Abstract
Background/Aim: We investigated factors affecting the long-term duration of bevacizumab-based maintenance therapy (BMT) and survival in patients with the first platinum-sensitive recurrence of ovarian cancer (PSR). Patients and Methods: We included patients with the first PSR in two tertiary centers from January 2015 till August 2021. All patients received six cycles of paclitaxel, carboplatin, and bevacizumab followed by BMT. We collected data including age at recurrence, histologic types, the status of BRCA mutation, platinum-free interval (PFI), extent of secondary cytoreductive surgery (SCS), presence of extra-abdominal disease, numbers of recurred lesions, cycles of BMT, progression-free survival (PFS), and cancer-specific survival (CSS). The median cycles of BMT were 13 (range=1-108). Results: A total 103 patients were included, who consisted of the short-term (<13 cycles; n=49; 47.6%) and long-term users of BMT (≥13 cycles; n=54; 52.4%). High-grade serous carcinoma (HGSC), PFI >12 months, and optimal cytoreduction during SCS were favorable factors for the long-term duration of BMT. Moreover, PFI >12 months and the long-term duration of BMT were factors for improved PFS, and HGSC and PFI >12 months were related to improved CSS. Conclusion: PFI >12 months may be associated with the long-term duration of BMT and improved survival in patients with the first PSR.
Ovarian cancer is the second most common female malignancy and the leading cause of death due to female cancer (1, 2). Despite the initial aggressive treatment, 22% of patients with ovarian cancer show platinum-resistant recurrence defined as relapse within six months from the last platinum-based chemotherapy, which requires non-platinum agents for overcoming platinum resistance. However, more than two-thirds of the patients ultimately relapse within one year (3). On the other hand, platinum-based chemotherapy is still effective for platinum-sensitive recurrence of ovarian cancer (PSR) defined as relapse after six months from completion of platinum chemotherapy, and maintenance therapy, such as angiogenic inhibitors or poly (ADP ribose) polymerase (PARP) inhibitors, are recommended to improve the prognosis (4).
The effect of bevacizumab, a monoclonal antibody that inhibits vascular endothelial growth factor, has been evaluated for treating platinum-sensitive recurrence in two randomized controlled trials. First, Ovarian Cancer Study Comparing Efficacy and Safety of Chemotherapy and Anti-Angiogenic Therapy in Platinum-Sensitive Recurrent Disease (OCEANS) trial showed better progression-free survival (PFS) in patients who received gemcitabine and carboplatin with bevacizumab than those treated with standard chemotherapy alone despite similar overall survival (OS) (5, 6). Second, NRG Oncology/Gynecologic Oncology Group study GOG-0213 (GOG-0213) also demonstrated that the combination using paclitaxel, carboplatin, and bevacizumab followed by bevacizumab-based maintenance therapy (BMT) improved PFS and OS, compared to chemotherapy alone without bevacizumab (7).
Even though some reports have shown the efficacy and safety of BMT for recurrent ovarian cancer (8-11), there is a lack of evidence regarding the factors associated with the duration of BMT after the completion of the combined treatment. Thus, we performed this study to predict the long-term use of BMT to improve the prognosis of the first PSR.
Patients and Methods
Patients. This study was conducted in two tertiary centers, and the protocol was approved by the institutional review board of the two institutions in advance (No, 2203-096-1305 and GCIRB2022-077). The requirement for written informed consent was waived by the IRB. We included patients over 18 years of age who received paclitaxel, carboplatin, and bevacizumab followed by BMT for treating the first PSR from January 2015 to August 2021.
The medical treatment consisted of six cycles of paclitaxel (175 mg/m2), carboplatin (area under the curve, 5.0), and bevacizumab (15 mg/kg) every three weeks. After the treatment, BMT continued until disease progression or serious toxicities were identified. In patients who underwent secondary cytoreductive surgery (SCS), bevacizumab was administered from the second cycle of the chemotherapy. The treatment response was evaluated every three cycles by Gynecologic Cancer Intergroup (GCIG) criteria or Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (12, 13).
Clinical data. We collected clinic-pathologic data including age at recurrence, histologic types, the status of BRCA mutation, platinum-free interval (PFI), presence of extra-abdominal disease, number of recurred lesions, the extent of SCS, cycles of BMT, PFS, and cancer-specific survival (CSS). The optimal cytoreduction was achieved when the residual tumor was less than 1 cm. PFS and CSS were defined as the interval from the date of the first recurrence to the date of the second recurrence, and as the interval from the date of diagnosis of ovarian cancer to the date of death due to the disease or last follow-up.
