Annual report of Gynecologic Oncology Committee, Japan Society of Obstetrics and Gynecology, 2013

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1 bs_bs_banner doi: /jog J. Obstet. Gynaecol. Res. Vol. 40, No. 2: , February 2014 Annual report of Gynecologic Oncology Committee, Japan Society of Obstetrics and Gynecology, 2013 Daisuke Aoki Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo, Japan Abstract We present the Patient Annual Report in 2011 and the Treatment Annual Report in 2005 that were collected and analyzed by the Japan Society of Obstetrics and Gynecology. Data on patients with cervical cancer, 7713 with endometrial cancer and 4672 with ovarian cancer in whom treatment was started in 2011 and data on the prognosis of 2985 patients with cervical cancer, 2812 with endometrial cancer, and 1839 with ovarian cancer who were started on treatment in 2005 were analyzed and summarized. Patient Annual Report in 2011: Stage 0 accounted for 58%, stage I for 24%, stage II for 9%, stage III for 5%, and stage IV for 4% of all the patients with cervical cancer. Stage 0 accounted for 6%, stage I for 61%, stage II for 8%, stage III for 18%, and stage IV for 7% of patients with endometrial cancer. Stage I accounted for 43%, stage II for 9%, stage III for 29%, and stage IV for 8% of patients with ovarian cancer. Treatment Annual Report in 2005: The 5-year overall survival rates of patients with cervical cancer were 91% in stage I, 78% in stage II, 57% in stage III, and 30% in stage IV. The 5-year overall survival rates of patients with endometrial cancer were 95% in stage I, 89% in stage II, 77% in stage III, and 23% in stage IV. The 5-year overall survival rates of patients with ovarian surface epithelialstromal tumors were 92% in stage I, 75% in stage II, 50% in stage III and 39% in stage IV. Key words: annual report, cervical cancer, endometrial cancer, gynecological cancer, Japan, ovarian cancer. Introduction The Japan Society of Obstetrics and Gynecology (JSOG) collects and analyzes annual data on the clinicopathologic factors and prognosis of gynecologic cancers from member institutions every year to investigate the trends in gynecologic cancers in Japan. Herein, we present the Patient Annual Report in 2011 and the Treatment Annual Report in (The data presented in this paper were quoted and modified from Acta Obstetrica et Gynaecologica Japonica 64 (12) , and Acta Obstetrica et Gynaecologica Japonica 65 (3) , ). Methods Data on patients in whom treatment was started in 2011 were collected, then were retrospectively analyzed and summarized in the Patient Annual Report in Data on the prognosis of patients who were started on treatment in 2005 were collected then were analyzed and summarized in the Treatment Annual Report in 2005, assuming that a 5-year follow-up period is necessary. This study was conducted with the approval of the ethics committee of JSOG. Patient Annual Report in 2011 The subjects included 9038 patients with stage 0 cervical cancer (carcinoma in situ), 6660 with stage I IV Received: November Accepted: November Reprint request to: Professor Daisuke Aoki, Department of Obstetrics and Gynecology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku , Tokyo, Japan. aoki@z7.keio.jp Daisuke Aoki, Chair of the Committee on Gynecologic Oncology, the Japan Society of Obstetrics and Gynecology The Author

