Appendix A

A modelling approach was used to predict the impact of the renewed National Cervical Screening Program (NCSP), when implemented in conjunction of these guidelines, on benefits, harms, cost-effectiveness and resource utilisation. The estimates presented here are an update of predictions that underpinned the Medical Services Advisory committee (MSAC) recommendations.^[1]

The findings are summarised in Chapter 5. Benefits, harms and cost-effectiveness of cervical screening in the renewed NCSP. This appendix briefly describes the modelling methods and details the updates included since the model platform was used for the MSAC evaluation. Updates affecting the overall effectiveness and costs associated with the renewed NCSP include changes in:

• guidelines for the management of women post colposcopy
• assumptions about compliance with colposcopy
• end age for screening.

Model platform

We used the same model platform that was used for the MSAC evaluation. This platform has been used for a number of human papillomavirus (HPV) vaccination evaluations as well as screening technology, screening interval and screening management evaluations performed on behalf of national cervical screening programs in Australia, New Zealand and England. A schematic of the model is shown in Figure A.1. The model consists of several elements:

1. a dynamic model of sexual behaviour, HPV transmission and vaccination in females and males based on vaccination uptake rates reported by the National HPV Vaccination Program Register
2. a multi-HPV-type model of the natural history of HPV infection, progression, regression, the development of cervical intraepithelial neoplasia (CIN) and invasive cervical cancer
3. a model of cervical screening, diagnosis and treatment of CIN
4. a multiple-cohort implementation which separately models HPV exposure, CIN development, screening, and all downstream processes, for each age cohort of females
5. a population component that applies demographic data to the outputs to estimate cross-sectional results.

A more detailed description of the model, including data sources, model validation and calibration targets and previous applications of the model, can be found in MSAC’s NSCP renewal executive summary report.^[1]

Figure A.1. Schematic diagram of model structure

This flow diagram represents the natural history assumptions specific to a single HPV type. If multiple HPV infections exist, each will have the same flow dynamics, but the rates of progression and regression occur independently for each HPV type.

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Screening compliance assumptions

When modelling the pre-renewed NCSP, we incorporated data on age-specific screening initiation and compliance with screening and management recommendations in Australian women, informed by an analysis of data obtained from Victoria Cervical Cytology Registry (VCCR). When modelling the renewed NCSP, assumptions were based on the introduction of a call-and-recall system, with women sent invitations at age 25 years. We assumed that the number of women who attend their first screening test at age 25 years (the new initiation age) will be at least equivalent to the number who, under the pre-renewed NCSP, had their first screening test before, or at, the age of 25. For the purposes of this modelled evaluation, we assumed that no screening occurs before the age of 25 years under the renewed NCSP. Compliance with re-attendance for women in routine screening under the renewed NCSP was evaluated assuming implementation of the call-and-recall screening organisation system. The behaviour of women under a call-and-recall system was informed by data from England, where such a system has been implemented. While the proportion of women who attend before or at the recommended screening interval (5 years under the renewed NCSP) is informed by the screening pattern observed in England, we assume that the coverage at 7 years is equivalent to that currently observed under the pre-renewed NCSP (i.e. that changing the recommended screening interval, by itself, will not change behaviour in very under-screened women). The modelled probability of re-attending, according to the time since last screening test, is shown in Figure A.2. We assumed that, for a given recall timeframe, the probability of attending a follow-up test in the renewed NCSP is equivalent to that currently observed under the pre-renewed NCSP. As part of the MSAC evaluation, we previously explored a range of screening attendance assumptions, including slower screening uptake rates and a less ‘efficient’ call-recall system (in which there was a higher rate of early re-attendance and a lower rate of on-time attendance). Details of the impact of these screening assumptions can be found in MSAC’s NSCP renewal executive summary report.^[1]

Figure A.2. Probability of re-attendance for women in routine screening

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Updates to the management of women post-colposcopy

We have incorporated into the model the new recommendations in these guidelines for post-colposcopy management. These include recommendations for women who were referred with a positive oncogenic HPV (16/18) test result, or women under follow-up with a positive oncogenic HPV (any type) test result, with each of the following colposcopy results (see Colposcopy terminology in Chapter 7. Colposcopy):

• i) normal transformation zone (TZ) (negative colposcopy)
• ii) abnormal TZ and histologically confirmed CIN2 or lesser-grade lesion
• iii) type 3 TZ.

