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I Jacobs, D Oram (1988)Screening for ovarian cancer
Biomed Pharmacother, 42
R. Hogg, M. Friedlander (2004)Biology of epithelial ovarian cancer: implications for screening women at high genetic risk.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 22 7
NH Nguyen, HE Averette, W Hoskins (1993)National survey of Ovarian Carcinoma VI. Critical assessment of current International Federation of Obstetrics and Gynaecology staging system
S Campbell, V Bhan, P Royston (1989)Transabdominal ultrasound screening for ovarian cancer
Br Med J, 299
S Sato, Y Yokoyama, T Sakamoto (2000)Usefulness of mass screening for ovarian carcinoma using transvaginal ultrasonography
JR Nagell, PD DePriest, MB Reedy, HH Gallion, FR Ueland, EJ Pavlik, RJ Kryscio (2000)The efficacy of transvaginal sonographic screening in asymptomatic women at risk of ovarian cancer
Gynecol Oncol, 77
I. Jacobs, S. Skates, N. Macdonald, U. Menon, A. Rosenthal, A. Davies, R. Woolas, A. Jeyarajah, K. Sibley, D. Lowe, D. Oram (1999)Screening for ovarian cancer: a pilot randomised controlled trial
The Lancet, 353
SJ Skates, F Xu, YH Yu (1995)Toward an optimal algorithm for ovarian cancer screening with longitudinal tumor markers
M Teeriello (1995)Early detection of ovarian cancer
CA Cancer J Clin, 45
TJ Crayford, S Campbell, TH Bourne (2000)Benign ovarian cysts and ovarian cancer: a cohort study with implications for screening
I. Jacobs, R. Bast (1989)The CA 125 tumour-associated antigen: a review of the literature.
Human reproduction, 4 1
JR Nagell, HD Gallion, EJ Pavlik (1995)Ovarian cancer screening
MR Law, JK Morris, NJ Wald (1999)The importance of age in screening for cancer
J Med Screen, 6
V Zurawski, H Orjaseter, A Anderson (1988)Elevated serum CA125 levels prior to the diagnosis of ovarian neoplasia: relevance for early detection of ovarian cancer
Int J Cancer, 42
14 Multidisciplinary Symposium — screening for cancer  Garber AM, Phelps CE. Economic foundation of cost-  Ekbom A, Helmick C, Zack M et al. Ulcerative colitis and eﬀectiveness analysis. J Health Econ 1997; 16: 1–31. colorectal cancer. A population-based study. N Engl J Med  Brown ML, Fintor L. Cost-eﬀectiveness of breast cancer 1990; 323: 1228–33. screening: preliminary results of a systematic review of the  Ekbom A, Helmick C, Zack M et al. Increased risk of literature. Breast Cancer Res Treat 1993; 25: 113–8. large-bowel cancer in Crohn’s disease with colonic  Fuchs CS, Giovannucci EL, Colditz G. A prospective study of involvement. Lancet 1990; 336: 357–9. family history and the risk of colorectal cancer. N Engl J Med  Vasen HF, Wijnen JT, Menko FH et al. Cancer risk in 1994: 331: 1669–74. families with hereditary non-polyposis colorectal cancer diag-  Ahsan H, Neugut AI, Garbowski CG et al. Family history nosed by mutation analysis. Gastroenterology 1996; 110: of colorectal adenomatous polyps and increased risk for 1020–7. colorectal cancer. Ann Intern Med 1998; 128: 900–5.  Helm JF, Sandler RS. Colorectal cancer screening. Med Clin  Winawer SJ, Zauber AG, Gerdes H et al. Risk of colorectal N Am 1999; 83: 1403–22. cancer in the families of patients with adenomatous polyps. The digital object identiﬁer for this article is: 10.1102/ National Polyp Study Workgroup. N Engl J Med 1996; 334: 82–7. 1470-7330.2001.008 B Rufford, U Menon and I Jacobs Gynaecology Cancer Research Unit, St Bartholomew’s and the Royal London Medical and Dental School, London, UK Introduction What to screen for A screening programme should ideally be based on the Ovarian cancer is the most common gynaecological detection of a pre-malignant condition in order to lower malignancy in the developed world. It also carries the disease incidence and maximize mortality reduction, as worst prognosis with an overall 5-year survival of 30%. is the case with the cervical screening programme. This is likely to be due to the disease frequently present- Although it is suggested that inclusion cysts and benign ing late, the ovary position within the peritoneal cavity and borderline ovarian tumours may be pre-malignant, resulting in minimal local irritation, or interference with this remains speculative. Crayford et al. recently ana- vital structures until ovarian enlargement is consider- lysed follow-up data from an ovarian cancer screening able, or metastasis occurs. Seventy per cent of women trial to assess whether removal of persistent ovarian are diagnosed with stage III or IV disease, with 5-year cysts was associated with a reduction in mortality from  survivals of 15–20% and less than 5%, respectively .  