An increase of serum CA-125 to two times of nadir level strongly predicts the image-identified recurrence of serous ovarian cancer

An increase of serum CA-125 to two times of nadir level strongly predicts the image-identified recurrence of serous ovarian cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article An increase of serum CA-125 to two times of nadir level strongly predicts the image-identified recurrence of serous ovarian cancer Kaiwen Du, Qiyu Yang, Jin Huang, David Wai Chan, Jinjin Li, Xiaoxia Chang, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3835030/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Using 35 U/ml as CA125 routine abnormal threshold may result in omissions in the recurrence detection of Ovarian cancer (OvCa). This study aimed to clarify the association between a biochemical recurrence (only the elevation of CA125) and an image-identified recurrence to predict the recurrent lesions better. 86 patients were enrolled from women diagnosed with stage I-IV serous ovarian, tubal, and peritoneal cancers from January 2013 to June 2019 at our center. The median CA125 level from 929.9 U/mL at diagnosis reduced to 7.8 U/mL at nadir during follow-up in all patients, and there was no difference between the neoadjuvant chemotherapy (NACT) and primary debulking surgery (PDS) group after initial treatment. Compared to CA125 level exceeding 35 U/ml, the 2×nadir of CA125 improve the sensitivity and the specificity of image-identified relapse ( P <0.001); the 2×nadir value can act as an earlier warning relapse signal with a longer median time to image-identified recurrence (2.7 vs. 0 months, P <0.001). Compared with 35 U/ml, CA125 reaching 2×nadir during the follow-up process might be a more sensitive and early recurrence signal in patients with serous OvCa. This criterion may help guide patients to be recommended for imaging examination to detect potential recurrence in time. Biological sciences/Cancer Biological sciences/Cancer/Cancer imaging Biological sciences/Cancer/Gynaecological cancer Biological sciences/Cancer/Tumour biomarkers Figures Figure 1 Figure 2 1. INTRODUCTION Ovarian cancer is the second deadliest gynecological cancer, with a 5-year survival rate of 50.8% 1 . Over 80% of these women are diagnosed as serous epithelial tissue 2 . The standard treatment involves cytoreduction surgery and chemotherapy. Primary debulking surgery (PDS) followed by platinum-based chemotherapy is the preferred initial treatment for advanced-stage ovarian cancer. Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) is an alternative option for those who cannot undergo PDS. While many randomized clinical trials have shown the non-inferiority of NACT in survival outcomes 3,4 , a recent study found that women in the NACT group experienced more recurrences in the pelvis or upper abdomen compared to the PDS group 5 . Regardless of the treatment option, complete resection of the tumor through surgery remains crucial in reducing the recurrence rate and improving survival. Ovarian cancer recurs in 25% of early-stage and more than 80% of advanced-stage women 6 . Effective follow-up tests are needed to detect recurrence or disease progression. Screening methods include physical examination, serum tumor biomarkers, and imaging techniques. The most widely used tumor biomarker is CA125, a glycoprotein found on the surface of ovarian cancer cells since 1981. Additional maker as HE4 have been introduced in Guideline, but CA125 seems to be the most reliable marker for disease monitoring 7 . The Gynecologic Cancer InterGroup has already accepted the research result by Rustin that CA125 levels more than twice the upper limit of normal predict tumor relapse 8 . However, using the traditional cut-off value of 35 U/mL for recurrence is being questioned. Studies have shown that even within the normal range(< 35 U/mL), three progressively rising CA125 at 1- to 3-month intervals 9 or an increase of more than 5 U/mL from 3 to 6 months after treatment 10 are associated with a higher risk of relapse. Therefore, a more sensitive cut-off point is needed. In fact, relying solely on CA125 levels is not sufficient to confirm recurrence. A rise to more than the cut-off value of CA125 several months before the evidence of image-identified recurrence or symptomatic clinical relapse is called biochemical recurrence. Early treatment based on elevated CA125 levels alone can cause anxiety and side effects without improving survival 11 . Excessive imaging screening would cause unnecessary anxiety and financial burden. Undoubtedly, predicting image-identified recurrence based on CA125 elevation is challenging but important. Additionally, initial treatment strategies can cause CA125 profiles to be worse in those having NACT than PDS as NACT patients have more advanced disease in the real clinical world. However, the tendency of significant deviation in CA125 will disappear following treatment, as CA125 will reduce to a low level after a combination of surgery and chemotherapy. Exploring the changing trends of CA125 profiles after the two distinct treatments in the real clinical world is expected to contribute more evidence to guide clinical practice in this area. In this study, the aim is to explore the association between biochemical recurrence (elevated CA125) and image-identified recurrence of ovarian cancer to improve the prediction of recurrent lesions requiring treatment. Additionally, a subgroup analysis was performed to clarify the effects of different initial treatments on the recurrent outcomes at the biomedical level and anatomical distribution. 2. MATERIAL AND METHODS 2.1 Study population All women diagnosed with International Federation of Gynecology and Obstetrics (FIGO, 2013) stage I-IV ovarian, tubal, and peritoneal cancers from January 2013 to June 2019 at the Department of Gynecology, The First Affiliated Hospital of Chongqing Medical University, China, were reviewed. We retrospectively collected clinical data of 86 women who met the following inclusion criteria: ( 1 ) All pathological types were serous; ( 2 ) Relapse was confirmed by imaging and was treated accordingly; ( 3 ) Without other malignancy; ( 4 ) Complete clinical data; ( 5 ) Regular follow-up; ( 6 ) platinum-sensitive recurrence. Those who achieved platinum-resistant recurrence and received previous treatment for biochemical recurrence were excluded. The criteria of platinum-sensitive recurrence: women relapsed after six months since receiving first-line chemotherapy on platinum-containing regimens. The criteria of platinum-resistant recurrence: women received first-line chemotherapy on platinum-containing regimens but relapsed in six months. According to initial treatments, 45 women receiving one to eight cycles of NACT (platinum-based chemotherapy) and IDS were assigned to the NACT group and forty-one women who received PDS to the PDS group. 2.2 Collection of clinical information of the enrolled women ( 1 ) Women’s baseline characteristics and initial treatment: age at diagnosis, body mass index (BMI), FIGO stage, primary tumor type, CA125 level at diagnosis, the median number of total chemotherapy cycles, surgical procedures, operation time, blood loss, surgical outcome, PARP inhibitor use, and histologic grade; ( 2 ) CA125 level per treatment phase: at diagnosis, before IDS, at the end of primary therapy, at nadir during follow-up, at 2 × nadir, at the image-identified recurrence, and time intervals between the key disease-progression points; ( 3 ) Women’ recurrent characteristics: imaging method, number of sites of recurrence, specific sites of recurrence (pelvis, upper abdomen/diaphragm, distant, lymphatic, carcinomatosis), and the extent of recurrence (intra-abdominal, extra-abdominal, ascites/effusion). 2.3 Follow-up Check-ups were performed every three months for the first year post-treatment, every three to six months for the second to fifth years, and annual follow-ups for the sixth year. The follow-up items included: gynecological examination, gynecological ultrasound, serum CA125, and other serum tumor markers. The CA125 was measured by the same assay during follow-up in each patient. An annual imaging check-up consisted of a chest high-resolution computerized tomography (HRCT) scan and an abdomen and pelvic contrast-enhanced computerized tomography (CT) or magnetic resonance imaging (MRI). Whole-body positron emission tomography-computed tomography (PET-CT) was performed if a distant metastasis was highly suspected. 2.4 Statistical analyses Continuous parameters were presented as the median with ranges and analyzed by the Mann-Whitney test. The categorical variables were described as numbers (percentages) and analyzed with the Wilcoxon rank sum test. 35 U/ml and 2×nadir of CA125 level were set as the cut-off values of relapse, and comparisons of correlated proportions were made using the McNemar test. The IBM SPSS Statistics 26.0 software was used for statistical analysis. Image-identified relapse was assessed using CA125 levels and then identified based on the receiver operating characteristic (ROC) curve. Violin plots and ROC curve were created with GraphPad Prism 9. P values < 0.05 were considered statistically significant. 2.5 Ethics statement This study was approved by the Ethical Committee of The First Affiliated Hospital of Chongqing Medical University (protocol code 2022-K404 and date of approval 1 September 2022) and conducted in accordance with the Declaration of Helsinki. Each patient had given written informed consent at the time of treatment for the future use of their clinical data. This study is compliant with all institutional and national guidelines and regulations for human subjects research. 