Abstract. Int J Gynecol Cancer 2006, 16,

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1 Int J Gynecol Cancer 2006, 16, Cervical cancer incidence and survival in Korea: H.H. CHUNG*, M.J. JANGy, K.W. JUNGy, Y.J. WONy, H.R. SHINy, J.W. KIM* & H.-P. LEE* (ON BEHALF OF THE MEMBERS FOR GYNECOLOGIC ONCOLOGY COMMITTEE OF KOREAN SOCIETY OF OBSTETRICS AND GYNECOLOGY) *Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, South Korea; and ykorea Central Cancer Registry, National Cancer Center, Gyeonggi-do, South Korea Abstract. Chung HH, Jang MJ, Jung KW, Won YJ, Shin HR, Kim JW, Lee H-P (On behalf of the members for Gynecologic Oncology Committee of Korean Society of Obstetrics and Gynecology). Cervical cancer incidence and survival in Korea: Int J Gynecol Cancer 2006;16: This study examined the incidence rates, histologic and stage distribution, and long-term survival rates of patients with cervical cancer in Korea. A total of 44,182 patients diagnosed with cervical cancer between 1993 and 2002 were reported to the Korea Central Cancer Registry and the Gynecologic Oncology Committee of Korean Society of Obstetrics and Gynecology. The age-standardized incidence rates were 19.0, 17.8, and 15.1 per 100,000 women in , , and , respectively. The incidence rates of adenocarcinoma (AC) have been in the range between 1.2 in and 1.4 in , while those of squamous cell carcinoma declined from 15.1 in to 12.2 in The 5-year relative survival rate was 79.2%. Relative survival rates, according to stage by the FIGO, at 5 years were 94.2%, 69.7%, 38.9%, and 21.1% for stages I, II, III, and IV respectively. Relative survivals improved between 1993 and 1997, probably due to the introduction of cervical cancer screening and effective treatment. The incidence rates of AC have been constant despite decreased cervical cancer in Korea. Introduction of cervical cancer screening and effective treatment may have contributed to the improved relative survival. KEYWORDS: adenocarcinoma, cervical cancer, incidence, Korea, survival. Address correspondence and reprint request to: Hyo-Pyo Lee, MD, PhD, Department of Obstetrics and Gynecology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul , South Korea. hplee@snu.ac.kr; and Hai-Rim Shin, MD, PhD, Korea Central Cancer Registry, National Cancer Center, 809 Madu 1-dong, Ilsandong-gu, Goyang-si, Gyeonggi-do , South Korea. hrshin@ncc.re.kr H.H. Chung and M.J. Jang contributed equally to this work. doi: /j x Although the incidence and mortality of cervical cancer have substantially declined worldwide over the past four decades (1) cervical cancer continues to be a leading cause of cancer death in women (2,3). Moreover, uterine cervical cancer is the second most frequently diagnosed malignancy in women worldwide (2,4) and the fifth most common cancer among women after breast, stomach, colon rectum, and thyroid cancer in Korea (5). An annual average incidence of cases was about 4360, composing 9.8% of all cancers in Korean women during (5). Uterine cervical cancer was the most common female cancer in the 1980s, but subsequently, the proportion of cervical cancer cases, among all cancer cases registered in the Korea Central Cancer Registry (KCCR), was reduced slightly. Moreover, a marked reduction in the incidence of this tumor has been documented over the past two decades, and this has been largely attributed to widespread screening and the early treatment of preinvasive lesions (6 8). However, no similar decrease has been reported in other developed countries (9,10). The purpose of the study was to assess the incidence rates, histologic and stage distribution, and long-term survival rates of patients with cervical cancer in Korea since the beginning of nationwide cancer registry in Although there have been reports on the reduced incidence of cervical cancer, especially for squamous cell carcinoma (SCC) as a result of cervical cancer screening, there has been systematic report of the data in Korea. Therefore, it was necessary to confirm the trend of incidence and survival of # 2006, Copyright the Authors Journal compilation # 2006, IGCS