ovarian cancer . No such reduction was found relative Despite an increase in understanding of the molecular to other cancers, although it is diﬃcult to interpret the events underlying malignancy, and advances in both ﬁndings in the absence of a control group, and incidence surgery and chemotherapy, the overall prognosis of may have been a more appropriate end-point than ovarian cancer has changed little over the last 30 years. mortality. In the absence of conﬁrmed pre-malignant However, women who are diagnosed at an early stage do change, screening for ovarian cancer is directed at have a signiﬁcantly improved prognosis, with survival of present to the detection of pre-clinical disease. above 80% in stage I disease, and above 90% in those  diagnosed at stage Ia . The best way of improving outcome may be, therefore, to detect the condition at an What is required from a screening test early stage, when the prognosis remains relatively good, via a screening programme. This is an exciting prospect A suitable screening test requires both high sensitivity and screening trials have shown some encouraging and speciﬁcity. Women who have a positive screen results. However, as yet screening has not been shown require further investigation, often in the form of ex- conclusively to reduce mortality from ovarian cancer. In ploratory surgery. It is therefore imperative to maximize addition, our lack of knowledge about disease progres- speciﬁcity in order to obtain a high positive predictive sion and of primary peritoneal cancer, as well as the value, and decrease the number of false-positive screens. possible surgical and psychological morbidity that may In the general population, a speciﬁcity of 99.6% is result from screening, should be considered. There are required to achieve a positive predictive value of  also, of course, cost implications. 10% , i.e. to limit the number of unnecessary surgical Multidisciplinary Symposium — screening for cancer 15 procedures to 10 for each case of cancer detected. A for each case of ovarian cancer detected has been   speciﬁcity lower than this is likely to be unacceptable in reduced from 50 to between 10 and 20 , when using this population, although may be acceptable to those an ultrasound-based screening strategy. with a strong family history of ovarian cancer. Screening strategies Screening tests There are three main strategies. An ultrasound approach The ovaries are not easily accessible. Although vaginal based on primary screening with transvaginal ultra- examination is important in assessing symptomatic sound, with repeat testing after a ﬁxed time interval if an women, it lacks both the sensitivity and speciﬁcity abnormality is detected. Multimodal screening which required for a ﬁrst-line screening test in asymptomatic incorporates primary screening using a tumour marker, women. In one study only 30% of women with ovarian usually CA125, with repeat assessment of the marker masses on transvaginal ultrasound had an abnormal and transvaginal ultrasound as a second-line test.  pelvic examination . Visualization or direct sampling to CA125 results are interpreted using the Risk of Cancer detect malignant disease, or perhaps in the future to algorithm previously alluded to. The third, combined, detect a pre-malignant condition, is being investigated in approach uses both serum CA125 and transvaginal preliminary studies using oﬃce laparoscopy and cyto- ultrasound as ﬁrst-line tests to maximize the detection logical examination of brush samples from the ovarian rate and its use is limited to screening the high-risk surface in screening high-risk populations. The possi- population. The optimal screening strategy is yet to be bility of using optical methods, such as optical spec- established. troscopy is also being investigated. However, the current accepted screening methods are serum tumour markers and ultrasound Doppler imaging. Target populations The bulk of ovarian cancers occur in the general popu- lation, and age greater than 50 years and post- Tumour markers menopausal status have been used to deﬁne those The most