Radiology and Oncology | Ljubljana | Slovenia | www.radioloncol.com Radiol Oncol 2021; 55(3): 341-346. doi: 10.2478/raon-2021-0013 341 research article Preoperative serum CA-125 level as a predictor for the extent of cytoreduction in patients with advanced stage epithelial ovarian cancer Sebastjan Merlo1,2, Nikola Besic2,3, Eva Drmota2, Nina Kovacevic1,2,4 1 Department of Gynaecological Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia 2 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 3 Department of Surgical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia 4 Faculty of Health Care Angele Boškin, Jesenice, Slovenia Radiol Oncol 2021; 55(3): 341-346. Received 25 November 2020 Accepted 9 February 2021 Correspondence to: Assist. Nina Kovačević M.D., Ph.D., Department of Gynaecological Oncology, Institute of Oncology Ljubljana, Zaloška cesta 2, SI-1000 Ljubljana, Slovenia. Phone: + 386 41 277 602; E-mail: nkovacevic@onko-i.si Disclosure: No potential conflicts of interest were disclosed. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Background. Ovarian cancer is the seventh most common cancer in women worldwide and the eighth most common cause of cancer death. Due to the lack of effective early detection strategies and the unspecific onset of symptoms, it is diagnosed at an advanced stage in 75% of cases. The cancer antigen (CA) 125 is used as a prognostic marker and its level is elevated in more than 85% of women with advanced stages of epithelial ovarian cancer (EOC). The standard treatment is primary debulking surgery (PDS) followed by adjuvant chemotherapy (ACT), but the later approach is neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS). Several studies have been conducted to find out whether preoperative CA-125 serum levels influence treatment choice, surgical resection and survival outcome. The aim of our study was to analyse experience of single institution as Cancer comprehensive center with preoperative usefulness of CA-125. Patients and methods. At the Institute of Oncology Ljubljana a retrospective analysis of 253 women with stage FIGO IIIC and IV ovarian cancer was conducted. Women were divided into two groups based on their primary treat- ment. The first group was the NACT group (215 women) and the second the PDS group (38 women). The differences in patient characteristics were compared using the Chi-square test and ANOVA and the Kaplan-Meier method was used for calculating progression-free survival (PFS) and overall survival (OS). Results. The median serum CA-125 level was higher in the NACT group than in the PDS group, 972 IU/ml and 499 IU/ ml, respectively. The PFS in the NACT group was 8 months (95% CI 6.4–9.5) and 18 months (95% CI 12.5–23.4) in the PDS group. The median OS was lower in the NACT group than in the PDS group, 25 months (95% CI 20.6–29.5) and 46 months (95% CI 32.9–62.1), respectively. Conclusions. Preoperative CA-125 cut off value of 500 IU/ml is a promising threshold to predict a successful PDS. Key words: ovarian cancer; tumour marker; CA-125; primary debulking surgery; neoadjuvant chemotherapy Introduction Ovarian cancer is the seventh most common cancer in women around the world, with approximately 240,000 new cases diagnosed each year. Epithelial ovarian cancer (EOC) is a very aggressive disease and is the eighth leading cause of cancer death with five-year survival rates below 45%.1 Of all patients diagnosed with EOC, approximately 15% of patients will have germline BRCA1 or BRCA2 mutation present. The cumulative ovarian cancer risk to age of 80 is 36–53% in BRCA1 mutation and 11–25% in BRCA2 mutation. Cumulative ovarian risk to age of 80 in population without BRCA mu- tation is 1–2%.2,3 Radiol Oncol 2021; 55(3): 341-346. Merlo S et al. / Preoperative serum CA-125 level and cytoreduction in ovarian cancer342 Due to the lack of effective screening strategies and the unspecific onset of symptoms, EOC is de- tected in 75% of cases at an advanced stage.4 The initial symptoms are persistent or frequent, non- specific and mainly include abdominal distension or flatulence, pelvic or abdominal pain, bloating, loss of appetite, unexplained weight loss, fatigue or changes in bowel habits. About 36% of women with unspecific clinical symptoms make several visits to their general practitioner before being di- agnosed with ovarian cancer.5 CA-125, also known as mucin 16 or MUC16, is a large membrane glycoprotein belonging