3. RESULTS 3.1 Baseline characteristics and initial treatment From January 2013 to June 2019, a total of 629 women with ovarian, tubal, and peritoneal cancer were initially enrolled. After the screening, 543 women were excluded due to incomplete information (n = 187), lost or irregular follow-up (n = 223), previous treatment for biochemical recurrence (n = 40), and non-serous pathological type (n = 93). Consequently, 86 women were finally included in the study. Among the 86 women with image-identified recurrence, 41 (47.7%) women underwent PDS followed by ACT, and 45 (52.3%) women underwent NACT followed by IDS, for the initial treatment. Women’ characteristics and treatment history are listed in Table 1 . At initial diagnosis, 68.3% of the women in the PDS arm had a serum CA125 level lower than 1000 U/mL, while 57.8% of the women in the NACT arm showed a CA125 over 1000 U/mL ( P = 0.003). Approximately 95.5% and 53.7% were classified in FIGO stage III/IV in the NACT and PDS groups, respectively ( P < 0.001). Likewise, the median number of chemotherapy cycles in the PDS arm is six compared to eight in the NACT arm ( P = 0.019). The two groups had similar baseline features, including age, BMI, and primary tumor type. High-grade serous histology was observed in nearly 90% of women in each group. Both complete and optimal surgeries were achieved in more than half of the women (53.7% vs. 53.3% in the PDS and NACT groups, respectively). No differences were observed in the surgical parameters between the two groups. Table 1 Baseline characteristics and initial treatment of 86 women with recurrent ovarian, tubal, and peritoneal cancer. ALL(N = 86) PDS (N = 41) NACT (N = 45) P -Value Age at diagnosis, years 53.2 (33–70) 51 (33–70) 54(40–70) 0.060 BMI, kg/m 2 23.3 (16.2–33.3) 23.1 (16.2–32.9) 22.7 (16.4–33.3) 0.489 FIGO stage I II III IV 1(1.2%) 20(23.3%) 39(45.3%) 26(30.2%) 1(2.4%) 18(43.9%) 15(36.6%) 7(17.1%) 0 2(4.4%) 24(53.3%) 19(42.2%) 2000 22(25.6%) 25(29.1%) 14(16.3%) 25(29.1%) 13(31.7%) 15(36.6%) 6(14.6%) 7(17.1%) 9(20%) 10(22.2%) 8(17.8%) 18(40%) 0.003* Median number of chemotherapy cycles 7 6 8 0.019* Surgical procedures Pelvic lymphadenectomy Para-aortic lymphadenectomy Abdominal organ resection Distant metastases resection 32(37.2%) 14(16.3%) 5(5.8%) 12(14.1%) 16(39%) 9(22%) 1(2.4%) 5(12.2%) 16(35.6%) 5(11.1%) 4(8.9%) 7(15.9%) 0.940 0.204 0.204 0.625 Operation time, min 188(85–450) 185(85–375) 190(95–450) 0.612 Blood loss, mL 200(20-4100) 200(20-4100) 300(50-1000) 0.302 Surgical outcome RT = 0 RT < 1cm RT ≥ 1cm 46(53.5%) 19(22.1%) 21(24.4%) 22(53.7%) 5(12.2%) 14(34.1%) 24(53.3%) 14(31.1%) 7(15.6%) 0.460 PARP inhibitor use 35(40.7%) 15 (36.6%) 20 (44.4%) 0.459 Histologic grade High-grade serous Low-grade serous Serous not specified 75(87.2%) 3(3.5%) 8(9.3%) 36(87.8%) 1(2.4%) 4(9.8%) 39(86.7%) 2(4.4%) 4(8.9%) 0.899 Note: All data are no. of women (%) unless noted otherwise. Abbreviations: PDS, primary debulking surgery; NACT, neoadjuvant chemotherapy; BMI, body mass index; FIGO, International Federation of Gynecology and Obstetrics; RT, residual tumor; PARP, poly (ADP-ribose) polymerase. *Statistically significant variables, and statistically significant results are indicated in bold. 3.2 CA125 values and time intervals between the key disease-progression points Serum CA125 values at various time points and time intervals were presented in Table 2 . For all the women, the median CA125 level at diagnosis was 929.9 U/mL, ranging from 40.5 to 16201 U/mL. Women in the NACT group showed a higher CA125 than those in the PDS group at diagnosis (1523.6 vs. 663.1 U/mL, P = 0.003). After initial treatment, the median CA125 value of 86 women decreased to nearly 10 U/mL, ranging from 2.7–30.9 U/mL. During follow-up, the median CA125 level at nadir was 7.8 U/mL in 86 women, and there was no difference between the two groups (7.6 vs. 8.3 U/mL, respectively). Subsequently, the disease progressed until imaging-recurrent evidence was detected. At this period, the median CA125 level in the PDS group (75.3 U/mL) was slightly higher than that in the NACT group (54.2 U/mL), but there was no significant difference between the two groups. In the PDS group, it took 7.5 months from surgery to the CA125 level reaching the nadir and then 11.4 months from the nadir level to image-identified recurrence. The NACT group took 6.7 months from surgery to the CA125 nadir level and 9.5 months from the nadir level to the image-identified recurrence. Although the PDS group is slightly longer than the NACT group in each timespan, there was still no statistical difference between the two groups. Table 2 CA125 levels at various time points and time intervals between the key disease-progression points of the recurrent women All (N = 86) PDS (N = 41) NACT (N = 45) P -Value CA125, U/mL At diagnosis 929.9 (40.5-16201) 663.1 (40.5-16201) 1523.6 (120.5-9820.9) 0.003* Pre-IDS 44.55(7-1609) At the end of primary therapy 10.35 (2.7–30.9) 10.3 (2.9–30.9) 10.6 (2.7–27.3) 0.815 Nadir 7.8 (4-36.3) 7.6 (4-36.3) 8.3 (4.3–23.6) 0.558 2 × nadir 20.5 (8.1–84.2) 16.27 (8.1–84.2) 22.6 (10.5–81.4) 0.190 At the image-identified recurrence 64 (5.3-897.6) 75.3 (7.4-897.6) 54.2 (5.3–570) 0.263 The time intervals of CA125 change, month from surgery to nadir 7.3 (3.37-29) 7.5 (4.3–28.5) 6.7 (3.3–29) 0.126 from the end of treatment to nadir 3.4 (0.6–24.6) 2.5 (0.7–19.3) 3.5 (0.6–24.6) 0.649 from the end of treatment to recurrence 15.6 (4.1–60.8) 16.8 (4.1–60.8) 14.1 (4.3–43.3) 0.265 from nadir to recurrence 10.7 (2.1–39.5) 11.4 (2.1–30.3) 9.5 (2.1–39.5) 0.705 from nadir to 2 × nadir 6.77 (1-20.7) 7.97 (1-20.7) 5.83 (1.4–16) 0.294 from 2 × nadir to recurrence a 2.67 (0-28.1) 2.57 (0-28.1) 2.77 (0-23.6) 0.591 from 35 U/mL to recurrence b 0 (0-14.5) 0 (0-12.1) 0 (0-14.5) 0.269 Abbreviations: IDS, interval debulking surgery. CA125 nadir value is the lowest biomarker value after primary therapy during follow-up. *Statistically significant variables and statistically significant results are indicated in bold. a Only 73 women analyzed the time interval from 2 × nadir U/mL when CA125 first appeared to recurrence due to 13 women undergoing relapse with the CA125 value below 2 × nadir U/mL. b Only 58 women analyzed the time interval from 35 U/mL when CA125 first appeared to recurrence due to 28 women undergoing relapse with the CA125 value below 35 U/mL. During follow-up, there are two CA125 cut-off values that have significant predictive value for recurrence, i.e., the upper limit of normal reference value 35 U/mL and the 2×nadir level. For all 86 women experiencing recurrence, 58 (67.4%) showed a CA125 level reaching 35 U/ml, while 73 (84.9%) showed a CA125 level getting 2×nadir before relapse. The difference was statistically significant ( P < 0.001). As shown in Table 3 , for the 28 women whose CA125 level never reached 35 U/mL before recurrence, 17 (60.7%) cases could be identified as high-risk populations if 2×nadir was valued. Moreover, as shown in Fig. 1 , if the CA125 concentration at the image-identified recurrence exceeded 35 U/mL, patients were assigned to the 35 U/ml group; If the CA125 concentration at the image-identified recurrence exceeded its 2×nadir, patients were assigned to the 2×nadir group. The median time interval from CA125 reaching 2×nadir to image-identified recurrence was 2.67 months (range: 0-28.1 months), while that from CA125 reaching 35 U/mL to image-identified recurrence was 0 months (range: 0-14.5 months), with a statistically significant difference ( P < 0.001). To predict clinical relapse, we used the ROC curve to analyze CA125 levels in the diagnosis of recurrence and the CA125 levels measured before the diagnosis of recurrence in 86 patients( P < 0.001). The sensitivity and the specificity for predicting clinical relapse were 82.6% and 73.3%, respectively, which were identified using a CA125 level of 2 ×nadir as the cut-off point (AUC: 0.835, 95%CI: 0.775–0.896). When the CA125 level was at 35 U/mL, the sensitivity and specificity for predicting clinical relapse were 67.4% and 80.2% respectively (Fig. 2 ). Table 3 The classification of 86 recurrent women based on different CA125 cutoff values. CA125 level reached its nadir ×2 level, N (%) All Yes No CA125 level reached 35 U/ml, N (%) Yes 56 (65.1%) 2 (2.3%) 58 (67.4%) * No 17 (19.8%) 11 (12.8%) 28 (32.6%) All 73 (84.9%) * 13 (15.1%) 86 (100%) *Statistically significant variables and statistically significant results are indicated in bold. 3.3 Recurrent characteristics As shown in Table 4 , most women were detected to have multiple recurrent lesions by the examination of PET-CT and MRI. The pelvis was the most common site of recurrence (62.8%) and was detected with a higher percentage in the NACT group than in the PDS group (71.1% vs. 53.7%, P = 0.094). The incidence of distant recurrences (brain/chest/liver/spleen parenchyma) in the NACT group was significantly higher than in the PDS group (46.7% vs. 17.1%, P = 0.003). An intra-abdominal relapse was far more common than an extra-abdominal one in all women (82.6% vs. 17.4%), with the same trend in both groups. Table 4 Recurrent characteristics of the 86 women. All (N = 86) PDS (N = 41) NACT (N = 45) P -Value Imaging method PET-CT MRI CT Puncture under color ultrasound 35(40.7%) 31(36.1%) 14(16.3%) 14(16.3%) 17(41.5%) 14(34.2%) 7(17.1%) 6(14.6%) 18(40%) 17(37.8%) 7(15.6%) 8(17.8%) 0.105 0.726 0.849 0.693 Number of sites of recurrence 1 2+ 28(32.6%) 58(67.4%) 14(34.1%) 27(65.9%) 14(31.1%) 31(68.9%) 0.764 Sites of recurrence Pelvis Upper abdomen/diaphragm Distant (brain/chest/liver/spleen parenchyma) Lymphatic Carcinomatosis Intra-/Extra-abdominal 54 (62.8%) 10 (11.6%) 28 (32.6%) 31 (36%) 27 (31.4%) 22 (53.7%) 4 (9.8%) 7 (17.1%) 15 (36.6%) 10 (24.4%) 32 (71.1%) 6 (13.3%) 21 (46.7%) 16 (35.6%) 17 (37.8%) 0.094 0.741 0.003* 0.921 0.182 0.629 Intra-abdominal Extra-abdominal Ascites/effusion 71 (82.6%) 15 (17.4%) 6 (7%) 33 (80.5%) 8 (19.5%) 2 (4.9%) 38 (84.4%) 7 (15.6%) 4 (8.9%) 0.678 Abbreviations: PET-CT, positron emission tomography-computed tomography; MRI, magnetic resonance imaging; CT, computed tomography. *Statistically significant variables and statistically significant results are indicated in bold. 4. DISCUSSION The 5-year and 12-year survival rates of recurrent ovarian cancer were less than 30% and 5%, respectively 12 . Monitoring recurrence is a key aspect of the overall management of women with EOC. With CA125 levels frequently rising several months before image-identified recurrence 11 , determining the imaging examination time based on the fluctuation of CA125 values could alleviate anxiety and reduce the economic burden for women with asymptomatic recurrence by avoiding multiple negative imaging examinations. Therefore, defining the CA125 cut-off that signifies the need for diagnostic imaging and therapy to relapse is critical to ensure effective management. However, using 35 U/ml as the CA125 abnormal threshold for all women in general may result in omissions or delays in recurrence detection. In this study, by using the ROC curve to analyze CA125 levels in the diagnosis of recurrence and the CA125 levels measured before the diagnosis of recurrence in 86 patients, we found that CA125 reaching 2×nadir during the follow-up process might be a more sensitive and early recurrence signal in women having completed initial treatments for serous ovarian cancer. Moreover, more than half