We have also incorporated new recommendations, according to these guidelines, for women referred to colposcopy who subsequently received pre-cancer treatment.

Table A.1 summarises updated post-colposcopy management for women referred with a positive oncogenic HPV (any type) test result and a liquid-based cytology (LBC) report of negative, possible low-grade squamous intraepithelial lesion (pLSIL) or low-grade squamous intraepithelial lesion (LSIL). Table A.2 shows updated post-colposcopy management for women who have an LBC prediction of possible high-grade squamous intraepithelial lesion (pHSIL) or high-grade squamous intraepithelial lesion (HSIL). These updates have been incorporated into the model.

Table A.1. Changes in post-colposcopy management for women with an LBC report of negative, pLSIL or LSIL, based on the renewed NCSP recommendations

	Normal TZ	Type 3 TZ	Colposcopy abnormal and biopsy < CIN2	Treated for CIN2+ and under test-of-cure
MSAC model assumptions*	Co-testing at 12 and 24 months Referral to colposcopy if any positive‡ at 12 months or 24 months	Co-testing at 12 and 24 months Referral to colposcopy any +ve test‡ at 12 or 24 months	Co-testing at 12 and 24 months Referral to colposcopy if pHSIL+ or if both oncogenic HPV +ve (any type) and pLSIL+ No referral to colposcopy if oncogenic HPV (any type) +ve and LBC negative, or oncogenic HPV not detected and cytology pLSIL/LSIL	Co-testing at 12 and 24 months Colposcopy if LBC pHSIL+ Otherwise, continue annual co-testing until 2 consecutive double negatives
Updated model assumptions†	HPV testing at 12 months Referral to colposcopy if oncogenic HPV (16/18) +ve, or oncogenic HPV (non 16/18) +ve with reflex LBC pHSIL+ Discharge to routine screening if oncogenic HPV not detected	HPV testing at 12 and 24 months Referral to colposcopy if oncogenic HPV +ve (any type)at either visit§ Return to routine screening if oncogenic HPV not detected at 12 months and 24 months	HPV testing at 12 months Referral to colposcopy if oncogenic HPV (16/18) +ve, or oncogenic HPV (non 16/18) +ve with reflex LBC pHSIL+ Discharge to routine screening if oncogenic HPV not detected	Co-testing at 12 and 24 months Colposcopy if cytology pHSIL+ or oncogenic HPV (16/18) +ve (irrespective of LBC) Otherwise, continue annual co-testing until 2 consecutive double negatives

TZ: transformation zone
Co-testing: HPV test and LBC
pHSIL+: possible HSIL or higher-grade lesion
pLSIL+: possible LSIL or higher-grade lesion
+ve: positive test result
* Model assumptions used for the MSAC evaluation (for the base case MSAC evaluation)
^† Model assumptions reflecting the updated recommendations in these guidelines
‡ Oncogenic HPV (any type) detected or any abnormality on LBC
§In the model, we assumed that women attending their visit at 24 months would be referred to colposcopy if they have a positive oncogenic HPV (16/18) test result, but not for a positive oncogenic HPV (not 16/18) test result.

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Table A.2. Changes in post-colposcopy management for women with an LBC report of pHSIL or HSIL, based on the renewed NCSP