to the wide mucin family, encoded by the homonymous MUC16 gene.6 It can be very useful and highly specific as a prognostic maker, but not as a diag- nostic tool due to lack of sensitivity.7 CA-125 level is increased in more than 85% of women with an advanced stage EOC but is only increased in 50% of stage I cancers.7,8 CA-125 level may also be in- creased in almost 6% of women without ovarian cancer due to adenomyosis, endometriosis, retro- grade menstrual bleeding or other non-malignant diseases.7 For decades the standard treatment for EOC has been primary debulking surgery (PDS) followed by platinum- and taxane-based adjuvant chemo- therapy (ACT). A more contemporary approach is neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS), but, opinions on the optimal treatment are still divided.9 Despite different treatment approaches, the prognosis is mainly influenced by the residual disease after surgical cytoreduction. Patients benefit most from complete gross resection or optimal cytoreduction (residual lesions with a diameter of 1 cm or less). Suboptimal cytoreduction with residual disease of more than 1 cm is associated with poorer sur- vival.10 Many studies have attempted to assess dif- ferent scoring systems which include preoperative serum CA-125 to determine the patient selection where optimal primary cytoreduction might be achievable but results and recommendations are inconsistent.11–16 The aim of our study was to analyse experience of single institution as Cancer comprehensive cen- tre with preoperative usefulness of CA-125. Patients and methods Study design A retrospective observational study was conducted at the Institute of Oncology Ljubljana, from January 2005 to December 2014. The data collection and its analysis were approved by Institutional Ethical committee. Patients Two hundred and fifty-three women with ad- vanced stage ovarian cancer were enrolled in the study. All women had histologically confirmed FIGO stage IIIC and IV EOC. Women were divided into two groups based on their initial treatment. The first group consisted of 215 women receiv- ing NACT (based on carboplatin and paclitaxel), followed by IDS. The second group consisted of 38 women treated with PDS, followed by ACT (3 courses of the same regimen as NACT). The selec- tion of women for the specific treatment was based on the ability to perform a complete gross resection or to achieve a residual disease of 1 cm or less. This decision was based on preoperative imaging stud- ies (abdominal and thoracic CT) and/or diagnostic laparoscopy in 173 patients. Levels of preoperative CA-125 did not influence the decision about pri- mary treatment modality. When option to achieve complete gross or at least optimal cytoreduction was considered low, NACT was selected. Patients were assessed as inoperable (low probability of < 1cm residual disease) if the tumour penetrated the pelvic wall, if carcinosis of the intestine, intes- tinal serosa or mesentery was present or if imaging studies showed tumour spread to distant organs. The time from NACT to IDS was 4–6 weeks and the interval from PDS to ACT was 3–4 weeks for all included women. Progression-free survival (PFS) was defined as the time from the date of completion of treatment to the first radiological evidence of progression. An increase of CA-125 serum level without clini- cal signs of recurrence was not counted as progres- sion, but triggered further radiological examina- tions. Overall survival (OS) was defined as the in- terval between the date of diagnosis and the date of death. The surviving patients were censored at the time of the last follow-up. The extent of residual disease was based on the diameter of the largest single lesion. At complete gross resection there were no macroscopic lesions, at optimal resection the lesions had a diameter of 1 cm or less and at suboptimal resection the le- sions were larger than 1 cm. The study excluded women with a history of other malignant tumours or chemotherapy, FIGO stage I or II ovarian cancer, or non-epithelial histology of ovarian cancer. Radiol Oncol 2021; 55(3): 341-346. Merlo S et al. / Preoperative serum CA-125 level and cytoreduction in ovarian cancer 343 Data collection Patients enrolled in the study were selected using the prospective clinical database of the Institute of Oncology Ljubljana. Clinical variables were col- lected from electronic hospital records, paper doc- umentation