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Research ArticleClinical Studies

Highly Aggressive Surgery Benefits in Patients With Advanced Ovarian Cancer

SHINICHI TATE, KYOKO NISHIKIMI, AYUMU MATSUOKA, SATOYO OTSUKA and MAKIO SHOZU
Anticancer Research July 2022, 42 (7) 3707-3716; DOI: https://doi.org/10.21873/anticanres.15860
SHINICHI TATE
Department of Gynecology, Chiba University Hospital, Chiba, Japan
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  • For correspondence: state@faculty.chiba-u.jp
KYOKO NISHIKIMI
Department of Gynecology, Chiba University Hospital, Chiba, Japan
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AYUMU MATSUOKA
Department of Gynecology, Chiba University Hospital, Chiba, Japan
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SATOYO OTSUKA
Department of Gynecology, Chiba University Hospital, Chiba, Japan
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MAKIO SHOZU
Department of Gynecology, Chiba University Hospital, Chiba, Japan
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Abstract

Background/Aim: We investigated whether highly aggressive surgery has survival and perioperative complication benefit in patients with advanced ovarian cancer. Patients and Methods: This retrospective study included 209 patients with stage III/IV ovarian cancer who underwent aggressive surgery [surgical complexity score (SCS) ≥8] between January 2008 and December 2018. Patients were categorized into the SCS 8-12 (less aggressive surgery, 83 patients) and SCS ≥13 (highly aggressive surgery, 126 patients) groups. Survival outcomes and perioperative complications between the groups were compared. Patient suitability for primary debulking surgery or neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) was based on the evaluation of performance status, tumor load, and ascites. If patients were suitable for NACT/IDS, the residual tumor margins were marked at the initial laparotomy. The previously marked lesions were removed during IDS, even in patients with macroscopic tumor resolution. Results: Prevalence rates of stage IV disease, poor performance status, presence of omental cake, peritoneal cancer index ≥15, and IDS performed were significantly higher in the highly aggressive surgery group than in the less aggressive surgery group. The median progression-free survival (PFS) and overall survival (OS) were not significantly different between the groups (PFS, 32 and 31 months, respectively; p=0.622; OS, 99 and 75 months, respectively; p=0.390). The incidence of severe perioperative complications was not significantly different between the less aggressive group (4.8%) and the highly aggressive surgery group (6.4%) (p=0.767). Conclusion: Highly aggressive surgery with appropriate selection regardless of the timing of cytoreduction benefits patients with advanced ovarian cancer.

Key Words:
  • Aggressive surgery
  • biological behavior
  • debulking surgery
  • neoadjuvant chemotherapy
  • ovarian cancer
  • survival outcomes

Aggressive surgery aims to achieve maximal cytoreduction and complete tumor removal in patients with advanced ovarian cancer because evidence of residual disease shows poor prognosis (1-3). In patients with high tumor load, aggressive surgery with complicated surgical procedures is required to achieve complete tumor removal (4). Tertiary centers perform highly aggressive surgery compared to regional hospitals without increased frequency of major complications (5). However, this surgical method may not overcome the nature of the tumor and may have higher incidence of perioperative complications due to its complexity (6, 7).

Several studies have shown that residual tumor size in advanced ovarian cancer is not associated with the surgical expertise of the gynecologic oncologist; rather, it depends on patient-related factors, such as the nature of the tumor (8, 9). In the SCOTROC-1 trial, Crawford et al. reported significant intergroup differences in survival outcomes based on the surgical procedures performed, but not in patients with a high initial tumor burden (8). Horowitz et al. performed a retrospective analysis of data from the Gynecologic Oncology Group 182 (GOG-182) trial and observed that survival outcomes were poorer in patients with upper abdominal diseases than in those without such conditions, even in those who underwent aggressive surgery for upper abdominal disease (9). Therefore, these authors concluded that aggressive surgery does not necessarily improve survival outcomes in patients with high tumor load, but only benefits patients with less advanced ovarian cancer. The preoperative status influences the risk of postoperative complications after aggressive surgery (7).

Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) is a therapeutic strategy used to reduce perioperative complications and improve complete tumor resection rates. IDS usually includes less complex procedures because the tumor shrinks after NACT. Three randomized trials (10-12) in patients who underwent either primary debulking surgery (PDS) or IDS did not report favorable survival outcomes, and PDS showed low complete resection rates (13). The SCORPION trial performed at a high-volume medical center with extensive surgical expertise was designed to overcome the limitations of previous studies (low cytoreduction rates in the PDS arm) and was performed in patients with high tumor loads (14). The complete tumor resection rates in the SCORPION trial were 48% and 77% in the PDS and IDS groups, respectively. However, no intergroup difference was observed in survival rates. In addition, higher surgical complexity during PDS increased perioperative complications and decreased the survival outcome, whereas the simplification of the surgical procedures during IDS reduced the complications but resulted in the same survival outcome with patients who received PDS with a high incidence of perioperative complications.

To reduce perioperative complications and avoid residual microscopic diseases after IDS, we introduced highly complex procedures during IDS to patients who have risk of major complications during PDS (15). The appropriate surgical margins for IDS with a favorable prognosis could be secured by resecting a lesion >1 cm before NACT even if it is invisible during IDS, because NACT could not eradicate the tumors (16). Sites with a high incidence of pathological residual tumor during IDS included the rectosigmoid colon, transverse mesentery, greater omentum, right diaphragm, paracolic gutters, and vesicouterine pouch. Microscopic residual disease remains after traditional IDS and can lead to subsequent intra-abdominal recurrence (17). Aggressive surgery at interval debulking after NACT improved survival outcomes and did not increase perioperative complications in patients with advanced ovarian cancer (16). Therefore, it is assumed that high-complexity surgery, regardless of the timing of debulking, leads to a favorable prognosis. In this study, we investigated whether high-complexity surgery, regardless of the timing, benefits patients with advanced ovarian cancer by comparing the survival outcomes and perioperative complications of highly aggressive surgery with less aggressive surgery in our hospital.

Patients and Methods

Study design and patient selection. This retrospective observational study included patients with advanced ovarian, fallopian tube, and primary peritoneal stage III/IV cancer [International Federation of Gynecology and Obstetrics (FIGO) classification, 2014 (18)] treated at Chiba University Hospital between January 2008 and December 2018 and was approved by the Institutional Review Board of Chiba University (approval number 2976). Figure 1 illustrates the patient selection process. The surgical complexity score (SCS) rates each method used for ovarian cancer surgery, and the sum of these scores represents the complexity of each procedure (6). This study included 209 patients who underwent aggressive surgery with an SCS of ≥8 due to a high tumor burden. Aggressive surgery for advanced ovarian cancer was introduced at our hospital in 2008, and gastrointestinal and upper abdominal surgeries for complete resection were performed by gynecologic oncologists (19). The aggressive surgery procedure was described in previous reports (15, 16). Clinical data were obtained from a patient database at our hospital: age, FIGO stage, performance status (PS), timing of debulking surgery, operative details, peritoneal cancer index (PCI) (20), bevacizumab administration, number of bevacizumab cycles administered, completeness of debulking surgery, and perioperative complications within 30 days of surgery. Patients were categorized into the SCS 8-12 (less aggressive surgery) and SCS ≥13 (highly aggressive surgery) groups, and intergroup comparison of survival outcomes and perioperative complications was done (21).

Figure 1.
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Figure 1.

Study protocol.

Selection of primary debulking surgery and neoadjuvant chemotherapy followed by interval debulking surgery. We employed the following treatment protocol: patient suitability for PDS or NACT/IDS was not determined by surgical resectability, but by evaluation of PS, tumor load, and amount of ascites. If patients had only one factor that was either poor PS (PS≥2), tumor loads with upper abdominal disease, or massive ascites (above the liver surface), we performed PDS aimed at complete resection. If patients had two or more of these factors, they were triaged to the NACT/IDS group and underwent diagnostic biopsy during laparotomy. In such cases, the surgeons marked the residual tumor margins (diameter >1 cm) using non-absorbable 3-0 black silk sutures for future resection and documented residual tumor distribution on the patient’s chart (15). As described in a previous report (16), IDS was considered in such patients based on the following criteria: (i) serum cancer antigen 125 (CA125) levels decreased to ≤15 IU/ml, (ii) Serum CA125 levels did not decline and tended to increase before reaching 15 IU/ml. The previously marked lesions were resected during IDS, even in patients with macroscopically confirmed tumor resolution. We speculated that the surgical procedures during IDS were aimed at offering surgery comparable to the initial optimal PDS (16).