	Normal TZ	Type 3 TZ	Colposcopy abnormal and biopsy < CIN2	Treated for CIN2+ and under test-of-cure
MSAC model assumptions*	Return for a LBC and colposcopic assessment at 6 and 12 months	Cold-knife cone biopsy is recommended. However, women who are concerned about fertility† can have a repeat colposcopy in 4 months. If the TZ is still not visible, diagnostic excision is recommended	Co-testing at 12 and 24 months Referral to colposcopy if pHSIL+ or if both oncogenic HPV (any type) +ve and pLSIL+ No referral to colposcopy if oncogenic HPV (any type) +ve and cytology negative, or oncogenic HPV not detected and LBC pLSIL/LSIL	Co-testing at 12 and 24 months Colposcopy if LBC pHSIL+ Otherwise, continue annual co-testing until 2 consecutive double negatives
Updated model assumptions**	Diagnostic excision of the TZ is recommended§ Women who had confirmed pHSIL and are concerned about fertility† can have a repeat assessment at 6 and 18 months with an HPV and LBC co-test‡	Diagnostic excision of the TZ is recommended regardless of whether the referring LBC is pHSIL or HSIL§	Diagnostic excision of the TZ is recommended Women who had confirmed pHSIL and are concerned about fertility† can have a repeat assessment at 12 and 24 months with an HPV and LBC co-test‡	Co-testing at 12 and 24 months Colposcopy if LBC pHSIL+ or oncogenic HPV (16/18) +ve (irrespective of LBC) Otherwise, continue annual co-testing until 2 consecutive double negatives

TZ: Transformation zone
pHSIL+: possible HSIL or higher-grade lesion
pLSIL+: possible LSIL or higher-grade lesion
*Model assumptions used for the MSAC evaluation (for the base case MSAC evaluation)
** Model assumptions reflecting the updated recommendations in these guidelines
^†Based on Australian fertility rates for 2011, we have estimated the probability that a woman would have no further births from the age of 35 on as 64%. By age 40, this has increased to 92% and by age 45 it is over 99%. We therefore assume the following for the purposes of this modelled evaluation:
(i) All women aged < 35 years will choose to defer excisional biopsy
(ii) 35% of women aged 35–39 will choose to defer excisional biopsy
(iii) 8% of women aged 40–44 years will choose to defer excisional biopsy
(iv) No women aged 45+ will choose to defer excisional biopsy.
§ We assume all women will undergo diagnostic excision of the transformation zone at this point.
^‡ It is assumed that:
(i) women have a co-test (HPV and LBC), along with a colposcopy, at both visits
(ii) a woman undergoes diagnostic excision of the transformation zone if oncogenic HPV (any type) is detected, or oncogenic HPV is not detected and LBC prediction is pHSIL/HSIL.
(iii) if oncogenic HPV is not detected and cytology is negative at both visits, women are referred to routine screening.

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Updates to colposcopy compliance assumptions

Modelling undertaken for the MSAC evaluation assumed that compliance with colposcopy referral was dependent on the accompanying cytology result, and was generally higher in women referred with a pHSIL/HSIL. This was based on observed data from the Victorian Cervical Cytology Register, and is likely due to the fact that, under the pre-renewal NCSP, women referred with a high-grade cytology prediction receive reminder letters and phone calls if they have not attended colposcopy within a certain interval (shorter than the interval for reminders sent for women without a high-grade cytology prediction). We sought advice on whether these assumptions should be revised by considering management protocols for following up women within the primary HPV screening arm of the Compass trial, given that the Compass protocol closely resembles the proposed clinical pathway recommended in this guideline. Based on Compass management, we assumed that:

• women who are referred for colposcopy (regardless of the reflex LBC result) are followed up in the same way as for women with a pHSIL/HSIL cytology under the pre-renewal NCSP
• women will attend colposcopy at a rate similar to what is observed in women who test pHSIL/HSIL on cytology under the pre-renewal NCSP program.

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Updates to HPV exit testing assumptions used in modelling

For the MSAC evaluation, when we provided predictions for women having primary HPV screening, we assumed that exit testing would be offered to women aged 60–64 years, which we described as screening ending at 64 years. As an exploratory analysis, we considered a scenario in which exit HPV testing would be offered to women aged 65–69 years, which we described as screening ending at 69 years. MSAC has since recommended that women have an exit HPV test between 70 and 74 years of age.

Furthermore, these new guidelines recommend women aged 70–74 years who have an are oncogenic HPV (any type) positive test result at their final screening test be referred directly to colposcopy, regardless of the HPV type or the reflex LBC result. This management process differs from the MSAC model, which assumed there was no referral to colposcopy for women who had an oncogenic HPV (not 16/18) positive test result but who had a negative LBC report. Therefore, we updated the model to account for this change in management of women at their final screening visit.

