Summary of Main Results
Standard treatment in advanced ovarian cancer is PCS, followed by adjuvant chemotherapy. In the preoperative evaluation of patients with suspected stage III-IV epithelial ovarian cancer, laparoscopic, radiological, and biochemical findings can be combined with scoring systems for surgery suitability (21, 22). Wright et al. recommended that NACT was preferred only in patients with a high perioperative risk profile and a low chance of achieving optimal cytoreduction in PCS (23). However, there are also studies indicating that 5–12% of the patients have a complete response after NACT, and the prognosis in these patients is excellent (24, 25). In our study, no significant difference was observed in DFS between the PCS and NACT groups.
Nevertheless, similar to most retrospective studies, OS was significantly longer in the PCS group. Considering those without residual tumor after surgery, survival was better in the PCS group than in the NACT group. There was no survival advantage between NACT vs PCS groups in platinum-sensitive patients. This result eliminates the importance of PCS as a first treatment option in platinum-sensitive cases. Since the surgical complication rate is generally low in the NACT, applying NACT as a first-line treatment can be a good option if the patient is platinum-sensitive. Even whether the patient is chemo-sensitive or –resistant is not known initially.
Results in the Context of Published Literature
Most retrospective studies revealed that PCS provides DFS and OS advantages over NACT. In the study by Rauh-Hain et al., which searched the US National Cancer Database and selected 2935 similar cases for both groups, the median OS was found to be 37.3 months in the PCS group and 32.1 months in the NACT group (p < 0.001) (26). Lyons et al. published a retrospective analysis of approximately 37.000 patients in the National Cancer Database, and the OS was longer in the PCS group (7). In another retrospective cohort study conducted by Matsuo et al., queried by the National Cancer Institute's Surveillance, Epidemiology, and End Results Program (SEER), ovarian cancer mortality (3-year cumulative incidence) was 41.9% in the PCS and 47.5% in the NACT group (p < 0.001) (8). Gao et al. found a difference of 5.5 months in DFS and 15.5 months in OS between two groups in favor of the PCS. However, no statistically significant difference was observed (9).
In our study, the decision of PCS or NACT was determined according to the initial clinical and radiological findings. In the NACT group, tumor load was rather extensive, patients were old, initial serum CA-125 levels were high, and the number of patients with stage IV and ECOG performance scores of 3–4 with comorbidities were much higher than in the PCS group. The distribution of patient characteristics between the two groups was non-homogeneous; that was the crucial bias in our study.
Prospective randomized trials have also been administered for NACT as an alternative therapy in advanced ovarian cancer. The first was completed in 2010 by the European Gynecological Cancer Research and Treatment Group (EORTC-GCG 55791). Although complete tumor resection was 19.4% in PCS and 51.2% in NACT, there was no significant difference in DFS and OS. No residue tumor was the most important independent prognostic factor (11). In another randomized controlled phase 3 trial, CHORUS was published in 2015, the complete cytoreduction rate was 17% in PCS and 39% in NACT, and there was no statistically significant difference in DFS and OS. It has been suggested that NACT was a good alternative treatment, especially in cases with low-performance scores, due to its lower morbidity and mortality rates (12).
The prospective, randomized, controlled phase 3 study SCORPION was emitted in 2020. The complete cytoreduction rate was 47.6% in PCS and 77% in the NACT group, and there was no significant difference between DFS and OS. However, postoperative death and major complication rates were significantly higher in the PCS group than in the NACT group (13).
Also, in the prospective randomized study (JCOG 0602) of the Japanese Gynecological Oncology Group issued in 2020, complete resection was found to be 12% in the PCS and 64% in the NACT group. The median DFS was 15.1 months in the PCS, 16.4 months in the NACT group, and the median OS was 49 months in the PCS and 44.3 months in the NACT group. The result of this study was a little different compared to other prospective randomized studies, and the authors concluded that a survival noninferiority of NACT was not confirmed in their study compared with PCS. NACT might not be replaced every time for PCS (27). In retrospective studies, survival was better in the PCS group; randomized and prospective studies revealed that survival outcomes in the NACT group are non-inferior to PCS. The results of incoming studies (TRUST (Clinical Trial NCT02828618) and SOC-2 (Clinical Trial NCT02859038)) have not been published yet.
No residual tumor after surgery is an important prognostic factor for survival. Recent studies have shown that ICS after NACT provides a high complete/optimal cytoreduction rate and less surgical morbidity (3–6, 27, 28). In our study, the rates of no residual tumor (R = 0) between the two groups favored the NACT group, similar to randomized controlled studies. DFS and OS were longer in R = 0 patients in the PCS group. DFS and OS were similar to the NACT group in the PCS group with residual tumors. Although there was no statistically significant result in two different retrospective studies, the tendency of OS advantage was found in the PCS group with no residual tumor (7, 9).
Platinum sensitivity is as important as no residual tumor in advanced ovarian cancer. However, there is still no marker that can be used in practice to predict platinum sensibility. On the other hand, ATP-dependent transporter gene (ABCB1), ATP binding cassette G2 (ABCG2) overexpression with Wnt/b-catenin pathway, astrocyte elevated gene-1 (AEG-1) expression, PI3K/Akt/mTOR pathway activation and TP53 K351N, PTEN, BRCA1/2, KRAS, BRAF, β-catenin gene mutations and chromosome instability are associated with platinum resistance (30–33, 34).
As most patients have both platinum-sensitive and platinum-resistant cells at the first diagnosis, approximately 80% of newly diagnosed epithelial ovarian cancer cases respond to first-line platinum-based chemotherapy. Despite this, approximately 70% of patients relapse, and most turn to the platinum-resistant phase (21). In our study, the rate of platinum resistance was 40.4% in the PCS and 47.4% in the NACT group.
Large tumors are poorly vascularized, and they are hypoxic and necrotic. The higher the tumor burden at the start of treatment, the greater the probability of tumor mutation and platinum resistance. Reducing the tumor burden with PCS minimizes the number of cells that can transform into platinum-resistant phenotypes. If the treatment is started with NACT, tumor cells have more probability of developing a platinum-resistant phase. Due to this condition, NACT is suggested not to be as effective as desired (9, 29).
According to Liu et al., most studies are limited because they are retrospective and biased in patient selection criteria, so it is difficult to conclude that NACT increases the likelihood of platinum resistance. However, the possibility of NACT causing more platinum resistance should not be ignored (35)
Strengths and Weaknesses
Our weaknesses are the non-homogeneous patient characteristics between the two groups and the retrospective study. Our strengths are the sufficient follow-up period and the number of patient groups.
Implications for Practice and Future Research
We could not find a study in the literature that PCS provides a survival advantage in chemotherapy-resistant patients. New studies are needed to compare our results. In addition, a method should be developed to determine the disease's sensitivity to chemotherapy.