Chemotherapy and bevacizumab administration. The first-line chemotherapeutic regimen used in this study included administration of weekly paclitaxel (80 mg/m2 on days 1,8, and 15 every 3 weeks) and carboplatin (area under the curve 2-3 on days 1, 8, and 15 every 3 weeks). Bevacizumab (15 mg/kg every 3 weeks) was administered to patients after it was approved for the treatment of ovarian cancer in Japan in November 2013. We did not use polyadenosine diphosphate-ribose polymerase (PARP) inhibitor maintenance treatment during this period.

Statistical analysis. Progression-free survival (PFS) was the primary endpoint of this study and was defined as the time interval between the date of treatment initiation and the date of diagnosis of the first recurrence. Overall survival (OS) was defined as the time interval between treatment initiation and the date of death, or last followup. The Kaplan–Meier method was used to estimate PFS and OS. The log-rank and Wilcoxon tests were used for intergroup comparisons of statistically significant differences. The chi-square test was used for intergroup comparisons of patient characteristics. Cox proportional hazards regression analysis was performed to analyze the prognostic factors associated with PFS and OS. All statistical analyses were two-sided and performed using the JMP statistical software, version 11.0 (SAS, Cary, NC, USA). Statistical significance was set at p<0.05.

Results

Patient characteristics. Table I shows the characteristics of the patients included in this study. The rates of stage IV disease, poor PS, presence of omental cake, PCI ≥15, and IDS were significantly higher in the highly aggressive surgery group than in the less aggressive surgery group. Serum CA 125 levels and amount of ascites at the time of initial surgery were higher in the highly aggressive surgery group. No significant intergroup differences were observed in age, primary tumor site, or histopathological findings. No significant intergroup difference was observed in the rate of completeness of resection [patients without any residual tumor: 74/83, (89%) in the less aggressive vs. 118/126 (94%) in the highly aggressive surgery group; p=0.245]. Among the 74 patients who underwent PDS, 22 (17%) underwent highly aggressive surgery. In contrast, 104 of 135 patients (83%) who underwent NACT/IDS had highly aggressive surgery. The median cycle of NACT was five [interquartile range (IQR)=5-7].

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Table I.

Patient characteristics.

Surgical procedures in aggressive surgery. Table II shows the surgical procedures used for aggressive surgery. There were significant differences in the procedures between the less aggressive and highly aggressive surgery groups as follows: pelvic lymphadenectomy, para-aortic lymphadenectomy, small bowel resection, large bowel resection, diaphragm stripping or resection, splenectomy, liver resection, and rectosigmoidectomy with reanastomosis. Figure 2 shows the extra-gynecologic surgeries performed; 34 (81%) of 42 patients with SCS 8-10 had rectosigmoidectomy with reanastomosis; 33 (80%) of 41 patients with SCS 11-12 had rectosigmoidectomy with reanastomosis and diaphragm stripping/resection; and 75 (78%) of 96 patients with SCS 13-15 had rectosigmoidectomy with reanastomosis, diaphragm stripping/resection, and splenectomy. All 30 patients with SCS 16-18 had rectosigmoidectomy with reanastomosis, diaphragm stripping/resection, splenectomy, and large bowel resection.

Figure 2.
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Figure 2.

Extra-gynecologic surgical procedures in aggressive surgery. RS: Rectosigmoidectomy with reanastomosis; D: diaphragm stripping or resection; S: splenectomy; L: large bowel resection.

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Table II.

Surgical procedures in aggressive surgery.

Bevacizumab administration. The percentage of patients who received bevacizumab was higher in the highly aggressive than in the less aggressive surgery group [patients who received bevacizumab: 30/83 (36%) in the less aggressive vs. 81/126 (64%) in the highly aggressive surgery group; p<0.0.01]. The median number of cycles received was 21 (IQR=19-21) and 20 (IQR=10-21) in the less aggressive and highly aggressive surgery groups, respectively.