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Note: The model incorporated assumptions about compliance with screening in the renewed NCSP after taking into account the introduction of a call-and-recall system for screening. The specific assumptions for adherence were described in detail in the MSAC evaluation^[2] and are summarised here (see screening compliance assumptions). The predicted impact of the renewed NCSP, and associated cervical cancer incidence and mortality reductions, are predicated on achieving the level of compliance assumed.

Incremental impact of the changes from the model used for MSAC

Table A.3 summarises the incremental impact of each change that was made from the model used for the MSAC evaluation. This was done to determine the relative impact of each change on overall model predictions. Incorporation of the new recommendations in these guidelines for women who were referred to colposcopy with a cytology report of negative or pLSIL/LSIL and had a (i) negative colposcopy, (ii) type 3 TZ (iii) a histologically confirmed < CIN2 lesion, or (iv) received treatment for CIN2/3, results in a further 3% reduction in cervical cancer incidence and mortality in unvaccinated cohorts and a 1–3% reduction in cohorts offered vaccination, compared with the prior predictions for the renewed NCSP. The change results in 2% more colposcopies in unvaccinated cohorts and 9% fewer colposcopies in cohorts offered vaccination.

Incorporation of the updated guidelines for women who were referred to colposcopy with a cytology report of pHSIL/HSIL and had a (i) negative colposcopy, (ii) type 3 TZ, or (iii) a biopsy-confirmed <CIN2 lesion results in a further 5–6% reduction in cervical cancer incidence and mortality in unvaccinated cohorts and a 4% reduction in cohorts offered vaccination, compared with the prior predictions for the renewed NCSP. This change has no effect on colposcopies in unvaccinated cohorts but increases colposcopies by a further 2% in cohorts offered vaccination.

Incorporating the changes to the compliance assumptions for women referred to colposcopy results in a further reduction of 2% in cervical cancer incidence and mortality in unvaccinated cohorts and a 1–2% reduction in cohorts offered vaccination, compared with the prior predictions for the renewed NCSP. The change results in an increase in colposcopy referrals of 7% in unvaccinated cohorts and 5% in cohorts offered vaccination. Incorporating the changes to the screening end-age, we predict a 2–3% reduction in cervical cancer incidence and mortality in both unvaccinated cohorts and cohorts offered vaccination, compared with the prior predictions for the renewed NCSP. This change results in a 1% increase in colposcopies for both unvaccinated cohorts and cohorts offered vaccination.

As an exploratory analysis, we also evaluated a scenario in which women were not managed differently at their final screening test at ages 70–74, and were instead managed the same way as women who tested HPV positive at younger ages (i.e. we assume that there is no special exit test offered to women at their final screen). In this case, we predict < 0.5% increase in cervical cancer incidence, compared with the scenario in which women are who have a positive oncogenic HPV (any type) test result are referred to colposcopy at their final test when aged 70–74 years. These findings suggest that extending the screening end-age has a substantial impact on effectiveness of the program, but providing different management for women who have an oncogenic HPV (any type) positive test result does not have as great an impact on effectiveness.

A.3. Changes in cervical cancer incidence, mortality and number of colposcopies predicted under the new model assumptions compared with pre-renewal NCSP

	Unvaccinated cohorts			Cohorts offered vaccination
	Cancer cases	Cancer deaths	Colposcopies	Cancer cases	Cancer deaths	Colposcopies
MSAC model*	–19%	–21%	+26%	–15%	–18%	–5%
Updated model†	–31%	–36%	+36%	–24%	–29%	–7%
	Incremental impact after incorporating each change
Referral LBC negative or pLSIL/LSIL and any of: a) colposcopy result Type 3 TZ b) histologically confirmed < CIN2 c) colposcopy negative d) treated for CIN2/3	–3%	–3%	2%	–1%	–3%	–9%
Referral LBC pHSIL/HSIL and any of: a) colposcopy result Type 3 TZ b) histologically confirmed < CIN2 c) colposcopy negative	–5%	–6%	0%	–4%	–4%	2%
Updated compliance assumptions	–2%	–3%	7%	–2%	–1%	5%
Exit HPV test offered at age 70–74 years (extend end-age by 5 years)	–2%	–3%	1%	–2%	–3%	1%

Note: Figures are based on the female Australian population as predicted for 2017. Due to rounding, direct adding of the incremental numbers may not result in the presented final impact number.
* Model assumptions used for the MSAC evaluation (for the base case MSAC evaluation)
† Model assumptions reflecting the updated recommendations in these guidelines.

