Changes in ovarian cancer survival during the 20years before the era of targeted therapy

Changes in ovarian cancer survival during the 20years before the era of targeted therapy Background: The survival of patients with ovarian cancer has improved because of surgery and chemotherapy. This study aimed to estimate the changes in survival rates among Korean women with ovarian cancer prior to the introduction of targeted therapy for ovarian cancer. Methods: Data were obtained from the Korea Central Cancer Registry regarding patients who were diagnosed with epithelial ovarian cancer between 1995 and 2014. The relative survival rates were calculated for 5-year periods using the Ederer II method. Cox proportional hazard models were created to assess the associations of demographic and clinicopathological factors with ovarian cancer survival. Results: During the study period, 22,880 women were diagnosed with epithelial ovarian cancer. The 5-year relative survival rate improved from 57.2% during 1995–1999 to 63.8% during 2010–2014 (P < 0.001). Survival outcomes improved between 1995 and 1999 and 2010–2014 for the serous and endometrioid carcinoma subtypes (P < 0.001). However, no improvements were observed for the mucinous and clear cell carcinoma subtypes (P = 0.189 and P = 0.293, respectively). Multivariate analysis revealed that younger age, early stage, recent diagnosis, primary surgical treatment, and non-serous histological subtype were favorable prognostic factors. Conclusion: Survival outcomes have improved for serous and endometrioid epithelial ovarian cancer in the last 20 years. However, no improvement was observed for patients with mucinous and clear cell carcinoma subtypes. Keywords: Ovarian cancer, Survival, Histology, Korea, Chemotherapy, Surgery Background goal of improving survival, and some of these strategies Ovarian cancer is the most common cause of gynecological have become standard treatments for ovarian cancer. cancer-related death in Korea, and causes approximately For example, debulking surgery has been emphasized 1021 deaths annually [1]. The incidence and mortality because optimal cytoreduction is one of the most signifi- of ovarian cancer have increased continuously, and cant predictors of survival [7], and previous studies have 2413 new cases were detected in 2014 [1–3]. revealed that optimal surgical cytoreduction improves Approximately 75% of the newly diagnosed patients survival in cases of advanced-stage disease [8]. In have advanced-stage disease, which partly explains the addition, paclitaxel plus cisplatin has been introduced as a high mortality rate for this cancer [4, 5]. front-line therapy for ovarian cancer, and provides better During the last 20 years, there has been an improve- survival outcomes than cyclophosphamide-based regimens ment in survival of patients with ovarian cancer [1, 4–6]. [9]. After then, platinum-based chemotherapy has been im- A number of strategies have been evaluated with the proved with less toxic and equivalent analogs, carboplatin [10, 11], and paclitaxel plus carboplatin is the most com- monly used first-line therapy for ovarian cancer. Moreover, * Correspondence: astra67@ncc.re.kr better survival rates have been observed in patients with re- Cancer Registration and Statistics Branch, National Cancer Center, Goyang, South Korea current disease, with a number of chemotherapies having Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Lee et al. BMC Cancer (2018) 18:601 Page 2 of 8 activity even in platinum-resistant settings. Although from the general population. We calculated the relative recent phase III trials have supported the introduction survival rates (RSRs) using the Ederer II method [20]. of targeted agents [12–14], their economic cost, lim- Furthermore, we divided the patients into 5-year cohorts ited insurance coverage, and low patient preference based on their diagnosis date to evaluate their 5-year have limited the use of these agents in routine clinical RSRs (1995–1999, 2000–2004, 2005–2009, and 2010– practice [15, 16]. In Korea, the addition of bevacizu- 2014). The Cox regression proportional hazard model mab to standard chemotherapy was approved in 2013, adjusted to estimate hazard ratio (HR) for the age at and the national insurer only began covering the cost diagnosis, SEER stage, year of diagnosis, primary of bevacizumab for platinum-resistant recurrent ovar- treatment (with or without surgery), and histological ian cancer in August 2015. Therefore, the present subtype [21]. The proportionality of hazards assump- study aimed to investigate the changes in the survival tion over time was tested for each factor [22]. All rates among Korean patients with ovarian cancer dur- analyses were performed using SAS software (version ing the last 20 years, and to identify unmet clinical 9.3; SAS Institute, Cary, NC, USA). needs that might be targeted to improve outcomes. Results Methods A total of 22,880 women were diagnosed with ovarian can- This study utilized data from the Korean National Cancer cer between 1995 and 2014, and their characteristics are Incidence Database (KNCIDB), which includes data from showninTable 1. The overall 5-year RSR significantly im- the Korea Central Cancer Registry (KCCR) and information proved during study period (57.2% during 1995–1999, regarding patients’ demographic characteristics, primary 60.2% during 2000–2004, 59.4% during 2005–2009, 63.8% cancer site, morphology, diagnosis date, and initial treat- during 2010–2014; P for trend < 0.001) (Fig. 1). Figure 2 ment. KCCR was launched as a nationwide hospital-based shows the survival outcomes according to histological sub- cancer registry in 1980 by the Ministry of Health and type, which improved for the serous and endometrioid car- Welfare, and subsequently expanded to cover the entire cinoma subtypes between 1995 and 1999 and 2010–2014 population in 1999. The present study evaluated survival (P for trend < 0.001). However, no significant improvements data from the KNCIDB. The ovary cancer cases were classi- were observed for the mucinous