Recommendations on screening for cervical cancer

Canadian Task Force on Preventive Health Care

doi:10.1503/cmaj.121505

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Cervical screening: making the right change is more important than concern about discord.
James A Dickinson

Posted on: 06 May 2013
Cervical Screening Guidelines -discordance discussed
K. Joan Murphy

Posted on: 22 March 2013

Posted on: (6 May 2013)

Cervical screening: making the right change is more important than concern about discord.

James A Dickinson, Chair, Cervical Guidelines Writing Group

Three recent publications have challenged parts of the new Canadian Task Force on Preventive Health Care (CTFPHC) guideline on Cervical Screening(1): the commentary by Dollin(2), the joint statement by the Society of Obstetricians and Gynaecologists, the Society of Gynaecological Oncologists, and the Society of Canadian Colposcopists(3), and the present letter by Drs. Murphy and Elit(4). These writers agree with the CTFPHC's recommendations for screening women from 30 to 70, then raise three main issues: age of commencement, whether to vary initiation according to women's individual preferences and risk assessment, and use of HPV testing.

Some of the comments have misquoted the CTFPHC, and we wish to clarify misunderstandings about the strength of the evidence, what evidence was used and why we did not recommend HPV screening, and the focus of the CTFPHC on women's needs rather than policy convenience.

Strength of evidence.
Murphy and Elit, and the three societies asserted that the evidence is weak for women between 20 and 29, and therefore the recommendations about raising the age of starting screening should be ignored and left at 21. They are wrong. Box 2(1) clearly describes moderate strength evidence for women aged 20 to 24, and 25 to 29. The recommendations are weak, because of the balance between small possible benefits and the definite harms. Therefore, women and their doctors need to discuss the recommendation and its implications to support women in deciding what starting age is appropriate.

The CTFPHC found strong evidence against pap testing women younger than 20, and strong evidence for screening in women older than 30, so that somewhere between these two ages the balance of potential benefits and likely harms changes to favour screening. When 10% of women under the age of 30 are given abnormal test results, and a large proportion then undergoes colposcopy and treatment, the harms are substantial by comparison with uncertain and very small numbers of potential cancer averted before the age of 30. Table 1 shows how small are the potential reductions in mortality: of the order of 1 per million per year for 20 to 24, and 1 per 100,000 per year for 25-29. For incidence, 1.4/100,000 for 20-24 yrs, and 3/100,000 respectively. Both the CTFPHC and the CCO review assessed three case-control studies that showed low effectiveness of screening for young women (particularly those under 25). Screening at this age appears to have little effect in reducing cancer in the succeeding five years. Thus, the potential for preventing cancer through initiation of screening at 21, and consequent treatment of precursors, as recommended by the joint societies statement(3), is uncertain and at best minimal. Even following the new guidelines for management of screen-detected abnormalities(5) will still entail substantial follow-up and some procedures on young women.

The harms of screening are not well measured: they include labelling, recovery from biopsy, the possibility of cervical incompetence and early pregnancy loss or premature delivery. Healthcare data in Canada is not routinely analysed in sufficient detail to measure how the balance changes by single years of age. However, based on the data that we have, while harms reduce with age, the incidence of disease rises steadily through this decade(6,7), and therefore the potential benefit may do so too.

The evidence used.
Dollin[2] and the joint societies' statement[3] asserted incorrectly that we based our findings solely on the outcome of mortality. To the contrary: the CTFPHC also considered the incidence of invasive cancer in each age group as a key determinant of whether to recommend screening.

Murphy and Elit(4)strongly support primary HPV screening to increase the efficacy of screening, and Dollin commends this approach.(Murphy is the lead author of Cancer Care Ontario's (CCO) cervical screening guidelines(8,9) which recommend HPV as primary screening test for women 30 and over, while Dollin and Elit were members of the advisory committee). It is disturbing that the CCO decision on HPV screening was based not on the results of trials but on the anticipated results from those trials ([6] p9 Table 2). The CTFPHC requires actual results be available before formulating its guidance.

