David Luesley

Management of women who test positive for high-risk types of human papillomavirus: the HART study

BACKGROUND Certain types of human papillomavirus (HPV) are the primary cause of almost all cervical cancers. HPV testing of cervical smears is more sensitive but less specific than cytology for detecting high-grade cervical intraepithelial neoplasia (CIN2+). HPV testing as a primary screening approach requires efficient management of HPV-positive women with negative or borderline cytology. We aimed to compare the detection rate and positive predictive values of HPV assay with cytology and to determine the best management strategy for HPV-positive women. METHODS We did a multicentre screening study of 11085 women aged 30-60 years. Women with borderline cytology and women positive for high-risk HPV with negative cytology were randomised to immediate colposcopy or to surveillance by repeat HPV testing, cytology, and colposcopy at 12 months. FINDINGS HPV testing was more sensitive than borderline or worse cytology (97.1% vs 76.6%, p=0.002) but less specific (93.3% vs 95.8%, p<0.0001) for detecting CIN2+. Of 825 randomised women, surveillance at 12 months was as effective as immediate colposcopy. In women positive for HPV at baseline, who had surveillance, 73 (45%) of 164 women with negative cytology and eight (35%) of 23 women with borderline cytology were HPV negative at 6-12 months. No CIN2+ was found in these women, nor in women with an initial negative HPV test with borderline (n=211) or mild (32) cytology. INTERPRETATION HPV testing could be used for primary screening in women older than 30 years, with cytology used to triage HPV-positive women. HPV-positive women with normal or borderline cytology (about 6% of screened women) could be managed by repeat testing after 12 months. This approach could potentially improve detection rates of CIN2+ without increasing the colposcopy referral rate.

Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): an open-label, randomised, controlled, non-inferiority trial.

BACKGROUND The international standard of care for women with suspected advanced ovarian cancer is surgical debulking followed by platinum-based chemotherapy. We aimed to establish whether use of platinum-based primary chemotherapy followed by delayed surgery was an effective and safe alternative treatment regimen. METHODS In this phase 3, non-inferiority, randomised, controlled trial (CHORUS) undertaken in 87 hospitals in the UK and New Zealand, we enrolled women with suspected stage III or IV ovarian cancer. We randomly assigned women (1:1) either to undergo primary surgery followed by six cycles of chemotherapy, or to three cycles of primary chemotherapy, then surgery, followed by three more cycles of completion chemotherapy. Each 3-week cycle consisted of carboplatin AUC5 or AUC6 plus paclitaxel 175 mg/m(2), or an alternative carboplatin combination regimen, or carboplatin monotherapy. We did the random assignment by use of a minimisation method with a random element, and stratified participants according to the randomising centre, largest radiological tumour size, clinical stage, and prespecified chemotherapy regimen. Patients and investigators were not masked to group assignment. The primary outcome measure was overall survival. Primary analyses were done in the intention-to-treat population. To establish non-inferiority, the upper bound of a one-sided 90% CI for the hazard ratio (HR) had to be less than 1.18. This trial is registered, number ISRCTN74802813, and is closed to new participants. FINDINGS Between March 1, 2004, and Aug 30, 2010, we randomly assigned 552 women to treatment. Of the 550 women who were eligible, 276 were assigned to primary surgery and 274 to primary chemotherapy. All were included in the intention-to-treat analysis; 251 assigned to primary surgery and 253 to primary chemotherapy were included in the per-protocol analysis. As of May 31, 2014, 451 deaths had occurred: 231 in the primary-surgery group versus 220 in the primary-chemotherapy group. Median overall survival was 22.6 months in the primary-surgery group versus 24.1 months in primary chemotherapy. The HR for death was 0.87 in favour of primary chemotherapy, with the upper bound of the one-sided 90% CI 0.98 (95% CI 0.72-1.05). Grade 3 or 4 postoperative adverse events and deaths within 28 days after surgery were more common in the primary-surgery group than in the primary-chemotherapy group (60 [24%] of 252 women vs 30 [14%] of 209, p=0.0007, and 14 women [6%] vs 1 woman [<1%], p=0.001). The most common grade 3 or 4 postoperative adverse event was haemorrhage in both groups (8 women [3%] in the primary-surgery group vs 14 [6%] in the primary-chemotherapy group). 110 (49%) of 225 women receiving primary surgery and 102 (40%) of 253 receiving primary chemotherapy had a grade 3 or 4 chemotherapy related toxic effect (p=0.0654), mostly uncomplicated neutropenia (20% and 16%, respectively). One fatal toxic effect, neutropenic sepsis, occurred in the primary-chemotherapy group. INTERPRETATION In women with stage III or IV ovarian cancer, survival with primary chemotherapy is non-inferior to primary surgery. In this study population, giving primary chemotherapy before surgery is an acceptable standard of care for women with advanced ovarian cancer. FUNDING Cancer Research UK and the Royal College of Obstetricians and Gynaecologists.

Loop diathermy excision of the cervical transformation zone in patients with abnormal cervical smears.