To find factors affecting the duration of BMT, we calculated the median number of cycles of BMT in patients included in this study. As a result, the median treatment cycle of BMT was 13 (range=1-108). Based on the median value, we classified all patients into short-term (<13 cycles) and long-term users of BMT (≥13 cycles). Among them, we additionally excluded nine patients because BMT was continued even though they were classified as short-term users at the time of the study.
Statistical analysis. The baseline characteristics of the two groups were compared by Pearson’s chi-squared or Fisher’s exact test. We adopted binary logistic regression to evaluate factors for the long-term duration of BMT by using an odds ratio (OR) and 95% confidence interval (CI). Moreover, Cox proportional hazards models with a hazard ratio (HR) and 95% CI were used to determine the prognostic factors for PFS and CSS. Statistical analysis was performed with SPSS Statistical Software (Version 22.0, SPSS Inc., Chicago, IL, USA). The results were statistically significant if p-value was less than 0.05.
Results
Population. A total of 103 patients were included, and the short-term and long-term users of BMT were 49 (47.6%) and 54 (52.4%), respectively. Table I depicts the clinicopathological characteristics of them. There were no differences in histologic types, the status of BRCA mutation, and extra-abdominal metastasis between the two groups. On the other hand, age <55 years, PFI >12 months, optimal cytoreduction during SCS, and complete or partial response were more common in the long-term users of BMT, whereas the short-term users had more recurred lesions at the diagnosis of the first PSR. Moreover, more patients among the short-term users of BMT discontinued it due to progressive disease (PD).
Clinicopathological characteristics of 103 patients with the first platinum-sensitive recurrence of ovarian cancer.
Factors affecting the long-term duration of bevacizumab-based maintenance therapy. Table II demonstrates factors associated with the long-term duration of BMT. In all patients, high-grade serous carcinoma (HGSC), PFI >12 months, and optimal cytoreduction during SCS were favorable factors for the long-term duration of BMT (adjusted ORs, 3.673, 3.762, and 6.306; 95%CIs=1.100-12.265, 1.520-9.313, and 1.674-23.756). When we excluded patients who discontinued BMT because of reasons other than PD, PFI >12 months, and optimal cytoreduction during SCS were the only favorable factors for the long-term duration of BMT (adjusted ORs, 7.290 and 7.201; 95%CIs=2.581-20.590 and 1.370-37.835; Table II).
Factors affecting the long-term duration of bevacizumab-based maintenance therapy for the first platinum-sensitive recurrence of ovarian cancer.
Survival. PFI >12 months and the long-term duration of BMT were factors for improved PFS (adjusted HRs=0.118 and 0.197; 95%CIs=0.111-0.319 and 0.116-0.337), whereas recurred lesions of 4-19 and ≥20 were unfavorable factors in all patients (adjusted HRs=2.676 and 3.396; 95%Cis=1.448-4.936 and 1.565-7.365). When we excluded patients who discontinued BMT due to reasons other than PD, the long-term duration of BMT was the only factor for improved PFS (adjusted HR=0.090; 95%CIs=0.047-0.173; Table III).
Factors affecting progression-free survival for the first platinum-sensitive recurrence of ovarian cancer.
Furthermore, HGSC and PFI >12 months were related to improved CSS in all patients (adjusted HRs=0.175 and 0.040; 95% CIs=0.048-0.635 and 0.009-0.183). When we conducted a subgroup analysis for patients who remained after exclusion of those who discontinued BMT because of reasons other than PD, HGSC and PFI >12 months were associated with improved CSS (adjusted HRs=0.171 and 0.055; 95%CIs=0.041-0.716 and 0.012-0.261) while recurred lesions of ≥20 decreased CSS (adjusted HRs=23.599; 95%CI=1.635-339.445; Table IV).
Factors affecting cancer-specific survival for the first platinum-sensitive recurrence of ovarian cancer.
Discussion
We performed this study to identify predictive factors for the long-term duration of BMT and their prognostic impact on survival in the first PSR. As a result, we found that PFI >12 months was commonly a favorable factor for predicting the long-term duration of BMT (≥13 cycles) and improving PFS and CSS in patients with the first PSR.