and pathology reports to determine eligibility for the study, general characteristics of the patients, FIGO stage, tumour classification and histological type. Vital status was determined by analysing electronic medical records. Data were collected on the patient’s age, body mass index (BMI), menopause status, preoperative CA-125, duration of follow-up and residual disease after surgery. Statistical analysis For demographic data, descriptive statistics were used. The median survival of the two groups was calculated based on the non-normal distribution. The differences in patient characteristics were com- pared using the Chi-square test and ANOVA. ROC analysis was performed to determine cuff off val- ues of serum CA-125 levels. PFS and OS and were estimated using the Kaplan-Meier method, and the rates in the two groups were compared using the log-rank test. P < 0.05 indicated that the difference between the groups was statistically significant. The statistical software SPSS for Windows version 26 was used for statistical analysis. Results A retrospective analysis of 253 patients with advanced stage EOC treated at the Institute of Oncology Ljubljana between January 2005 and December 2014 was performed. There were 215 (84.9%) women enrolled in the NACT group and 38 (15.1%) women in the PDS group. The character- istics of the patients are shown in Table 1. Patients in the PDS group were statistically significantly younger (53.7 vs. 62.2 years), with lower disease stage (FIGO IIIC 89.5% vs. 66.6%) and had lower CA-125 levels (499 IU/ml vs. 972 IU/ml). In patients with NACT, 57.6% (124/215) had complete gross resection, 14.0% (30/215) had opti- mal resection and 28.4% (61/215) had suboptimal resection (p = 0.002; Table 1). In women with PDS, 23.7% (9/38) had complete gross resection, 18.4% (7/38) had optimal resec- tion and 57.9% (22/38) had suboptimal resection. Patients with complete gross resection had low- TABLE 1. Clinical characteristics (N = 253) Characteristic PDS(N = 38) NACT (N = 215) P value Age-years Median 53.7 62.2 < 0.001 Range 29–84 39–85 BMI-kg/m2 Median 24.5 23.8 0.210 Range 17.4–45.2 18.2–32.1 Parity-number Median 2 2 0.080 Range 0–5 0–4 Menopause-years Median 50 51.5 0.340 Range 37–60 45–58 ASA score 1 7 (18.4) 23 (10.7) 0.780 2 22 (57.9) 141 (65.6) 3 9 (23.7) 49 (22.8) 4 0 (0) 2 (0.9) WHO performance status 0 26 (68.4) 96 (44.7) 0.130 1 8 (21.0) 85 (40.0) 2 4 (10.6) 26 (12.1) 3 0 (0) 5 (2.3) 4 0 (0) 3 (1.4) FIGO stage IIIC 34 (89.5) 143 (66.6) 0.010 IV 4 (10.5) 72 (33.4) Histologic type Serous 32 (84.2) 202 (94.0) 0.100 Endometrioid 6 (15.8) 8 (3.7) Mucinous 0 (0) 3 (1.4) Clear-cell 0 (0) 2 (0.9) Preoperative CA-125– IU/ml Median 499 972 0.058 Range 59–5739 10–31481 Surgical outcome Complete gross resection 9 (23.7) 124 (57.6) 0.002 Optimal visible residual (≤1 cm) 7 (18.4) 30 (14.0) Suboptimal (>1 cm) 22 (57.9) 61 (28.4) Hospitalisation time-days Median 10 9 0.555 Range 7–28 5–59 ASA = American Society of Anesthesiologist; BMI = body mass index; FIGO = International Federation of Gynecology and Obstetrics; NACT = neoadjuvant chemotherapy; PDS = primary debulking surgery; WHO = World Health Organization Radiol Oncol 2021; 55(3): 341-346. Merlo S et al. / Preoperative serum CA-125 level and cytoreduction in ovarian cancer344 est CA-125 level at the time of diagnosis, 359 IU/ ml respectively. Highest CA-125 level was found in the group with suboptimal resection, 1522 IU/ ml, respectively. CA-125 level in NACT group with complete gross resection at the time of diagnosis was 943 IU/ mL and after NACT 25 IU/ml (97.3% decline). CA- 125 level in NACT group with optimal resection at the time of diagnosis was 1006 IU/ml and after NACT 36 IU/ml (96.4% decline). Serum CA-125 level in NACT group with suboptimal resection at the time of diagnosis was 1063 IU/ml and after NACT 68 IU/ml (93.6% decline) (Table 2). Cut off values of serum CA-125 levels and sen- sitivity to obtain complete gross or optimal cytore- duction are shown in Table 3. If CA-125 preopera- tive serum level is 250 IU/ml, there is 74 % chance to obtain at least optimal cyoreduction (Table 3). PFS in the NACT group was 8 months (95% CI: 6.4–9.5) and 18 months (95% CI: 12.5–23.4) in the PDS group (P = 0.008). The median OS in the NACT group was 25 months (95% CI: 20.6-29.5) and 46 months (95% CI: 32.9–62.1) in the PDS group (p = 0.009). Discussion PDS followed by platinum- and taxane-based ACT was the