and clear cell carcinoma fied according to the International Classification of Diseases subtypes (P for trend = 0.189 and 0.293, respectively). for Oncology, 3rd edition [17] and converted according to Table 2 shows the 5-year RSRs of patients with ovarian the International Statistical Classification of Diseases and cancer according to histological subtype and SEER stage. Related Health Problems, 10th edition (ICD-10: C-56) [18]. The overall 5-year RSRs improved from 59.4% during We included only cases of epithelial ovarian cancer, 2005–2009 to 63.8% during 2010–2014 (P < 0.001). diagnosed between 1995 and 2014. All cases of Improved survivals were also observed for early-stage ser- non-epithelial ovarian cancer (e.g. sex-cord stromal tumors ous carcinoma (from 77.7% during 2005–2009 to 84.1% and germ cell tumors) were excluded. All cases followed during 2010–2014). Furthermore, there was a significant until 31 December 2015. increase in the 5-year RSR for advanced-stage serous car- The present study’s retrospective design was approved cinoma, from 44.1% during 2005–2009 to 49.5% during by the institutional review board of the National Cancer 2010–2014. However, women with non-serous carcinoma Center (NCC2017–0168). subtypes did not experience a survival improvement, with Age at the diagnosis was classified as < 40 years old, the exception of women with early-stage endometrioid 40–59 years old, and > 59 years old. Histological sub- carcinoma. types were categorized as serous carcinoma, mucinous Table 3 shows the results for the age-based changes in carcinoma, endometrioid carcinoma, clear cell carcin- the 5-year RSRs. During 2005–2009 and 2010–2014, oma, and others. Staging information was based on the patients who were 40–59 years old and > 59 years old Surveillance, Epidemiology, and End Results (SEER) experienced an increased 5-year survival rate, although summary staging [19], which categorizes cancer spread younger patients did not experience a survival improve- from its origin (localized, regional, and distant), because ment, regardless of their cancer stage. Patients who the KCCR has collected this information since 2005. underwent surgery had a significantly higher 5-year RSR, Primary treatments within 4 months were categorized as compared to patients who did not undergo surgery, and surgery, chemotherapy, and others. this association strengthened over time. For the survival analyses, we obtained the data from In the Cox multivariate model, the significant prog- KNCIDB and the mortality data from Statistics Korea. nostic factors were age at diagnosis, SEER stage, primary Relative survival is the ratio of the observed survival rate treatment, and histological subtype. Furthermore, year of among patients with cancer, compared to the expected diagnosis was an independent prognostic factor, with pa- survival rate among age- and sex-matched individuals tients who were diagnosed during 2010–2014 being 27% Lee et al. BMC Cancer (2018) 18:601 Page 3 of 8 Table 1 Basic characteristics according to the time period of ovarian cancer diagnosis Total 1995–1999 2000–2004 2005–2009 2010–2014 (n = 22,880) (n = 3740) (n = 4863) (n = 6317) (n = 7960) No. of cases % p-value No. of cases % No. of cases % No. of cases % No. of cases % p-value Age (years) <.0001 <.0001 < 40 3849 16.8 945 25.3 910 18.7 990 15.7 1004 12.6 40–59 12,169 53.2 1813 48.5 2526 51.9 3378 53.5 4452 55.9 > 59 6862 30.0 982 26.3 1427 29.3 1949 30.9 2504 31.5 SEER Stage <.0001 <.0001 Localized 3865 16.9 –– –– 1683 26.6 2182 27.4 Regional 2564 11.2 –– –– 1053 16.7 1511 19.0 Distant 6795 29.7 –– –– 2843 45.0 3952 49.6 Unspecified 9656 42.2 –– –– 738 11.7 315 4.0 Primary treatment <.0001 <.0001 Surgery only 6007 26.3 1213 32.4 1252 25.7 1626 25.7 1916 24.1 Chemotherapy only 1680 7.3 326 8.7 371 7.6 414 6.6 569 7.1 Surgery + Chemotherapy 13,262 58.0 1745 46.7 2713 55.8 3805 60.2 4999 62.8 Others 1931 8.4 456 12.2 527 10.8 472 7.5 476 6.0 Histology <.0001 <.0001 Serous carcinoma 10,837 47.4 1459 39.0 2119 43.6 3186 50.4 4073 51.2 Mucinous carcinoma 4005 17.5 916 24.5 1027 21.1 951 15.1 1111 14.0 Endometrioid carcinoma 2191 9.6 399 10.7 494 10.2 580 9.2 718 9.0 Clear cell carcinoma 1923 8.4 164 4.4 327 6.7 551 8.7 881 11.1 Others 3924 17.2 802 21.4 896 18.4 1049 16.6 1177 14.8 SEER Surveillance, Epidemiology, and End Results less likely to die, compared to patients who were diag- cancer. Among women with serous carcinoma, the nosed during 1995–1999 (hazard ratio: 0.73; 95% confi- risk of death from ovarian cancer during 2010–2014 dence interval: 0.65–0.81) (Table 4). was 4.7% lower, compared to during 2005–2009, and 8.5% lower compared to during 1995–1999. Improvement of Discussion survival was found for both early stage and distant Between 1995 and 2014, there has been a gradual in- stage. However, no improvements were observed for crease in the survival of Korean patients with ovarian patients with the mucinous and clear cell carcinoma subtypes. The current approach to managing ovarian cancer in- volves cytoreductive surgery followed by chemotherapy, and a decrease in the proportion of patients without de- finitive treatment has been observed during the last 20 years (from 12.2% during 1995–1999 to 6.0% during 2010–2014). Thus, an increasing number of Korean pa- tients have benefited from surgery and chemotherapy, and adherence to the standard treatment guidelines is an independent predictor of improved survival [23, 24]. Furthermore, in the present study, the multivariate ana- lysis revealed that surgery was independently associated with better outcomes. The use of platinum-based chemotherapy has im- proved with the development of less toxic analogs (car- boplatin), as well as research regarding the optimal dose, Fig. 1 Relative survival rate of ovary cancer by time period schedule, sequence, and duration of treatment. In this Lee et al. BMC Cancer (2018) 18:601 Page 4 of 8 Fig. 2 Trends in relative survival rate according to histology and the time period (a) serous carcinoma (b) mucinous carcinoma (c) endometrioid carcinoma (d) clear cell carcinoma context, the Gynecologic Oncology Group (GOG) 0111 Table 3 Five-year relative survival rate, by age and primary and OV10 studies revealed that cisplatin plus paclitaxel treatment was superior to cisplatin plus cyclophosphamide [9, 25]. 