Cytological surveillance compared with immediate referral for colposcopy in management of women with low grade cervical abnormalities: multicentre randomised controlled trial
BMJ 2009; 339 doi: https://doi.org/10.1136/bmj.b2546 (Published 29 July 2009) Cite this as: BMJ 2009;339:b2546
- TOMBOLA Group
- Correspondence to: J Little, Canada Research Chair in Human Genome Epidemiology, Department of Epidemiology and Community Medicine, University of Ottawa, 451 Smyth Rd, Ottawa, Ontario K1H 8M5, Canada jlittle{at}uottawa.ca
- Accepted 3 April 2009
Abstract
Objectives To examine the effectiveness of cytological surveillance in primary care compared with immediate referral for colposcopic examination in women with low grade abnormal results on cervical cytology tests.
Design Multicentre individually randomised controlled trial.
Setting NHS cervical screening programmes in Grampian, Tayside, and Nottingham.
Participants 4439 women, aged 20-59, with a cytology result showing borderline nuclear abnormalities or mild dyskaryosis, October 1999-October 2002.
Interventions Cytological screening every six months in primary care (n=2223) or referral for colposcopy and related interventions (n=2216). All women were followed for three years, concluding with an exit appointment at which colposcopic examination was undertaken. Colposcopists assessing outcome at this appointment were blinded to randomisation.
Main outcome measures Primary end point: cumulative incidence of cervical intraepithelial neoplasia grade II or more severe disease. Other end points: cervical intraepithelial neoplasia grade III or worse, clinically significant anxiety and depression, other self reported after effects, and rates of non-attendance. Analysis was by intention to treat; all those randomised were included.
Results The cumulative incidence of cervical intraepithelial neoplasia grade II or worse was 79 per 1000 person years in the colposcopy arm and 58 per 1000 person years in the cytological surveillance arm (relative risk 1.37, 95% confidence interval 1.19 to 1.57). This difference was less marked for cervical intraepithelial neoplasia grade III or more severe disease, but the incidence was still higher in the colposcopy arm (relative risk 1.26, 1.04 to 1.53). Among women randomised to immediate colposcopy, 79% (74.9% to 82.5%) of cases of cervical intraepithelial neoplasia grade II or worse were diagnosed at the time of the immediate colposcopy, while among women randomised to cytological surveillance, 77% (72.1% to 81.2%) of cases were detected by surveillance cytology and related interventions. Similar proportions of women were anxious or depressed in the two arms. A higher proportion of women in the colposcopy arm reported after effects, and these were of longer duration and more severe. Non-attendance was low in both arms.
Conclusion The more marked difference between the arms in the occurrence of cervical intraepithelial neoplasia grade II or worse than in the occurrence of grade III or worse can probably be accounted for by the spontaneous regression of some cases of grade II neoplasia. Compared with cytological surveillance, a policy of immediate colposcopy detects more cervical intraepithelial neoplasia grade II or worse, and some more grade III or worse, but might lead to overtreatment. Such a policy is associated with a higher rate of reported after effects, which are more severe and of longer duration than those associated with cytological surveillance.
Trial registration ISRCTN 34841617.
Footnotes
We are grateful for the cooperation and assistance that we received from NHS staff in the coordinating centres and clinical sites. We thank the women who participated in TOMBOLA. We thank Paul Boyle and Zhiqiang Feng for providing data on deprivation categories and Valery L’Heureux for administrative assistance.
The TOMBOLA Group
Grant holders: Maggie Cruickshank, Graeme Murray, David Parkin, Louise Smart, Eric Walker, Norman Waugh (principal investigator 2004-7) (University of Aberdeen and NHS Grampian, Aberdeen); Mark Avis, Claire Chilvers, Katherine Fielding, Rob Hammond, David Jenkins, Jane Johnson, Keith Neal, Ian Russell, Rashmi Seth, Dave Whynes (University of Nottingham and Nottingham NHS, Nottingham); Ian Duncan, Alistair Robertson (University of Dundee and NHS Tayside, Dundee, Tayside); Julian Little (principal investigator 1999-2004) (University of Ottawa, Ottawa, Canada); Linda Sharp (National Cancer Registry, Cork); Ian Russell (Bangor University, Bangor); Leslie Walker (University of Hull, Hull).