standard treatment for patients with ad- vanced stage EOC until 2016, when the American Society of Clinical Oncology (ASCO) and the Society of Gynecologic Oncology (SGO) developed new clinical practice guidelines.17 According to these guidelines in patients with high likelihood of achieving cytoreduction with residual disease < 1cm (ideally no visible disease) with acceptable morbidity, PDS is recommended over NACT. For women with high perioperative risk or a low likelihood of achieving a cytoreduc- tion with residual disease < 1cm (ideally no vis- ible disease) NACT is the treatment of choice. For women who are fit for PDS but cytoreduction with residual disease < 1cm (ideally no visible disease) is unlikely, NACT is also the treatment of choice. IDS should be performed after three to six cycles of NACT for women who respond to chemother- apy or with stable disease.9,17 Patients with disease progression during NACT have a poor prognosis. Options include alternative chemotherapy regi- mens, inclusion in clinical trials and/or discontinu- ation of active cancer therapy and initiation of pal- liative supportive care. The role of surgery in pal- liative care is limited.18,19 There were studies published before year 2016 which showed non-inferiority of NACT compared to PDS.20–23 Therefore also at our institute patients were treated with NACT where low chances to achieve at least optimal PDS were expected. We studied the use of preoperative serum CA- 125 levels to predict the likelihood of achieving at least optimal PDS or IDS in patients with advanced stage EOC. Many studies have attempted to assess the abil- ity of preoperative serum CA-125 level and vari- ous scoring systems to determine the patient selec- tion where optimal primary cytoreduction can be achieved. As expected, our results confirmed that the higher the CA-125 level is, the lower is probabil- ity to achieve optimal cytoreduction. At the pre- operative CA-125 cut off value of 500 IU/ml the probability of achieving complete gross or at least TABLE 2. Median and range CA-125 levels in different surgical outcomes in primary debulking surgery (PDS) and = neoadjuvant chemotherapy (NACT) group Surgical outcomes PDS (N = 38) NACT (N = 215) P value CA-125 at diagnosis IU/ml Complete gross resection 35959–5739 943 10–12803 0.006 Optimal resection 51285–1117 1006 48–24824 Suboptimal resection 1522200–3569 1063 28–31481 CA-125 post NACT IU/ml Complete gross resection 255–2074 0.020 Optimal resection 3615–2180 Suboptimal resection 689–2657 CA-125 = cancer antigen 125 TABLE 3. Statistical cut off values of serum CA-125 level and probability to obtain complete gross or optimal cytoreduction CA-125 level (IU/ml) Sensitivity (%) Number and percentage of patients 50 96.5 9 3.5 % 100 86.5 33 13.0 % 250 74.0 66 26.1 % 500 58.0 98 38.7 % 750 50.0 128 50.6 % 1000 42.0 150 59.3 % CA-125 = cancer antigen 125 Radiol Oncol 2021; 55(3): 341-346. Merlo S et al. / Preoperative serum CA-125 level and cytoreduction in ovarian cancer 345 optimal cytoreduction in patients with advanced stage EOC was 58%. The probability increased to 74% at the cut off value of 250 IU/ml. These results add further data on usefulness of CA-125 levels as predictive factor for type of resection and are con- sistent with results published by other authors.12,13 Vorgias et al.12 and Kang et al.13 showed that CA-125 level above 500 IU/ml correlates with a more complex and radical surgical procedure and a worse outcome. Cut off value of 500 IU/ml had sensitivity ranging from 49% to 78% and specific- ity ranging from 59% to 77%. They reported that CA-125 levels above 500 IU/ml were strongly cor- related with a suboptimal cytoreduction and poor- er overall survival in patients with advanced EOC. Furthermore, Arab et al.11 established a model for predicting optimal surgical outcome, in which a CA- 125 value of 420 IU/ml or less, the absence of massive ascites and liver metastases were shown to be sig- nificant factors in achieving optimal cytoreduction. However, Chi et al.14 reported that preoperative CA-125 value of more than 500 IU/ml had no pre- dictive usefulness on the surgical outcome after an extensive upper abdominal surgery. A preopera- tive value of CA-125 above 500 IU/ml was associ- ated with a probability of only 22% for optimal cy- toreduction, but when extensive upper abdominal surgery was performed, the rate of optimal cytore- duction increased to 75% and