2005–2009 2010–2014 p-value In addition, the GOG 0158 and Arbeitsgemeinschaft (n = 6317) (n = 7960) Gynäkologische Onkologie Ovarian Cancer Study Group Age (AGO-OVAR) studies demonstrated that carboplatin Early stage 81.5 86.3 <.0001 < 40 89.1 91.6 0.203 Table 2 Five-year relative survival rate, by SEER stage and histologic subtype 40–59 83.9 88.1 <.0001 2005–2009 2010–2014 p-value > 59 66.8 77.0 0.001 (n = 6317) (n = 7960) Distant stage 38.7 43.9 <.0001 Early stage 81.5 86.3 <.0001 < 40 46.2 44.7 0.808 Serous carcinoma 77.7 84.1 <.0001 40–59 44.9 50.5 <.0001 Mucinous carcinoma 87.6 88.6 0.379 > 59 28.2 34.1 0.002 Endometrioid carcinoma 88.5 93.6 0.047 Surgery Clear cell carcinoma 86.4 87.4 0.673 Early stage 81.5 86.3 <.0001 Distant stage 38.7 43.9 <.0001 with surgery 82.6 87.1 <.0001 Serous carcinoma 44.1 49.5 <.0001 without surgery 62.3 60.7 0.383 Mucinous carcinoma 30.2 31.5 0.247 Distant stage 38.7 43.9 <.0001 Endometrioid carcinoma 50.3 60.1 0.752 with surgery 42.5 47.6 <.0001 Clear cell carcinoma 38.0 22.5 0.012 without surgery 24.0 27.2 0.413 SEER Surveillance, Epidemiology, and End Results a a Early stage: local + regional Early stage: local + regional Lee et al. BMC Cancer (2018) 18:601 Page 5 of 8 Table 4 Estimated hazard ratio of ovarian cancer prior to the era of targeted therapy N No. of deaths Adjusted HR 95% CI p-value Age (years) < 40 3849 988 ref. ref. – 40–59 12,169 4992 1.71 (1.60–1.84) <.0001 > 59 6862 4328 3.00 (2.79–3.22) <.0001 SEER Stage Early stage 6429 1113 ref. ref. – Distant stage 6795 3777 3.23 (3.02–3.46) <.0001 Year of diagnosis 1995–1999 3740 2230 ref. ref. – 2000–2004 4863 2671 0.89 (0.84–0.95) 0.000 2005–2009 6317 3227 0.94 (0.85–1.03) 0.185 2010–2014 7960 2180 0.73 (0.65–0.81) <.0001 Primary treatment With surgery 19,776 8122 ref. ref. – Without surgery 1772 1233 1.49 (1.39–1.58) <.0001 Histology Serous carcinoma 10,837 5325 ref. ref. – Mucinous carcinoma 4005 1226 0.71 (0.67–0.76) <.0001 Endometrioid carcinoma 2191 670 0.69 (0.63–0.75) <.0001 Clear cell carcinoma 1923 507 0.80 (0.73–0.88) <.0001 Others 3924 2580 1.49 (1.42–1.57) <.0001 Early stage: local + regional, HR, hazard ratio; ref., reference; CI, confidence interval; SEER, Surveillance, Epidemiology, and End Results adjusted for Age, SEER stage, Year of Diagnosis, Primary treatment and Histology plus paclitaxel was not inferior to cisplatin plus pacli- adopted radical surgery and a multidisciplinary taxel [10, 11]. Thus, the incorporation of paclitaxel into approach that includes general surgeons, thoracic first-line therapy has improved the ovarian cancer sur- surgeons, and urologists. This approach might also vival rate. This change was adopted by Korean gyneco- explain the improvement in survival between 2005 logic oncologists during 2000–2004, and may partially and 2009 and 2010–2014, and could highlight the im- explain the improvement in survival between 1995 and portance of surgery in the era of chemotherapy using 1999 and 2010–2014. paclitaxel plus carboplatin. However, after the incorporation of paclitaxel into Furthermore, advances in chemotherapy for the recur- first-line chemotherapy, the first-line chemotherapy rent and supportive care settings might help improve options have not substantially changed during the last survival outcomes [6]. During the next decades, decade. Although a randomized phase III trial re- enormous changes in survival are expected based on the vealed a survival benefit after treatment using intra- incorporation of targeted treatments for ovarian cancer. peritoneal chemotherapy [26], this procedure has not For example, the combination of bevacizumab plus been widely accepted in Korea. The Japanese Gynecologic paclitaxel and carboplatin provides a survival benefit in Oncology Group (JGOG) 3016 study also revealed the su- patients with advanced-stage ovarian cancer. In addition, periority of dose-dense weekly paclitaxel plus carboplatin, the GOG 218 and International Collaboration on compared to the standard dosing of paclitaxel [27], al- Ovarian Neoplasms trial 7 (ICON 7) studies revealed a though this approach also has limited acceptance in progression-free survival benefit in the first-line setting Korea. [13, 28], while three randomized phase III trials revealed Previous studies have emphasized the importance of a survival benefit the recurrent setting [12, 14, 29]. debulking surgery for ovarian cancer. Bristow et al. Moreover, mature data from phase II and III trials with found that maximal cytoreduction was one of the PARP inhibitors will be available in the next few years, most powerful determinants of survival among and Study 19 has already revealed a remarkable survival patients with advanced disease during the platinum benefit after olaparib treatment for patients with a BRCA era [8]. Thus, many Korean gynecologic oncologists mutation and platinum-sensitive recurrence [30]. Based on Lee et al. BMC Cancer (2018) 18:601 Page 6 of 8 these results, the Korean Food and Drug Administration International Federation of Gynecology and Obstetrics approved bevacizumab in 2013 and olaparib in 2016. (FIGO) staging and survival information such as re- Nevertheless, targeted drugs were rarely used during the currence and the cause of death. Hence, we could not present study’s period, and only a few patients would have identify the specific cause of death for each case. In received targeted drugs in clinical trials. addition, the sociodemographic information such as Despite the progress in treating serous carcinoma dur- region, residence and hospital cannot be obtained ing the last 20 years, we did not observe any survival im- from the KCCR database for research purpose. There- provements for the mucinous and clear cell carcinoma fore, we could not analyze the data obtained for the subtypes. Although epithelial