1. MS&E 220 Project Yuan Xiang Chew, Elizabeth A Hastings, Morris Jinhui Zhang Probabilistic Analysis of Cervical Cancer Screening and Vaccination

2. Executive summary Using a dynamic model with statistics from literature, we modeled the development of cervical cancer in women between the age 18 and 65. Our results show that a combination of screening at an interval of 5 years with vaccination using the drug Gardasil would lead to cost savings in Pap smear screening while achieving a lower lifetime probability of cancer (0.807%) as compared to the lifetime probability from biennial screening as recommended by the National Cancer Institute (0.812%). This is a conservative recommendation given that the vaccine effectiveness that we used (50%) is the lower limit of the reported statistics. Performing a sensitivity analysis, increasing the vaccine effectiveness will not change our recommendation.

3. Background Cervical Cancer: Cervical cancer is the second most common type of cancer in women. Nearly all cervical cancers are caused by certain strains of the human papillomavirus (HPV). Before becoming cancerous, precursor legions called cervical intraepithelial neoplasia (CIN) form. Traditional approaches to reducing the prevalence of cervical cancer have focused on early detection and treatment. If detected at pre-cancerous stages a large proportion, approximately 85% to 98%, of the legions can be treated and prevented from becoming cancerous. Prevention and Treatment of Cervical Cancer: The most widely adopted screening method to detect precursor legions is the Pap smear. The American Cancer Society recommends that women between the ages of approximately 18 and 65 receive Pap smears biennially. The mortality rate from cervical cancer has dropped by 70% overall since the introduction of Pap smears. The sensitivity of Pap smears is not accurately known, and estimates range from 51% to 80%. A more recent method to reduce the occurrence of and mortality from cervical cancer is through vaccination. The Gardasil vaccine was approved by the FDA and introduced in the U.S. in 2006. The vaccine is recommended only for women under 26 years old, and it is estimated that it prevents 96% to 100% of the two HPV strains that lead to 70% to 80% of cervical cancers. The duration of the vaccine’s effectiveness, however, is unclear other than that is it greater than five years. The American Cancer Society recommends that women who receive the vaccine continue biennial screening.

4. Objectives Understand how changing the frequency of screening changes the probability that a woman will develop or die from cervical cancer in her lifetime. Recommend screening routines that are optimal in promoting health while being cost effective.

5. Model

6. Key assumptions in model Cervical cancer risk exists from age 15 to 60. Progression from Well to CIN stages is governed by a probability density function of age (statistically fitted). Transition probabilities from CIN to Cancer and to Death are given by literature values. Screening and diagnosis lowers the transition probabilities as treatment is dispensed. If a patient survives 5 year of Cancer, she returns to the state of Well.

7. Effects of Vaccination The combined lifetime probability is much lower for the case of using the vaccine with screening than just screening alone.

8. Effects of Screening Frequency (No vaccination) This figure shows that the probability of developing cancer decreases as screening frequency increases. With scenarios where screening occurs every 2 years to every 5 years, the PMF is wavy because if a legion is detected through screening, the likelihood of going back to the well state increases as the patient in theory undergoes preventive treatment. Therefore, the probability of developing cancer is lowest in the year following screening.

9. Effects of Screening Frequency (No vaccination) Figure 4 shows that the cumulative lifetime probability of developing cancer is 4.473% where there is no screening, compared to 0.574% with annual screening. Decreasing the frequency of screening from every year to every two years increases the probability from 0.574% to 0.756%. The probability increases by an additional 0.1% to 0.2% for further decreases in screening frequency. All screening scenarios, even every five years, leads to a significantly lower probability of developing cancer as opposed to no screening. This figure shows that the cumulative lifetime probability of developing cancer is 4.473% where there is no screening, compared to 0.574% with annual screening. Decreasing the frequency of screening from every year to every two years increases the probability from 0.574% to 0.756%. The probability increases by an additional 0.1% to 0.2% for further decreases in screening frequency. All screening scenarios, even every five years, leads to a significantly lower probability of developing cancer as opposed to no screening.

10. Combined Effects of Screening and Vaccination This graph shows that the vaccine has a significant effect with zero screening, and combining the vaccine with screening every five years results in a lower probability of developing cancer than screening each year without the vaccine. It can also be seen that with the vaccine, screening every five years will result in approximately the same probability as screening yearly without vaccine.

11. Cost Effective Recommendation Achieve same risk with lower cost by screening every 5 years, with vaccination Traditional biennial screening without vaccine

12. Sensitivity Analysis For the patient to switch to screening once in 3 years and maintain the same combined probability of death and cancer as the recommended case, the screening effectiveness would have to reach 99.7%, which is unrealistic today. If the patient switches to screening every year, the screening effectiveness can fall to 50.3% before the combined probability will fall below that of the recommended case.

13. Conclusion Recommendations To maintain current risk of cervical cancer while reducing cost: Screen every 5 years Use vaccine To decrease risk of cervical cancer below current risk at lowest cost: Screen more often that every 5 years Use vaccine If vaccine is not used, base case biennial screening recommended (in line with National Cancer Institute’s recommendation) Further Study Compare the lives saved and cost of preventing cervical cancer to the lives saved and cost for lowering the risk of other diseases. If lowering the risk of cervical cancer below its current rate compares favorably in terms of cost-benefit with other health investments, support increased vaccination and screening funding. Consider use of vaccine in developing countries where access to screening is limited.