2 1834 H.H. Chung et al. patients with cervical cancer for future planning. We also compared the survival patterns of patients according to age, stage, year of diagnosis, and histologic findings. Materials and methods We analyzed the cervical cancer data from the KCCR and the Gynecologic Oncology Committee of the Korean Society of Obstetrics and Gynecology, which began a gynecologic cancer registry in 1991 and consists of gynecologists. The KCCR is a nationwide, hospital-based cancer registry that has been in operation since The KCCR has constructed the Korea National Cancer Incidence database by merging the KCCR database and all nine population-based regional cancer registry databases, the site-specific cancer registry databases, data from the additional medical record review survey, and the cancer mortality database. The information available comprises demographic characteristics of the patients, date of diagnosis, primary site and histologic type of the tumor according to the International Classification of Diseases for Oncology, the FIGO stage, and treatment modality. For the histologic type, cases were divided into SCC (large cell nonkeratinizing type, large cell keratinizing type), small cell neuroendocrine carcinoma (SC), adenocarcinoma (AC), and adenosquamous carcinoma (ASC). Patients were divided into the following groups according to the age: younger than 40, years, years, and 60 and older. Incidence rates per 100,000 women were computed for age-groups. Direct standardization was used to the world standard population. The analysis of survival was based on 5-year relative survival rates. The actuarial method was used for calculations, and a relative survival analysis was performed using SAS (11). The relative survival represents an estimate of the ratio between the proportion of survivors and the proportion of survivors in a group of the general population with same age distribution and birth cohort but without the disease under study. Relative survival was modeled using the life table regression model (12). The model provides estimates of excess hazard ratios (relative excess risk, RER) adjusted simultaneously for potential confounding factors. The number of cervical cancer cases that were first diagnosed between 1 January 1993 and 31 December 2002 was 44,182. Death certificate cases were received from the Korea National Statistical Office, and death certificate only accounted for 1022 (2.3%) cases. Of 44,182 incidence cases, the 1022 death certificate only cases and 741 cases that had been lost to follow-up were excluded from the survival analysis. Cases were followed until 31 December Results Table 1 shows the overall age-standardized incidence rates (ASR) and ASRs according to age-group and histologic type during the periods , , and The overall incidence rates were 19.0, 17.8, and 15.1 per 100,000 women during , , and , respectively. The incidence according to the histologic type showed that the incidence rates of AC were in the range of 1.2 during to 1.4 during , while those of SCC declined from 15.1 to The incidence in women aged years had significantly decreased from 56.4 in to 40.1 in Figure 1 shows the change of age-specific incidence rates during the three periods. The incidence rates in cases aged Table 1. Cervical cancer incidence per 100,000 in Korea, Categories Total no. of patients ASR All 44, Age at diagnosis (years) , , , Histologic type SCC 35, Squamous, L, NK 15, Squamous, L, K SC AC ASC L, large cell; NK, nonkeratinizing; K, keratinizing.