Murphy and Elit (4) and the joint statement(3) assert that the CTFPHC should have examined evidence about precursor lesions (CIN 2 & 3) and their reduction by HPV testing and treatment. These lesions are indeed precursors, but what proportion regress and what proportion actually progress to cancer, and how much time is required for progression to occur? The evidence is limited, but it appears only a small fraction of precursors progress to cancer. The CCO review quotes several sources that concur (6)(evidentiary base page 3). Experience with many different diseases shows that relying on such surrogate endpoints often leads to false conclusions(10). Therefore the CTFPHC recommendations are conservative, do not rely on surrogate outcomes, and have reserved judgment on the benefits of HPV technology until better evidence is available.

Focus on women's needs.
Murphy and Elit(4) declare that it is more important for an organised screening program to start uniformly at age 21 than for women to make choices. "While initiation of screening based on individual preference and/or risk assessment... is neither reliable, practical nor necessary as a routine." The CTFPHC emphasises the uncertainty of the evidence, and therefore of the decision on starting to screen. The implication of the weak recommendation is to assist practitioners to discuss this uncertainty with women, who can then make decisions based on their own values and beliefs. In the current era of patient empowerment, at least their recommendations should encourage, and provide the numerical information that will enable such discussion - yet the published summaries and recommendation statements from CCO or the societies do not provide such important context. Screening programs can then focus on monitoring and increasing uptake for women over age 30, for whom recommendations are strong, because benefit is clear. We appreciate the work of the provincial screening programs and believe Drs. Murphy and Elit do them a disservice by suggesting that they cannot convey the potential risks and benefits of screening

Regardless of what we do for women below age 30, the majority of advanced cervical cancer occurs among older women who have not been tested at all, so reaching out to such underscreened women is the most important factor in reducing this disease, more than changing the test. In addition, though regular pap tests reduce incidence by over 80%, some cancers develop even among screened women, so they should still seek care for these symptoms and doctors should still investigate them.

We note that in 1991, the same group of three societies spoke out against the recommendation to reduce screening intervals to three years(11), despite the clear evidence for that change. Continuing annual screening means Canadian women have had three times more tests than they needed, and thereby were exposed to extra false positives and interventions. Once again, by refusing to accept the evidence that a later start to screening is appropriate, they persist with the North American program of overscreening. The CTFPHC understands that for many members of these societies, the new guidelines may be troublesome, since they would change long-established patterns of practice. Such change should not be made without good evidence, but change is necessary when the evidence warrants it. More credence must be given to the substantial evidence from European countries that demonstrates the lack of harms from a later start age(12).

In conclusion, we stand by the recommendations of the CTFPHC: to start pap testing in the mid twenties, after discussion with the woman involved. The CTFPHC awaits the conclusion of HPV testing trials with interest, but is unwilling to accept outcomes based only on surrogates. Instead, we wish to know whether these approaches reduce incidence and mortality from cancer. We urge provincial guideline groups and individual doctors to focus on communicating risk information to women who can then make personal choices: this includes those women who are currently having regular tests and those who are not. To assist in this process, we have produced education tools, which are available on the CTFPHC website[13].

References.