ovarian cancer has signifi- indicators related to the health system. Second, there cant heterogeneity and the histological subtype is a is no detailed information regarding the surgery and well-known prognostic factor, the current management chemotherapy, such as surgeon specialty, extent of strategies do not consider the histological subtype. debulking, residual disease, neoadjuvant or postopera- Previous studies have confirmed that patients with mu- tive chemotherapy, and the specific regimens. Thus, cinous tumors have inferior long-term survival, com- as we observed an improved survival rate among pa- pared to the serous or endometrioid subtypes, which is tients who underwent surgery, it is possible that this related to a poor response to platinum-based chemo- finding was biased by the selection of healthier pa- therapy [31, 32]. However, advances in the pathological tients in the surgery group. Third, central pathology diagnosis of ovarian mucinous carcinoma have allowed reviews are not performed for patients who are regis- pathologists to distinguish between primary and meta- tered in the KCCR. static mucinous carcinoma, which has led pathologist to suggest that primary ovarian mucinous tumors are rare Conclusion [33]. The GOG 241 study aimed to compare the efficacy Ovarian cancer survival has improved in Korea during the of carboplatin plus paclitaxel +/− bevacizumab to that of last 20 years. However, no improvements were observed oxaliplatin plus capecitabine +/− bevacizumab as for the mucinous and clear cell carcinoma subtypes. Given first-line chemotherapy for patients with mucinous the low survival rate in cases with advanced-stage mucin- adenocarcinoma, although there has been limited enroll- ous/clear cell subtypes, clinical trials with novel treatment ment in that study because of this subtype’s rarity. strategies are urgently needed to improve clinical out- The incidence of clear cell carcinoma has increased comes in these cases. markedly in Korea across all age groups since 1999 [2]. Abbreviations Previous reports have confirmed that women with endo- FIGO: International Federation of Gynecology and Obstetrics; metriosis have an elevated risk of developing clear cell GOG: Gynecologic Oncology Group; ICD-10: International Statistical carcinoma, and this trend is expected to continue in the Classification of Diseases and Related Health Problems, 10th edition; KCCR: Korea Central Cancer Registry; KNCIDB: Korean National Cancer near future, based on the increasing incidence of endo- Incidence Database; RER: Relative excess risks; RSR: Relative survival rate; metriosis in Korea [34, 35]. The JGOG 3017 study com- SEER: Surveillance, Epidemiology, and End Results pared the efficacy of irinotecan plus cisplatin versus paclitaxel plus carboplatin as a first-line chemotherapy Funding This study was supported in part by a National Cancer Center Grant (Grant [36], although no subtype-specific survival benefits were No. NCC-1610200) and a new faculty research seed money grant of Yonsei observed for the irinotecan plus cisplatin regimen. Chan University College of Medicine for 2017 (Grant No. 2017–32-0033). The et al. did not report any change in survival rates for pa- funding bodies played no role in the design and conduct of the study; collection, analysis, and interpretation of data; writing of the manuscript, and tients with clear cell carcinoma after analyzing the data the decision to submit the manuscript for publication. available on the Surveillance Epidemiology and End Re- sults Database [4]. Therefore, treatment using existing Availability of data and materials anticancer agents has limited ability to improve the All data generated or analyzed during this study are included in this published article. prognosis of patients with clear cell carcinoma. The present study also revealed poor survival outcomes and Authors’ contributions no improvement in the outcomes for advanced-stage JYL and YJW were responsible for the study design. BL and YJW participated clear carcinoma. in data collection. BL analyzed the data. JYL, MCL, BL, KWJ and YJW were involved in the interpretation of the data. JYL and YJW drafted the The present study is one of the largest population-based manuscript. JYL, SK, YTK, MCL, JWK, S-YP and YJW revised the manuscript. All studies to evaluate the survival rate of ovarian cancer authors critically read the drafts of this paper and approved its final version. using available histological and cancer stage data. Although the present study’s findings are strengthened by Ethics approval and consent to participate Ethical approval for the research protocol was provided by the institutional the large nationally representative sample of Korean review board of the National Cancer Center (NCC2017–0168) which waived women, there are also several limitations. First, the KCCR the requirement for informed consent. The authorization for data processing database does not include disease information such as was obtained from the National ‘Cancer Control Act’. Lee et al. BMC Cancer (2018) 18:601 Page 7 of 8 Competing interests chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA The authors declare that they have no competing interests. open-label randomized phase III trial. J Clin Oncol. 2014;32(13):1302–8. 15. Cohn DE, Barnett JC, Wenzel L, Monk BJ, Burger RA, Straughn JM Jr, Myers ER, Havrilesky LJ. 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Changes in ovarian cancer survival during the 20years before the era of targeted therapy

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Biomedicine; Cancer Research; Oncology; Surgical Oncology; Health Promotion and Disease Prevention; Biomedicine, general; Medicine/Public Health, general
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Abstract

