This large, population-based cohort study with more than 300
000 woman-years of observation in the CIN cohort provided important information that could contribute to evidence-based guidelines for follow-up of women treated for CIN. For women under surveillance after treatment, risks for subsequent CIN 2/3 declined to that of incident CIN in low-risk women by 6 years after treatment. Rates of subsequent CIN 2/3 increased with age and initial CIN grade and varied by treatment, being highest for women older than 40 years who were treated for either CIN 2 or CIN 3 with cryotherapy. Previously, large population-based cohort studies from Sweden in 1989 (11
) and 2007 (12
) reported on invasive cancer rates after treatment for CIN but did not have information on the recurrence of CIN or whether women were under surveillance after treatment. In our study, we found that invasive cancer risk was markedly higher in women after treatment of CIN, even among those undergoing active surveillance, compared with a cohort of women without previous CIN.
Overall rates of CIN 2/3 declined rapidly for the first 2 years after treatment; however, during the first 6 years of follow-up, these rates ranged from 5% for women initially treated for CIN 1 to 14% for women treated for CIN 3. In ALTS, women with initial low-grade squamous epithelial lesions who were referred for early colposcopy had rates of subsequent CIN 2/3 of 8%–13% during a 24-month follow-up (13
). Others (7
) have estimated rates of subsequent CIN after treatment that ranged from 1% to 21%.
In this observational study, rates of subsequent CIN 2/3 could be measured only for women who chose to obtain follow-up cytology. We focused on estimating the risk of subsequent CIN in the women under active surveillance. This group of women included a mean of 32
314 (87%) of the 37
142 women in the CIN cohort and 48
424 (68%) of the 71
213 women in the comparison cohort over the first 10 years. Our rates of CIN 2/3 cannot be applied to women who were lost to follow-up after treatment. Because of the linkage to the British Columbia Cancer Registry, however, we were able to identify all women who were diagnosed with invasive cervical cancer in British Columbia and thus to estimate the risk of subsequent invasive cancer for the entire cohort, with the exception of those who migrated out of the province. The lower rates of invasive cancers after the first 8 years of follow-up that appeared in women under active surveillance compared with women the overall CIN cohort indicate the importance of long-term surveillance of women after treatment for CIN.
It is biologically plausible that long-term cryotherapy efficacy may be lower than that of excisional procedures because removing rather than destroying tissue may provide greater protection. Higher cancer rates after cryotherapy may also be related to altered ability to adequately sample the transformation zone after treatment, perhaps because structural changes of the cervix after treatment for CIN differ between excisional and ablative procedures. Alternatively, our exclusion of women with incomplete excisional procedures (ie, those without clear surgical margins) may have underestimated the subsequent recurrence risk in women undergoing loop electrosurgical excision procedure and cone biopsy. The effect of treatment type on subsequent CIN has been inconsistent across studies. A meta-analysis of randomized controlled trials of CIN treatment outcomes by Nuovo et al. (15
) found that the median follow-up time for these trials was only 12 months, with CIN rates of 5%–15%, and no statistically significant outcome differences between treatment modalities. No invasive cancers were reported during the follow-up of 3811 women in these studies. Two more recent randomized controlled trials concluded that women treated by loop electrosurgical excision procedure had a lower rate of CIN after treatment than those treated with cryotherapy (16
) or laser vaporization (17
). A report (18
) of follow-up for 2116 women treated by cryotherapy, laser excision or ablation, or loop electrosurgical excision procedure for all grades of CIN in the United Kingdom found that the rate of invasive cervical cancer after treatment was 5.8 cancers per 1000 women for an 8-year period, whereas a long-term follow-up study (19
) of 4417 women treated for CIN 3 with cone biopsy and whose excised specimen had clear margins found no woman with invasive cervical cancer during a median follow-up of 8.9 years. A recent international systematic review of invasive cancer risk after treatment for CIN found no statistically significant differences in the risk of invasive disease across treatment types (3
The invasive cervical cancer rate in the CIN treatment cohort of 37 cancers per 100
000 woman-years fell between the rate in a Finnish cohort of 23 cancers per 100
000 woman-years (20
) and the rate in an international systematic review of cohort studies of 56 cancers per 100
000 woman-years (8
). The ongoing higher rate of invasive cancer among women in the CIN cohort, despite the decline in the rates of CIN 2/3, was also observed in the systematic review (8
) and supports an underlying increased risk in this group. However, the optimal length and intensity of surveillance for this group remains unclear. Among the women who developed invasive cancers in our study, the relatively high proportion of stage I cancers (77%) attests to the benefits of ongoing surveillance, as compared with only 53% of cervical cancers that were diagnosed at stage I in the US Surveillance, Epidemiology and End Results cancer registry for the period from 1988 through 2003 (2
Our study had several limitations. Interpretation of our results is limited by the nature of observational cohort data. Treatment patterns shifted in British Columbia over the study period, so that loop electrosurgical excision procedure became more common and laser excision and ablation became less common. Most treatment was provided in the provincial colposcopy clinics and hence was more likely to be relatively uniform and in accordance with guidelines for the study period. However, we were not able to document the presence of satisfactory colposcopy results among the women who were treated with cryotherapy or laser ablation. Although guidelines in British Columbia endorsed cryotherapy or laser ablation for women with satisfactory colposcopy only, we did not know how many women were treated in accordance with guidelines.
We have limited information on regional differences in surveillance practices or changes over time in British Columbia because most surveillance was provided by general practitioners. To evaluate further whether variation in treatment protocols or surveillance practices may have contributed to our findings, we examined the outcomes of women who were initially treated at a single urban tertiary hospital that treated and followed the highest volume of women with CIN in British Columbia and that also used consistent protocols. These outcomes were similar to those of overall dataset (data not shown). Testing for HPV was not performed in British Columbia during the study period, so we were limited to evaluating outcomes on the basis of surveillance with cervical cytology. Our analysis included only variables available in the database and could not examine the associations of socioeconomic status or race or ethnicity with outcomes.
The higher risk of CIN 2/3 and invasive cancer after treatment for women who were treated with cryotherapy, particularly for those treated for CIN 3, was substantial and differs from outcomes reported in some randomized trials (15
). If confirmed, this finding creates a dilemma for providers and their patients when making decisions about treatment of CIN. In contrast to cryotherapy, excisional methods of treatment have been associated with an increased risk of both early complications of hemorrhage in randomized trials (15
) and with an increased risk of preterm delivery and low birth weight in subsequent pregnancies in retrospective studies (21
). Further, cryotherapy is less costly to provide and the technique is easier to learn, making it more readily available in low-resource settings in which most women needing treatment for CIN reside (23
). Future randomized trials will need longer term follow-up to define the impact of treatment choice on subsequent CIN and invasive cancer.
These findings support the recent shift in the ASCCP guidelines for women who have been treated for CIN from indefinite annual screening to a return to routine screening after an initial period of more intensive follow-up that may take the form of cytology, HPV testing, or cytology with colposcopy during the first 6–18 months. Given the rapid decline in subsequent diagnoses of CIN 2/3 after the first 2 years but the ongoing elevated risk of invasive cervical cancer, it appears that consistency of follow-up for 10–20 years may be important for detecting disease after treatment. More intensive follow-up strategies are likely to be important for those women older than 40 years who were treated for CIN 3, particularly if they were treated with cryotherapy. Cost-effectiveness studies are needed to define optimal surveillance strategies that may differ by CIN grade, treatment type, and age.