Long term outcomes for women treated for cervical precancerBMJ 2014; 348 doi: https://doi.org/10.1136/bmj.f7700 (Published 14 January 2014) Cite this as: BMJ 2014;348:f7700
- M Arbyn, coordinator1,
- M Kyrgiou, MD2,
- J Gondry, professor3,
- K U Petry, professor4,
- E Paraskevaidis, professor5
- 1Unit of Cancer Epidemiology, Scientific Institute of Public Health, B1050 Brussels, Belgium
- 2West London Gynaecological Cancer Center, Queen Charlotte’s and Chelsea-Hammersmith Hospital, Imperial Healthcare NHS Trust, London, UK
- 3Department of Obstetrics and Gynaecology, University Hospital of Amiens, Amiens, France
- 4Department of Obstetrics and Gynaecology, Klinikum Wolfsburg, Wolfsburg, Germany
- 5Department of Obstetrics and Gynaecology, University Hospital of Ioannina, Ioannina, Greece
Although the risk of cervical cancer after treatment for screen detected cervical precancer is low compared with non-treated women, the incidence of invasive cervical cancer is still significantly higher than in the general population.1 These findings are confirmed by Strander and colleagues (doi:10.1136/bmj.f7361) in a trend analysis that linked data from pathology, cancer, and cause of death registries that have covered the whole Swedish population for more than half a century.2 The authors report that the risk of developing or dying from cervical or vaginal cancer in women with a history of treatment for CIN3 (cervical intraepithelial neoplasia grade 3) is two to three times higher than in the general population. Furthermore the increase in risk among women treated for CIN3 rises significantly with older age and more recent year of treatment.
These results agree with previous data suggesting that the rates of residual or recurrent high grade CIN after treatment are higher for older than for younger women.3 4 Endocervical precancerous lesions, a predisposing factor for recurrence, are more common in older women than in younger ones. The lower recurrence rates in younger women that are independent of the completeness of excision suggest that age specific immunity may also contribute to the ultimate cure of cervical precancer.4
It is worrying that Strander and colleagues found that women who received local treatment more recently were at greater risk of developing cervical and vaginal cancer.2 The authors suggest that the use of less aggressive treatments in the two most recent decades may have adversely affected oncological outcomes. The trend in treatment was driven by an increasing awareness that extensive procedures are associated with poor reproductive outcomes. Recent meta-analyses of reports published since the end of the 1970s and registry based cohort studies have shown that pregnant women with a history of excisional treatment of CIN have a greater risk of premature delivery, particularly if the excised cones were large.5 6 7 Researchers from Norway have also described a parallel trend between less aggressive treatment for cervical precancer and a lower risk of preterm delivery.8
The study population comprising more than three million women years of follow-up after treatment gave the current trend analysis enough power to identify significant differences between different subgroups of women. (Nevertheless, an age-period interaction term was not included in the log-linear model and this could have informed readers about the age specificity of the period effect.) Further analysis of the Swedish data on compliance with follow-up could provide important information on the possible reasons for treatment failure. The suggestion of reduced therapeutic effectiveness over time might also be partly explained by the decreased use of hysterectomy over the past two decades. A separate analysis of cervical and vaginal cancer rates, adjusted for rates of hysterectomy and for trends in the dimensions of excised cones, would help interpret the observed period effect.
Research is needed to identify accurate biomarkers that predict a woman’s future risk of cancer. A recent review concluded that testing for DNA from human papilloma virus helps to identify early treatment failure (recurrence within two years of treatment for cervical precancer), with higher sensitivity and similar specificity to follow-up cytology or histological assessment of the section margins.9 However, longer term data are limited. A cohort study from the Netherlands assessed the predictive value of combined cytological and virological follow-up for 10 years after treatment for cervical precancer.10 The overall cumulative incidence of recurrent CIN2 or worse was 17%, and that for CIN3 or worse was 9%. In women with two negative tests (cytology and high risk human papillomavirus DNA) at six and 24 months post-treatment, the risk of these outcomes was similar to that in women who tested negative for cervical precancer at baseline screening. Further cohort studies with long term follow-up are needed to confirm these results and to generate more evidence on the safety of different follow-up protocols for women treated for cervical precancer.
Currently, colposcopists who treat women with high grade CIN lesions must choose between complete excision to obtain free margins or a more prudent approach, especially if a further pregnancy is desired.11 Published and aggregated data still leave considerable room for doubt about the magnitude of the association between the extent of treatment and risk of later preterm delivery. Divergent findings may be explained by variability in therapeutic practices, particularly the size of the cone excised.12 The COSPCC study—a meta-analysis of individual patient data—should allow more precise measurement of the obstetric and oncological safety associated with different treatment options, while accounting for patient and lesion characteristics. The study should also provide more detailed evidence on how to balance treatment decisions.
However, Strander and colleagues’ study makes it clear that women who have been treated for a high grade intraepithelial cervical lesion, particularly those aged 50 years or more, require careful surveillance, and that measures should be taken to assure full compliance with follow-up. The data also underline the need for better standardisation and quality assurance in colposcopic practice to achieve an optimal balance between risk of cancer and obstetric safety.
Cite this as: BMJ 2014;348:f7700
Competing interests: We have read and understood the BMJ Group policy on declaration of interests and declare the following interests: MA has received grants from the seventh Framework Programme of DG Research of the European Commission, through the COHEAHR Network (grant 603019); from FNRS (Fonds National de la Recherche Scientifique), through TELEVIE, Brussels, Belgium (ref 7.4.628.07.F); and from the European Federation of Colposcopy. MA and JG were supported by the Institut National du Cancer (Paris, France) through the COSPCC study.
Provenance and peer review: Commissioned; not externally peer reviewed.