Background: The survival of patients with ovarian cancer has improved because of surgery and chemotherapy. This study aimed to estimate the changes in survival rates among Korean women with ovarian cancer prior to the introduction of targeted therapy for ovarian cancer. Methods: Data were obtained from the Korea Central Cancer Registry regarding patients who were diagnosed with epithelial ovarian cancer between 1995 and 2014. The relative survival rates were calculated for 5-year periods using the Ederer II method. Cox proportional hazard models were created to assess the associations of demographic and clinicopathological factors with ovarian cancer survival. Results: During the study period, 22,880 women were diagnosed with epithelial ovarian cancer. The 5-year relative survival rate improved from 57.2% during 1995–1999 to 63.8% during 2010–2014 (P < 0.001). Survival outcomes improved between 1995 and 1999 and 2010–2014 for the serous and endometrioid carcinoma subtypes (P < 0.001). However, no improvements were observed for the mucinous and clear cell carcinoma subtypes (P = 0.189 and P = 0.293, respectively). Multivariate analysis revealed that younger age, early stage, recent diagnosis, primary surgical treatment, and non-serous histological subtype were favorable prognostic factors. Conclusion: Survival outcomes have improved for serous and endometrioid epithelial ovarian cancer in the last 20 years. However, no improvement was observed for patients with mucinous and clear cell carcinoma subtypes. Keywords: Ovarian cancer, Survival, Histology, Korea, Chemotherapy, Surgery Background goal of improving survival, and some of these strategies Ovarian cancer is the most common cause of gynecological have become standard treatments for ovarian cancer. cancer-related death in Korea, and causes approximately For example, debulking surgery has been emphasized 1021 deaths annually [1]. The incidence and mortality because optimal cytoreduction is one of the most signifi- of ovarian cancer have increased continuously, and cant predictors of survival [7], and previous studies have 2413 new cases were detected in 2014 [1–3]. revealed that optimal surgical cytoreduction improves Approximately 75% of the newly diagnosed patients survival in cases of advanced-stage disease [8]. In have advanced-stage disease, which partly explains the addition, paclitaxel plus cisplatin has been introduced as a high mortality rate for this cancer [4, 5]. front-line therapy for ovarian cancer, and provides better During the last 20 years, there has been an improve- survival outcomes than cyclophosphamide-based regimens ment in survival of patients with ovarian cancer [1, 4–6]. [9]. After then, platinum-based chemotherapy has been im- A number of strategies have been evaluated with the proved with less toxic and equivalent analogs, carboplatin [10, 11], and paclitaxel plus carboplatin is the most com- monly used first-line therapy for ovarian cancer. Moreover, * Correspondence: astra67@ncc.re.kr better survival rates have been observed in patients with re- Cancer Registration and Statistics Branch, National Cancer Center, Goyang, South Korea current disease, with a number of chemotherapies having Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Lee et al. BMC Cancer (2018) 18:601 Page 2 of 8 activity even in platinum-resistant settings. Although from the general population. We calculated the relative recent phase III trials have supported the introduction survival rates (RSRs) using the Ederer II method [20]. of targeted agents [12–14], their economic cost, lim- Furthermore, we divided the patients into 5-year cohorts ited insurance coverage, and low patient preference based on their diagnosis date to evaluate their 5-year have limited the use of these agents in routine clinical RSRs (1995–1999, 2000–2004, 2005–2009, and 2010– practice [15, 16]. In Korea, the addition of bevacizu- 2014). The Cox regression proportional hazard model mab to standard chemotherapy was approved in 2013, adjusted to estimate hazard ratio (HR) for the age at and the national insurer only began covering the cost diagnosis, SEER stage, year of diagnosis, primary of bevacizumab for platinum-resistant recurrent ovar- treatment (with or without surgery), and histological ian cancer in August 2015. Therefore, the present subtype [21]. The proportionality of hazards assump- study aimed to investigate the changes in the survival tion over time was tested for each factor [22]. All rates among Korean patients with ovarian cancer dur- analyses were performed using SAS software (version ing the last 20 years, and to identify unmet clinical 9.3; SAS Institute, Cary, NC, USA). needs that might be targeted to improve outcomes. Results Methods A total of 22,880 women were diagnosed with ovarian can- This study utilized data from the Korean National Cancer cer between 1995 and 2014, and their characteristics are Incidence Database (KNCIDB), which includes data from showninTable 1. The overall 5-year RSR significantly im- the Korea Central Cancer Registry (KCCR) and information proved during study period (57.2% during 1995–1999, regarding patients’ demographic characteristics, primary 60.2% during 2000–2004, 59.4% during 2005–2009, 63.8% cancer site, morphology, diagnosis date, and initial treat- during 2010–2014; P for trend < 0.001) (Fig. 1). Figure 2 ment. KCCR was launched as a nationwide hospital-based shows the survival outcomes according to histological sub- cancer registry in 1980 by the Ministry of Health and type, which improved for the serous and endometrioid car- Welfare, and subsequently expanded to cover the entire cinoma subtypes between 1995 and 1999 and 2010–2014 population in 1999. The present study evaluated survival (P for trend < 0.001). However, no significant improvements data from the KNCIDB. The ovary cancer cases were classi- were observed for the mucinous and clear cell carcinoma fied according to the International Classification of Diseases subtypes (P for trend = 0.189 and 0.293, respectively). for Oncology, 3rd edition [17] and converted according to Table 2 shows the 5-year RSRs of patients with ovarian the International Statistical Classification of Diseases and cancer according to histological subtype and SEER stage. Related Health Problems, 10th edition (ICD-10: C-56) [18]. The overall 5-year