Reviewer's report
Title:Analysis of 3 strategies to increase screening coverage for cervical cancer
in the general population of women from 60 to 70 years of age: A randomized
controlled trial. The CRICERVA Study
Version: 3Date:26 March 2013
Reviewer: Paolo Giorgi Rossi
Reviewer's report:
Major compulsory
There are three main flows in the study design that cannot be fully resolved, but
tat could be discussed and taken into account in the analyses:
• the population is preselected for “answering the CRIVERVA trial call”. If you
want to study the participation to screening programme preselecting only women
who are interested in participating in a study aout screening does not allow you
to see the real effectivenes of the intervention. I know that this is a point
frequently discussed with the Ethic review boards, but the validity of the results in
terms of both relative risk to aprticipate and impact on total Pap-test coverage
are not valid. Nevertheless the pre-selection of interested women should reduce
the differences that you could observe in the whole population (through a ceiling
effect), so if you observe any differnce, the study results are quite interesting. If I
correctly understand table 2, the authors applied an extreme Intention to treat
analysis to address this point, and this is an interesting solution.
• The randomisation unit is the BHCA, and it seems you have only four BHCA
and four arms. Statistical analysis: given the randomization unit, this cluster
randomised trial has most of the problems of the non randomised intervention
studies (pre-post or geographical controls), randomization only exclude a self
selection bias, but does not guarantee homogenous grops for unrevealed
“prognostic” variables. I suggest to use confidence intervals instead of p values,
to adjust all the effect estimates for all those variables you present in table 1 that
are associated with the outcome. This limit should be discussed, in particular the
meaning of statistical tests (that I suggest to drop in the analysis of the
differences among arms for the main outcome and to use only confidence
intervals). Please consider that if you adopt a correct estimate of the variance
with a random effect model taking into account the possible clusetring on the
randomisation unit, the variance estimate should be infinite and all the p test not
feasible as well as the confidence intervals of the relative risks will be by
definition 0 to infinite.
• The restriction of the analysis to the 60-70 years old women. It is not clear if the
restriction was planned in the study protocol or if it is a post hoca nalysis. We do
not know if the results about younger women will be published elsewhere or not. I
tried to understand this point in the BMC HSR paper, but I did not find the
answers.
It is important to include a flow chart of the study to understand the target
population, the randomised population (are they the same?), who actually
received the intervention and who responded.
finally there are too many spelling errors and the English (even if I am not a
English speaking reviewer) is hard to understand.
minor compulsory comments:
Abstract:
poblational, please translate in English
CRICERVA not CRIVERVA.
results: “Almost 50% of those (n=1184) were excluded for several reasons (i.e.
hysterectomy, immunosuppression, appropriate screening, etc)” . It should be
better explained that women with a previous Pap in private system are excluded
andt those are the vast majority of the excluded. Not including the previously
screened in private system, is not only an exclusion criterion, but it changes the
objective and the study design. Furthermore this is not explicitely reported in the
methods of the paper. The only clear description of this point is in figure 1.
The percentages reported for the intervention 3 are wrong: 14.5% initial
coverage??.
Conclusions: authors report: “the third intervention obtained a participation of
71.08% and increased coverage around 30.1%”, consistently with the results
reported for the othe groups, it could be clearer to report the the final coverage
(74.6%).
esplicitamente, come c’è poi in Figure 1, che sono state escluse le donne
screenate con sistema privato (o viene dato per scontato?). Oltretutto, non
essendo detto ciò esplicitamente nel testo, ha senso allora dire nei results
dell’articolo: “Although most of the participants in all the groups reported the use
of public health care centres for undergoing the screening (51 %), the use of
private centres was not homogeneous among the groups.”? Se poi queste sono
state escluse…
Introduction:
Paragraph 2 and 3 are not consistent with the focus of the paper.
The second part (pagg 6-8) should be shortened, many parts are not useful for
international readers.
The mention to HPV test in screening is not properly referenced (better to refer to
the 3 o4 four main studies, naucler 2007, bulkmann 2007, ronco 2010, kitchner
2008).
References to literature about methods to increase participation could be more
accurate and up to date: everett 2011, Ferroni 2013.