of the women (17, 60.71%) who never reached the upper limit of the normal range of 35 U/mL at the time of relapse showed a CA125 level over 2×nadir. The combination of 2×nadir and 35 U/mL predicted outcomes better than 35 U/mL alone, which could significantly improve the detection rate of relapse. Many studies have redefined the value of CA125 in predicting relapse. A rise of 5 U/mL or 10 U/mL from the nadir CA125 level has been associated with recurrence in women who had a complete response to therapy 13 . Wang et al. proposed that the CA125 level of 1.68 × nadir was defined as the indicator of recurrent disease 14 . In a French multicenter study, nadir CA125 values below 20 kU/L were associated with more prolonged OS (Overall Survival) and DFS (Disease-free Survival) (P < 0.0001) 15 . However, these studies aimed to reveal the association between CA125 elevation and the ultimate recurrence without proposing a specific follow-up strategy. In the only randomized trial ever performed of CA125 monitoring after the initial treatment, patients who only experienced the increase of CA125 were assigned to early treatment, and patients with clinical or symptomatic relapse were assigned to delayed treatment 11 . The results showed no evidence of the survival benefit of early treatment. This finding challenged the widespread belief by denying routine recommend of CA125 follow-up and the early treatment of relapse based on a raised CA125 concentration alone. Actually, monitoring CA125 has been a routine in conventional follow-up, and effective but slightly expensive imaging examinations, such as computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography/computed tomography (PET/CT), were used as an additional check when CA125 is abnormal 16–17 . Therefore, our study wants to analyze and investigate the correlation between early and delayed treatment groups in the study mentioned above, whether the raised CA125 concentration alone can predict the clinical recurrence of the delayed treatment group. It is essential but challenging for asymptomatic women to determine the optimal imaging examination timing based on the fluctuation of CA125. Some gynecologic oncologists advocate a wait-and-see approach, but the duration of the waiting period and the recurrence surveillance are unclear 18 . Asymptomatic women waiting for symptoms may suffer from anxiety, leading to decreased quality of life and unnecessary imaging examinations 11 . Despite the SGO and NCCN guidelines recommending that imaging only be used when clinically indicated, more than 75% of ovarian cancer women were still receiving routine surveillance for non-indication imaging 19,20 . Hence, a clear cut-off of the CA125 level to start the diagnostic imaging was required. According to our results, when the CA125 level reaches 2 × nadir or 35 U/mL, an imaging examination at this follow-up visit or the subsequent follow-up would be recommended. More specifically, imaging examinations should be performed once the CA125 level exceeds 35 U/mL or within three months for women whose CA125 level is consistently lower than 35 U/mL but reaches 2×nadir. In the study of Wang et al, comparing with a CA125 level > 1.68×nadir at relapse, women with CA125 level ≤ 1.68×nadir at relapse can extend the overall and progression-free survival durations 14 . In the present study, the sensitivity attained using a CA125 level of 2 × nadir was relatively high (82.6%). However, our findings did not reveal a relationship between the CA125 levels at image-identified relapse and overall survival. The possible reason was that not every asymptomatic woman start treatment immediately after observing image-identified relapse. Given the selection bias inherent to retrospective studies, attempts to translate the above-mentioned favorable outcome to all recurrent OvCa women should be approached with caution. Our study aimed not only to predict recurrence, but also to clarify the time point to start image examination and appropriate therapy according to the CA125 levels. Based on the current results, our team would further verify the improvement effect of intervention at 2×nadir CA125 value on survival outcomes by performing prospective trials. Several differences were noticed between the NACT and PDS groups, including those in the FIGO stage, CA125 at diagnosis, the number of chemotherapy cycles, and the incidence of distant metastasis. These differences might be related to the severity of the disease itself in the two groups of women. Gynecologic oncologists would like to use platinum-based chemotherapy several times in advance to reduce the tumor size of women with advanced OC, aiming to achieve optimal surgery 3,4,21,22 . In our study, the tendency of significant deviation in CA125 was disappeared following treatment, as CA125 decreased to nearly 10 U/mL, ranging from 2.7–30.9 U/mL. It is not what we expected that the changing trends of follow-up CA125 profiles after the two distinct treatments in the real clinical world was still no statistical difference. Additionally, there is evidence that most EOC and primary peritoneal cancers originated from the umbrella end of the fallopian tube. The standard treatment for these three types of cancers is almost identical to clinical guidelines. Therefore, five women with fallopian tube cancer and five women with peritoneal cancer in this study were not excluded. Limitations of this study include its retrospective and unicentric nature and the relatively small sample size. Another drawback is that we mainly focused on CA125 without considering the predictive function of other tumor biomarkers 23 . 5. CONCLUSION To sum up, our results showed that the CA125 level of 2× nadir indicates the need to initiate imaging examination within three months to detect recurrent serous ovarian, tubal, and peritoneal cancers. As the combination of 2×nadir and 35 U/mL predicted outcomes better than either alone, it may be a practical and low-cost method for oncologists to manage women with serous OvCa. Abbreviations CA125, Cancer Antigen 125; OvCa, Ovarian cancer; EOC , epithelial ovarian cancer; NACT, neoadjuvant chemotherapy; IDS, interval debulking surgery; PDS , primary debulking surgery; FIGO, International Federation of Gynecology and Obstetrics; RT, residual tumor. Declarations Acknowledgments The authors would like to thank the patients and their families for their participation in this project. Author contributions K.W.D. wrote the manuscript, performed statistical analyses, developed the idea and concept, and prepared all figures and tables. Q.Y.Y. assisted with statistical analyses and helped with manuscript writing. J.J.L., X.X.C., and H.J.W. assisted with sample collection and manuscript writing. J.H. and D.W.C. assisted with concept development and manuscript writing. J.Y.T. oversaw the project, assisted with concept development, and assisted with manuscript writing. All authors reviewed the manuscript. Funding This research received no external funding except for the Open Access Publication Funds of Chongqing Medical University, China. Additional information Competing interest The authors declare no competing interests. Data Availability Statement The datasets analyzed during the current study are not publicly available due to privacy and ethical restrictions but are available from the corresponding author on reasonable request. References Title of Cancer Stat Facts: Ovarian Cancer. Available from: https://seer.cancer.gov/statfacts/html/ovary.html. Accessed on August 1, 2023. Lheureux, S., Braunstein, M. & Oza, A. M. Epithelial ovarian cancer: Evolution of management in the era of precision medicine. CA. Cancer J. Clin. caac.21559 (2019) doi:10.3322/caac.21559. Kehoe, S. et al. Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): an open-label, randomised, controlled, non-inferiority trial. The Lancet 386 , 249–257 (2015). Vergote, I., Amant, F. & Ehlen, T. Neoadjuvant Chemotherapy or Primary Surgery in Stage IIIC or IV Ovarian Cancer. N. Engl. J. Med. 11 (2010) doi:10.1056/NEJMoa0908806. Mitsopoulos, V., Innamaa, A., Lippiatt, J., Collins, S. & Biliatis, I. Differences in Patterns of Recurrence Between Primary and Interval Debulking Surgery for Advanced Ovarian Cancer. Anticancer Res. 42 , 2003–2008 (2022). Salani, R. et al. Posttreatment surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic Oncologists recommendations. Am. J. Obstet. Gynecol. 204 , 466–478 (2011). Ferraro, S. et al. Serum human epididymis protein 4 vs. carbohydrate antigen 125 in ovarian cancer follow-up. Clin. Biochem. 60 , 84–90 (2018). Rustin, G. J. S., Nelstrop, A. E., Tuxen, M. K. & Lambert, H. E. Defining progression of ovarian carcinoma during follow-up according to CA 125: A North Thames Ovary Group study. Ann. Oncol. 7 , 361–364 (1996). Wilder, J. L. et al. Clinical implications of a rising serum CA-125 within the normal range in patients with epithelial ovarian cancer: a preliminary investigation☆. Gynecol. Oncol. 89 , 233–235 (2003). Piatek, S. et al. Rising serum CA-125 levels within the normal range is strongly associated recurrence risk and survival of ovarian cancer. J. Ovarian Res. 13 , 102 (2020). Rustin, G. J. Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial. 376 , 9 (2010). Charkhchi, P. et al. CA125 and Ovarian Cancer: A Comprehensive Review. Cancers 12 , 3730 (2020). Gadducci, A. & Cosio, S. Surveillance of patients after initial treatment of ovarian cancer. Crit. Rev. Oncol. Hematol. 71 , 43–52 (2009). Wang, F. et al. CA-125–indicated asymptomatic relapse confers survival benefit to ovarian cancer patients who underwent secondary cytoreduction surgery. J. Ovarian Res. 6 , 14 (2013). Riedinger, J. M. et al. CA 125 half-life and CA 125 nadir during induction chemotherapy are independent predictors of epithelial ovarian cancer outcome: results of a French multicentric study. Ann. Oncol. 17 , 1234–1238 (2006). Salani, R., Khanna, N., Frimer, M., Bristow, R. E. & Chen, L. An update on post-treatment surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic Oncology (SGO) recommendations. Gynecol. Oncol. 146 , 3–10 (2017). Tanner, E. J. et al. Surveillance for the detection of recurrent ovarian cancer: Survival impact or lead-time bias? Gynecol. Oncol. 117 , 336–340 (2010). Fleming, L. Playing the Waiting Game … The Asymptomatic Patient with Recurrent Ovarian Cancer Detected Only by Rising Ca125 Levels. Scott. Med. J. 46 , 81–83 (2001). Rimel, B. J. et al. Improving quality and decreasing cost in gynecologic oncology care. Society of gynecologic oncology recommendations for clinical practice. Gynecol. Oncol. 