2 Annual report of gynecologic cancers in Japan cervical cancer, 440 with stage 0 endometrial cancer (atypical endometrial hyperplasia), 7273 with stage I IV endometrial cancer, 4672 with ovarian cancer, and 1420 with ovarian tumors of borderline malignancy in whom the diagnosis was made histopathologically in each of the 305 member institutions of JSOG and who were started on treatment between January and December Clinical stages for cervical cancer and surgical stages for endometrial and ovarian cancer, including borderline malignancy, were based on the International Federation of Obstetricians and Gynaecologists (FIGO) 1988 staging system. Data on the age, clinical stage, histological type, and treatment were collected for patients with cervical cancer. Data on the age, surgical stage, histological type, and treatment were collected for patients with endometrial cancer patients. Data on the age, surgical stage, histological type and treatment were collected for the patients with ovarian cancer and ovarian tumors of borderline malignancy. Patient information was anonymized in a linkable fashion and then the patient information was registered on the website of JSOG from each institution. After two or more members of the Committee on Gynecologic Oncology checked the integrity of the collected data, the data were statistically analyzed. Treatment Annual Report in 2005 In all, 218 institutions collected data on the 3-year and 5-year prognoses of patients registered in any of the member institutions of JSOG between January and December 2005 and reported in the Patient Annual Report in The patients in the 218 institutions included 5083 with cervical cancer, 4266 with endometrial cancer, and 3066 with ovarian cancer. Data from institutions in which 20% or more of the registered patients were untraceable were not included in the analysis of the treatment outcome and the prognosis, because such data would reduce the reliability of the treatment outcome and the prognosis. Accordingly, the data of 2985 patients with cervical cancer, 2812 with endometrial cancer, and 1839 with ovarian cancer were included in the analysis of the treatment outcome and the prognosis. Personal information was anonymized in a linkable fashion and then information on the prognosis was registered on the website of JSOG. Thereafter, the data were statistically analyzed at the Biostatistics Center, Kurume University. Statistical analysis Overall survival rates were analyzed by the Kaplan Meier method, and statistical significance was determined using the log rank test. Results Patient Annual Report in Cervical cancer Age distribution (Fig. 1). Patients aged 40 49, 30 39, and years accounted for 24.8%, 20.2% and 18.4% of all the registered cases, respectively, showing that the disease predominantly affected women in their 40s. Stages (Fig. 2). Stage 0 accounted for 57.6%, stage I for 24.1% (stage Ia1, 6.0%; stage Ia2, 0.7%; stage Ib1, Figure 1 Age distribution of patients with stage I IV cervical cancer by clinical stage in 2011., stage I;, stage II;, stage III;, stage IV. Figure 2 Distribution of clinical stages in patients with cervical cancer in *Subclassification unknown The Author 339

3 D. Aoki 12.5%; stage Ib2, 3.5%; subclassification unknown, 1.4%), stage II for 9.4% (stage IIa, 2.6%; stage IIb, 6.8%; subclassification unknown, 0%), stage III for 4.9% (stage IIIa, 0.6%; stage IIIb, 4.3%; subclassification unknown, 0%), and stage IV for 4.1% (stage IVa, 1.1%; stage IVb, 3.0%; subclassification unknown, 1.1%) of all the patients. Histological types (Table 1). Squamous cell carcinoma was the most commonly encountered histopathologic type, accounting for 73.9% of all cases; adenocarcinoma accounted for 23.7% of all cases. The other rare histological types encountered are shown in Table 1. Treatment (Fig. 3). Of the patients, 37.8% underwent surgery alone, 20.2% received chemotherapy and other therapies in addition to radiotherapy, 13.4% received chemotherapy and other therapies in addition to surgery, 11.7% received radiotherapy alone, and 5.3% received radiotherapy in addition to surgery. Other therapies shown in the figure include immunotherapy and hormone therapy. 2. Endometrial cancer Age distribution (Fig. 4). Patients aged 50 59, 60 69, and years accounted for 30.1%, 28.9%, and 15.7%, respectively, of all cases, showing that the disease predominantly affected women in their 50s. On the other hand, patients aged younger than 40 years accounted for only 5.5% of all the cases. Surgical stages (Fig. 5). Stage 0 accounted for 5.7%, stage I for 60.6% (stage Ia, 18.9%; stage Ib, 29.6%; stage Ic, 11.8%; subclassification unknown, 0.3%), stage II for 8.1% (stage IIa, 3.1%; stage IIb, 4.6%; subclassification unknown, 0.4%), stage III for 18.4% (stage IIIa, 9.4%; stage IIIb, 0.4%; stage IIIc, 7.6%; subclassification unknown, 1.0%), and stage IV for 7.2% (stage IVa, 0.3%; stage IVb, 6.6%; subclassification unknown, 0.3%) of all the patients. Figure 3 Distribution of treatment methods in patients with cervical cancer by clinical stage in 2011., stage I;, stage II;, stage III;, stage IV. Figure 4 Age distribution of patients with stage I IV endometrial cancer by surgical stage in 2011., stage I;, stage II;, stage III;, stage IV. Figure 5 Distribution of surgical stages in patients with endometrial cancer in *Subclassification unknown The Author

