Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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Is there a correlation between developing cancer and treatment method
- C J Geary (20 November 2005)
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Author's reply
- Ilkka Kalliala (24 November 2005)
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Long-lasting increased risk of cervical cancer after treatment of CIN: explanations and implications for follow-up.
- Guglielmo Ronco, Nereo Segnan (25 November 2005)
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Re: Long-lasting increased risk of cervical cancer after treatment of CIN: explanations and implications for follow-up.
- Ilkka Kalliala, Pekka Nieminen and Ahti Anttila (14 December 2005)
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C J Geary, Biomedical Scientist 2* Cytology, Nottingham City Hospital NG5 1PB
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I note that there were a range of treatment methods used in the treatment of these women. This probably reflects the general development and then selection of the favoured treatment method in the UK and elsewhere in that time period. I am interested to know if the authors examined whether the later development of cancer in anyway correlated with the method of treatment used. National Health Service Cervical Screening Programme (NHS CSP) guidelines in NHS CSP Publication No 20: Colposcopy and Programme Management April 2004, Section 6.4, Eds Luelsey and Leeson) advises that biopsies (such as punch or Large Loop Excision of the Transformation Zone - LLETZ) should be taken prior to the use of local destructive methods (e.g. laser vapourisation). Past practice has included the use of these destructive methods as a primary rather than secondary treatment. This recommendation is because the destructive methods do not allow for assessment of the presence of invasion. The publication then states that: "Retrospective studies of invasive disease presenting after destructive treatment indicate that failure to exclude invasive carcinoma prior to treatment is the most important aetiological factor." They go on to say that large studies have shown that there is a only a small risk of inadvertant/inappropriate treatment of invasive/glandular lesions (although these seem to be mostly using cold coagulation). I wondered if the some of small number of women going on to develop cancer in the study could be accounted for by this reason? Competing interests: I work in cervical screening in the UK |
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Ilkka Kalliala, researcher Department of Obstetrics and Gynaecology, Helsinki University Central Hospital, Box 140, FIN-00029,
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Thank you for your interest in our work. As stated in the original paper and in the rapid response by C J Geary (20 November 2005) there were four different methods in our study used to treat cervical intraepithelial neoplasia (CIN). As suggested in the response this indeed reflects the general development that occurred between 1974 and 2001. Different methods of treatment were used in different time periods. In some years also two different methods might have been on use at the same time (for example cold coagulation and laser excision or vaporisation in the mid 1980's). We indeed are very much interested whether the treatment methods used correlates with the later development of cervical or any other cancers. We are currently running analyses on that and other cancer correlations in our study population, and we hope we are able to publish those results in the next six months. Response also highlighted that failure to exclude invasive carcinoma prior to treatment is an important aetiological factor in later cancer incidence. We tried to eliminate that by setting the six months lag-period in the beginning of our follow-up. On behalf of our working group, Ilkka Kalliala Competing interests: Author of the referred study |
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Guglielmo Ronco, Responsible cervical screening evaluation Unit of Cancer Epidemiology, CPO Piemonte, 10128 Torino, Italy, Nereo Segnan
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The article by Kalliala and colleagues(1) shows, in women treated for Cervical Intraepithelial Neoplasia, an increased risk of cervical cancer (RR=2.8) compared to the general female Finnish population. Cervical cancer risk was increased for 20 years after treatment and also for women treated for CIN1, a lesion frequently regressing spontaneously. Data also show significantly increased incidence of cancer of other sites, including anus, vulva and vagina and lung or trachea. The relative risks for these other sites are comparable to or larger than those for cervical cancer. It is possible that invasive cervical cancers resulted from progression of the treated CIN. However another possible explanation is that treated women were at increased risk of CIN due to behavioural (or genetic) reasons that also led to increased risk of new CIN, resulting in invasive cervical cancer. For example, a high number of sexual partners could have resulted in HPV infection, leading both to the treated CIN and to increased subsequent risk of invasive cervical cancer, possibly through new HPV infection and/or new CIN. This behaviour could have increased the risk of eventual anal, vulvar or vaginal cancer, that are associated to HPV infection(2). Cigarette smoking is a determinant of cervical cancer(3) and is plausibly associated to sexual behaviour. This could explain the increased incidence of cancer of the lung or trachea. Unfortunately, the result of an increased risk of cervical cancer for many years does not, as itself, provide evidence about the most appropriate follow-up of these women, in order to control their risk. It would be interesting to know if there was a different pattern of visits and screening between treated women who developed and who didn’t develop invasive cancer (for example considering the interval from last cytology). Does the observed long-lasting increased risk imply the need for long-lasting high intensity of screening in these women? References 1) Kalliala I, Anttila A, Pukkala E, Nieminen P. Risk of cervical and other cancersafter trestment of cervical intraepithelial neoplasia: retrospective cohort study. BMJ 2005;331:1183-5. 2) International Agency for Research on Cancer. Human papillomaviruses. IARC Monographs on the evaluation of carcinogenic risk to humans vol. 64. IARC, Lyon 1995. 3) Plummer M, Herrero R, Franceschi S, Meijer CJ, Snijders P, Bosch FX, de Sanjose S, Munoz N, IARC Mult-centr Cervical Cancer Study Group. Smoking and cerivcal cancer: pooled analysis of the IARC multi-centric case-control study. Cancer Causes Control 2003;14:805-14. Competing interests: None declared |
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Ilkka Kalliala, researcher Department of Obstetrics and Gynaecology, Helsinki University Central Hospital, Box 140, FIN-00029, Pekka Nieminen and Ahti Anttila
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In their rapid response Dr. Guglielmo Ronco et al. highlighted some important issues. We agree with their interpretations of invasive cervical cancer resulting either from progression of a treated CIN or from an entirely new (secondary) CIN due to increased behavioural or genetic risk factors. It is not easy, if not impossible, to separate these in a long- lasting follow-up study. We agree also on their comment on cigarette smoking: accordingly, it is important to consider how women are informed about this and to intervene to stop smoking during the follow-up process. Ronco et al. were also interested to know if there was a different pattern of visits and screening between treated women who developed and who didn't develop invasive cancer. Comparison of SIRs do not constitute a relevant basis to such a comparison; instead, internal comparisons e.g. with proportional hazards model between patient groups would be a more solid method. There was still a very small number of cervical cancer cases observed, which makes the statistical power for internal comparisons limited. These analyses are currently in progress. How these women should be followed-up in order to control their risk? According to our data about visits per woman, a sub-group of no follow-up visits was a problem when considering the subsequent risk of invasive cancer. So it is important to achieve the correct diagnosis also with the milder lesions and continue follow-up also after the treatment of the lesion. First with more intense fashion, (e.g. according to the local practice), but later at least within the screening programmes (smears taken every 3-5 years) for 20 years. It is also possible that in the future HPV-DNA-test would bring additional information about risk factors among women and would so alter the follow-up process and may reduce the overall number of follow-up visits in the future. We unfortunately are not quite aware how the follow-up process is arranged and monitored in other countries, for example how long are women followed-up, how often do these women drop out of the process, how many cancers are detected and so on. The whole subject of CIN progression and the manner of follow-up process certainly, at least in our point of view, is something that should be further studied. Thank you for your valuable comments. Ilkka Kalliala, Pekka Nieminen and Ahti Anttila Competing interests: Authors of the study considered |
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