137 , 280–284 (2015). Esselen, K. M. et al. Use of CA-125 Tests and Computed Tomographic Scans for Surveillance in Ovarian Cancer. JAMA Oncol. 2 , 1427 (2016). Fagotti, A. et al. Randomized trial of primary debulking surgery versus neoadjuvant chemotherapy for advanced epithelial ovarian cancer (SCORPION-NCT01461850). Int. J. Gynecol. Cancer 30 , 1657–1664 (2020). Onda, T. et al. Comparison of survival between primary debulking surgery and neoadjuvant chemotherapy for stage III/IV ovarian, tubal and peritoneal cancers in phase III randomised trial. Eur. J. Cancer 130 , 114–125 (2020). Vallius, T. et al. Postoperative human epididymis protein 4 predicts primary therapy outcome in advanced epithelial ovarian cancer. Tumor Biol. 39 , 101042831769118 (2017). Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3835030","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":266078814,"identity":"9634cf02-7707-4297-83c9-c32a3fb89231","order_by":0,"name":"Kaiwen Du","email":"","orcid":"","institution":"The First Affiliated Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Kaiwen","middleName":"","lastName":"Du","suffix":""},{"id":266078815,"identity":"6754a250-3642-4ded-a225-d4d242cf81b2","order_by":1,"name":"Qiyu Yang","email":"","orcid":"","institution":"The First Affiliated Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Qiyu","middleName":"","lastName":"Yang","suffix":""},{"id":266078816,"identity":"a513efed-42a3-4f93-8515-113816faeee8","order_by":2,"name":"Jin Huang","email":"","orcid":"","institution":"The Chinese University of Hong Kong","correspondingAuthor":false,"prefix":"","firstName":"Jin","middleName":"","lastName":"Huang","suffix":""},{"id":266078817,"identity":"19e98421-256d-4683-8b9c-e34420667249","order_by":3,"name":"David Wai Chan","email":"","orcid":"","institution":"The Chinese University of Hong Kong-Shenzhen","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"Wai","lastName":"Chan","suffix":""},{"id":266078818,"identity":"ba6ae9db-6eb8-4834-959f-966ccba0b374","order_by":4,"name":"Jinjin Li","email":"","orcid":"","institution":"The First Affiliated Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jinjin","middleName":"","lastName":"Li","suffix":""},{"id":266078819,"identity":"845eacb0-71a6-4663-b00a-f80d3e2b0008","order_by":5,"name":"Xiaoxia Chang","email":"","orcid":"","institution":"The First Affiliated Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xiaoxia","middleName":"","lastName":"Chang","suffix":""},{"id":266078820,"identity":"6ac7d8c8-612c-4ebb-bf76-6d4c06c4c57f","order_by":6,"name":"Hanjie Wang","email":"","orcid":"","institution":"The First Affiliated Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hanjie","middleName":"","lastName":"Wang","suffix":""},{"id":266078821,"identity":"c23d8aaa-d55a-4aa1-bef9-d569e777a4e1","order_by":7,"name":"Junying Tang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0UlEQVRIiWNgGAWjYLACCQjF+IDBgAjVPEhamA2I1wIFbBJEucme/ezhF5ZtDPJ8186YVf4ouCPPwH746Aa8tvDkpVlItjEYzrydY3abx+CZYQNPWtoN/A7LMTMAakkwAGlhMDjM2CDBY4ZfC/8bhJbCHwaH7QlrkcgxfgDTwsBjcDiRsJYbb8wYJM6B/JJWLA3UktxGyC/s/TnGnyXKgCF2O3njxx9/Dtv2sx8+hlcLELBJS7L9Z2A4AOMSUA4CzB8//GFAaBkFo2AUjIJRgA4AWRNGInuc5XEAAAAASUVORK5CYII=","orcid":"","institution":"The First Affiliated Hospital of Chongqing Medical University","correspondingAuthor":true,"prefix":"","firstName":"Junying","middleName":"","lastName":"Tang","suffix":""}],"badges":[],"createdAt":"2024-01-04 16:59:36","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3835030/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3835030/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":49440779,"identity":"af0f23a0-2d6a-462e-93be-dc571867a735","added_by":"auto","created_at":"2024-01-10 21:55:35","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":36163,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe time interval characteristics of the 35 U/m group and the 2×nadir group in 86 women.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIf the CA125 concentration at the image-identified recurrence exceeded 35 U/mL, patients were assigned to the 35 U/ml group; If the CA125 concentration at the image-identified recurrence exceeded its 2×nadir, patients were assigned to the 2×nadir group. (A) 35 U/ml group: violin plot of time intervals between firstly reaching 35 U/mL of CA125 and image-identified recurrence in fifty-eight women (58, 67.4%) ;(B) 2×nadir group: violin plot of time intervals between firstly reaching 2×nadire U/mL of CA125 and image-identified recurrence in seventy-three women (73, 84.9%). Inside each violin plot is a box plot showing the quartile, median, and range distribution. There are significant differences between red violin and blue violin distributions in each plot.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3835030/v1/e0bd418ab480fadfb9b3bdd9.jpg"},{"id":49440780,"identity":"62f3a052-701d-4aef-a7c8-2cd446e6280c","added_by":"auto","created_at":"2024-01-10 21:55:35","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":55513,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eROC curve for image-identified relapse by CA125 level (The sensitivity and the specificity of CA125 level of 2 ×nadir as the cut-off point for predicting clinical relapse were 82.6% and 73.3%, respectively. \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e\u0026lt;0.001, AUC: 0.835, 95%CI: 0.775-0.896).\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3835030/v1/b51249ad3d0157b4bc67d5f3.jpg"},{"id":49440956,"identity":"14aedfe9-60b9-4fcf-b45f-3b7c0115f2d4","added_by":"auto","created_at":"2024-01-10 22:03:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":502216,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3835030/v1/0618dc42-e6db-4905-be78-481e407ddaa7.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"An increase of serum CA-125 to two times of nadir level strongly predicts the image-identified recurrence of serous ovarian cancer","fulltext":[{"header":"1. INTRODUCTION","content":"\u003cp\u003eOvarian cancer is the second deadliest gynecological cancer, with a 5-year survival rate of 50.8%\u003csup\u003e1\u003c/sup\u003e. Over 80% of these women are diagnosed as serous epithelial tissue \u003csup\u003e2\u003c/sup\u003e. The standard treatment involves cytoreduction surgery and chemotherapy. Primary debulking surgery (PDS) followed by platinum-based chemotherapy is the preferred initial treatment for advanced-stage ovarian cancer. Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) is an alternative option for those who cannot undergo PDS. While many randomized clinical trials have shown the non-inferiority of NACT in survival outcomes\u003csup\u003e3,4\u003c/sup\u003e, a recent study found that women in the NACT group experienced more recurrences in the pelvis or upper abdomen compared to the PDS group\u003csup\u003e5\u003c/sup\u003e. Regardless of the treatment option, complete resection of the tumor through surgery remains crucial in reducing the recurrence rate and improving survival.\u003c/p\u003e \u003cp\u003eOvarian cancer recurs in 25% of early-stage and more than 80% of advanced-stage women\u003csup\u003e6\u003c/sup\u003e. Effective follow-up tests are needed to detect recurrence or disease progression. Screening methods include physical examination, serum tumor biomarkers, and imaging techniques. The most widely used tumor biomarker is CA125, a glycoprotein found on the surface of ovarian cancer cells since 1981. Additional maker as HE4 have been introduced in Guideline, but CA125 seems to be the most reliable marker for disease monitoring\u003csup\u003e7\u003c/sup\u003e. The Gynecologic Cancer InterGroup has already accepted the research result by Rustin that CA125 levels more than twice the upper limit of normal predict tumor relapse\u003csup\u003e8\u003c/sup\u003e. However, using the traditional cut-off value of 35 U/mL for recurrence is being questioned. Studies have shown that even within the normal range(\u0026lt;\u0026thinsp;35 U/mL), three progressively rising CA125 at 1- to 3-month intervals\u003csup\u003e9\u003c/sup\u003e or an increase of more than 5 U/mL from 3 to 6 months after treatment\u003csup\u003e10\u003c/sup\u003e are associated with a higher risk of relapse. Therefore, a more sensitive cut-off point is needed.\u003c/p\u003e \u003cp\u003eIn fact, relying solely on CA125 levels is not sufficient to confirm recurrence. A rise to more than the cut-off value of CA125 several months before the evidence of image-identified recurrence or symptomatic clinical relapse is called biochemical recurrence. Early treatment based on elevated CA125 levels alone can cause anxiety and side effects without improving survival\u003csup\u003e11\u003c/sup\u003e. Excessive imaging screening would cause unnecessary anxiety and financial burden. Undoubtedly, predicting image-identified recurrence based on CA125 elevation is challenging but important. Additionally, initial treatment strategies can cause CA125 profiles to be worse in those having NACT than PDS as NACT patients have more advanced disease in the real clinical world. However, the tendency of significant deviation in CA125 will disappear following treatment, as CA125 will reduce to a low level after a combination of surgery and chemotherapy. Exploring the changing trends of CA125 profiles after the two distinct treatments in the real clinical world is expected to contribute more evidence to guide clinical practice in this area.\u003c/p\u003e \u003cp\u003eIn this study, the aim is to explore the association between biochemical recurrence (elevated CA125) and image-identified recurrence of ovarian cancer to improve the prediction of recurrent lesions requiring treatment. Additionally, a subgroup analysis was performed to clarify the effects of different initial treatments on the recurrent outcomes at the biomedical level and anatomical distribution.