the preoperative CA- 125 value was no longer an independent predictor of surgical outcome.14 If optimal PDS is not achievable or patients are not suitable for extensive surgery, NACT and IDS are indicated. These patients usually have higher preoperative CA-125 levels and a higher disease burden than patients treated with a PDS. This was also the case in our patients where patients with NACT and IDS had higher disease stage (FIGO IV 33.4% vs. 10.5%) and higher preoperative CA-125 levels (972 IU/ml vs. 499 IU/ml). Rodriguez et al.15 reported that a preoperative CA-125 level of less than 100 IU/ml may be a suit- able predictor of complete gross resection rather than optimal cytoreduction. According to our re- sults preoperative CA-125 levels of less than 100 IU/ml can be expected in only 13% of patients. At an arbitrary cut off value of 250 IU/ml the prob- ability to obtain complete gross or optimal cytore- duction is 75% and roughly one forth (26.1%) of all patients with EOC belong to this group. If we increase the cut off value to 500 IU/ml about one third (38.7%) of patients will be included and the probability to obtain complete gross or optimal cy- toreduction will be 58%. After NACT the role of CA-125 to predict com- plete gross or optimal cytoreduction is even more complex. Pelissier et al.16 found out that a preop- erative CA-125 level of less than 75 IU/ml after the third cycle of NACT predicted a complete IDS. CA- 125 of less than 200 IU/ml can be an independent predictor of complete gross IDS and also a predic- tor of chemosensitivity according to Zeng et al.24. However, after NACT the percentage of reduction is probably even more important than the absolute decrease in the CA-125 value. A reduction of at least 90% indicates a better response of the tumour to treatment and therefore correlates with a better surgical outcome and better overall survival.25 Our study showed that patients with CA-125 se- rum reduction of more than 96.4% achieved higher complete gross and optimal IDS rate in comparison to patients with lover reduction of serum CA-125 level. It is well established that CA-125 serum lev- el represents the tumour burden in most patients with advanced stage EOC. Sharp CA-125 serum level reduction during NACT might reflect the chemosensitivity of the tumour. This might be a predictive factor for surgical outcome. However, we cannot predict in advance the reduction of CA- 125 level and therefore cannot predict the benefit of NACT. A study published by Gupta et al.26 showed that a 95% reduction of CA-125 levels and an absolute preoperative CA-125 level of 100 IU/ml or less pre- dicted complete gross resection after NACT. Kessous et al.27 think that the regression coef- ficient is impractical for clinical daily routine and found out that an early reduction of CA-125 levels by the third cycle of NACT can best predict surgi- cal outcome and patients overall survival. Our study showed that NACT group had short- er OS and PSF compare to PDS group. The median PFS and OS for patients in the NACT group was 8 and 25 months, compared to 25 and 49 months in the PDS group, respectively. This is consistent with data published by Mueller et al.28 but in contrast to EORTC/NCIC and CHORUS study.20,29 The expla- nation for our results is that women treated with NACT had a higher disease burden, a higher FIGO stage, a higher CA-125 level at time of diagnosis and were older in comparison to PDS group. Patients included in before mentioned three studies were of comparable age, FIGO stage and had comparable preoperative CA-125 levels. According to Maner and Machida NACT can be associated with lower peri- and postoperative morbidity and mortality and shorter hospital stay but PDS may offer a better chance of survival in Radiol Oncol 2021; 55(3): 341-346. Merlo S et al. / Preoperative serum CA-125 level and cytoreduction in ovarian cancer346 selected patients.30,31 Median hospital stay in our patients treated with IDS (9 days) was not differ- ent from patients treated with PDS (10 days, p = 0.555) which is consistent with the study published by du Bois.32 However, patients treated with PDS had better survival as already mentioned. There are limitations to our study among which are its retrospective nature and that there were no generally accepted selection criteria at that time for which patients are candidates for PDS or NACT. 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