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研究生:蔡亞倫
研究生(外文):TSAI, YA-LUN
論文名稱:COVID-19對於台灣子宮頸癌篩檢之影響:世代研究
論文名稱(外文):Impact of COVID-19 on Cervical Cancer Screening in Taiwan: a cohort study
指導教授:譚家偉譚家偉引用關係
指導教授(外文):TAM, KA-WAI
口試委員:黃采薇金宏諺譚家偉
口試委員(外文):HUANG, TSAI-WEICHIN, HUNG-YENTAM, KA-WAI
口試日期:2023-07-19
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:臨床醫學研究所碩士班
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2023
畢業學年度:111
語文別:英文
論文頁數:49
中文關鍵詞:新冠肺炎子宮頸抹片子宮頸癌篩檢延遲診斷
外文關鍵詞:COVID-19Pap smearcervical cancer screeningdelayed diagnosis
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COVID-19疫情期間因社交距離措施如:避免接觸、 減少外出、以及城市三級警戒,導致一般常規的癌症篩檢、檢查、手術等都有中斷或是延後的現象。一般四癌篩檢尤其子宮頸癌篩檢,因需要與醫療人員近距離接觸,也需要在醫院或診所等醫療場所採檢,因疫情嚴峻時民眾不敢外出,所以大部分病患選擇延後篩檢。

子宮頸癌症為最可避免及預防的癌症種類,又因子宮頸癌好發在曾經有性行為且感染人類乳突病毒之女性,往往新診斷病人年紀較其他癌症更年輕。國民健康署自1985年起提供30歲以上婦女子宮頸抹片服務,推動至今使子宮頸癌標準化發生率及死亡率下降7成左右。2020年國人癌症登記資料分析,子宮頸癌排序已下降為女性第10位,共1,436人,平均年齡為40-50歲,發生年齡中位數為58歲。為了避免新癌症診斷率上升以及後續開刀、化學治療、及放射治療而造成各家庭不同層面壓力,也同時可以減少社會經濟負擔,因此嘗試以數字量化這三年來疫情後癌症篩檢改變可能造成的影響。早期發現癌症不但可增加存活率,並可減少各層面的花費,國健署統計早期(0-1期)平均花費19萬與晚期(2-4期)平均花費47萬,相差近2.5倍[1]。此研究目的希望了解COVID-19疫情期間因各式社交距離措施而減少常規子宮頸抹片篩檢量是否與疫情後子宮頸抹片異常、癌前病變及子宮頸癌症新診斷率有相關性。

此研究為6年回溯性觀察性世代研究,探討疫情前(2017-2019)及疫情中(2020-2022)之間的個案數,抹片異常比例,還有癌症發生率之差異。資料收集於衛福部雙和醫院以及國泰綜合醫院兩大醫院,為多中心研究。資料收集由兩位研究者分析,納入條件為過去六年在這兩個醫療院所所有接受子宮頸抹片篩檢之婦女,排除條件為無性經驗之婦女,及醫院附屬健康檢查中心所施行之抹片篩檢個案。主要探討抹片篩檢量是否下降,抹片異常之病患是否延遲回診,以及需回診之病患之追蹤消失率是否增加。另外,次要分析探討抹片異常比例及子宮頸癌診斷率在疫情前跟疫情中是否有差異。

這六年期間總共166,983婦女接受子宮頸癌症篩檢,在比較前三年(疫情前,2017-2019年)與後三年(疫情後,2020-2022年),發現總子宮頸抹片人次下降約4.5%,代表100位婦女中就有將近五位沒追蹤抹片。除此之外,數據中也發現總抹片陽性率從2.44%上升至3.61% (p<0.001),尤其是子宮頸鱗狀上皮細胞異常比例(49.00% vs 58.92%,p<0.001)以及子宮頸異常腺體細胞(7.78% vs 11.73%,p<0.001)大幅上升。其他與鱗狀上皮細胞並相關的LSIL(20.26% vs 13.79%)及HSIL(12.57% vs 9.03%)比例有下降,是否此高危險族群因疫情而延遲診斷有待後續追蹤。針對有施行切片之婦女,發現疫情中確定診斷時間相較疫情前多了約7天(33.9041.4天vs 40.5748.55天p<0.001),以及追蹤消失率從7.92%下降至4.69% (p<0.001)。