\u003c/p\u003e"},{"header":"2. MATERIAL AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study population\u003c/h2\u003e \u003cp\u003e All women diagnosed with International Federation of Gynecology and Obstetrics (FIGO, 2013) stage I-IV ovarian, tubal, and peritoneal cancers from January 2013 to June 2019 at the Department of Gynecology, The First Affiliated Hospital of Chongqing Medical University, China, were reviewed. We retrospectively collected clinical data of 86 women who met the following inclusion criteria: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) All pathological types were serous; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) Relapse was confirmed by imaging and was treated accordingly; (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) Without other malignancy; (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) Complete clinical data; (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) Regular follow-up; (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) platinum-sensitive recurrence. Those who achieved platinum-resistant recurrence and received previous treatment for biochemical recurrence were excluded. The criteria of platinum-sensitive recurrence: women relapsed after six months since receiving first-line chemotherapy on platinum-containing regimens. The criteria of platinum-resistant recurrence: women received first-line chemotherapy on platinum-containing regimens but relapsed in six months. According to initial treatments, 45 women receiving one to eight cycles of NACT (platinum-based chemotherapy) and IDS were assigned to the NACT group and forty-one women who received PDS to the PDS group.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Collection of clinical information of the enrolled women\u003c/h2\u003e \u003cp\u003e(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) Women\u0026rsquo;s baseline characteristics and initial treatment: age at diagnosis, body mass index (BMI), FIGO stage, primary tumor type, CA125 level at diagnosis, the median number of total chemotherapy cycles, surgical procedures, operation time, blood loss, surgical outcome, PARP inhibitor use, and histologic grade; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) CA125 level per treatment phase: at diagnosis, before IDS, at the end of primary therapy, at nadir during follow-up, at 2 \u0026times; nadir, at the image-identified recurrence, and time intervals between the key disease-progression points; (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) Women\u0026rsquo; recurrent characteristics: imaging method, number of sites of recurrence, specific sites of recurrence (pelvis, upper abdomen/diaphragm, distant, lymphatic, carcinomatosis), and the extent of recurrence (intra-abdominal, extra-abdominal, ascites/effusion).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Follow-up\u003c/h2\u003e \u003cp\u003eCheck-ups were performed every three months for the first year post-treatment, every three to six months for the second to fifth years, and annual follow-ups for the sixth year. The follow-up items included: gynecological examination, gynecological ultrasound, serum CA125, and other serum tumor markers. The CA125 was measured by the same assay during follow-up in each patient. An annual imaging check-up consisted of a chest high-resolution computerized tomography (HRCT) scan and an abdomen and pelvic contrast-enhanced computerized tomography (CT) or magnetic resonance imaging (MRI). Whole-body positron emission tomography-computed tomography (PET-CT) was performed if a distant metastasis was highly suspected.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Statistical analyses\u003c/h2\u003e \u003cp\u003eContinuous parameters were presented as the median with ranges and analyzed by the Mann-Whitney test. The categorical variables were described as numbers (percentages) and analyzed with the Wilcoxon rank sum test. 35 U/ml and 2\u0026times;nadir of CA125 level were set as the cut-off values of relapse, and comparisons of correlated proportions were made using the McNemar test. The IBM SPSS Statistics 26.0 software was used for statistical analysis. Image-identified relapse was assessed using CA125 levels and then identified based on the receiver operating characteristic (ROC) curve. Violin plots and ROC curve were created with GraphPad Prism 9. \u003cem\u003eP\u003c/em\u003e values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Ethics statement\u003c/h2\u003e \u003cp\u003e This study was approved by the Ethical Committee of The First Affiliated Hospital of Chongqing Medical University (protocol code 2022-K404 and date of approval 1 September 2022) and conducted in accordance with the Declaration of Helsinki. Each patient had given written informed consent at the time of treatment for the future use of their clinical data. This study is compliant with all institutional and national guidelines and regulations for human subjects research.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. RESULTS","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Baseline characteristics and initial treatment\u003c/h2\u003e \u003cp\u003eFrom January 2013 to June 2019, a total of 629 women with ovarian, tubal, and peritoneal cancer were initially enrolled. After the screening, 543 women were excluded due to incomplete information (n\u0026thinsp;=\u0026thinsp;187), lost or irregular follow-up (n\u0026thinsp;=\u0026thinsp;223), previous treatment for biochemical recurrence (n\u0026thinsp;=\u0026thinsp;40), and non-serous pathological type (n\u0026thinsp;=\u0026thinsp;93). Consequently, 86 women were finally included in the study.\u003c/p\u003e \u003cp\u003eAmong the 86 women with image-identified recurrence, 41 (47.7%) women underwent PDS followed by ACT, and 45 (52.3%) women underwent NACT followed by IDS, for the initial treatment. Women\u0026rsquo; characteristics and treatment history are listed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. At initial diagnosis, 68.3% of the women in the PDS arm had a serum CA125 level lower than 1000 U/mL, while 57.8% of the women in the NACT arm showed a CA125 over 1000 U/mL (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003). Approximately 95.5% and 53.7% were classified in FIGO stage III/IV in the NACT and PDS groups, respectively (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Likewise, the median number of chemotherapy cycles in the PDS arm is six compared to eight in the NACT arm (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.019). The two groups had similar baseline features, including age, BMI, and primary tumor type. High-grade serous histology was observed in nearly 90% of women in each group. Both complete and optimal surgeries were achieved in more than half of the women (53.7% vs. 53.3% in the PDS and NACT groups, respectively). No differences were observed in the surgical parameters between the two groups.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics and initial treatment of 86 women with recurrent ovarian, tubal, and peritoneal cancer.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eALL(N\u0026thinsp;=\u0026thinsp;86)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePDS (N\u0026thinsp;=\u0026thinsp;41)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNACT (N\u0026thinsp;=\u0026thinsp;45)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-Value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at diagnosis, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53.2 (33\u0026ndash;70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e51 (33\u0026ndash;70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e54(40\u0026ndash;70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.060\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI, kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23.3 (16.2\u0026ndash;33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23.1 (16.2\u0026ndash;32.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22.7 (16.4\u0026ndash;33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.489\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFIGO stage\u003c/p\u003e \u003cp\u003eI\u003c/p\u003e \u003cp\u003eII\u003c/p\u003e \u003cp\u003eIII\u003c/p\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1(1.2%)\u003c/p\u003e \u003cp\u003e20(23.3%)\u003c/p\u003e \u003cp\u003e39(45.3%)\u003c/p\u003e \u003cp\u003e26(30.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(2.4%)\u003c/p\u003e \u003cp\u003e18(43.9%)\u003c/p\u003e \u003cp\u003e15(36.6%)\u003c/p\u003e \u003cp\u003e7(17.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e2(4.4%)\u003c/p\u003e \u003cp\u003e24(53.3%)\u003c/p\u003e \u003cp\u003e19(42.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001*\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor origin\u003c/p\u003e \u003cp\u003eOvary\u003c/p\u003e \u003cp\u003eFallopian tube\u003c/p\u003e \u003cp\u003ePeritoneum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76(88.4%)\u003c/p\u003e \u003cp\u003e5(5.8%)\u003c/p\u003e \u003cp\u003e5(5.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38(92.7%)\u003c/p\u003e \u003cp\u003e3(7.3%)\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38(84.4%)\u003c/p\u003e \u003cp\u003e2(4.4%)\u003c/p\u003e \u003cp\u003e5(11.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.194\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCA125 at diagnosis, U/mL\u003c/p\u003e \u003cp\u003e\u0026le;500\u003c/p\u003e \u003cp\u003e\u0026le;1000\u003c/p\u003e \u003cp\u003e\u0026le;2000\u003c/p\u003e \u003cp\u003e\u0026gt;2000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22(25.6%)\u003c/p\u003e \u003cp\u003e25(29.1%)\u003c/p\u003e \u003cp\u003e14(16.3%)\u003c/p\u003e \u003cp\u003e25(29.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13(31.7%)\u003c/p\u003e \u003cp\u003e15(36.6%)\u003c/p\u003e \u003cp\u003e6(14.6%)\u003c/p\u003e \u003cp\u003e7(17.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9(20%)\u003c/p\u003e \u003cp\u003e10(22.2%)\u003c/p\u003e \u003cp\u003e8(17.8%)\u003c/p\u003e \u003cp\u003e18(40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.003*\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian number of chemotherapy cycles\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.019*\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurgical procedures\u003c/p\u003e \u003cp\u003ePelvic lymphadenectomy\u003c/p\u003e \u003cp\u003ePara-aortic lymphadenectomy\u003c/p\u003e \u003cp\u003eAbdominal organ resection\u003c/p\u003e \u003cp\u003eDistant metastases resection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32(37.2%)\u003c/p\u003e \u003cp\u003e14(16.3%)\u003c/p\u003e \u003cp\u003e5(5.8%)\u003c/p\u003e \u003cp\u003e12(14.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16(39%)\u003c/p\u003e \u003cp\u003e9(22%)\u003c/p\u003e \u003cp\u003e1(2.4%)\u003c/p\u003e \u003cp\u003e5(12.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16(35.6%)\u003c/p\u003e \u003cp\u003e5(11.1%)\u003c/p\u003e \u003cp\u003e4(8.9%)\u003c/p\u003e \u003cp\u003e7(15.