4 Annual report of gynecologic cancers in Japan Table 1 Histological types of cervical cancer in 2011 Histological type No. of % patients Squamous cell carcinoma, classification unknown Squamous cell carcinoma, keratinizing type Squamous cell carcinoma, non-keratinizing type Adenocarcinoma, classification unknown Mucinous adenocarcinoma, endocervical type Mucinous adenocarcinoma, intestinal type Endometrioid adenocarcinoma Clear cell adenocarcinoma Serous adenocarcinoma Mesonephric adenocarcinoma Adenosquamous carcinoma Glassy cell carcinoma Adenoid cystic carcinoma Adenoid basal cell carcinoma Carcinoid Small cell carcinoma Undifferentiated carcinoma Carcinosarcoma Others Unknown (samples not taken) Total 6660 Table 2 Histological types of endometrial cancer in 2011 Histological type No. of % patients Endometrioid carcinoma Endometrioid adenocarcinoma Adenosquamous carcinoma Adenoacanthoma Serous adenocarcinoma Clear cell adenocarcinoma Mucinous adenocarcinoma Squamous cell carcinoma Mixed carcinoma Undifferentiated carcinoma Carcinofibroma Carcinosarcoma Classification unknown Total 7273 Histological types (Table 2). Endometrioid carcinoma was the most common, accounting for 83.1% of all the tumors. Other histological types included serous adenocarcinoma (4.6%), clear cell adenocarcinoma (2.4%), and mixed carcinoma (2.2%). Carcinosarcoma was observed in 5.0% of the patients. Treatment (Fig. 6). Of the patients, 54.4% underwent surgery alone, 38.6% received chemotherapy and other therapies, such as hormone therapy after surgery, and 1.2% received radiotherapy after surgery. Other therapies shown in the figure include immunotherapy. 3. Ovarian cancer Age distribution (Fig. 7). Patients aged 60 69, 50 59, and years accounted for 27.2%, 25.1%, and 20.0%, respectively, of all the cases, showing that the disease predominantly affected women in their 50s and 60s. Surgical stages (Fig.8). Stage I accounted for 43.0% (stage Ia, 16.6%; stage Ib, 0.8%; stage Ic, 25.6%), stage II for 8.9% (stage IIa, 0.8%; stage IIb, 0.9%; stage IIc, 7.1%), stage III for 29.3% (stage IIIa, 1.1%; stage IIIb, 3.9%; stage IIIc, 24.3%), and stage IV for 8.0% of all the patients. Neoadjuvant chemotherapy was given to 10.6% of the patients. Histological types (Table 3). Surface epithelial-stromal tumors accounted for 92.4%: serous adenocarcinoma accounted for 32.7%, clear cell adenocarcinoma for 23.7%, endometrioid adenocarcinoma for 16.2%, and mucinous adenocarcinoma for 11.8% of all the tumors. Sex cord-stromal and germ cell tumors were observed in 0.2% and 4.3% of the patients, respectively. Treatment (Fig.9). Of the patients, 78.2% received chemotherapy after surgery, 19.3% underwent surgery alone, and 1.7% received chemotherapy alone The Author 341

5 D. Aoki Figure 6 Distribution of treatment methods in patients with endometrial cancer by surgical stage in 2011., stage I;, stage II;, stage III;, stage IV. Figure 7 Age distribution of patients with ovarian cancer by surgical stage in 2011., stage I;, stage II;, stage III;,stage IV;, unknown;, neoadjuvant hemotherapy. Figure 8 Distribution of surgical stages in patients with ovarian cancer in Figure 9 Distribution of treatment methods in patients with ovarian cancer by surgical stage in 2011., stage I;, stage II;,stage III;, stage IV;, unknown;, neoadjuvant hemotherapy The Author