3 Incidence and survival rates of cervical cancer in Korea 1835 Figure 1. Age-specific incidence rate for cervical cancer years have shown a decreasing trend, while the incidence rates were increased in older than 60 years age-groups. The ASR of invasive SCC declined from 1993 to 2002, while that of invasive AC remained relatively constant for the periods of time studied (Fig. 2). Most patients with FIGO stage IA1 were younger than 50 years, while the number of patients with FIGO stage IIA and IIB increased as age increased. SCC was the most frequent histologic type; patients with stage IIB disease were most prevalent followed by stages IB1, IIB, and IA1 disease. Table 2 summarizes the 5-year relative survival of patients with cervical cancer according to histologic type and FIGO stage. The overall 5-year relative survival was 79.2% in this study. A significant difference in 5-year relative survival was observed versus histologic type (Fig. 3). The survival of patients with ASC of cervix was higher than that of patients with large cell nonkeratinizing type SCC 2 years after initial diagnosis; at 3 years, the survival times intersected and the difference was statistically significant. The Figure 2. Cervical cancer incidence trends in Korea, survival of ASC was slightly better than that of AC, but there was no statistical significance. The 5-year relative survival of SC was significantly lower than that of large cell SCC (78.9% for nonkeratinizing type, 75.9% for keratinizing type) but not different from those of AC or ASC. There was considerable difference among the relative survivals according to the FIGO stage (Fig. 4). The survivals of patients with stage IA2 and IB1 disease were about the same in this study, and the survival of those with stage IB2 disease was slightly better than those with stage IIA. We estimated the RER and its 95% confidence intervals according to certain variables (Table 3). In this analysis, we found that the FIGO stage and histologic type of cervical cancer were both important independent factors for survival. As shown in the table, earlyonset cervical cancer was a risk factor for poor survival with the years age-group as a reference. Discussion This study is the first to report on the incidence and survival of cervical cancer patients in Korea. The Korean Gynecologic Oncology Committee (KGOC) under the Korean Society of Obstetrics and Gynecology began a gynecologic cancer registry in 1991, and with the help of KCCR and Korea National Statistical Office, this population-based analysis of cancer incidence and survival was made possible. A decreasing trend in the incidence of cervical cancer in Korea is evident. Widespread screening and early treatment of preinvasive lesions may largely account for these improvements. Westernized behavior and dietary patterns may have also influenced the incidence, but further investigation is needed to confirm this. We compared the distributions of patients by stage and age using data from the FIGO annual reports on cervical cancer treatment results (13). The patterns of stage distribution, based on age, were found to be different. The majority of patients with stage IA1 disease belonged to younger age-groups (ie, the 39 years and the 40- to 49-year-old groups); more patients in this study had stage IIA disease than in the FIGO annual reports on cervical cancer. Moreover, patients with stage IIB disease in this study were predominantly in the years age-groups, whereas in the FIGO annual reports on cervical cancer treatment results, the predominance was in the years age-groups. Of note, a declining incidence of SCC with relatively constant incidence of AC was evident in this study. Despite decreasing SCC incidence rates over the past

4 1836 H.H. Chung et al. Table 2. Five-year relative survival of patients with cervical cancer according to age, histologic type, FIGO stage, and treatment modalities Categories Relative survival (%) 1 year 2 years 3 years 4 years 5 years 95% CI All (n ¼ 42,419) Histology SCC, L, NK (n ¼ 15,132) SCC, L, K (n ¼ 5817) SC (n ¼ 284) AC (n ¼ 3087) ASC (n ¼ 955) FIGO stage I(n¼14,408) II (n ¼ 7346) III (n ¼ 1451) IV (n ¼ 699) L, large cell; NK, nonkeratinizing; K, keratinizing. 10 years, invasive AC incidence rates have not declined. Therefore, the expected effect of screening is not yet evident as a decline in AC incidence rates. However, there are many reports that have shown the incidence of AC increasing with decreased incidence of SCC (14 20). Most of this relative increase in AC appears to be related to a decrease in the incidence of SCC, secondary to the implementation of the screening program. Other possible reasons for the increase in invasive AC include an increased recognition and detection of AC. Enhanced collection of cells from the upper portion of the endocervical canal (21), leading to improved detection of AC lesions and contributing to the observed increase in the incidence of earlier stage invasive AC (22). In addition, there is a trend for women to have fewer children at older ages; this has been associated with an increased risk for AC and, thus, also may contribute to the simultaneous rise in invasive AC. In Korea, there is a trend to have fewer children and more young women are taking oral contraceptives than in the past. Further time and study are needed to confirm these trends in Korea. The large cell nonkeratinizing type SCC had a higher relative survival (78.9%, 95% CI %) than the other histologic types; patients with SC were found to have poor relative survival (68.5%, 95% CI %) although only 284 cases were registered. Clear cell carcinoma of the cervix was registered separately from 2002 and had previously been classified among other histologies. Therefore, as the number of patients with this histology was relatively small, these data are not included in the analysis. Figure 3. Relative survival of patients with cervical cancer in Korea according to histologic type. Figure 4. Relative survival of patients with cervical cancer in Korea according to FIGO stage.