Canadian Task Force on Preventive Health Care. Recommendations on screening for cervical cancer. CMAJ 2013. DOI:10.1503/cmaj.121505
Dollin J. Commentary: Preventing cervical cancer: beyond following guidelines. CMAJ 2013. DOI;10.1503/caj.121781
Society of Obstetricians and Gynaecologists of Canada, Society of Gynecological Oncology of Canada, Society of Canadian Colposcopists. Position statement: recommendations on screening for cervical cancer. 20 Feb 2013.
Murphy J, Elit L. Cervical screening guidelines - discordance discussed. CMAJ e-letter 22 Mach 2013
Bentley J and the Executve Council of the Canadian Society of Colposcopists. Colposcopic Management of Abnormal Cervical Cytology and Histology. J Obstet Gynaecol Can 2012;34(12):1188-1202
Dickinson JA, Stankiewicz A, Popadiuk C, Pogany L, Onysko J, Miller AB. Reduced cervical cancer incidence and mortality in Canada: national data from 1932 to 2006. BMC Public Health 2012;12:992
Popadiuk C, Stankiewicz A, Dickinson J, Pogany L, Miller AB, Onysko J.Invasive cervical cancer incidence and mortality among Canadian women aged 15 to 29 and the impact of screening. J Obstet Gynaecol Can. 2012 Dec;34(12):1167-76.
Murphy J, Kennedy ER, Dunn S, McLachlin M, Fung MFK, Gzik D, Shier M, Paszat L. Cervical Screeening: a guideline for clinical practice in Ontario. J Obstet Gynecol Can. 2012;34(5):453-58.
Murphy J, Kennedy ER, Dunn S, McLachlin M, Fung MFK, Gzik D, Shier M, Paszat L Cervical Screening Evidence-based series 15-9. Cancer Care Ontario. http://www.cancercare.on.ca/toolbox/qualityguidelines/clin-program/screening-ebs/
Accessed April 11 2013
Yudkin J, Lipska K, Montori V The idolatry of the surrogate.
BMJ 2011;343:d7995 doi: 10.1136/bmj.d7995 (Published 28 December 2011)
Stuart GC, O'Connell G, Ferenczy A. Screening for cancer of the cervix. CMAJ 1991 145:1195b-1195
Sasieni P, Castanon A, Cuzick J The impact of cervical screening on young women: a critical review of the literature 2002-2009. NHSCCSP Doc no 31. Feb 2010.
http://www.cancerscreening.nhs.uk/cervical/publications/nhscsp31.pdf
Accessed April 12 2013-04-12
CTFPHC website: http://canadiantaskforce.ca/resources/

TABLE. Changes in incidence and mortality of cervical cancer in Canada [6]

	1952-1956		1972-1976		2002-2006		Change over time
Age	N	Rate/10⁵	N	Rate/10⁵	N	Rate/10⁵	%	Rate
Incidence
15-19	n/a	n/a	9	0.3	9	0.2	35	0.1
20-24	n/a	n/a	143	2.7	70	1.3	52	1.4
25-29	n/a	n/a	629	9.1	355	6.7	26	2.4
30-34	n/a	n/a	643	17.1	689	12.7	26	4.4
Mortality
15-19	0	0	*	*	0	0.0	+	+
20-24	9	0.3	5	0.1	9	0.2	+	+
25-29	51	1.7	30	0.6	31	0.6	+	+
30-34	137	4.7	66	1.8	65	1.2	75, 32++	0.6

n/a not available, since national incidence data not collected
* Data suppressed, since numbers less than 5.
+ Not calculated since cell sizes too small to produce meaningful result.
++ change between 1952-6 to 2002-6, then 1972-6 to 2002-6

Conflict of Interest:

None declared

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Competing Interests: None declared.

Posted on: (22 March 2013)

