2+ 64.9% (20.1 to 86.3), CIN3+ 73.5% (3.4 to 95.2)). This suggests that ‘recurrence’ is often in fact subsequent disease due to infection in adjacent areas of genital epithelium, disseminated from either the primary productive lesion/s or the same or a new male partner. A nonrandomised trial of 737 women aged 20–45 also found a lower rate of recurrent cervical disease among those who were vaccinated post-LEEP treatment for high-grade CIN (2.5 vs 7.2%; P < 0.01). Together, these studies suggest that these women, who have already demonstrated an inability to clear persistent oncogenic HPV infection and so are actually the very women who would have benefited from primary HPV vaccination, have a significant capacity to benefit from secondary vaccination. The high antibody levels following vaccination seem to effectively prevent new areas of epithelial infection, whether due to dissemination from existing sites of HPV infection or from new HPV exposure, and thus disease. It is therefore reasonable to discuss the potential benefits of vaccination with women postdiagnosis/ treatment of high-grade CIN. Key points relating to HPV vaccination in this setting are given in Box 1. Most importantly, women must be counselled that vaccination will not treat existing areas of infection or disease nor prevent all future HPV infections and that therefore attendance at follow-up and future screening remain critical. Also, note that women who have received previous HPV vaccine doses do not need to restart the course. Box 1 Key points