6 Annual report of gynecologic cancers in Japan Table 3 Histological types of ovarian cancer in 2011 Histological type No. of % patients Serous adenocarcinoma Mucinous adenocarcinoma Endometrioid adenocarcinoma Clear cell adenocarcinoma Undifferentiated carcinoma Mixed-type adenocarcinoma Adenosarcoma (homologous) Adenosarcoma (heterologous) Mesodermal mixed tumor (homologous) Mesodermal mixed tumor (heterologous) Stromal sarcoma Malignant Brenner tumor Transitional cell carcinoma Unclassifiable Others Sertoli-stromal cell tumor (poorly differentiated) Fibrosarcoma Others Immature teratoma G Dysgerminoma Yolk sac tumor Malignant mixed germ cell tumor Malignant mixed germ cell tumor: yolk sac tumor+dysgerminoma Malignant mixed germ cell tumor: yolk sac tumor+immature teratoma Malignant mixed germ cell tumor: others Mature cystic teratoma with malignant transformation Embryonal carcinoma Polyembryoma Choriocarcinoma Others Sarcoma Carcinoma of the rete ovarii Small cell carcinoma Hepatoid carcinoma Squamous cell carcinoma Gestational choriocarcinoma Malignant lymphoma (primary) Unclassifiable Tumor possibly originating from the Wolffian duct Others Total Ovarian tumors of borderline malignancy Surgical stages (Fig. 10). Stage I accounted for 93.0% (stage Ia, 65.0%; stage Ib, 2.3%; stage Ic, 25.7%), stage II for 1.8% (stage IIa, 0.2%; stage IIb, 0.5%; stage IIc, 1.1%), stage III for 4.5% (stage IIIa, 1.0%; stage IIIb, 1.1%; stage IIIc, 2.4%), and stage IV for 0.4% of all the patients. Neoadjuvant chemotherapy was given to 0.4% of the patients. Histological types (Table 4). Mucinous tumors accounted for 59.2%, serous tumors for 21.2%, endometrioid tumors for 2.3%, and mixed tumors for 2.3% of all the tumors. In addition, granulosa cell tumors accounted for 6.5% and immature teratomas (G1, G2) for 2.9% of the tumors. Treatment (Fig. 11). Of the patients, 93.0% underwent surgery alone, and 6.9% received chemotherapy after surgery. Treatment Annual Report in Cervical cancer Overall survival by clinical stage (Fig. 12). The overall survival rates by clinical stage are shown in Figure The Author 343

7 D. Aoki Figure 10 Distribution of surgical stages in patients with ovarian tumor of borderline malignancy in Figure 11 Distribution of treatment methods in patients with ovarian tumor of borderline malignancy by surgical stage in 2011., stage I;, stage II;, stage III;, stage IV;, unknown;, neoadjuvant hemotherapy. Table 4 Histological types of ovarian tumor of borderline malignancy Histological type No. of % patients Serous tumor Mucinous tumor Endometrioid tumor Clear cell tumor Proliferating Brenner tumor Mixed tumor Unclassifiable Others Granulosa cell tumor Sertoli-stromal cell tumor (moderately differentiated) Gynandroblastoma Steroid cell tumor (unclassifiable) Others Immature teratoma (G1, G2) Carcinoid Neuroectodermal tumor Others Tumor of borderline malignancy other than the above: gonadoblastoma Tumor of borderline malignancy other than the above: mixed germ cell sex cord-stromal tumor Tumor of borderline malignancy other than the above: others Total The Author

