THURSDAY, SEPTEMBER 7 9

FM4.04.03 CEREBRAL PALSY - MEDICO-LEGAL ISSUES A. Women’s & Children’s Hospital, University of Adelaide. South Australia

Recent epidemiological, laboratory and clinical research suggests that in the large majority of cases, the meuropathology of cerebral palsy begins antenatally and in some very preterm babies can occur neonatally and rarely is due to primary asphyxia. The term <<birth asphyxia>> and probably even the word <<damage>> are hard to define or prove and can be emotive words not accurately relfecting the underlying causation or pathology. Hereditary clotting disorders, intrauterine infection, chronic fetal blood obstruction and fetal cerebral thrombosis are some of the probable silent mechanisms of cerebral palsy. The resulting developmental brain dysfunction may only be detected indirectly for the first time in labour or soon after delivery if the neuropathology involves centres controlling cardioresiratory function etc. There are no peripartum clinical policies that have been shown in randomised trials to reduce cerebral palsy rates, eg, early induction, electronic intrapartum fetal monitoring or elective caesarean section. Although it is occasionally possible that prolonged acute asphyxia in a neurologically intact fetus can result in the neuropathology of cerebral palsy, it can be hard to be sure that it did not exist prior to the labour, that the asphyxia was long enough and severe enough to cause irreversible neuropathology and that there was the opportunity to limit the asphyxia to a period where the neuropathology could be avoided or ameliorated. In this multidisciplinary area with little data to support that differences in clinical management alter outcome some medico-legal witnesses have opined their certainty about causation and that the outcome could have been prevented with different management. The effect of non-evidence-based medico-legal opinion has had reaching adverse effects on obstetric practice and services. Recently in international multidisciplinary task force on cerebral palsy met over two years and reviewed the current literature on cerebral palsy causation. It offered a template of objective evidence to define the few cases of cerebral plasy possibly associated with acute intrapartum asphyxia. It is another step to prove that this asphyxia was preventable and the the neuropathology could have been prevented. Witnesses should be well-qualified, and well read, currently practising, keep to their area of expertise and be well aware of the limitations of perinatal care in this area. Reference: MacLennan AH for the International Cerebral Palsy Task Force. A template for defining a causal relation between acute intrapartum events and cerebral palsy: international consensus statement. BMJ 1999; 319: 1054-59

ON4.04 OVARIAN CANCER SCREENING

ON4.04.01 SCREENING FOR FAMILIAL OVARIAN CANCER Beth Y. Karlan, Cedars-Sinai Medical Center, Los Angeles, California, USA

In 1994, the NIH consensus conference on ovarian cancer recommended that at least annual screening with pelvic examinations, CA125 determinations, and transvaginal sonography be performed for women whose pedigrees suggested a hereditary ovarian cancer syndrome. This statement was based on expert opinion due to the lack of data demonstrating a reduction in ovarian cancer mortality as a result of these interventions. Since that time, BRCAI and BRCA2 have been identified as genes responsible for the majority of hereditary ovarian cancers, and clinical genetic testing for mutations in these genes in unaffected and affected individuals has become widely available. Although confidentiality issues and questions regarding clinical recommendations still remain, we can now identify a cohort of presymptomatic women genetically at high risk for ovarian cancer. This rapidly growing population of high risk women presents an opportunity and obligation to find an effective means of ovarian cancer screening. Strategies for the early detection of ovarian cancer in this heritable risk cohort need to take into account the growing body of data pointing to a “field effect” or multifocal origin of disease in a significant proportion of these cases. This peritoneal serous papillary carcinoma phenotype would favor screening strategies that focus on serologic testing early tumor biomarkers rather than “end organ” imaging techniques such as ultrasound. In contrast, the “acquired risk” cohorts, such as infertile

nulliparous women and older postmenopausal women, seem predisposed to accumulate somatic mutations leading to the development of the more common monoclonal ovarian cancer with early morphologic changes in the ovary. This pattern of disease may be more amenable to early detection using modalities such as transvaginal sonography and/or color doppler imaging. Intensive efforts are underway to identify new biomarkers for ovarian cancer. Lysophosphatidic acid is one such marker which is elevated in early stage ovarian cancer as well as in peritoneal serous papillary carcinomas. Molecular techniques such as representational difference analysis are being used to discover other potential markers, which may be useful for early detection. Newer imaging techniques such as 3-D ultrasound, PET and spectroscopy are being studied for their early diagnostic capabilities. Screening with peritoneal cytology and “ovarian pap tests” are in early clinical trials. These approaches and others will be required to overcome ovarian cancer’s diagnostic obstacles, but their solutions will yield high dividends in potential targets for prevention and treatment.

ON4.04.03 EARLY DETECTION OF OVARIAN CANCER: METHODOLOGICAL CONSIDERATIONS Nicole Urban, Fred Hutchinson Cancer Research Center, Seattle, WA, United States

Introduction. A screening strategy should be cost-effective in a public health context as well as feasible for testing in a randomized controlled trial (RCT). Strategies have been identified that are potentially cost- effective’ but the expected costs of a RCI to test their efficacy have not been reported. Methods. For several candidate strategies we estimated 1) the size of the trial required for specified length and power, and 2) the costs of the trial for specified protocol, length and size. The required size of the trial was estimated using a previously described microsimulation model of ovarian cancer screening, revised to simulate a RCT. Various trial designs were simulated to optimize trial length. The endpoint for the trial was cause-specific mortality. The power was calculated for an unweighted logrank statistic. Total direct costs of the trial were estimated using a previously described model of the costs of a large prevention trial, revised to reflect the design and protocols for the screening trial strategies. Cost-effectiveness of the strategies is reported for a scenario in which the screening strategy is used in all women aged 50-80 outside the context of a trial. Costs and benefits are discounted at 3%. Results. Trial costs increase with trial size, which decreases as the mortality reduction expected from a screening strategy rises. Expected mortality reduction varies 2-fold among strategies, while estimates of trial costs vary about 3-fold. Conclusions. Choice of a screening strategy to test in a RCI depends on its expected mortality reduction as well as its cost-effectiveness

ON4.05 CERVICAL INTRAEPITHELIAL NEOPLASIA - TREATMENT

ON4.05.01 TREATMENT OF CIN: BURN FREEZE OR CUT? Grainne FlannellL National Maternity Hospital, Dublin, Ireland

The ultimate test of any treatment of pre-invasive cervical abnormalities is the number of women who develop invasive cancer of the cervix despite treatment. Other criteria include the recurrence of cervical intraepithelial neoplasia (GIN) as well as the physical and psychological impact of the procedure on women. Any treatment should be safe, effective and cost efficient. In the fifty years since Papanicolau described the smear test many treatments have been described. In the pre-colposcopy era, hysterectomy was commonly utilised to treat the woman with an abnormal smear. The cone biopsy allowed successful treatment while retaining fertility. Ablative treatments including radical diathermy, cryotherapy, cold coagulation and laser ablation facilitated outpatient treatment under local anaesthetic. While these treatments are reasonably effective they are only applicable to selected women with a satisfactory colposcopic examination, an ectocervical lesion and no colposcopic suspicion of invasive cancer. These treatments provide an incomplete histological