5 Incidence and survival rates of cervical cancer in Korea 1837 Table 3. Estimated RER a of cervical cancer in Korea Categories RER 95% CI LR test Age at diagnosis (years) Reference FIGO stage I 1.00 Reference,.0001 II III IV Histologic type SCC 1.00 Reference,.0001 AC ACS RER, relative excess risks; LR, likelihood risk. a All estimates are simultaneously adjusted for all other factors. In this study, the 5-year survival for cases with ASC was between those with large cell nonkeratinizing SCC and those with large cell keratinizing SCC. Interestingly, the survival of patients with ASC of the cervix was longer than that of patients with large cell nonkeratinizing SCC over 2 years after the initial diagnosis; they intersected after 3 years from the initial diagnosis. AC, particularly ASC, have in general been regarded as having a poorer prognosis than squamous lesions; some have regarded these lesions as more radioresistant than SCC (23). The prognosis for patients with ASC, regardless of grade of tumor differentiation, generally was reported to be poor, with an approximately 63% 5-year survival rate for patients with all tumor grades (24). In this study, the 5-year survival rate for ASC was 77.3% (95% CI %) and was slightly better than that for AC (74.4%, 95% CI %) although there was no statistical significance. The main causal factor for the development of both SCC and AC of the uterine cervix has been reported to be infection with high-risk types of human papillomavirus (HPV) (25,26). HPV types are known to be associated with substantial differences in histologic types. AC is more often associated with HPV 18 than with SCC (26 28), and HPV 18 has been shown to be associated with a poorer prognosis than other HPV types (29,30). An intrinsic difference between neoplastic conversion of squamous and columnar epithelium might also contribute to prognostic differences, independent of HPV infection. In this study, relative survivals improved according to the year of diagnosis between 1993 and Compared with the summary value, relative survivals have increased, significantly, with the year of diagnosis. This continuous increase in relative survival may be explained in several ways. First, nationwide cancer screening might have contributed to earlier cancer detection. Cervical cancer is now a preventable disease and any woman presenting with invasive cervical cancer should be considered as a screening failure. In terms of the mortality rate analysis, it is important to note that the incidence of cervical cancer among older women, ie, when tumors are likely to be nonlocalized at diagnosis, has continuously decreased. Moreover, it may take several years for the observed increased incidence among young women to affect overall mortality figures. Relative survival was found to differ significantly according to FIGO stage. This study showed that relative survival rates for FIGO stages IA2 and IB1 and for stages IB2 and IIA disease were similar. As the FIGO staging system was revised in 1994, diagnostic data collected before this date were excluded from this study. Patient age was also found to be associated with survival differences. For FIGO stage I cases, survival was better among younger patients. However, in FIGO stages II, III, and IV, younger patients had poorer survival than older patients although this trend was not statistically significant. This difference was possibly due to increased tumor aggressiveness in younger patients. In conclusion, our study observed a reduced incidence rate and an improved survival rate in patients with cervical cancer in Korea, with a constant incidence of AC. The pattern for trends in incidence and survival shows that early detection is important to reduce the mortality from cervical cancer. However, the interpretation of the data from this study was limited by changes in diagnostic practices and terminology. In addition, our findings for SC and clear cell carcinoma were limited by small numbers in these groups. Future analyses with longer follow-up periods and with a greater emphasis on histologic diversity are needed. Future epidemiologic studies on cervical carcinoma that include molecular testing for HPV and other factors might be useful for developing more effective cancer prevention strategies. Acknowledgments This work was supported in part by grants from the National Cancer Center, Korea ( ), and by Korean Gynecologic Cancer Foundation, and by the Korean Society of Obstetrics and Gynecology (KSOG). The authors thank members of Gynecologic Oncology Committee of KSOG who participated in this study: Jae-Wook Kim, Sung-Eun Namkoong, Jung-Eun Mok, Hyung Moon, Il-Soo Park, Ho-Suk Saw, Kyung-Hee Lee,

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