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.940\u003c/p\u003e \u003cp\u003e0.204\u003c/p\u003e \u003cp\u003e0.204\u003c/p\u003e \u003cp\u003e0.625\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOperation time, min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e188(85\u0026ndash;450)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e185(85\u0026ndash;375)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e190(95\u0026ndash;450)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.612\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood loss, mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e200(20-4100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e200(20-4100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e300(50-1000)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.302\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurgical outcome\u003c/p\u003e \u003cp\u003eRT\u0026thinsp;=\u0026thinsp;0\u003c/p\u003e \u003cp\u003eRT\u0026thinsp;\u0026lt;\u0026thinsp;1cm\u003c/p\u003e \u003cp\u003eRT\u0026thinsp;\u0026ge;\u0026thinsp;1cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46(53.5%)\u003c/p\u003e \u003cp\u003e19(22.1%)\u003c/p\u003e \u003cp\u003e21(24.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22(53.7%)\u003c/p\u003e \u003cp\u003e5(12.2%)\u003c/p\u003e \u003cp\u003e14(34.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24(53.3%)\u003c/p\u003e \u003cp\u003e14(31.1%)\u003c/p\u003e \u003cp\u003e7(15.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.460\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePARP inhibitor use\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35(40.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (36.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20 (44.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.459\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistologic grade\u003c/p\u003e \u003cp\u003eHigh-grade serous\u003c/p\u003e \u003cp\u003eLow-grade serous\u003c/p\u003e \u003cp\u003eSerous not specified\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e75(87.2%)\u003c/p\u003e \u003cp\u003e3(3.5%)\u003c/p\u003e \u003cp\u003e8(9.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36(87.8%)\u003c/p\u003e \u003cp\u003e1(2.4%)\u003c/p\u003e \u003cp\u003e4(9.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39(86.7%)\u003c/p\u003e \u003cp\u003e2(4.4%)\u003c/p\u003e \u003cp\u003e4(8.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.899\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eNote: All data are no. of women (%) unless noted otherwise.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAbbreviations: PDS, primary debulking surgery; NACT, neoadjuvant chemotherapy; BMI, body mass index; FIGO, International Federation of Gynecology and Obstetrics; RT, residual tumor; PARP, poly (ADP-ribose) polymerase.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e*Statistically significant variables, and statistically significant results are indicated in bold.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.2 CA125 values and time intervals between the key disease-progression points\u003c/h2\u003e \u003cp\u003eSerum CA125 values at various time points and time intervals were presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. For all the women, the median CA125 level at diagnosis was 929.9 U/mL, ranging from 40.5 to 16201 U/mL. Women in the NACT group showed a higher CA125 than those in the PDS group at diagnosis (1523.6 vs. 663.1 U/mL, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003). After initial treatment, the median CA125 value of 86 women decreased to nearly 10 U/mL, ranging from 2.7\u0026ndash;30.9 U/mL. During follow-up, the median CA125 level at nadir was 7.8 U/mL in 86 women, and there was no difference between the two groups (7.6 vs. 8.3 U/mL, respectively). Subsequently, the disease progressed until imaging-recurrent evidence was detected. At this period, the median CA125 level in the PDS group (75.3 U/mL) was slightly higher than that in the NACT group (54.2 U/mL), but there was no significant difference between the two groups. In the PDS group, it took 7.5 months from surgery to the CA125 level reaching the nadir and then 11.4 months from the nadir level to image-identified recurrence. The NACT group took 6.7 months from surgery to the CA125 nadir level and 9.5 months from the nadir level to the image-identified recurrence. Although the PDS group is slightly longer than the NACT group in each timespan, there was still no statistical difference between the two groups.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCA125 levels at various time points and time intervals between the key disease-progression points of the recurrent women\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll (N\u0026thinsp;=\u0026thinsp;86)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePDS (N\u0026thinsp;=\u0026thinsp;41)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNACT (N\u0026thinsp;=\u0026thinsp;45)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-Value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCA125, U/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAt diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e929.9 (40.5-16201)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e663.1 (40.5-16201)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1523.6 (120.5-9820.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.003*\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePre-IDS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e44.55(7-1609)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAt the end of primary therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.35 (2.7\u0026ndash;30.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.3 (2.9\u0026ndash;30.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.6 (2.7\u0026ndash;27.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.815\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNadir\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.8 (4-36.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.6 (4-36.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.3 (4.3\u0026ndash;23.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.558\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2 \u0026times; nadir\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20.5 (8.1\u0026ndash;84.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.27 (8.1\u0026ndash;84.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22.6 (10.5\u0026ndash;81.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.190\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAt the image-identified recurrence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64 (5.3-897.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75.3 (7.4-897.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e54.2 (5.3\u0026ndash;570)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.263\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThe time intervals of CA125 change, month\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003efrom surgery to nadir\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.3 (3.37-29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.5 (4.3\u0026ndash;28.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.7 (3.3\u0026ndash;29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.126\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003efrom the end of treatment to nadir\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.4 (0.6\u0026ndash;24.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.5 (0.7\u0026ndash;19.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.5 (0.6\u0026ndash;24.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.649\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003efrom the end of treatment to recurrence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.6 (4.1\u0026ndash;60.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.8 (4.1\u0026ndash;60.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14.1 (4.3\u0026ndash;43.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.265\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003efrom nadir to recurrence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.7 (2.1\u0026ndash;39.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.4 (2.1\u0026ndash;30.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.5 (2.1\u0026ndash;39.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.705\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003efrom nadir to 2 \u0026times; nadir\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.77 (1-20.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.97 (1-20.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.83 (1.4\u0026ndash;16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.294\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003efrom 2 \u0026times; nadir to recurrence\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.67 (0-28.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.57 (0-28.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.77 (0-23.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.591\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003efrom 35 U/mL to recurrence\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0-14.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0-12.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0-14.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.269\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAbbreviations: IDS, interval debulking surgery.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eCA125 nadir value is the lowest biomarker value after primary therapy during follow-up.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e*Statistically significant variables and statistically significant results are indicated in bold.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003ea\u003c/sup\u003eOnly 73 women analyzed the time interval from 2 \u0026times; nadir U/mL when CA125 first appeared to recurrence due to 13 women undergoing relapse with the CA125 value below 2 \u0026times; nadir U/mL.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003eb\u003c/sup\u003eOnly 58 women analyzed the time interval from 35 U/mL when CA125 first appeared to recurrence due to 28 women undergoing relapse with the CA125 value below 35 U/mL.