extensively studied tumour marker is the large eligible for screening. One study looked at national glycoprotein CA125, ﬁrst discovered in 1981. It is statistics to determine the number of years of life lost  elevated to above 30 U/ml in over 80% of patients with through deaths from a particular cancer at each age . ovarian cancer. Levels correlate well with the stage of It concluded that screening would be most eﬀective, i.e. disease and are raised in 50% of stage I, and 90% of save the most number of lives per person screened, if  stage II ovarian tumours . However, levels may be done 5 years before loss of life peaked. The peak raised in a variety of other physiological and pathologi- occurred in ovarian cancer during the age range 55–59 cal conditions, which may be gynaecological or non- years, and the authors’ argument provides further justi- gynaecological, benign or malignant. An algorithm has ﬁcation for using 50 years as the cut-oﬀ to commence been developed in post-menopausal women from the population screening. Approximately 5–10% of ovarian general population that determines the risk of ovarian cancers are inherited, and the optimal strategy for  cancer based on CA125 proﬁle with time . This is based screening the population at risk of familial ovarian on the observation that women with ovarian cancer tend cancer needs to be developed. Risk may be assessed on to have increasing levels of CA125, whereas women the basis of family history, genetic predisposition, or without ovarian cancer tend to have static or decreasing both. Mutations in BRCA1 and BRCA2 genes account levels, even if they remain above a cut oﬀ of 30 U/ml. for about 75% of families with a highly penetrant The greater the rate of rise in CA125 levels, the greater dominantly inherited breast or ovarian cancer family the risk of ovarian cancer. Other tumour markers that history. Mutation analysis therefore has an important have been investigated include OVX1 and, more recently role in the management of high-risk populations. plasma lysophosphatidic acid (LPA). Screening trials Ultrasound Although over 25 prospective screening studies for Ultrasound has been used as a screening test for ovarian ovarian cancer have been published, none have been cancer for over a decade. Although speciﬁcity was poor able to demonstrate conclusively a reduction in mor- with transabdominal scanning, it was much improved tality from ovarian cancer in the screened group, for with the introduction of transvaginal scanning, colour either the general or the high-risk population. Jacobs et ﬂow Doppler imaging and morphological scoring sys- al. recently reported the ﬁndings of the ﬁrst randomized  tems. Malignant masses have increased blood ﬂow in controlled trial of ovarian cancer screening . Post- diastole, helping to distinguish them from benign ones. menopausal women aged 45 years or older were ran- The number of women undergoing surgical investigation domized to a control group (n = 10 977) or to a screened 16 Multidisciplinary Symposium — screening for cancer group (n = 10 958). The screened group underwent a multicentre National Familial Ovarian Cancer annual multimodal screening for 3 years. All women Screening Study (UK-FOCSS) involving 5000 women is were followed up to see whether they developed invasive being set up in the UK. A similar trial is underway in the epithelial ovarian cancer. Compliance was excellent and USA. the positive predictive value of a positive screen was high at 21%. Although the study was too small to assess impact on mortality, median survival (72.9 months) was Conclusion signiﬁcantly higher in women with ovarian cancer in the Ovarian cancer most commonly presents as advanced screened group than in those in the control group (41.8 stage disease with a poor prognosis. In the absence months). Other recently reported transvaginal ultra-   sound trials from Kentucky and from Japan of a known pre-malignant condition, the ability to detect have also recently reported encouraging results. The early-stage disease is clearly desirable. However, despite Kentucky trial showed a 5-year survival of 83.6 10.8% numerous screening studies, some showing some very in the screened group, and the Japanese trial found there encouraging results, there is not yet any conclus- was an increase in the percentage of stage I tumours ive evidence