Women treated for high-grade cervical intraepithelial neoplasia (CIN3) have an increasing risk for invasive cancer after the age of 60, particularly if the treatment was recent, according to a Swedish population-based cohort study published onlineJanuary 14 in BMJ.
This finding suggests that women treated for the high-grade lesions need to be followed for a long time.
Investigators analyzed more than 3 million women-years' worth of data collected over a 50-year span from women with CIN3. They found that the risk for morbidity from cervical or vaginal cancer was 2.39-fold greater in women with CIN3 than in the general population (95% confidence interval [CI], 2.26 - 2.53), and the risk for mortality was 2.35-fold greater (95% CI, 2.11 - 2.61).
Of 150,833 women identified through Swedish Cancer Registry and Swedish Cause of Death Register records, 1089 women progressed to cervical cancer and 147 developed invasive vaginal disease, leading to 302 and 53 deaths, respectively.
Investigators found that the excess risk increased with age, accelerating after age 60 and again after age 70. The mortality rate is 50 per 100,000 women by age 72, and the morbidity rate is 100 per 100,000 after age 75.
"The high absolute risks of acquiring cervical or vaginal cancer and dying of these diseases when women previously treated for CIN3 reach old age are unique findings, with no other published studies on the subject to our knowledge," write lead author Björn Strander, MD, PhD, from the Regional Cancer Center at Sahlgrenska University Hospital in Göteborg, Sweden, and colleagues. They note, however, that the overall risk remains low.
Investigators also discovered that the risk for invasive disease increased with recent treatment, doubling from 2.05 (95% CI, 1.83 - 2.30) for women treated from 1958 to 1970 to 4.52 (95% CI, 3.47 - 5.80) for those treated from 2001 to 2008.
After adjustment for duration of follow-up and treatment period, investigators discovered a 5-fold increase in the risk for treatment in women 60 to 69 years, compared with women 30 to 39 years.
"We should take these data seriously and accept the warning that we have to follow women for long periods of time, particularly those receiving treatment at an older age," Marc Arbyn, MD, Msc, DrTH, from the unit of cancer epidemiology at the Scientific Institute of Public Health in Brussels, who is lead author of an accompanying editorial, told Medscape Medical News.
Dr. Arbyn explained that cervical screening programs in most countries do not follow women after the age of 65.
Much remains unclear about the risk escalation. But potential risk factors include incomplete treatment of CIN3, an increased baseline risk for cancer, and a less intense or protracted period of surveillance. "We have no data on how these treated women were actually followed," Dr. Strander and colleagues emphasize.
Dr. Arbyn concurs. "We must be careful not to overinterpret these data," he said, noting that age-specific immunity, anatomic changes, and reduced hysterectomy rates might also play a role in the findings.
"Older women may have lower immunity, which would explain why they develop invasive cancer after treatment and die from that cancer," Dr. Arbyn said. He explained that younger women are able to get rid of residual disease, and they have similar cure rates, independent of positive or negative margins; older women with positive margins are at increased risk for failure.
"It is also more technically challenging to treat precancer in older women because the cervical surface where cancer occurs is not as well exposed or visible on colposcopic exam," Dr. Arbyn said. He noted that the junction between squamous epithelium and the cylindric epithelium moves inward with age, particularly after menopause.
Dr. Arbyn also pointed out that hysterectomy rates have greatly declined. "It used to be that 20% to 25% of women in many countries lacked a cervix by age 60, which would eliminate their risk for cervical cancer," he said.
"An individual patient meta-analysis is needed to determine the margins of obstetric and oncologic safety associated with different treatment options while accounting for patient and lesion characteristics," Dr. Arbyn concluded. He stressed that full compliance with current screening guidelines and intensive post-CIN3 follow-up is definitely required in the interim.
The study was supported by the Halland County Scientific Board and the Swedish Cancer Society. The authors have disclosed no relevant financial relationships. Dr. Arbyn reports receiving grants from the seventh Framework Programme of DG Research of the European Commission, the Fonds National de la Recherche Scientifique, the European Federation of Colposcopy, and the Institut National du Cancer in Paris.
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