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eDuring follow-up, there are two CA125 cut-off values that have significant predictive value for recurrence, i.e., the upper limit of normal reference value 35 U/mL and the 2\u0026times;nadir level. For all 86 women experiencing recurrence, 58 (67.4%) showed a CA125 level reaching 35 U/ml, while 73 (84.9%) showed a CA125 level getting 2\u0026times;nadir before relapse. The difference was statistically significant (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). As shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, for the 28 women whose CA125 level never reached 35 U/mL before recurrence, 17 (60.7%) cases could be identified as high-risk populations if 2\u0026times;nadir was valued. Moreover, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, if the CA125 concentration at the image-identified recurrence exceeded 35 U/mL, patients were assigned to the 35 U/ml group; If the CA125 concentration at the image-identified recurrence exceeded its 2\u0026times;nadir, patients were assigned to the 2\u0026times;nadir group. The median time interval from CA125 reaching 2\u0026times;nadir to image-identified recurrence was 2.67 months (range: 0-28.1 months), while that from CA125 reaching 35 U/mL to image-identified recurrence was 0 months (range: 0-14.5 months), with a statistically significant difference (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). To predict clinical relapse, we used the ROC curve to analyze CA125 levels in the diagnosis of recurrence and the CA125 levels measured before the diagnosis of recurrence in 86 patients(\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The sensitivity and the specificity for predicting clinical relapse were 82.6% and 73.3%, respectively, which were identified using a CA125 level of 2 \u0026times;nadir as the cut-off point (AUC: 0.835, 95%CI: 0.775\u0026ndash;0.896). When the CA125 level was at 35 U/mL, the sensitivity and specificity for predicting clinical relapse were 67.4% and 80.2% respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe classification of 86 recurrent women based on different CA125 cutoff values.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eCA125 level reached its nadir \u0026times;2 level, N (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAll\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCA125 level reached 35 U/ml, N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e56 (65.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (2.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e58 (67.4%) *\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (19.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (12.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28 (32.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAll\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e73 (84.9%) *\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (15.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e86 (100%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e*Statistically significant variables and statistically significant results are indicated in bold.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Recurrent characteristics\u003c/h2\u003e \u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, most women were detected to have multiple recurrent lesions by the examination of PET-CT and MRI. The pelvis was the most common site of recurrence (62.8%) and was detected with a higher percentage in the NACT group than in the PDS group (71.1% vs. 53.7%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.094). The incidence of distant recurrences (brain/chest/liver/spleen parenchyma) in the NACT group was significantly higher than in the PDS group (46.7% vs. 17.1%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003). An intra-abdominal relapse was far more common than an extra-abdominal one in all women (82.6% vs. 17.4%), with the same trend in both groups.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRecurrent characteristics of the 86 women.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll (N\u0026thinsp;=\u0026thinsp;86)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePDS (N\u0026thinsp;=\u0026thinsp;41)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNACT (N\u0026thinsp;=\u0026thinsp;45)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-Value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImaging method\u003c/p\u003e \u003cp\u003ePET-CT\u003c/p\u003e \u003cp\u003eMRI\u003c/p\u003e \u003cp\u003eCT\u003c/p\u003e \u003cp\u003ePuncture under color ultrasound\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35(40.7%)\u003c/p\u003e \u003cp\u003e31(36.1%)\u003c/p\u003e \u003cp\u003e14(16.3%)\u003c/p\u003e \u003cp\u003e14(16.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17(41.5%)\u003c/p\u003e \u003cp\u003e14(34.2%)\u003c/p\u003e \u003cp\u003e7(17.1%)\u003c/p\u003e \u003cp\u003e6(14.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18(40%)\u003c/p\u003e \u003cp\u003e17(37.8%)\u003c/p\u003e \u003cp\u003e7(15.6%)\u003c/p\u003e \u003cp\u003e8(17.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.105\u003c/p\u003e \u003cp\u003e0.726\u003c/p\u003e \u003cp\u003e0.849\u003c/p\u003e \u003cp\u003e0.693\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of sites of recurrence\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e2+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28(32.6%)\u003c/p\u003e \u003cp\u003e58(67.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14(34.1%)\u003c/p\u003e \u003cp\u003e27(65.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14(31.1%)\u003c/p\u003e \u003cp\u003e31(68.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.764\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSites of recurrence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePelvis\u003c/p\u003e \u003cp\u003eUpper abdomen/diaphragm\u003c/p\u003e \u003cp\u003eDistant (brain/chest/liver/spleen parenchyma)\u003c/p\u003e \u003cp\u003eLymphatic\u003c/p\u003e \u003cp\u003eCarcinomatosis\u003c/p\u003e \u003cp\u003eIntra-/Extra-abdominal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54 (62.8%)\u003c/p\u003e \u003cp\u003e10 (11.6%)\u003c/p\u003e \u003cp\u003e28 (32.6%)\u003c/p\u003e \u003cp\u003e31 (36%)\u003c/p\u003e \u003cp\u003e27 (31.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (53.7%)\u003c/p\u003e \u003cp\u003e4 (9.8%)\u003c/p\u003e \u003cp\u003e7 (17.1%)\u003c/p\u003e \u003cp\u003e15 (36.6%)\u003c/p\u003e \u003cp\u003e10 (24.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32 (71.1%)\u003c/p\u003e \u003cp\u003e6 (13.3%)\u003c/p\u003e \u003cp\u003e21 (46.7%)\u003c/p\u003e \u003cp\u003e16 (35.6%)\u003c/p\u003e \u003cp\u003e17 (37.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.094\u003c/p\u003e \u003cp\u003e0.741\u003c/p\u003e \u003cp\u003e\u003cb\u003e0.003*\u003c/b\u003e\u003c/p\u003e \u003cp\u003e0.921\u003c/p\u003e \u003cp\u003e0.182\u003c/p\u003e \u003cp\u003e0.629\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntra-abdominal\u003c/p\u003e \u003cp\u003eExtra-abdominal\u003c/p\u003e \u003cp\u003eAscites/effusion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e71 (82.6%)\u003c/p\u003e \u003cp\u003e15 (17.4%)\u003c/p\u003e \u003cp\u003e6 (7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (80.5%)\u003c/p\u003e \u003cp\u003e8 (19.5%)\u003c/p\u003e \u003cp\u003e2 (4.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38 (84.4%)\u003c/p\u003e \u003cp\u003e7 (15.6%)\u003c/p\u003e \u003cp\u003e4 (8.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.678\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAbbreviations: PET-CT, positron emission tomography-computed tomography; MRI, magnetic resonance imaging; CT, computed tomography.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e*Statistically significant variables and statistically significant results are indicated in bold.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4. DISCUSSION","content":"\u003cp\u003eThe 5-year and 12-year survival rates of recurrent ovarian cancer were less than 30% and 5%, respectively\u003csup\u003e12\u003c/sup\u003e. Monitoring recurrence is a key aspect of the overall management of women with EOC. With CA125 levels frequently rising several months before image-identified recurrence\u003csup\u003e11\u003c/sup\u003e, determining the imaging examination time based on the fluctuation of CA125 values could alleviate anxiety and reduce the economic burden for women with asymptomatic recurrence by avoiding multiple negative imaging examinations. Therefore, defining the CA125 cut-off that signifies the need for diagnostic imaging and therapy to relapse is critical to ensure effective management.\u003c/p\u003e \u003cp\u003eHowever, using 35 U/ml as the CA125 abnormal threshold for all women in general may result in omissions or delays in recurrence detection. In this study, by using the ROC curve to analyze CA125 levels in the diagnosis of recurrence and the CA125 levels measured before the diagnosis of recurrence in 86 patients, we found that CA125 reaching 2\u0026times;nadir during the follow-up process might be a more sensitive and early recurrence signal in women having completed initial treatments for serous ovarian cancer. Moreover, more than half of the women (17, 60.71%) who never reached the upper limit of the normal range of 35 U/mL at the time of relapse showed a CA125 level over 2\u0026times;nadir. The combination of 2\u0026times;nadir and 35 U/mL predicted outcomes better than 35 U/mL alone, which could significantly improve the detection rate of relapse.