雙和醫院為中永和大型醫院,負責社區服務照顧各鄰里婦女,因此與衛生所合作定期推出抹片車活動讓各地區婦女都能夠接受子宮頸癌篩檢。在疫情嚴峻時大眾怕感染肺炎,不敢就醫,但因新北市政策沒停止社區篩檢,因此有出巡迴抹片車,維持抹片篩檢量能(抹片車篩檢量 40.96% vs 40.83%,p=0.683)。單獨看分析雙和醫院抹片總量也是疫情前後無顯著差異(n=53,902 vs n=53,855)。另外,在雙和醫院維持抹片量之下卻發現抹片陽性比率大幅增加(n=1130 vs n=2197,p<0.001)。

COVID-19疫情間接對癌症篩檢造成間接性的影響非同小可。未來幾年重心必須放在如何恢復抹片篩檢量能及找出高危險族群讓因疫情延遲篩檢的這些人能夠維持健康,減少生病後家庭的負擔。

On March 11, 2019, after the World Health Organization (WHO) declared COVID-19 a pandemic, many elective procedures and cancer screening procedures were postponed due to measures of avoiding contact, stay at home orders, and citywide lockdowns around the world. Cancer screenings such as cervical cancer, colon cancer, and breast cancer screening were interrupted or postponed in most countries, with reports of significantly reduced volume and delayed diagnosis. These cancer screenings, especially cervical cancer screening, requires a visit to a medical facility and close contact with medical staff. During the peak of the pandemic, most of the population chose to avoid medical care unless necessary and delayed elective or routine screenings.

Cervical cancer is one of the most preventable and treatable types of cancer. As cervical cancer is most prevalent in women who previously had sexual exposure and infection with human papillomavirus, most patients are generally younger in age than those with other cancers. Since 1985, the Taiwanese Health Promotion Administration has subsidized for an annual pap smear for women over 30 years old. Since initiation until today, the overall incidence of cervical cancer has decreased by 70%. According to the 2020 cancer registry, cervical cancer is now the 10th in ranking for female cancer, affecting 1,436 newly diagnosed women per year, with an average age or 40-50 years old (median 58 years old). For every new diagnosis of cervical cancer with subsequent surgery, chemotherapy, and radiation therapy, there may be increased stress of each family and increased socioeconomic burden of the society. Early detection not only can increase survival rates but can also decrease expenses on different levels. Medical treatment costs can increase 2.5-fold from NTD$190,000 (USD$6200) for early cancer diagnosis (stage 0-1) to NTD$470,000 (USD$15,000) for advanced stage cancer (stage 2-4). Hence, we would like to numerically quantify how the COVID-19 pandemic can indirectly affect regular cancer screening. We hypothesize that due to the interruption and delay in cancer screening, there may be substantial differences in screening volume, time to diagnosis abnormal pap smear rate, and cervical cancer rate as compared with previous years.

This is a 6-year, multi-center, retrospective observational cohort study, comparing the total screened volume, abnormal pap smear rate and cancer diagnosis rate between the pre-pandemic (2017-2019) and the pandemic (2020-2022) period. Data was collected at two institutions: Ministry of Health Shuang-Ho Hospital, New Taipei City, and Cathay General Hospital, Taipei City. The data was analyzed by two reviewers. All women eligible to receive a pap smear within this time frame were included in this study. Women who had no sexual experience, or those who received pap smear at a hospital affiliated health exam center were excluded. The aim of this study is to understand the impact of interruption of cervical cancer screening during the COVID-19 pandemic and its implication on pap smear abnormalities, delay in diagnosis, and cervical cancer diagnosis. We aim to determine whether there is a difference in total screened volume, delay in time to diagnosis, change in positive pap smear rate, cancer incidence, and loss to follow-up rate between the pre-pandemic and pandemic time frame.

We performed a retrospective data analysis on 166,983 women in this 6-year time frame who have received pap smear. Pre-pandemic (2017-2019) and pandemic (2020-2022) data comparison showed that there was a decrease in 4.5% for total screened population, signifying that nearly 5 in about 100 women will have missed their regular checkup. Furthermore, we observed an increase in the proportion of positive pap smears, significantly increasing from 2.44% to 3.61% (p<0.001), especially for ASCUS (49.00% vs 58.92%, p<0.001) and AGC/AIS (7.78% vs 11.73%, p<0.01). However, the proportion of squamous lesions such as LSIL (20.26% vs 13.79%) and HSIL (12.57% vs 9.03%) significantly decreased (p<0.001). Whether or not these high-risk population had delayed outpatient visits indirectly related to the pandemic will need further clarification. For women who had received further procedures such as biopsy or conization for pathology, we noted a delay in nearly 7 days for definitive diagnosis (33.9041.4 vs 40.5748.55 days, p<0.001). Loss to follow-up rate had decreased from 7.92% to 4.69% (p<0.001) during the pandemic.