8 Annual report of gynecologic cancers in Japan Figure 12 Overall survival in patients with stage I IV cervical cancer by clinical stage in Log rank P < , International Federation of Gynecology and Obstetrics (FIGO) stage I;, FIGO stage II;, FIGO stage III;, FIGO stage IV. Figure 13 Overall survival in patients with stage I IV cervical cancer by histological type in Log rank P < , squamous carcinoma;, adenosquamous carcinoma;, adenocarcinoma;, others. The 5-year overall survival rates were 91.3% in stage I patients (stage Ia1, 98.9%; stage Ia2, 100%; stage Ib1, 90.8%; stage Ib2, 79.0%), 77.8% in stage II patients (stage IIa, 86.7%; stage IIb, 73.9%), 56.9% in stage III patients (stage IIIa, 68.0%; stage IIIb, 56.2%), and 30.1% in stage IV patients (stage IVa, 42.7%; stage IVb, 22.7%). There were significant differences between stages I and II (P < 0.001), stages II and III (P < 0.001), and stages III and IV (P = 0.003). Overall survival by histological type (Fig. 13). The overall survival rates by the histological type are shown in Figure 13. The 5-year overall survival rates were 80.4%, 75.7%, 74.0%, and 59.4% in patients with squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, and other cancers, respectively. Patients with squamous cell carcinoma had a significantly better prognosis than those with adenocarcinoma (P = 0.004), adenosquamous carcinoma (P < 0.001), and other cancers (P < 0.001). 2. Endometrial cancer Overall survival by surgical stage (Fig. 14). The overall survival rates by surgical stage are shown in Figure 14. The 5-year overall survival rates were 95.1% in stage I patients (stage Ia, 97.6%; stage Ib, 95.9%; stage Ic, 89.7%), 89.2% in stage II patients (stage IIa, 91.2%; stage IIb, 88.9%), 76.8% in stage III patients (stage IIIa, 85.3%; stage IIIb, 42.4%; stage IIIc, 23.1%), and 23.1% in stage 2014 The Author 345

9 D. Aoki Figure 14 Overall survival in patients with stage I IV endometrial cancer by surgical stage in Log rank P < , International Federation of Gynecology and Obstetrics (FIGO) stage I;, FIGO stage II;, FIGO stage III;, FIGO stage IV. Table 5 Five-year survival rates of endometrial cancer patients by stage and histological type FIGO Stage Histology Patients treated 5-year survival No. % % I Endometrioid type Serous, Mucinous, Clear cell type Others No description II Endometrioid type Serous, Mucinous, Clear cell type Others No description III Endometrioid type Serous, Mucinous, Clear cell type Others No description IV Endometrioid type Serous, Mucinous, Clear cell type Others No description FIGO, International Federation of Obstetricians and Gynaecologists. IV patients (stage IVa, 45.5%; stage IVb, 20.7%). There were significant differences between stages I and II (P < 0.001), stages II and III (P < 0.001), or stages III and IV (P < 0.001). Overall survival by histological type (Table 5). The 5-year overall survival rates were 95.6%, 88.9%, and 76.1% in patients with G1, G2, and G3 endometrioid adenocarcinoma, respectively. Comparison of the survival among the stages revealed 5-year overall survival rates of 96.5%, 87.7% and 86.6% in patients with stage I endometrioid carcinoma, serous/mucinous/clear adenocarcinoma and other histological types, respectively; 91.9%, 77.4% and 77.2% in patients with stage II endometrioid carcinoma, serous/mucinous/clear adenocarcinoma and other histological types, respectively; 83.6%, 54.8% and 64.3% in patients with stage III endometrioid carcinoma, serous/mucinous/clear adenocarcinoma and other histological types, respectively; and 25.6%, 19.4%, and 20.5% in patients with The Author

10 Annual report of gynecologic cancers in Japan Figure 15 Overall survival in patients with ovarian cancer by surgical stage in Log rank P < , International Federation of Gynecology and Obstetrics (FIGO) stage I;, FIGO stage II;, FIGO stage III;, FIGO stage IV. Figure 16 Overall survival in patients with ovarian cancer by histological type in Log rank P < , serous;, mucinous;, endometrioid;, clear;, other. stage IV endometrioid carcinoma, serous/mucinous/ clear adenocarcinoma and other histological types, respectively. 3. Ovarian cancer Overall survival by surgical stage (Fig. 15). The overall survival rates by surgical stage are shown in Figure 15. When compared among stages of surface epithelialstromal tumors, the 5-year overall survival rates were 91.7% in stage I patients (stage Ia, 93.1%; stage Ib, 100%; stage Ic(b), 91.9%; stage Ic(1), 88.9%; stage Ic(2), 87.2%; stage Ic(a), 90.2%), 74.8% in stage II patients (stage IIa, 81.8%; stage IIb, 76.9%; stage IIc(b), 79.6%; stage IIc(1), 85.7%; stage IIc(2), 72.7%; stage IIc(a), 67.0%), 49.6% in stage III patients (stage IIIa, 82.4%; stage IIIb, 69.4%; stage IIIc, 45.6%), and 38.6% in stage IV patients. There were significant differences between stages I and II (P < 0.001), stages II and III (P < 0.001), and stages III and IV (P < 0.001). The above analysis did not include patients who received neoadjuvant chemotherapy, and the 5-year overall survival rate of the patients who received neoadjuvant chemotherapy was 37.1%. Overall survival by histological type (Fig. 16). The overall survival rates by the histological type are shown in Figure 16. Patients with serous adenocarcinoma had a significantly poorer prognosis than those with 2014 The Author 347