Survival analysis and severe perioperative complications. Figure 3 shows the PFS and OS in this study. The median follow-up period was 48.8 months (IQR=30.6-65.1). The median PFS in this study was 31.5 months [95% confidence interval (CI)=27.3-34.6]. The median PFS in the less aggressive and highly aggressive surgery groups was 32.0 months (95%CI=24.0-45.2) and 31.0 months (95%CI=27.4-34.1), respectively (log-rank test, p=0.622; Wilcoxon test, p=0.926; Figure 3A). The median OS was 80.0 months (95%CI=64.9-106.3). The median OS in the less aggressive and highly aggressive surgery groups was 98.8 months (95%CI=58.9-not reached) and 74.7 months (95%CI=55.8-106.3), respectively (log-rank test, p=0.390; Wilcoxon test, p=0.799; Figure 3B). Based on the surgical achievement, patients with no residual tumor showed better prognosis than in those with any residual tumor in terms of PFS and OS. The median PFS in patients with no residual tumor and in those with residual tumor was 32.0 months (95%CI=27.5-35.3) and 23.0 months (95%CI=9.5-32.6), respectively (logrank test, p=0.068; Wilcoxon test, p=0.006; Figure 4A). In comparison, the median OS in patients with no residual tumor and any residual tumor was 98.8 months (95%CI=68.8-110.2) and 53.7 months (95%CI=25.8-58.2), respectively (log-rank test, p=0.005; Wilcoxon test, p=0.012; Figure 4B).

Figure 3.
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Figure 3.

Progression-free survival and overall survival between less and highly aggressive surgery groups. A) Progression-free survival; B) overall survival.

Figure 4.
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Figure 4.

Progression-free survival and overall survival between patients who received debulking surgery with no and any residual tumor. A) Progression-free survival; B) overall survival.

Severe perioperative complications [Clavien-Dindo grade (18) ≥IIIb] occurred in 4 (4.8%) and 8 patients (6.4%) in the less aggressive and highly aggressive surgery groups, respectively (p=0.767).

Association between survival outcomes and peritoneal cancer index and presence of omental cake. The median PCI was 15 in all patients included. Based on median PCI values, patients were categorized into low PCI (<15) and high PCI (≥15) groups. No significant intergroup difference was observed in the PFS [low PCI: 32.4 months (95%CI=25.4-42.7) and high PCI: 29.7 months (95%CI=25.0-34.0)] (logrank test, p=0.476; Wilcoxon test, p=0.420). Based on the presence of an omental cake during the initial surgery, patients were categorized into positive and negative omental cake groups. No significant intergroup difference was observed in the PFS [negative omental cake group: 32.0 months (95%CI=25.2-36.1) and positive omental cake group: 31.0 months (95%CI=25.5-34.6) log-rank test, p=0.745; Wilcoxon test, p=0.894].

Survival outcomes before and after bevacizumab approval. In this study, 66 and 143 patients received initial treatment before and after bevacizumab approval, respectively. No significant intergroup difference was observed in the PFS [PFS before bevacizumab approval: 26.1 months (95%CI=22.4-35.8); PFS after bevacizumab approval: 32.7 months (95%CI=27.3-34.6); log-rank test, p=0.244; Wilcoxon test, p=0.335] and OS [OS before bevacizumab approval: 74.7 (95%CI=57.6-106.3); OS after bevacizumab approval: not reached (95%CI=70.7-not reached); log-rank test, p=0.063; Wilcoxon test, p=0.100].

Multivariate analysis of prognostic factors associated with progression-free and overall survival. Cox proportional hazards regression analysis was performed to analyze the prognostic factors associated with PFS and OS (Table III). Bevacizumab administration [hazard ratio (HR)=0.66; 95%CI=0.47-0.93, p=0.018] and completeness of resection (HR=0.51; 95%CI=0.28-0.92; p=0.026) were independently associated with PFS in all patients. Completeness of resection (HR=0.36; 95%CI=0.19-0.69; p=0.002) was independently associated with OS in all patients.

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Table III.

Multivariable Cox proportional analysis of risk factors for progression-free survival and overall survival for advanced ovarian cancer with high complexity surgery.