Shuang-Ho Hospital is a large medical center in Chung-Ho and Yong-Ho, and to provide services for women living in suburban locations, the nearby public health centers would work with doctors from hospitals to provide pap smear services for the population. During the peak of the pandemic, there were still mobile unit sessions for pap smears, thus the volume of screened cases from mobile units remained similar before and during the pandemic (40.96% vs 40.83%, p=0.683). Furthermore, there were no significant differences between the total number of pap smear cases before and during the pandemic at SHH (53,902 vs 53,855, 0.04% difference). While maintaining the total screened volume, we observed a large 32% increase in the proportion of positive (abnormal) pap smears at SHH (n=1130 vs n=2197, p<0.001).
There exists a substantial indirect impact of the COVID-19 pandemic on cancer screening. Much attention and effort need to be placed on recovery strategies such as improving screening volume and how to identify those at high risk due to interruption and delay of cervical cancer screening to maintain a healthy population and decreasing individual burden.

致謝 (Extended thanks to) i
縮寫表(Abbreviations) iii
目錄 (Contents) iv
中文摘要 (Abstract in Chinese) 1
英文摘要 (Abstract in English) 3
緒論 (Introduction) 6
Cervical cancer 6
HPV 7
HPV vaccination 8
Cervical cancer screening in Taiwan 9
Pap smear pathology 10
Normal pap smear 10
Positive (abnormal) pap smear 11
ASCUS 11
LSIL 11
HSIL/ASC-H 11
AGC/AIS 12
Carcinoma 12
Others 12
Choice of study location 12
Hypothesis 13
Aim 14
研究方法與材料 (Materials and Methods) 15
Study design 15
Inclusion criteria 15
Exclusion criteria 15
Pap smear screening 16
Positive (abnormal) pap smear results 16
IRB 17
Primary outcomes 17
Secondary outcomes 17
Statistical analysis 18
結果 (Results) 19
Primary Outcomes 19
Total screened population 19
Time to diagnosis 20
Loss to follow-up 20
Secondary Outcomes 21
Positive (abnormal) pap smear 21
ASCUS 21
LSIL 22
HSIL 22
ASC-H 22
AGC/AIS 23
Cancer positive rate 23
Confounding factors 23
Mobile unit screening sessions and participation 25
討論 (Discussion) 27
Global trend 27
Simulation models 28
Mobile screening unit 28
Data from this study 27
Special cases 33
Recovery strategies 33
Strengths 34
Limitations 35

結論與展望 (Conclusion and Perspective) 36
圖表 (Tables and Figures) 37
附錄 (Appendix) 42
參考文獻 (Reference) 47

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13.Davies, J.M., et al., Cervical cancer and COVID-an assessment of the initial effect of the pandemic and subsequent projection of impact for women in England: A cohort study. BJOG, 2022. 129(7): p. 1133-1139.
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19.Human Papillomavirus Vaccine. 2023; Available from: https://www.cdc.gov/hpv/hcp/protecting-patients.html.
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25.Massad, L.S., et al., 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. Obstet Gynecol, 2013. 121(4): p. 829-846.
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28.Arshi J, F.F., Atypical Glandular Cells (AGS), in Treasure Island (FL): StatPearls Publishing. 2022, StatPearls
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31.Battisti, F., et al., Cancer screening programmes in Italy during the COVID-19 pandemic: an update of a nationwide survey on activity volumes and delayed diagnoses. Ann Ist Super Sanita, 2022. 58(1): p. 16-24.
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34.Gourd, E., COVID-19 pandemic causes cervical cancer screening crisis. Lancet Oncol, 2021. 22(8): p. 1060.
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38.Castanon, A., et al., Recovery strategies following COVID-19 disruption to cervical cancer screening and their impact on excess diagnoses. Br J Cancer, 2021. 124(8): p. 1361-1365.
39.Croswell, J.M., et al., Cancer screening in the U.S. through the COVID-19 pandemic, recovery, and beyond. Prev Med, 2021. 151: p. 106595.
40.Ngu, S.F., et al., Human Papillomavirus Self-Sampling for Primary Cervical Cancer Screening in Under-Screened Women in Hong Kong during the COVID-19 Pandemic. Int J Environ Res Public Health, 2022. 19(5).
41.Arbyn, M., et al., Detecting cervical precancer and reaching underscreened women by using HPV testing on self samples: updated meta-analyses. BMJ, 2018. 363: p. k4823.

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