Even though the median treatment cycle of BMT cycles was determined considering the study period, it is comparable to the value from GOG-213 and OCEANS trials where the median treatment cycles were 16 (range=1-111) and 12 (range=1-43), respectively (5, 7). Moreover, the long-term duration of BMT improved only PFS, which was similar to the results from these two trials.
Optimal cytoreduction during SCS was a factor for the long-term duration of BMT, whereas it was not a factor for improving PFS and CSS. This finding was similar to the result from GOG-213, where SCS did not lead to longer survival than chemotherapy alone in patients with the first PSR who received BMT (14). However, GOG-123 also showed that R0 resection was associated with longer survival, which means that we can expect a surgical effect on improved survival if the criteria of optimal cytoreduction are adjusted from R1 to R0 in this study. The reason is that the gross removal of hypoxic tumors can result in reperfusion and thereby increase the penetration of drug in microscopic residual tumors (15).
In particular, PFI >12 months, the only factor for the long-term duration of BMT and improved PFS, has been considered as an important prognostic factor in PSR because longer PFI may have a greater chance to show response to chemotherapy (16, 17). Previous studies reported that over-expression of cyclin and reduced levels of anti-angiogenic proteins were related to longer PFI in recurrent ovarian cancer (18, 19). Thus, notable survival benefit has been shown in patients with PFI >12 months, compared to those with PFI <6 months or 6-12 months (20).
Moreover, PFI >12 months was no longer associated with improved PFS, whereas the long-term duration of BMT was the only factor for better PFS when we excluded patients who discontinued BMT due to reasons other than PD. This means that biological factors including mesothelin and fms-like tyrosine kinase-4 may be strongly related to the long-term duration of BMT and survival (21). Especially, the mesenchymal tumor type among the four The Cancer Genome Atlas (TCGA) has been shown to derive a PFS benefit from the treatment of bevacizumab (22). Since the mesenchymal tumor type shows clinical phenotype including upper abdominal or omental tumors and ascites, these features can be clinical candidates for predicting the long-term duration of BMT in the first PSR.
This study is the first research to demonstrate predictive factors for the duration of BMT in patients diagnosed with the first PSR. However, this study has some limitations as follows: First, 26 patients (25.2%) are continuing BMT, thus the median treatment cycle of BMT and its prognostic value would change if the study period increases. Second, clinical candidates including the amount of ascites and R0 resection were not included in this study, which should be considered as potential factors affecting the long-term duration of BMT and survival in large-scale studies.
Bevacizumab and three PARP inhibitors (olaparib, niraparib, and rucaparib) were the recommended maintenance therapy in the first PSR. However, there is limited data on factors to identify patients who can benefit from BMT. We found PFI >12 months was predictive of long-term duration of BMT and better survival in the first PSR. These results could be useful to anticipate the efficacy of BMT. Further prospective studies are warranted to confirm our results and elaborate the criteria to choose candidates to receive BMT for the first PSR.
Conclusion
PFI >12 months was a factor to predict the long-term duration of BMT (≥13 cycles) and survival in patients with the first PSR. Thus, these findings could help gynecologic oncologists when counseling about the possibility of the long-term duration of BMT to the patients.
Acknowledgements
The Authors deeply appreciate Deampac Corp. (Wonju, Republic of Korea), and Precision Medicine for Peritoneal Metastasis Corp. (Wonju, Republic of Korea) for their support.
Footnotes
Authors’ Contributions
Seungho Lee and Hee Seung Kim designed the study. Soo Hyun Oh, Soo Jin Park, and Seungmee Lee collected and analyzed the data. All Authors wrote and revised the article and approved the final manuscript.
Funding
This research was supported by Commercializations Promotion Agency for R&D Outcomes grant funded by the Korea government (the Ministry of Science and ICT) (Project No. 1711151316) and Seoul National University Hospital (No. 0620211700, 0320232140, 0420222060, and 0320212060).
Conflicts of Interest
Soo Jin Park and Hee Seung Kim are the Chief Technology Officer and Chief Executive Officer, respectively, in Dreampac Corp. (Wonju, Republic of Korea). Moreover, Seungmee Lee and Soo Hyun Oh are the Chief Executive Officer and a director of Precision Medicine for Peritoneal Metastasis Corp. (Wonju, Republic of Korea). The other Authors have no conflicts of interest to declare in relation to this study.
- Received September 12, 2023.
- Revision received September 27, 2023.
- Accepted September 28, 2023.
- Copyright © 2024 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