11 D. Aoki mucinous adenocarcinoma (P < 0.001), endometrioid adenocarcinoma (P < 0.001) and clear cell adenocarcinoma (P < 0.001). Discussion The FIGO 1988 staging classification was adopted for this statistical analysis of cervical, endometrial and ovarian cancers. In regard to the clinical staging of cervical cancer, the diagnosis of stage I cervical cancer is influenced by the type of specimen examined, that is, cervical biopsy, cervical conization or total hysterectomy specimens, and it is expected that there may be differences in the interpretation among institutions as well. In addition, stage IVb is also interpreted differently among institutions, and it is possible that some patients may have been diagnosed as having stage IVb due to the presence of distant metastases or para-aortic lymphadenopathy on CT and other imaging diagnosis. In the analysis of endometrial and ovarian cancers, surgical staging classification was adopted and the diagnosis without surgery was performed only in a small number of cases comprising 4.5% and 2.1% of patients with endometrial and ovarian cancer, respectively. This suggested that summarized distribution of the surgical stages was still reliable. In regard to the histological types, there is a problem not in cervical, endometrial cancers or ovarian surface epithelial-stromal tumors, but in ovarian sex cordstromal and germ cell tumors: there are a small number of patients with these ovarian tumors and only an insufficient number of cases can be accumulated in a year. Therefore, the influence even from a single case can be large, leading to over- or under-estimation. Consequently, it seems impossible to compare and analyze the changes over time. Prognosis was analyzed by the Kaplan Meier method. Terminal-stage patients are often transferred to other medical institutions in Japan, and in such cases, information on the patients cannot often be obtained after hospital transfer, which leads to unknown prognosis. Fatal cases are considered to account for most of these prognosis-unknown cases. Therefore, if all these prognosis-unknown cases are counted as alive dropouts, the prognosis may be better estimated even by the Kaplan Meier method. Accordingly, in the present study, information from institutions in which the prognosis was untraceable for 20% or more of the cases was excluded from the analysis. Among the patients with known prognosis, 58.7% of patients with cervical cancer, 65.9% of patients with endometrial cancer, and 60.0% of patients with ovarian cancer were included in the analysis of the prognosis. However, in this method of analysis, it tends to be more difficult to collect information on patients from larger medical institutions, and future investigations are considered necessary to allow more accurate information on the prognosis to be reflected in the Treatment Annual Reports. Conclusion The Patient Annual Report and Treatment Annual Report on gynecologic tumors (cervical, endometrial, and ovarian cancers and ovarian tumors of borderline malignancy) in Japan are presented in this paper. Acknowledgment The author thanks the member institutions of the Japan Society of Obstetrics and Gynecology for its cooperation in providing data on patients with gynecologic tumors, and the Biostatistics Center, Kurume University for the data analysis. The author also thanks all members of the committee on gynecologic oncology of the Japan Society of Obstetrics and Gynecology and Dr Wataru Yamagami in the Department of Obstetrics and Gynecology, School of Medicine, Keio University for their contribution to summarizing the data and Ms Miyuki Nakai and Ms Keiko Abe for their secretarial help. Disclosure There is no conflict of interest. References 1. Aoki Y. The Patient Annual Report in Acta Obstet Gynaecol Jpn 2012; 64: Aoki Y. The Treatment Annual Report in Acta Obstet Gynaecol Jpn 2013; 65: The Author

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