RSRs improved from 59.4% during We included only cases of epithelial ovarian cancer, 2005–2009 to 63.8% during 2010–2014 (P < 0.001). diagnosed between 1995 and 2014. All cases of Improved survivals were also observed for early-stage ser- non-epithelial ovarian cancer (e.g. sex-cord stromal tumors ous carcinoma (from 77.7% during 2005–2009 to 84.1% and germ cell tumors) were excluded. All cases followed during 2010–2014). Furthermore, there was a significant until 31 December 2015. increase in the 5-year RSR for advanced-stage serous car- The present study’s retrospective design was approved cinoma, from 44.1% during 2005–2009 to 49.5% during by the institutional review board of the National Cancer 2010–2014. However, women with non-serous carcinoma Center (NCC2017–0168). subtypes did not experience a survival improvement, with Age at the diagnosis was classified as < 40 years old, the exception of women with early-stage endometrioid 40–59 years old, and > 59 years old. Histological sub- carcinoma. types were categorized as serous carcinoma, mucinous Table 3 shows the results for the age-based changes in carcinoma, endometrioid carcinoma, clear cell carcin- the 5-year RSRs. During 2005–2009 and 2010–2014, oma, and others. Staging information was based on the patients who were 40–59 years old and > 59 years old Surveillance, Epidemiology, and End Results (SEER) experienced an increased 5-year survival rate, although summary staging [19], which categorizes cancer spread younger patients did not experience a survival improve- from its origin (localized, regional, and distant), because ment, regardless of their cancer stage. Patients who the KCCR has collected this information since 2005. underwent surgery had a significantly higher 5-year RSR, Primary treatments within 4 months were categorized as compared to patients who did not undergo surgery, and surgery, chemotherapy, and others. this association strengthened over time. For the survival analyses, we obtained the data from In the Cox multivariate model, the significant prog- KNCIDB and the mortality data from Statistics Korea. nostic factors were age at diagnosis, SEER stage, primary Relative survival is the ratio of the observed survival rate treatment, and histological subtype. Furthermore, year of among patients with cancer, compared to the expected diagnosis was an independent prognostic factor, with pa- survival rate among age- and sex-matched individuals tients who were diagnosed during 2010–2014 being 27% Lee et al. BMC Cancer (2018) 18:601 Page 3 of 8 Table 1 Basic characteristics according to the time period of ovarian cancer diagnosis Total 1995–1999 2000–2004 2005–2009 2010–2014 (n = 22,880) (n = 3740) (n = 4863) (n = 6317) (n = 7960) No. of cases % p-value No. of cases % No. of cases % No. of cases % No. of cases % p-value Age (years) <.0001 <.0001 < 40 3849 16.8 945 25.3 910 18.7 990 15.7 1004 12.6 40–59 12,169 53.2 1813 48.5 2526 51.9 3378 53.5 4452 55.9 > 59 6862 30.0 982 26.3 1427 29.3 1949 30.9 2504 31.5 SEER Stage <.0001 <.0001 Localized 3865 16.9 –– –– 1683 26.6 2182 27.4 Regional 2564 11.2 –– –– 1053 16.7 1511 19.0 Distant 6795 29.7 –– –– 2843 45.0 3952 49.6 Unspecified 9656 42.2 –– –– 738 11.7 315 4.0 Primary treatment <.0001 <.0001 Surgery only 6007 26.3 1213 32.4 1252 25.7 1626 25.7 1916 24.1 Chemotherapy only 1680 7.3 326 8.7 371 7.6 414 6.6 569 7.1 Surgery + Chemotherapy 13,262 58.0 1745 46.7 2713 55.8 3805 60.2 4999 62.8 Others 1931 8.4 456 12.2 527 10.8 472 7.5 476 6.0 Histology <.0001 <.0001 Serous carcinoma 10,837 47.4 1459 39.0 2119 43.6 3186 50.4 4073 51.2 Mucinous carcinoma 4005 17.5 916 24.5 1027 21.1 951 15.1 1111 14.0 Endometrioid carcinoma 2191 9.6 399 10.7 494 10.2 580 9.2 718 9.0 Clear cell carcinoma 1923 8.4 164 4.4 327 6.7 551 8.7 881 11.1 Others 3924 17.2 802 21.4 896 18.4 1049 16.6 1177 14.8 SEER Surveillance, Epidemiology, and End Results less likely to die, compared to patients who were diag- cancer. Among women with serous carcinoma, the nosed during 1995–1999 (hazard ratio: 0.73; 95% confi- risk of death from ovarian cancer during 2010–2014 dence interval: 0.65–0.81) (Table 4). was 4.7% lower, compared to during 2005–2009, and 8.5% lower compared to during 1995–1999. Improvement of Discussion survival was found for both early stage and distant Between 1995 and 2014, there has been a gradual in- stage. However, no improvements were observed for crease in the survival of Korean patients with ovarian patients with the mucinous and clear cell carcinoma subtypes. The current approach to managing ovarian cancer in- volves cytoreductive surgery followed by chemotherapy, and a decrease in the proportion of patients without de- finitive treatment has been observed during the last 20 years (from 12.2% during 1995–1999 to 6.0% during 2010–2014). Thus, an increasing number of Korean pa- tients have benefited from surgery and chemotherapy, and adherence to the standard treatment guidelines is an independent predictor of improved survival [23, 24]. Furthermore, in the present study, the multivariate ana- lysis revealed that surgery was independently associated with better outcomes. The use of platinum-based chemotherapy has im- proved with the development of less toxic analogs (car- boplatin), as well as research regarding the optimal dose, Fig. 1 Relative survival rate of ovary cancer by time period schedule, sequence, and duration of treatment. In this Lee et al. BMC Cancer (2018) 18:601 Page 4 of 8 Fig. 2 Trends in relative survival rate according to histology and the time period (a) serous carcinoma (b) mucinous carcinoma (c) endometrioid carcinoma (d) clear cell carcinoma context, the Gynecologic Oncology Group (GOG) 0111 Table 3 Five-year relative survival rate, by age and primary and OV10 studies revealed that cisplatin plus paclitaxel treatment was superior to cisplatin plus cyclophosphamide [9, 25]. 