The main treatment options for AEOC patients include PDS followed by platinum-based chemotherapy and NACT followed by IDS. In the National Comprehensive Cancer Network (NCCN) guidelines, it is recommended that for patients with pelvis and upper abdomen involvements (assessed as stage IIB and above), maximum efforts should be made to surgically remove pelvic, abdominal, and retroperitoneal tumor lesions. Optimal cytoreduction was regarded as the largest residual tumor diameter of ≤ 1 cm, with ultimately no visual residue [17]. Our study retrospectively analyzed the clinical data and prognosis of patients treated with PDS and NACT and who achieved optimal cytoreductive surgery. In addition, we explored the use of initial serum CA125 and HE4 values to predict the likelihood of complete surgical resection of stage III ovarian cancer.
The serum tumor biomarker CA-125 plays a particularly important role in the diagnosis and monitoring of epithelial ovarian cancer treatment response and in the assessment of disease progression. It is widely accepted that preoperative serum CA125 levels correlate with tumor burden, and therefore, several studies attempted to evaluate preoperative serum CA-125 levels to obtain optimal surgical resection rates. In recent years, serum HE4 has also developed into a promising biomarker for ovarian cancer. A sustained proliferation and impaired differentiation of ovarian epithelial cells lead to a high expression of HE4, which interferes with cancer cells’ adhesion and invasion [18]. Some studies considered HE4 as a predictor of optimal tumor resection rates [19].
In this study, we objectively defined R0 as complete gross cytoreduction. Our results show that patients with stage III ovarian cancer have a 63.9% chance of achieving R0 when the CA-125 cut-off is 500 IU/ml and a 65.8% chance if the HE4 cut-off is 250 pmol/L. Moreover, our results demonstrated that serum CA125 and HE4 levels are inversely correlated with tumor resection rates, with higher values of both biomarkers correlating with a lower the rate of complete tumor resection. In earlier studies, the CA-125 values above 500 IU/ml were found to be associated with more complex operations and poorer prognosis. In addition, CA-125 levels above 500 IU/ml were strongly associated with suboptimal debulking surgery in AOEC patients [20–21]. Recently published studies have shown that there is a 58% probability of achieving a complete gross or at least optimal cytoreduction in patients with advanced ovarian cancer at a preoperative CA-125 cut-off value of 500 IU/ml [22]. Our results were consistent with this study and provided practical clinical data on CA-125 levels as a predictor of ovarian cancer surgical resection rates. When referring to HE4, we found that 250 pmol/L was a suitable cut-off value for predicting R0. There are fewer studies on serum HE4 predictive value for advanced ovarian cancer optimal cytoreduction, but studies on its predictive value for surgical outcome have almost always established its validity.
After thorough assessments, if PDS is not appropriate, patients can receive 3 to 6 cycles of platinum based NACT before IDS. These patients tended to have higher CA125 and HE4 levels and a heavier tumor burden. The decrease in CA-125 percentage after NACT seems to be more important than the reduction in the CA-125 value. In the study of Mahdi et al., it was shown that a reduction in CA125 of at least 90%, had a better treatment response which may be associated with better surgical outcomes [23]. As expected, the present study revealed that the PDS group had a lower initial serum CA125 value (759.5 IU/ml vs. 1359.6 IU/ml, p ≤ 0.001) and HE4 value (244 pmol/L vs. 661 pmol/L, p ˂ 0.001). In the NACT group, we found a 96.30% and a 96.23% reduction in CA125 and HE4 values, respectively. In the majority of AEOC, serum CA-125 and HE4 levels correlate with disease burden. Therefore, the dramatic reduction in serum CA-125 and HE4 levels after NACT, may reflect chemotherapy sensitivity, which may become a predictor of surgical outcome. In a recent study, it was reported that decreases in CA-125 levels of more than 95% and preoperative CA-125 values below 100 IU/ml are predictive factors of complete surgical gross excision after NACT [24].
Additionally, we compared the survival prognosis of patients in the NACT and PDS groups. The median DFS was 20 months in the NACT group and 20.5 months in the PDS group (p = 0.851), with no DFS significant difference between the two groups. A phase III clinical trial called The Surgical Complications Related to Primary or Interval Debulking in Ovarian Neoplasm (SCORPION) study also found that NACT and PDS are equally effective, but their adverse events are different [5]. None of our patients received a maintenance treatment with poly (ADP-ribose) polymerase (PARP) inhibitor, and our interpretation of this result is that rigorous preoperative assessment and advanced surgical techniques are prerequisites to ensure the achievement of surgical cytoreduction was.
Our study has some weaknesses. Firstly, this study is a single-center retrospective analysis. Secondly, the study sample was not sufficiently large, and its increase is needed to validate the results. Third, we used serum CA125 and HE4 separately as predictors of surgical outcomes, which was due to the inconsistent magnitude of change in these two non-invasive biomarkers.
In conclusion, survival prognosis in stage III ovarian cancer patients, treated with PDS and NACT followed by IDS, have a similar efficacy. Initial serum CA125 and HE4 values can be used as predictors of optimal surgical cytoreduction. The serum CA125 and HE4 levels of 500IU/ml and 250 pmol/L are appropriate cut-off values for predicting no gross residual lesions. Nevertheless, more evidence from prospective, multicenter and large sample studies, is needed.