Staff in clinical sites and coordinating centres: Breda Anthony, Sarah Bell, Adrienne Bowie, Katrina Brown, Joe Brown, Kheng Chew, Claire Cochran, Seonaidh Cotton, Jeannie Dean, Kate Dunn, Jane Edwards, David Evans, Julie Fenty, Al Finlayson, Marie Gallagher, Nicola Gray, Maureen Heddle, Alison Innes, Debbie Jobson, Mandy Keillor, Jayne MacGregor, Sheona Mackenzie, Amanda Mackie, Gladys McPherson, Ike Okorocha, Morag Reilly, Joan Rodgers, Alison Thornton, Rachel Yeats (Grampian); Lindyanne Alexander, Lindsey Buchanan, Susan Henderson, Tine Iterbeke, Susanneke Lucas, Gillian Manderson, Sheila Nicol, Gael Reid, Carol Robinson, Trish Sandilands (Tayside); Marg Adrian, Ahmed Al-Sahab, Elaine Bentley, Hazel Brook, Claire Bushby, Rita Cannon, Brenda Cooper, Ruth Dowell, Mark Dunderdale, E Gabrawi, Li Guo, Lisa Heideman, Steve Jones, Salli Lawson, Zoë Philips, Christopher Platt, Shakuntala Prabhakaran, John Rippin, Rose Thompson, Elizabeth Williams, Claire Woolley (Nottingham).
Statistical analysis: Massoud Boroujerdi, Seonaidh Cotton, Kirsten Harrild, John Norrie.
External trial steering committee: Nicholas Day (chair, 1999-2004), Theresa Marteau (chair 2004-), Mahesh Parmar, Julietta Patnick, Ciaran Woodman.
External data monitoring and ethics committee: Doug Altman (chair), Sue Moss, Michael Wells.
Contributors: Julian Little, Linda Sharp, Seonaidh Cotton, Maggie Cruickshank, Ian Duncan, Kirsten Harrild, David Jenkins, Louise Smart, Norman Waugh, Claire Cochran, Nicola Gray, Rob Hammond, Keith Neal, Alison Thornton, and Claire Woolley carried out these analyses and wrote the paper. JL is guarantor.
Funding: This study was supported by the Medical Research Council (grant No G9700808) and the NHS in England and Scotland. The MRC had no role in design, data collection, analysis, interpretation, or the writing of the report.
Competing interests: During the past five years ID has served on British and European Boards advising GlaxoSmithKline regarding the connection between human papillomavirus and cervical neoplasia, for which he has received expenses and fees for professional services. He has participated in a symposium sponsored by GlaxoSmithKline as part of a EUROGIN conference in Paris and was partly sponsored as a result. He has assisted in GlaxoSmithKline’s and MSD Sanofi Pasteur’s education programmes increasing professional awareness of the link between the human papillomavirus and cervical neoplasia, receiving fees for his professional services in creating a set of educational slides and lecturing to doctors and nurses. JL has received fees from GlaxoSmithKline as a member of an independent data and safety monitoring committee for a trial of the efficacy of vaccination against HSV. NG was reimbursed for attending an international clinical advisory board on health related quality of life issues related to cervical cancer in April 2005 by GlaxoSmithKline. From 2003 until September 2007 DJ was director of clinical research into papillomavirus vaccines for GlaxoSmithKline Biologicals and continues to act as a consultant to GSK.
Ethical approval: This study was approved by the joint research ethics committee of NHS Grampian and the University of Aberdeen, the Tayside committee on medical research ethics, and the Nottingham research ethics committee. All participants provided informed consent.
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