2005–2009 2010–2014 p-value In addition, the GOG 0158 and Arbeitsgemeinschaft (n = 6317) (n = 7960) Gynäkologische Onkologie Ovarian Cancer Study Group Age (AGO-OVAR) studies demonstrated that carboplatin Early stage 81.5 86.3 <.0001 < 40 89.1 91.6 0.203 Table 2 Five-year relative survival rate, by SEER stage and histologic subtype 40–59 83.9 88.1 <.0001 2005–2009 2010–2014 p-value > 59 66.8 77.0 0.001 (n = 6317) (n = 7960) Distant stage 38.7 43.9 <.0001 Early stage 81.5 86.3 <.0001 < 40 46.2 44.7 0.808 Serous carcinoma 77.7 84.1 <.0001 40–59 44.9 50.5 <.0001 Mucinous carcinoma 87.6 88.6 0.379 > 59 28.2 34.1 0.002 Endometrioid carcinoma 88.5 93.6 0.047 Surgery Clear cell carcinoma 86.4 87.4 0.673 Early stage 81.5 86.3 <.0001 Distant stage 38.7 43.9 <.0001 with surgery 82.6 87.1 <.0001 Serous carcinoma 44.1 49.5 <.0001 without surgery 62.3 60.7 0.383 Mucinous carcinoma 30.2 31.5 0.247 Distant stage 38.7 43.9 <.0001 Endometrioid carcinoma 50.3 60.1 0.752 with surgery 42.5 47.6 <.0001 Clear cell carcinoma 38.0 22.5 0.012 without surgery 24.0 27.2 0.413 SEER Surveillance, Epidemiology, and End Results a a Early stage: local + regional Early stage: local + regional Lee et al. BMC Cancer (2018) 18:601 Page 5 of 8 Table 4 Estimated hazard ratio of ovarian cancer prior to the era of targeted therapy N No. of deaths Adjusted HR 95% CI p-value Age (years) < 40 3849 988 ref. ref. – 40–59 12,169 4992 1.71 (1.60–1.84) <.0001 > 59 6862 4328 3.00 (2.79–3.22) <.0001 SEER Stage Early stage 6429 1113 ref. ref. – Distant stage 6795 3777 3.23 (3.02–3.46) <.0001 Year of diagnosis 1995–1999 3740 2230 ref. ref. – 2000–2004 4863 2671 0.89 (0.84–0.95) 0.000 2005–2009 6317 3227 0.94 (0.85–1.03) 0.185 2010–2014 7960 2180 0.73 (0.65–0.81) <.0001 Primary treatment With surgery 19,776 8122 ref. ref. – Without surgery 1772 1233 1.49 (1.39–1.58) <.0001 Histology Serous carcinoma 10,837 5325 ref. ref. – Mucinous carcinoma 4005 1226 0.71 (0.67–0.76) <.0001 Endometrioid carcinoma 2191 670 0.69 (0.63–0.75) <.0001 Clear cell carcinoma 1923 507 0.80 (0.73–0.88) <.0001 Others 3924 2580 1.49 (1.42–1.57) <.0001 Early stage: local + regional, HR, hazard ratio; ref., reference; CI, confidence interval; SEER, Surveillance, Epidemiology, and End Results adjusted for Age, SEER stage, Year of Diagnosis, Primary treatment and Histology plus paclitaxel was not inferior to cisplatin plus pacli- adopted radical surgery and a multidisciplinary taxel [10, 11]. Thus, the incorporation of paclitaxel into approach that includes general surgeons, thoracic first-line therapy has improved the ovarian cancer sur- surgeons, and urologists. This approach might also vival rate. This change was adopted by Korean gyneco- explain the improvement in survival between 2005 logic oncologists during 2000–2004, and may partially and 2009 and 2010–2014, and could highlight the im- explain the improvement in survival between 1995 and portance of surgery in the era of chemotherapy using 1999 and 2010–2014. paclitaxel plus carboplatin. However, after the incorporation of paclitaxel into Furthermore, advances in chemotherapy for the recur- first-line chemotherapy, the first-line chemotherapy rent and supportive care settings might help improve options have not substantially changed during the last survival outcomes [6]. During the next decades, decade. Although a randomized phase III trial re- enormous changes in survival are expected based on the vealed a survival benefit after treatment using intra- incorporation of targeted treatments for ovarian cancer. peritoneal chemotherapy [26], this procedure has not For example, the combination of bevacizumab plus been widely accepted in Korea. The Japanese Gynecologic paclitaxel and carboplatin provides a survival benefit in Oncology Group (JGOG) 3016 study also revealed the su- patients with advanced-stage ovarian cancer. In addition, periority of dose-dense weekly paclitaxel plus carboplatin, the GOG 218 and International Collaboration on compared to the standard dosing of paclitaxel [27], al- Ovarian Neoplasms trial 7 (ICON 7) studies revealed a though this approach also has limited acceptance in progression-free survival benefit in the first-line setting Korea. [13, 28], while three randomized phase III trials revealed Previous studies have emphasized the importance of a survival benefit the recurrent setting [12, 14, 29]. debulking surgery for ovarian cancer. Bristow et al. Moreover, mature data from phase II and III trials with found that maximal cytoreduction was one of the PARP inhibitors will be available in the next few years, most powerful determinants of survival among and Study 19 has already revealed a remarkable survival patients with advanced disease during the platinum benefit after olaparib treatment for patients with a BRCA era [8]. Thus, many Korean gynecologic oncologists mutation and platinum-sensitive recurrence [30]. Based on Lee et al. BMC Cancer (2018) 18:601 Page 6 of 8 these results, the Korean Food and Drug Administration International Federation of Gynecology and Obstetrics approved bevacizumab in 2013 and olaparib in 2016. (FIGO) staging and survival information such as re- Nevertheless, targeted drugs were rarely used during the currence and the cause of death. Hence, we could not present study’s period, and only a few patients would have identify the specific cause of death for each case. In received targeted drugs in clinical trials. addition, the sociodemographic information such as Despite the progress in treating serous carcinoma dur- region, residence and hospital cannot be obtained ing the last 20 years, we did not observe any survival im- from the KCCR database for research purpose. There- provements for the mucinous and clear cell carcinoma fore, we could not analyze the data obtained for the subtypes. Although epithelial ovarian cancer has signifi- indicators related to the health system. Second, there cant heterogeneity and the histological subtype is a is no detailed information regarding the surgery and well-known prognostic factor, the current management chemotherapy, such as surgeon specialty, extent of strategies do not consider the histological subtype. debulking, residual disease, neoadjuvant or postopera- Previous studies have confirmed that patients with mu- tive