OBJECTIVE--To determine the efficacy and morbidity of fine loop diathermy excision of the cervical transformation zone as applied to the management of outpatients with abnormal cervical smears. DESIGN--Prospective programme trial with six month follow up. SETTING--Two hospital based colposcopy clinics. PATIENTS--616 Patients aged 16-60 with abnormal cervical smears. INTERVENTIONS--After colposcopic and cytological assessment excision of the cervical transformation zone by fine loop diathermy under local anaesthesia in the outpatient department. MAIN OUTCOME MEASURES--Time to complete the treatment, immediate morbidity in terms of discomfort and bleeding, and cytological and colposcopic findings at six months. RESULTS--Treatment was completed in a mean of 3.47 minutes (SD 1.99). Immediate morbidity was minimal, and histological specimens were adequate in over 90% of cases. Almost two thirds of patients were treated at their first visit to the clinic. 58 Patients (9.4%) failed to attend for follow up at six months and one had had a hysterectomy. Of the 557 patients who attended for colposcopic and cytological follow up at six months, 506 (91%) were normal cytologically and 19 (3.4%) had histologically confirmed persistence of cervical intraepithelial neoplasia. The overall confirmed failure rate of the technique was 4.4%. CONCLUSION--Loop diathermy excision is an effective treatment with low morbidity and is an appropriate modality for patients with abnormal cervical smears.

Colposcopically directed punch biopsy: a potentially misleading investigation

Objective— To determine the relation between the histology of an initial colposcopically directed punch biopsy and a subsequent diathermy loop excision biopsy of the transformation zone, and the effect of lesion size on this relation.

Complications of cone biopsy related to the dimensions of the cone and the influence of prior colposcopic assessment

Summary. A retrospective study of the complications of cone biopsy showed that among 9 15 women examined between the years 1976 and 1982, 121 (13%) had primary or secondary haemorrhage, 153 (17%) cervical stenosis and 39 (4%) subsequent infertility or an abnormal pregnancy. Cervical stenosis was commonest among women who had had long cones removed. Stenosis occurred more often in the group of women who had been assessed by colposcopy before operation but this was due to the fact that prior colposcopy selected a favourable group of patients with lesions of limited extent that were susceptible to treatment by local destructive therapy, so that prior colposcopic assessment resulted in the removal of longer cones.

Vulvar intraepithelial neoplasia: long term follow up of treated and untreated women.

Objective To investigate the long term outcome of patients with vulvar intraepithelial neoplasia.

Regression, relapse, and live birth rates with fertility-sparing therapy for endometrial cancer and atypical complex endometrial hyperplasia: a systematic review and metaanalysis

OBJECTIVE The objective of the study was to evaluate the regression, relapse, and live birth rates of early-stage endometrial cancer (EC) and atypical complex hyperplasia (ACH) with fertility-sparing treatment. STUDY DESIGN This was a metaanalysis of the proportions from observational studies with a random-effects model and a meta-regression to explore for heterogeneity. RESULTS Thirty-four observational studies, evaluating the regression, relapse, and live birth rates of early-stage EC (408 women) and ACH (151 women) with fertility-sparing treatment. Fertility-sparing treatment for EC achieved a pooled regression rate of 76.2%, a relapse rate of 40.6%, and a live birth rate of 28%. For ACH the pooled regression rate was 85.6%, a relapse rate of 26%, and a live birth rate of 26.3%. Twenty women were diagnosed with ovarian cancer (concurrent or metastatic) during follow-up (3.6%) and 10 progressed to higher than stage I EC (1.9%) from which 2 women died. CONCLUSION Fertility-sparing treatment of EC and ACH is feasible and selected women can satisfy their reproductive wishes.

Failure of second-look laparotomy to influence survival in epithelial ovarian cancer.

The survival benefit of second-look laparotomy after completion of primary chemotherapy in patients with epithelial ovarian cancer has been assessed in a prospective randomised trial of 166 patients. Patients were randomised into three groups. All were initially treated with cisplatin (100 mg/m2 x 5) after primary laparotomy. Group A (n = 53) was scheduled to have a second-look laparotomy, followed by cyclical oral chlorambucil. Group B (n = 56) was scheduled to have a second-look laparotomy, followed by total abdominal and pelvic irradiation, and group C (n = 57) received oral chlorambucil as for group A but had no second-look operation. With a median follow up of 46 months (range 21-64), no differences in survival were noted between the three groups. The median survival for group A was 21 months (95% CI 11-31 months), for group B 15 months (11-19), and for group C 17 months (8-26). Thus second-look laparotomy after completion of first-line single-agent cisplatin chemotherapy did not confer any survival benefit on patients with epithelial ovarian cancer.

Is stage I epithelial ovarian cancer overtreated both surgically and systemically ? Results of a five-year cancer registry review

Objective To review the incidence of Stage I epithelial ovarian carcinoma in the West Midlands region and to identify prognostic factors that have a significant effect on survival.

A prospective study of conization of the cervix in the management of cervical intraepithelial glandular neoplasia (CIGN)—a preliminary report

Objective To assess the efficacy of cervical conization as primary management of cervical intraepithelial glandular neoplasia (CIGN).