Intention-to-treat analysis. Figure 1 shows the intention-to-treat analysis. A total of 306 patients with advanced ovarian, fallopian tube, and primary peritoneal stage III/IV cancer were treated at Chiba University Hospital between January 2008 and December 2018. The median PFS and OS in all patients were 28.4 months (95%CI=25.7-33.1) and 76.5 months (95%CI=62.4-101). Thirty-two patients had surgery with low SCS (0-3) and their median PFS and OS were 8.1 months (95%CI=4.5-11.1) and 12.9 months (95%CI=4.8-33.6). Sixty-five patients received surgery with moderate SCS (4-7) and their median PFS and OS was 35.2 months (95%CI=24.6-infinity) and 88.9 months (95%CI=51.4-101.6). There was no significant difference between moderate and high SCS in PFS (log-rank test, p=0.196; Wilcoxon test, p=0.781) and OS (logrank test, p=0.615; Wilcoxon test, p=0.515).

Discussion

Highly aggressive surgery benefits patients with advanced ovarian cancer comparable to less aggressive surgery. One of the reasons for the better survival is that approximately 80% of patients who underwent NACT/IDS underwent highly aggressive surgery. Our selection criteria for the timing of debulking were decided by three patient factors: PS, tumor loads with upper abdominal disease, and massive ascites. NACT was consequently performed in patients with high disease loads, such as those with high PCI or in those with an omental cake. As previously stated, NACT/IDS in this study was aimed at resection of disseminated lesions (diameter >1 cm) detected prior to the initial treatment since NACT alone could not eradicate tumors (16). Highly aggressive surgery after NACT consequently improved survival without increasing perioperative morbidity. In comparison, PDS was performed in patients with relatively low disease loads, such as those with low PCI or in those without an omental cake. Less aggressive surgery was associated with fewer perioperative complications. Both treatment strategies contributed to the favorable survival outcomes and low perioperative complication rates for the intergroups. The results suggest that aggressive surgery with appropriate selection, regardless of the timing of debulking, benefits patients with both less and highly advanced ovarian cancer.

Few reports examined the differences in prognosis stratified by surgical complexity. Horowitz et al. reported that patients with high SCS had significantly poorer PFS than those with moderate and low SCS, and that OS was similar among patients with high, moderate, and low SCS (9). They concluded that the prognosis was affected by the initial disease status and not by the surgical effort. Contrary to their report, PFS and OS were not different between the less aggressive surgery group and highly aggressive surgery groups in our study. Moreover, the prognosis in all cohorts in this study was more favorable (median PFS, 31.5 months; OS, 80.0 months) than their results (median PFS, 14.9 months; OS, 44.2 months). The high rate of NACT/IDS in highly aggressive surgery in this study may explain the difference observed in their prognosis. NACT improved the general condition of patients with an increased initial disease burden and enabled highly aggressive surgery depending on the initial disease burden. In a previous study (16), patients who underwent resection of lesions >1 cm in diameter before NACT (even those that were invisible during IDS) were observed to have a significantly prolonged PFS compared to patients who only underwent resection of grossly visible residual disease after NACT. Despite successful complete macroscopic resection in traditional IDS, microscopic residual disease may remain and cause recurrence (16). The prolonged PFS observed in highly aggressive surgery groups was attributed to this factor that contributed to the differences between our study and those of the SCORPION (14) or other NACT trials (10-12).

Perioperative morbidity rates in this study were low in patients who underwent both highly and less aggressive surgeries. Moreover, perioperative complications usually occur in patients undergoing highly aggressive surgery. Our result was different from another study (14) on high SCS surgery for advanced ovarian cancer. In most hospitals, highly aggressive surgery is performed during PDS and simple surgery during IDS. In the SCORPION (14), among 75 of 84 (89%) patients in the PDS group with high SCS, 39 (46.4%) had major complications. In our study, among 11 of 74 patients (14.9%) in the IDS group with high SCS, 7 (9.5%) had major complications. The highly aggressive surgery was performed in 22 of 74 (29.7%) patients in the PDS and in 104 of 135 patients (77.0%) in the IDS groups.

In a previous study, NACT/IDS not only simplified the surgical procedure, but also did not increase the perioperative morbidity rates in those with high SCS (16). Although a predictive index score for achieving complete cytoreduction at PDS has been proposed by Petrillo et al. (22), perioperative complications were not considered in the score. Even if a highly complex surgical procedure can achieve complete cytoreduction with PDS, NACT/IDS appears to be a more favorable strategy in patients with a predictive index score of 8-12 (13).