Cervical Screening Guidelines -discordance discussed
K. Joan Murphy, Clinical Lead, Ontario Cervical Screening Program
Other Contributors:
To the Editor, CMAJ: The recent interest in cervical cancer screening as evidenced by the publication of multiple guidelines is important for women at risk for this disease, which includes every woman who is or ever has been sexually active who has not undergone removal of her cervix.
However, publication of discordant recommendations leads to confusion for patients and their primary care providers. In the last y...
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To the Editor, CMAJ: The recent interest in cervical cancer screening as evidenced by the publication of multiple guidelines is important for women at risk for this disease, which includes every woman who is or ever has been sexually active who has not undergone removal of her cervix.
However, publication of discordant recommendations leads to confusion for patients and their primary care providers. In the last year Cancer Care Ontario (CCO) and the Canadian Task Force on Preventive Health Care (CTFPHC) each undertook an evidence based review process. Their guidelines are similar in that they recommend a triennial screening interval and cessation of screening at 70 for women who have been adequately screened and whose screening is negative.
The recommendations differ on the recommended screening test (cytology vs. HPV testing) and the age of initiation of screening (21 vs. 25 respectively). CCO's guidelines clearly recommend the implementation of HPV testing as the primary screen test for women 30 and over; in the interim while funding of HPV testing is explored with the Ontario Ministry of Health, triennial cytology starting at age 21 is recommended. The CTFPHC does not support primary HPV testing.
Why the discord? In part, this is explained by the specific questions each guideline process asked and in particular the outcomes they determined to be of interest. The CTFPHC examined studies that address incidence of and mortality from cervical cancer and excluded in its evidence review studies whose end points included reduction in rates of significant precursor lesions (>/= CIN2/3).
The CCO process accepted that CIN 3 is a clear precursor of cervical cancer and recognized that, given that HPV testing has only become available during the era in which cervical cancer is considered a preventable disease, though certainly outcomes of great interest and high relevance, neither incidence of nor mortality from invasive cervical cancer is now an ethical end-point in a study population. Thus the CCO guideline developed in conjunction with the Program in Evidence Based Care (PEBC) at McMaster University defined as its primary outcomes of interest the relative rates of CIN 2/3 as well as incidence of and mortality due to invasive cervical cancer.
Studies were included if they contained a randomized comparison of cytology and HPV as the primary screen test with data for two or more screening rounds in the setting of an organized screening program. The PEBC reviewers and central review process were satisfied by their review of the evidence that within an organized program, the increased sensitivity of HPV testing over cytology, the high NPV of HPV testing and the prolonged screening interval allowed by these characteristics of HPV testing clearly make HPV as the primary test with cytology for triage the preferred algorithm. Furthermore, it is likely that as the immunized population reaches screening age and thus the prevalence of cytologic changes due to oncogenic HPV should be significantly reduced, cytology as the primary screen test for significant cervical dysplasia may perform even less well in comparison to HPV as a primary screen test.
It should be noted that whereas the CTFPHC publication cites Ontario and Quebec as recommending "a combination of HPV and cytology testing," Ontario clearly recommends primary HPV testing with cytology triage; it does NOT recommend co-testing.
As regards age of initiation of screening, the literature to inform this element of organized screening is not definitive. Though such thresholds must be informed by the evidence available, the applicable evidence is of low quality, as reflected by the GRADE category, and the final recommendation must be determined by consensus and by contextual issues.
CCO accepted 21 as the age of initiation with the stated intention being to review the literature again to re-evaluate the optimal age of initiation and the optimal screening tool for women under 30 if/when primary HPV testing is implemented. CCO's primary objective is to discourage screening of women under 21, an age group in which the potential harms of screening far outweigh the benefits. We believe that within an organized screening program internal consistency is important for clinicians and for women and for evaluation of the program. While initiation of screening based on individual preference and/or risk assessment as endorsed by CTFPHC may be appropriate in unusual cases, it is neither reliable, practical nor necessary as a routine.
We agree with the CTFPHC that as further evidence evolves that cervical screening best practices both in the developed and the developing worlds must be aligned with that evidence so that women can be protected from this preventable disease and also from harmful and/or unnecessary interventions due to screening and/or procedures intended to identify or treat precursor lesions. We believe that the evidence strongly supports primary HPV screening is a significant step toward both increasing the efficacy of screening and decreasing its harms.
It is well proven that cervical cancer screening saves lives. Designing an optimal system that maximizes disease prevention and minimizes potential harms and redundancy is the mandate for screening programs.
K. Joan Murphy, MD, FRCSC, Division of Gynecologic Oncology, UHN Associate Professor, Univ. of Toronto Clinical Lead, Ontario Cervical Screening Program, Cancer Care Ontario
Laurie Elit, MD, FRCSC, Juravinski Cancer Centre, Hamilton Health Sciences Centre Professor, McMaster University Lead Scientist, Ontario Cervical Screening Program, Cancer Care Ontario
Conflict of Interest:
None declared
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Competing Interests: None declared.