Overall benefits of the renewed NCSP incorporating these guideline recommendations

The impact of the Renewed NCSP on predicted cervical cancer cases, deaths, colposcopies and treatments for CIN2/3, is shown in Table A.4. Under the renewed NCSP when these guidelines are incorporated, we predict a 31–36% reduction in cervical cancer cases and death in unvaccinated cohorts, and a 24–29% reduction in cohorts offered vaccination, compared with the pre-renewal NCSP. This is equivalent to 265 fewer cancer cases and 82 fewer deaths annually in unvaccinated cohorts, and 85 fewer cancer cases and 28 fewer deaths annually in cohorts offered vaccination.

Table A.4. Predicted annual numbers of cervical cancer cases and deaths for the pre-renewal NCSP and the renewed NCSP (showing differences in case numbers and relative percentage differences)

	Pre-renewal NCSP		Renewed NCSP
	If HPV vaccination had not been introduced	For cohorts offered vaccination as 12 year olds	If HPV vaccination had not been introduced	For cohorts offered vaccination as 12 year olds
Cervical cancer cases	850	353	584 (–265; –31%)	267 (–85; –24%)
Cervical cancer deaths	227	94	145 (–82; –36%)	66 (–28; –29%)

Note: Figures are based on female Australian population as predicted for 2017.

We also predict an increase in colposcopies for unvaccinated cohorts, but this increase will not be seen in cohorts offered vaccination. Although there would have been a substantial increase in colposcopies if HPV vaccination had not been introduced, it should be noted that 70% of these additional colposcopies would have occurred in women less than 35 years of age. However, all of these women will have been offered vaccination by 2017, when these new clinical guidelines will be implemented. After taking into account the effect of HPV vaccination, the overall impact of the renewed NCSP on colposcopy and treatment-related harms is expected to be as good or better, when compared to the pre-renewal NCSP.

Costs and cost-effectiveness

Table A.5 shows the estimated cost of the NCSP before and after renewal. If HPV vaccination had not been introduced, a 19% reduction in program costs is predicted under the renewed NCSP. For cohorts offered vaccination, a 26% reduction is predicted under the renewed NCSP. This is equivalent to a cost saving of $41 million per annum for unvaccinated cohorts and $50 million per annum for vaccinated cohorts. It should be noted that these cost savings may not be fully realised, since they are predicated on the assumption that there will be an overall reduction in GP visits due to a reduced number of screening visits. In practice, however, these screening visits may be replaced by routine visits for other conditions with no obvious reduction in costs to the health system.

Since the renewed NCSP is predicted to be both cost saving and life–year saving, it is not possible to calculate an incremental cost-effectiveness ratio compared with the pre-renewal NCSP. Table A.5 shows the disaggregated discounted costs and life–years predicted for the pre-renewal NCSP and the renewed NCSP.

Table A.5. Predicted annual cost of the program and the predicted discounted costs and effects for the pre-renewal NCSP and the renewed NCSP (showing differences in costs and relative percentage differences)

	Pre-renewal NCSP		Renewed NCSP
	If HPV vaccination had not been introduced	For cohorts offered vaccination as 12 year olds	If HPV vaccination had not been introduced	For cohorts offered vaccination as 12 year olds
Annual cost* of the screening program	$223 million	$192 million	$182 million (–$41 million; –19%)	$142 million (–$50 million; –26%)
Discounted costs†	$383	$325	$304	$227
Discounted life-years†	21.6219	21.6239	21.6229	21.6242

Note: Calculations of the annual cost of the screening program are based on female Australian population as predicted for 2017. ^†Discounting at 5% per annum starting from 12 years of age.

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After incorporating the management recommendations in these guidelines, the renewed NCSP is expected to be even more effective than previously estimated for the MSAC evaluation. After taking into account the impact of vaccination, the effect on colposcopies and treatment rates is expected to be consistent with current levels. The renewed NCSP is also is predicted to be both cost saving and life–years saving.

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