Whether aggressive cytoreductive surgery overcomes the extent of peritoneal dissemination remains debatable. In contrast to the SCOTROC-1 (8) and GOG-182 studies (9), aggressive surgery overcame the biological behavior of advanced ovarian cancer in our study. In the SCOTROC-1 and GOG-182 trials, the complete resection rate was low in patients with a high disease burden. Therefore, aggressive surgery was not beneficial to patients with a residual tumor measuring ≥2 cm in diameter in the SCOTROC-1 trial and patients with a high disease score with upper abdominal involvement in the GOG-182 study. In addition, PCI (23-25) or omental cake (8), which was previously reported as an indicator of biological aggressiveness (4), was not identified as a prognostic factor for advanced ovarian cancer in this study. In a previous study (26), no residual disease and high SCS were significant prognostic factors for PFS and OS; however, PCI did not show such an association in advanced ovarian cancer. Aggressive surgery or selecting PDS or IDS could essentially overcome the extent of peritoneal dissemination in patients with a high PCI score, and those who undergo procedures with high SCS.

Multivariable analysis revealed that complete resection remained the most significant prognostic factor, even in patients who underwent procedures with high SCS. In some patients with high tumor loads, aggressive surgery does not always ensure complete resection without any residual tumor. Therefore, it can be deduced that aggressive surgery may not completely overcome the biological aggressiveness of the cancer. In the SCORPION trial, survival outcomes did not differ between patients with stage III and IV tumors, and in patients with no residual tumor versus those with some evidence of residual tumor. Some patients with high tumor load who underwent complete resection might have had occult residual disease that was not macroscopically visible (14). Alternatively, it has been observed that the surgical burden associated with aggressive surgery may result in compromised immunity, which may negatively affect survival outcomes comparable to those of residual disease (14).

This study had several limitations. First, this retrospective study only included patients who underwent highly aggressive surgery for advanced ovarian cancer. Intergroup comparisons may have introduced several confounding factors. Multivariable analysis revealed that bevacizumab administration and completeness of resection were independently associated with PFS in all patients, and completeness of resection was independently associated with OS in all patients. Second, bevacizumab administration (after November 2013) may have led to a better prognosis in some patients. However, survival outcomes before and after bevacizumab approval were compared, and there were no significant differences in outcomes between the two periods. Third, the results may not be generalizable due to the singlecenter study design. However, treatment homogeneity and clinical data integrity are strengths of this study. Lastly, in the last years, the introduction of PARP inhibitor in first-line treatment have improved patient prognosis (27). This study did not include patients who received maintenance PARP inhibitor treatment; therefore, it is unclear whether our results are consistent with studies associated with the current treatment protocol used in clinical practice that included the administration of maintenance PARP inhibitors.

In conclusion, aggressive surgery after NACT improved survival outcomes and did not increase perioperative complications in patients with highly advanced ovarian cancer who were unfamiliar with PDS. The results suggest that regardless of the timing of debulking, aggressive surgery benefits patients with both less and highly advanced ovarian cancer.

Footnotes

  • Authors’ Contributions

    Conceptualization, S.T. and M.S.; methodology, S.T.; formal analysis, S.T.; investigation, S.T.; data curation, S.T. and K.N.; writing – original draft preparation, S.T.; writing – review and editing, S.T., K.N., A.M., and S.O.; visualization, S.T.; supervision, M.S.; project administration, S.T. All Authors have read and agreed to the published version of the manuscript.

  • Conflicts of Interest

    The Authors declare no conflicts of interest in relation to this study. No financial support was received.

  • Received May 29, 2022.
  • Revision received June 16, 2022.
  • Accepted June 17, 2022.
  • Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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Highly Aggressive Surgery Benefits in Patients With Advanced Ovarian Cancer
SHINICHI TATE, KYOKO NISHIKIMI, AYUMU MATSUOKA, SATOYO OTSUKA, MAKIO SHOZU
Anticancer Research Jul 2022, 42 (7) 3707-3716; DOI: 10.21873/anticanres.15860

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Highly Aggressive Surgery Benefits in Patients With Advanced Ovarian Cancer
SHINICHI TATE, KYOKO NISHIKIMI, AYUMU MATSUOKA, SATOYO OTSUKA, MAKIO SHOZU
Anticancer Research Jul 2022, 42 (7) 3707-3716; DOI: 10.21873/anticanres.15860
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Keywords

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