Pag 6: Five
“possible reasons for women not to undergo screening are of note: (a) the
perception of
vulnerability, (b) the benefits of screening perceived, (c) anxiety, (d) perturbation,
and
(e) the fear of cancer, family difficulties or personal circumstances (16).” The
reasons reported in point (e) are quite different: fear of cancer and logistical
barriers. In my opinion, the logisical barriers have been greatly ignored by the
litterature about reasons for non compliance and the few studies that investigated
these reasons found strong association between non compliance and the
presence of logistical barriers.
For the lack of organised screening (your ref 15) see also the more general
papers by Palencia 2010 and Ferroni 2013.
Pa 8 first line:
Methods:
the randomization process is not described: “The process of randomisation,
participant selection and sample size are described in the study protocol (5).”
Few words are sufficient to explain how did you randomised the groups.
Pag 8: “All the women were adequately informed about the screening procedures
and the
significance of the results of both cervical cytology and HPV DNA tests when
they
came for the visit.” It is not clear when and who was invited for the visit.
Furthermore in the “Study arms” the authors state: “Each of the 4 participating
centres were assigned one study arm”. This is the only point in which it is clear
that the trial is cluster randomised and you have (N units of randomisation) = (N
interventions). Even in the protocol full text “Economic evaluation of three
populational screening strategies for cervical cancer in the county of Valles
Occidental: CRICERVA clinical trial” the authors state: “The randomisation unit
was BHCA”, but it is implicit that you have only 4 BHCA. The randomisation unit
should be mentioned clearly in the abstract and the study design should be
correctly mentioned in the title.
Pag 9: “#All the participants were given a structured interview” 100%
participation? Are they all the randomised or only those responding to the “call”.
Please add a flow chart!
Statistical analysis: given the randomization unit, this cluster randomised trial has
most of the problems of the non randomised intervention studies (pre-post or
geographical controls), randomization only exclude a self selection bias, but does
not guarantee homogenous grops for unrevealed “prognostic” variables. The
authors should use appropriate statistical methods do adjust for variable that are
not evenly distributed to
Inclusion criteria: not participants??
Exclusion are not exclusions at all (correct, but the term is misleading)
Only reading the results it is clear how the date are treated (ITT).
Results:
See general comments: avoid all the comparisons with p. and put confidence
intervals. Produce adjusted estimates of the intervention effect.
pag 11: 1,276 (NOT 276) in IG2 (cfr Fig 1).
pag 13: please report how many are cytology positive and how many HPV+. The
prevalence of HPV+ is very low, this finding should be discussed.
Discussion
See general comments.
Your results should be commented comparing with previous studies see everett
for a systematic review of this kind of RCTs, but also Ferroni for the invitation
letter and phone calls.
The use of co-testing (cytology plus HPV) has been proposed in the US
guidelines, but in Europe most of the agencies and the upcoming EU guidelines
will recommend the use of a sequential strategy: HPV and cytology triage only for
those HPV positive. This has been proved to be a much more cost effective
strategy, with almost the same health benefits and much less costs.
page 15: "Thus, these data allow identification of 100-fold more pathology than
what would be expected in the general population (19) of the same age whereof
the incidence of invasive cervical cancer is estimated to be 7x100,000." this
sentence makes confusion of prevalence and incidence: detection rate is related
to the prevalence of pre-cancers and asymptomatic cancers. Furthermore, since
most CIN2/3 does not progress to cancer, only the two prevalent cancers should
be compared with the incidence (still a quite difficult comparison, since we do not
know in how many years the two cancer would become symptomatic, i.e. the true
person years needed to transform the prevalent asymptomatic disease in
incidence).
pag 15: "These data indicate that screening with the detection of HPV in this age
cohort may be a good strategy if the are then triaged using cervical cytology if the
initial test is positive." I would say the opposite: in this age group (not cohort) a
strategy with direct referral to colposcopy without triage could be acceptable,
particularly for those women without previous screening tests, given a high
prevalence of precancers and cancers in HPV+.
references
references should be updated.
Many papers are translated in Spanish
There are many spelling mistakes.
Level of interest: An article of importance in its field
Quality of written English: Not suitable for publication unless extensively edited
Statistical review: Yes, and I have assessed the statistics in my report.
Declaration of competing interests:
'I declare that I have no competing interests'