Preoperative serum CA-125 level as a predictor for the extent of cytoreduction in patients with advanced stage epithelial ovarian cancer

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 mutation is 1–2%.^2,3

Due to the lack of effective screening strategies and the unspecific onset of symptoms, EOC is detected in 75% of cases at an advanced stage.⁴ The initial symptoms are persistent or frequent, nonspecific 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 diagnosed 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 diagnostic 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 increased in almost 6% of women without ovarian cancer due to adenomyosis, endometriosis, retrograde 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 chemotherapy (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 survival.¹⁰ Many studies have attempted to assess different 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, 12, 13, 14, 15, 16}

The aim of our study was to analyse experience of single institution as Cancer comprehensive centre with preoperative usefulness of CA-125.

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 characteristics 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 optimal 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 resection and 57.9% (22/38) had suboptimal resection. Patients with complete gross resection had lowest 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 sensitivity to obtain complete gross or optimal cytoreduction are shown in Table 3. If CA-125 preoperative 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).

PDS followed by platinum- and taxane-based ACT was the standard treatment for patients with advanced 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 cytoreduction with residual disease < 1cm (ideally no visible 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 chemotherapy or with stable disease.^9,17 Patients with disease progression during NACT have a poor prognosis. Options include alternative chemotherapy regimens, inclusion in clinical trials and/or discontinuation of active cancer therapy and initiation of palliative supportive care. The role of surgery in palliative care is limited.^18,19

There were studies published before year 2016 which showed non-inferiority of NACT compared to PDS.^{20, 21, 22, 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 ability of preoperative serum CA-125 level and various scoring systems to determine the patient selection where optimal primary cytoreduction can be achieved.

As expected, our results confirmed that the higher the CA-125 level is, the lower is probability to achieve optimal cytoreduction. At the preoperative CA-125 cut off value of 500 IU/ml the probability of achieving complete gross or at least 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 consistent 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 specificity ranging from 59% to 77%. They reported that CA-125 levels above 500 IU/ml were strongly correlated with a suboptimal cytoreduction and poorer 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 significant factors in achieving optimal cytoreduction.

However, Chi et al.¹⁴ reported that preoperative CA-125 value of more than 500 IU/ml had no predictive usefulness on the surgical outcome after an extensive upper abdominal surgery. A preoperative value of CA-125 above 500 IU/ml was associated with a probability of only 22% for optimal cytoreduction, but when extensive upper abdominal surgery was performed, the rate of optimal cytoreduction 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 suitable predictor of complete gross resection rather than optimal cytoreduction. According to our results 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 probability to obtain complete gross or optimal cytoreduction 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 cytoreduction will be 58%.

After NACT the role of CA-125 to predict complete gross or optimal cytoreduction is even more complex. Pelissier et al.¹⁶ found out that a preoperative 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 predictor 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 serum 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 level 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 predicted complete gross resection after NACT.

Kessous et al.²⁷ think that the regression coefficient 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 surgical outcome and patients overall survival.

Our study showed that NACT group had shorter 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 explanation 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 selected patients.^30,31 Median hospital stay in our patients treated with IDS (9 days) was not different 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.

Preoperative CA-125 cut off value of 500 IU/ml is a promising threshold to predict a successful PDS. After NACT a decline of CA-125 of more than 96.4% predicts at least optimal cytoreduction of IDS.