Pregnancy Bliss | Reproductive Health Answers
Published: Friday, November 18, 2011 - 20:56
Epidemiologic studies have consistently shown that IUCDs use reduces the risk for endometrial cancer, but the device's effect on the risk for cervical cancer has not been determined, say the researchers, led by Xavier Castellsagué, MD, from the Institut Català d'Oncologia in Catalonia, Spain.
Their paper published in The Lancet Oncology medical journal quotes previous studies which reported "inconsistent results" in cervical cancer, and none accounted for either human papillomavirus (HPV) status or cervical (Pap) smear history. IUCDS use has been suspected of causing cervical cancer since its clinical introduction in the 1930s, add the authors.
45% reduction in risk
The epidemiologic study of nearly 20,000 women found that women who used IUCDSs had a 45% reduced risk for cervical cancer, compared with never users.
Specifically, the researchers found a "strong" inverse association between ever-use of IUCDs and cervical cancer (odds ratio [OR], 0.55; P < .0001) after adjustment for "relevant co-variates." Those variables include the number of previous cervical (Pap) smear tests that a woman has undergone.
A protective association was also noted for the two major cervical cancer histologic types — squamous cell carcinoma (OR, 0.56; P < .0001) and adenocarcinoma or adenosquamous carcinoma (OR 0.46; P = .035). There was evidence that IUCD use did not protect women against HPV infection, but did protect against the development of cervical cancer.
The researchers summarized what all these associations mean.
"The associations found in our study strongly suggest that IUCD use does not modify the likelihood of prevalent HPV infection, but might affect the likelihood of HPV progression to cervical cancer," they write.
In an accompanying editorial, Karl Ulrich Petry, MD, from ‘The Klinikum’ Wolfsburg in Germany described the results as “surprising” and that they should "restored confidence in the safety of IUCDs," He also concludes that the study "provides high-level evidence to contradict a widespread assumption that IUCDS use increases the risk of cervical cancer,"
Possible mechanism of cervical cancer prevention
The mechanism of action by which IUCDSs protects against cervical cancer is not known, but the authors offer several possible explanations.
"One of the mechanisms by which IUCDs might exert this protective effect is through the induction of a reactive, chronic, low-grade, sterile inflammatory response in the endometrium, endocervical canal, and cervix that could modify, via changes in the local mucosal immune status, the course of HPV infections," write the authors.
Another possible explanation accommodates an interesting finding in the study.
The investigators found that there was no difference in the protective effect by years of IUCDS use. Short-term users and those with use as long as 9 years were found to be protected, according to the odds ratio estimates.
"It can be postulated that the local trauma to the cervical tissue associated with insertion or removal of the device induces local small foci of chronic inflammation and a long-lasting immune response similar to that noted in patients after colposcopically guided punch biopsies," write the authors.
A theory that incorporates the concept of local trauma and subsequent immune response also appeals to Dr. Petry, the editorialist.
"I postulate that the tissue trauma associated with loop insertion induces a cellular immune response that might finally clear persistent HPV infections and pre-invasive lesions," he writes.
The study's findings challenge some key elements of the "current model of the natural history of cervical cancer," adds Dr. Petry.
If prospective trials confirm the protective role of cervical trauma via the IUCDS loop insertion, then the medical world would "need to accept," he says, "that most studies of the natural course of cervical lesions in fact describe an artificial course, manipulated by biopsies cervical brushes, loop insertion, and other procedures."
The implications are profound, he suggests.
"It is very likely that we under-estimated the true risk of progression of HPV infections and associated lesions, based on studies that relied on biopsy-proven diagnoses."
All of this means that "today's standard information for patients that less than 1% of HPV infections progress to cancer" does not reflect the true natural history that exists outside of clinical interventions, such as biopsies, Dr. Petry says. "The 6.5% lifetime risk for cervical cancer observed in remote areas without screening probably mirrors the true natural risk," he adds.
The issue of possible screening bias
The study consisted of a pooled analysis of individual data from two large studies by the International Agency for Research on Cancer and Institut Català d'Oncologia research program on HPV and cervical cancer.
One study included data from 10 case–control studies of cervical cancer conducted in 8 countries; the other included data from 16 HPV prevalence surveys of women from the general population in 14 countries. There were 2205 women with cervical cancer and 2214 matched control women without cervical cancer from the case–control studies, and 15,272 healthy women from the HPV surveys.
"An important challenge" in interpreting the results can be found in the possible effect of a screening bias, say the authors. The insertion, follow-up, and removal of IUCDs often involves "several visits to the gynaecologist, providing many opportunities for these women to be directly diagnosed or screened for cervical cancer, through visual identification or repeated cervical cytology."
This is important because "the reduced risk of cervical cancer seen in IUCD users might not be due to the biological effect of the device, but rather to the higher likelihood of more intensive cervical screening or diagnosis in these women compared with non-users," the authors point out.
But the investigators accounted for that possibility. "We estimated associations by specific strata of number of previous Pap smears women had until 12 months before diagnosis or study entry," they write. They did not find that more visits resulted in a significantly different likelihood of cervical cancer. "History of previous Pap smears did not significantly affect the observed inverse association between IUCDS use and risk of cervical cancer," they conclude.
Furthermore, the study population is an argument against the potential for screening bias, they say. "Since most of the populations included in these analyses are from developing areas of the world, where screening is opportunistic and has little effect in preventing cervical cancer, it is unlikely that screening bias would explain the observed inverse association."