\u003c/p\u003e \u003cp\u003eMany studies have redefined the value of CA125 in predicting relapse. A rise of 5 U/mL or 10 U/mL from the nadir CA125 level has been associated with recurrence in women who had a complete response to therapy\u003csup\u003e13\u003c/sup\u003e. Wang et al. proposed that the CA125 level of 1.68 \u0026times; nadir was defined as the indicator of recurrent disease\u003csup\u003e14\u003c/sup\u003e. In a French multicenter study, nadir CA125 values below 20 kU/L were associated with more prolonged OS (Overall Survival) and DFS (Disease-free Survival) (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003csup\u003e15\u003c/sup\u003e. However, these studies aimed to reveal the association between CA125 elevation and the ultimate recurrence without proposing a specific follow-up strategy. In the only randomized trial ever performed of CA125 monitoring after the initial treatment, patients who only experienced the increase of CA125 were assigned to early treatment, and patients with clinical or symptomatic relapse were assigned to delayed treatment\u003csup\u003e11\u003c/sup\u003e. The results showed no evidence of the survival benefit of early treatment. This finding challenged the widespread belief by denying routine recommend of CA125 follow-up and the early treatment of relapse based on a raised CA125 concentration alone. Actually, monitoring CA125 has been a routine in conventional follow-up, and effective but slightly expensive imaging examinations, such as computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography/computed tomography (PET/CT), were used as an additional check when CA125 is abnormal\u003csup\u003e16\u0026ndash;17\u003c/sup\u003e. Therefore, our study wants to analyze and investigate the correlation between early and delayed treatment groups in the study mentioned above, whether the raised CA125 concentration alone can predict the clinical recurrence of the delayed treatment group. It is essential but challenging for asymptomatic women to determine the optimal imaging examination timing based on the fluctuation of CA125. Some gynecologic oncologists advocate a wait-and-see approach, but the duration of the waiting period and the recurrence surveillance are unclear\u003csup\u003e18\u003c/sup\u003e. Asymptomatic women waiting for symptoms may suffer from anxiety, leading to decreased quality of life and unnecessary imaging examinations\u003csup\u003e11\u003c/sup\u003e. Despite the SGO and NCCN guidelines recommending that imaging only be used when clinically indicated, more than 75% of ovarian cancer women were still receiving routine surveillance for non-indication imaging\u003csup\u003e19,20\u003c/sup\u003e. Hence, a clear cut-off of the CA125 level to start the diagnostic imaging was required. According to our results, when the CA125 level reaches 2 \u0026times; nadir or 35 U/mL, an imaging examination at this follow-up visit or the subsequent follow-up would be recommended. More specifically, imaging examinations should be performed once the CA125 level exceeds 35 U/mL or within three months for women whose CA125 level is consistently lower than 35 U/mL but reaches 2\u0026times;nadir.\u003c/p\u003e \u003cp\u003eIn the study of Wang et al, comparing with a CA125 level\u0026thinsp;\u0026gt;\u0026thinsp;1.68\u0026times;nadir at relapse, women with CA125 level\u0026thinsp;\u0026le;\u0026thinsp;1.68\u0026times;nadir at relapse can extend the overall and progression-free survival durations\u003csup\u003e14\u003c/sup\u003e. In the present study, the sensitivity attained using a CA125 level of 2 \u0026times; nadir was relatively high (82.6%). However, our findings did not reveal a relationship between the CA125 levels at image-identified relapse and overall survival. The possible reason was that not every asymptomatic woman start treatment immediately after observing image-identified relapse. Given the selection bias inherent to retrospective studies, attempts to translate the above-mentioned favorable outcome to all recurrent OvCa women should be approached with caution. Our study aimed not only to predict recurrence, but also to clarify the time point to start image examination and appropriate therapy according to the CA125 levels. Based on the current results, our team would further verify the improvement effect of intervention at 2\u0026times;nadir CA125 value on survival outcomes by performing prospective trials.\u003c/p\u003e \u003cp\u003eSeveral differences were noticed between the NACT and PDS groups, including those in the FIGO stage, CA125 at diagnosis, the number of chemotherapy cycles, and the incidence of distant metastasis. These differences might be related to the severity of the disease itself in the two groups of women. Gynecologic oncologists would like to use platinum-based chemotherapy several times in advance to reduce the tumor size of women with advanced OC, aiming to achieve optimal surgery\u003csup\u003e3,4,21,22\u003c/sup\u003e. In our study, the tendency of significant deviation in CA125 was disappeared following treatment, as CA125 decreased to nearly 10 U/mL, ranging from 2.7\u0026ndash;30.9 U/mL. It is not what we expected that the changing trends of follow-up CA125 profiles after the two distinct treatments in the real clinical world was still no statistical difference. Additionally, there is evidence that most EOC and primary peritoneal cancers originated from the umbrella end of the fallopian tube. The standard treatment for these three types of cancers is almost identical to clinical guidelines. Therefore, five women with fallopian tube cancer and five women with peritoneal cancer in this study were not excluded. Limitations of this study include its retrospective and unicentric nature and the relatively small sample size. Another drawback is that we mainly focused on CA125 without considering the predictive function of other tumor biomarkers\u003csup\u003e23\u003c/sup\u003e.\u003c/p\u003e"},{"header":"5. CONCLUSION","content":"\u003cp\u003eTo sum up, our results showed that the CA125 level of 2\u0026times; nadir indicates the need to initiate imaging examination within three months to detect recurrent serous ovarian, tubal, and peritoneal cancers. As the combination of 2\u0026times;nadir and 35 U/mL predicted outcomes better than either alone, it may be a practical and low-cost method for oncologists to manage women with serous OvCa.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCA125, Cancer Antigen 125; OvCa, Ovarian cancer; EOC\u003cstrong\u003e,\u0026nbsp;\u003c/strong\u003eepithelial ovarian cancer;\u0026nbsp;NACT, neoadjuvant chemotherapy; IDS, interval debulking surgery; PDS\u003cstrong\u003e,\u0026nbsp;\u003c/strong\u003eprimary debulking surgery; FIGO, International Federation of Gynecology and Obstetrics; RT, residual tumor.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank the patients and their families for their participation in this project.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eK.W.D. wrote the manuscript, performed statistical analyses, developed the idea and concept, and prepared all figures and tables. Q.Y.Y. assisted with statistical analyses and helped with manuscript writing. J.J.L., X.X.C., and H.J.W. assisted with sample collection and manuscript writing. J.H. and D.W.C. assisted with concept development and manuscript writing. J.Y.T. oversaw the project, assisted with concept development, and assisted with manuscript writing. All authors reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no external funding except for the Open Access Publication Funds of Chongqing Medical University, China.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interest\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets analyzed during the current study are not publicly available due to privacy and ethical restrictions but are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eTitle of Cancer Stat Facts: Ovarian Cancer. 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Cancer\u003c/em\u003e \u003cstrong\u003e130\u003c/strong\u003e, 114\u0026ndash;125 (2020).\u003c/li\u003e\n\u003cli\u003eVallius, T. \u003cem\u003eet al.\u003c/em\u003e Postoperative human epididymis protein 4 predicts primary therapy outcome in advanced epithelial ovarian cancer. \u003cem\u003eTumor Biol.\u003c/em\u003e \u003cstrong\u003e39\u003c/strong\u003e, 101042831769118 (2017).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3835030/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3835030/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eUsing 35 U/ml as CA125 routine abnormal threshold may result in omissions in the recurrence detection of Ovarian cancer (OvCa). This study aimed to clarify the association between a biochemical recurrence (only the elevation of CA125) and an image-identified recurrence to predict the recurrent lesions better. 86 patients were enrolled from women diagnosed with stage I-IV serous ovarian, tubal, and peritoneal cancers from January 2013 to June 2019 at our center. The median CA125 level from 929.9 U/mL at diagnosis reduced to 7.8 U/mL at nadir during follow-up in all patients, and there was no difference between the neoadjuvant chemotherapy (NACT) and primary debulking surgery (PDS) group after initial treatment. Compared to CA125 level exceeding 35 U/ml, the 2×nadir of CA125 improve the sensitivity and the specificity of image-identified relapse (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001); the 2×nadir value can act as an earlier warning relapse signal with a longer median time to image-identified recurrence (2.7 vs. 0 months,\u003cem\u003e P\u003c/em\u003e\u0026lt;0.001). Compared with 35 U/ml, CA125 reaching 2×nadir during the follow-up process might be a more sensitive and early recurrence signal in patients with serous OvCa. This criterion may help guide patients to be recommended for imaging examination to detect potential recurrence in time.\u003c/p\u003e","manuscriptTitle":"An increase of serum CA-125 to two times of nadir level strongly predicts the image-identified recurrence of serous ovarian cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-10 21:55:30","doi":"10.21203/rs.3.rs-3835030/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-03-18T22:55:32+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-03-07T05:56:37+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-02-21T15:37:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"46454bd2-42b5-4068-a73a-c030092d0b7a","date":"2024-02-09T09:16:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"430a8ce7-52f6-422f-8c40-2e235a5de58b","date":"2024-02-04T17:24:05+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-02-04T09:11:42+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-02-04T08:33:15+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-01-09T07:46:41+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-01-09T07:17:35+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-01-04T16:58:30+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4aec842c-40c4-487d-a18f-b423a4d5d4dd","owner":[],"postedDate":"January 10th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":28032971,"name":"Biological sciences/Cancer"},{"id":28032972,"name":"Biological sciences/Cancer/Cancer imaging"},{"id":28032973,"name":"Biological sciences/Cancer/Gynaecological cancer"},{"id":28032974,"name":"Biological sciences/Cancer/Tumour biomarkers"}],"tags":[],"updatedAt":"2024-06-24T06:37:13+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-10 21:55:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3835030","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3835030","identity":"rs-3835030","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}