chemotherapy, and the specific regimens. Thus, cinous tumors have inferior long-term survival, com- as we observed an improved survival rate among pa- pared to the serous or endometrioid subtypes, which is tients who underwent surgery, it is possible that this related to a poor response to platinum-based chemo- finding was biased by the selection of healthier pa- therapy [31, 32]. However, advances in the pathological tients in the surgery group. Third, central pathology diagnosis of ovarian mucinous carcinoma have allowed reviews are not performed for patients who are regis- pathologists to distinguish between primary and meta- tered in the KCCR. static mucinous carcinoma, which has led pathologist to suggest that primary ovarian mucinous tumors are rare Conclusion [33]. The GOG 241 study aimed to compare the efficacy Ovarian cancer survival has improved in Korea during the of carboplatin plus paclitaxel +/− bevacizumab to that of last 20 years. However, no improvements were observed oxaliplatin plus capecitabine +/− bevacizumab as for the mucinous and clear cell carcinoma subtypes. Given first-line chemotherapy for patients with mucinous the low survival rate in cases with advanced-stage mucin- adenocarcinoma, although there has been limited enroll- ous/clear cell subtypes, clinical trials with novel treatment ment in that study because of this subtype’s rarity. strategies are urgently needed to improve clinical out- The incidence of clear cell carcinoma has increased comes in these cases. markedly in Korea across all age groups since 1999 [2]. Abbreviations Previous reports have confirmed that women with endo- FIGO: International Federation of Gynecology and Obstetrics; metriosis have an elevated risk of developing clear cell GOG: Gynecologic Oncology Group; ICD-10: International Statistical carcinoma, and this trend is expected to continue in the Classification of Diseases and Related Health Problems, 10th edition; KCCR: Korea Central Cancer Registry; KNCIDB: Korean National Cancer near future, based on the increasing incidence of endo- Incidence Database; RER: Relative excess risks; RSR: Relative survival rate; metriosis in Korea [34, 35]. The JGOG 3017 study com- SEER: Surveillance, Epidemiology, and End Results pared the efficacy of irinotecan plus cisplatin versus paclitaxel plus carboplatin as a first-line chemotherapy Funding This study was supported in part by a National Cancer Center Grant (Grant [36], although no subtype-specific survival benefits were No. NCC-1610200) and a new faculty research seed money grant of Yonsei observed for the irinotecan plus cisplatin regimen. Chan University College of Medicine for 2017 (Grant No. 2017–32-0033). The et al. did not report any change in survival rates for pa- funding bodies played no role in the design and conduct of the study; collection, analysis, and interpretation of data; writing of the manuscript, and tients with clear cell carcinoma after analyzing the data the decision to submit the manuscript for publication. available on the Surveillance Epidemiology and End Re- sults Database [4]. Therefore, treatment using existing Availability of data and materials anticancer agents has limited ability to improve the All data generated or analyzed during this study are included in this published article. prognosis of patients with clear cell carcinoma. The present study also revealed poor survival outcomes and Authors’ contributions no improvement in the outcomes for advanced-stage JYL and YJW were responsible for the study design. BL and YJW participated clear carcinoma. in data collection. BL analyzed the data. JYL, MCL, BL, KWJ and YJW were involved in the interpretation of the data. JYL and YJW drafted the The present study is one of the largest population-based manuscript. JYL, SK, YTK, MCL, JWK, S-YP and YJW revised the manuscript. All studies to evaluate the survival rate of ovarian cancer authors critically read the drafts of this paper and approved its final version. using available histological and cancer stage data. Although the present study’s findings are strengthened by Ethics approval and consent to participate Ethical approval for the research protocol was provided by the institutional the large nationally representative sample of Korean review board of the National Cancer Center (NCC2017–0168) which waived women, there are also several limitations. First, the KCCR the requirement for informed consent. The authorization for data processing database does not include disease information such as was obtained from the National ‘Cancer Control Act’. Lee et al. BMC Cancer (2018) 18:601 Page 7 of 8 Competing interests chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA The authors declare that they have no competing interests. open-label randomized phase III trial. J Clin Oncol. 2014;32(13):1302–8. 15. Cohn DE, Barnett JC, Wenzel L, Monk BJ, Burger RA, Straughn JM Jr, Myers ER, Havrilesky LJ. A cost-utility analysis of NRG oncology/gynecologic oncology group protocol 218: incorporating prospectively collected quality- Publisher’sNote of-life scores in an economic model of treatment of ovarian cancer. Springer Nature remains neutral with regard to jurisdictional claims in Gynecol Oncol. 2015;136(2):293–9. published maps and institutional affiliations. 16. Lee JY, Kim K, Lee YS, Kim HY, Nam EJ, Kim S, Kim SW, Kim JW, Kim YT. Author details Treatment preferences of advanced ovarian cancer patients for adding Department of Obstetrics and Gynecology, Institute of Women’s Life bevacizumab to first-line therapy. Gynecol Oncol. 2016;143(3):622–7. Medical Science, Yonsei University College of Medicine, Seoul, South Korea. 17. Fritz A, Percy C, Jack A, Shanmugaratnam K, Sobin L, Parkin DM, Whelan S. Gynecologic Cancer Branch & Center for Uterine Cancer, National Cancer International classification of diseases for oncology. 3rd ed. Geneva, Center, Goyang, South Korea. 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BMC CancerSpringer Journals

Published: May 29, 2018

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