that screening reduces ovarian cancer diagnosed and treated in the department from 29.7% to mortality. Although there is insuﬃcient evidence to 58.8% after the trial was initiated. These results need to implement general population screening for ovarian be interpreted with caution due to the lack of control cancer at present, this evidence will, we hope, be avail- groups, but all emphasize the need for a randomized able in the future as results from large trials such as control trial. This needs to, in addition to establishing UKCTOCS become available. the impact of screening on ovarian cancer mortality, comprehensively tackle the issues of target population, compliance, health economics and physical and psycho- References logical morbidity of screening. Such a trial has now  Teeriello M et al. Early detection of ovarian cancer. CA been initiated, the UK Collaborative Trial of Ovarian Cancer J Clin 1995; 45: 71–87. Cancer Screening (UKCTOCS), funded by the Medical  Nguyen NH, Averette HE, Hoskins W et al. National survey Research Council, the Cancer Research Campaign, the of Ovarian Carcinoma VI. Critical assessment of current Imperial Cancer Research Fund and NHS Research and International Federation of Obstetrics and Gynaecology staging system. Cancer 1993; 72: 3007–11. Development and co-ordinated by the Gynaecology  Crayford TJ, Campbell S, Bourne TH et al. Benign ovarian Cancer Research Unit at St Bartholomew’s Hospital, cysts and ovarian cancer: a cohort study with implications for London. The three-armed randomized control trial aims screening. Lancet 2000; 355: 1060–3. to recruit 200 000 post-menopausal women, aged 50–74  Jacobs I, Oram D. Screening for ovarian cancer. Biomed Pharmacother 1988; 42: 589–96. years, randomized in a 1:1:2 ratio to ultrasound screen-  Van Nagell JR, Gallion HD, Pavlik EJ et al. Ovarian cancer ing, multimodal screening using the Risk of Ovarian screening. Cancer 1995; 6: 2086–91. Cancer algorithm and a control group who will not be  Zurawski V, Orjaseter H, Anderson A et al. Elevated serum screened. Participants will be invited from regional CA125 levels prior to the diagnosis of ovarian neoplasia: age/sex registers, overcoming the inherent ﬂaws of self- relevance for early detection of ovarian cancer. Int J Cancer 1988; 42: 677–80. referral. Screening will occur in 12 collaborating gynae-  Skates SJ, Xu F, Yu YH et al. Toward an optimal algorithm cological oncology centres in the UK and participants for ovarian cancer screening with longitudinal tumor markers. randomized to screening will undergo six screens at Cancer 1995; 76(Suppl 10): 2004–10. annual intervals. All participants will be followed up by  Campbell S, Bhan V, Royston P et al. Transabdominal ultrasound screening for ovarian cancer. Br Med J 1989; 299: postal questionnaire and via the cancer registry. The 1363–7. primary end-point of the study is ovarian cancer mor-  Van Nagell JR Jr, DePriest PD, Reedy MB, Gallion HH, tality 7 years after randomization. Additional end-points Ueland FR, Pavlik EJ, Kryscio RJ. The eﬃcacy of trans- include quality of life, health economics, morbidity and vaginal sonographic screening in asymptomatic women at risk compliance with screening. The performance of the two of ovarian cancer. Gynecol Oncol 2000; 77: 350–6.  Law MR, Morris JK, Wald NJ. The importance of age in screening strategies will also be compared. The results of screening for cancer. J Med Screen 1999; 6: 16–20. this trial will form the basis for making an informed  Jacobs IJ, Skates SJ, Macdonald N et al. Screening for decision about the implementation of general popu- ovarian cancer: a pilot randomised control trial. Lancet 1999; lation screening for ovarian cancer. The adoption of 353: 1207–10.  Sato S, Yokoyama Y, Sakamoto T et al. Usefulness of annual screening as standard practice in the high-risk mass screening for ovarian carcinoma using transvaginal population makes it impossible to institute a random- ultrasonography. Cancer 2000; 89: 582–8. ized control trial with a control group who are not screened in this group. However, in order to develop an The digital object identiﬁer for this article is: 10.1102/ optimal screening strategy in the high-risk population, 1470-7330.2001.009
Cancer Imaging – Springer Journals
Published: May 5, 2015
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