Abstract
Background/Aim: In recent years, the usefulness of poly ADP-ribose polymerase (PARP) inhibitors as subsequent maintenance therapy with poly ADP-ribose polymerase (PARP) inhibitors has been reported. However, it has been reported shown that platinum-based chemotherapy has a low response rate and short progression-free survival for recurrent platinum-sensitive ovarian cancer during treatment with PARP inhibitor therapy. This retrospective study evaluated platinum-based chemotherapy with bevacizumab (BEV) followed by BEV maintenance in these recurrent patients. Patients and Methods: Efficacy and safety were evaluated in 23 patients with ovarian, fallopian tube, or primary peritoneal cancer diagnosed with platinum-sensitive recurrence during PARP inhibitor treatment (administered from April 2019 to December 2022). Platinum-based chemotherapy included either paclitaxel with carboplatin, paclitaxel with cisplatin, docetaxel with carboplatin, or doxorubicin with carboplatin. BEV was administered in combination with any of these chemotherapies agents. Chemotherapy was administered for 6 cycles and BEV was administered up to 21 cycles. Results: The median numbers of cycles of platinum-based chemotherapy and BEV administration were 6 and 8, respectively. Complete response was observed in four patients (17.4%), partial response in 15 (65.2%), stable disease in two (8.7%), and progressive disease in two (8.7%). Objective response and disease control rates were 82.6% and 91.3%, respectively. Grade 3 or higher hematological toxicity occurred in 8 patients, with leukopenia, neutropenia in 14, anemia in 5, and thrombocytopenia in 4. On the other hand, non-hematological toxicities included hypertension in three patients, proteinuria in two, constipation in one, and carboplatin hypersensitivity in four. Only one patient discontinued chemotherapy due to an adverse event of proteinuria. No treatment-related deaths occurred. Conclusion: Platinum-based chemotherapy with BEV followed by BEV maintenance for platinum-sensitive recurrence during PARP inhibitor treatment was shown to be efficacious and safe. This combination should be further evaluated in larger randomized clinical trials.
The incidence of ovarian cancer is increasing yearly, and it is the third most common gynecological malignancy after cervical and endometrial cancer. In 2020, there were 21,750 estimated new diagnoses of ovarian cancer and 13,940 deaths due to the disease in the USA; deaths due to ovarian cancer were higher than those due to endometrial and cervical cancers (1). Paclitaxel and carboplatin (TC) therapy is the gold-standard chemotherapy regimen for epithelial ovarian, fallopian tube, or primary peritoneal carcinoma based on clinical studies, such as the GOG111, OV-10, GOG158, and AGO trials (2-5). Recently, the usefulness of subsequent maintenance therapy with poly ADP-ribose polymerase (PARP) inhibitors was reported (6-8), and they have been adopted and widely used in current clinical practice. However, reports on the treatment of recurrence after maintenance therapy are limited. Platinum-based chemotherapy for platinum-sensitive recurrence during PARP inhibitor treatment has been reported to result in a poor response rate (RR) and short progression-free survival (PFS) (9-12). At our Institution, bevacizumab (BEV) is used in platinum-based chemotherapy for platinum-sensitive recurrent cancers. We investigated whether the combination of platinum-based chemotherapy with BEV followed by BEV maintenance could contribute to improved outcomes in platinum-sensitive recurrence during PARP inhibitor treatment. We conducted a non-interventional retrospective study to clarify this clinical question at a multicenter Institution.
Patients and Methods
Study design. This study was approved by the Institutional review board of the Iwate Medical University, School of Medicine (Approval No. MH2022-113). The need for informed consent was waived on account of the nature of the study. Platinum-sensitive patients were defined as those who relapsed more than six months after the last platinum administration date. In addition, platinum-free interval (PFI) was defined as the time from the last platinum administration to subsequent disease progression on radiographic assessment using Response Evaluation Criteria in Solid Tumors (RECIST) criteria (13).
Patients. Twenty-three patients who received platinum-based chemotherapy with BEV followed by BEV maintenance for ovarian, fallopian tube, or primary peritoneal cancer were diagnosed with platinum-sensitive recurrence during PARP inhibitor administration at the Department of Obstetrics and Gynecology, Iwate Medical University Hospital and the Department of Obstetrics and Gynecology, Hachinohe Red Cross Hospital from April 2019 to December 2022 were included.
Treatment. Platinum-based combination chemotherapy selected for treatment included TC therapy [paclitaxel dose of 175 mg/m2 on day 1 and carboplatin at an area under the curve (AUC) of 5 on day 1, every 3 weeks], paclitaxel + cisplatin (TP) therapy (paclitaxel dose of 175 mg/m2 on day 1 and cisplatin dose of 50 mg/m2 on day 1, every 3 weeks), docetaxel + carboplatin (DC) therapy (docetaxel dose of 60 mg/m2 on day 1 and carboplatin at an AUC of 5 on day 1, every 3 weeks), and pegylated liposomal doxorubicin (PLD) + carboplatin (PLDC) therapy (PLD dose of 30 mg/m2 on day 1 and carboplatin at an AUC of 5 on day 1 every 4 weeks). BEV was administered at a dose of 15 mg/kg every three weeks along with TC, TP, and DC therapies and at a dose of 10 mg/kg every two weeks along with PLDC therapy. BEV dosing was determined according to our criteria (Table I). Treatment continued until serious adverse events (AEs) occurrence or until disease progression. As a rule, chemotherapy was administered for 6 cycles, and BEV was used for up to a maximum of 21 cycles, based on the OCEANS study (14).
Dosing criteria for bevacizumab administration in patients with ovarian, fallopian tube, and primary peritoneal cancer.
Endpoints/variables. The primary endpoint was PFS, and the secondary endpoints were antitumor efficacy, AEs, and overall survival (OS). Antitumor efficacy was assessed using RECIST version 1.1 (13). The incidence and severity of AEs and treatment-related AEs were evaluated according to the Common Toxicity Criteria for Adverse Events version 5.0 JCOG Japanese version (CTCAE version 5.0-JCOG) (15).
Statistical analysis. The data cutoff was set as December 31, 2022. PFS and OS were calculated from the start date of platinum-based combination chemotherapy with BEV to the documented date of progression, death, or last follow-up, whichever occurred first. The effect on survival was assessed by constructing Kaplan-Meier curves with a log-rank test.
In addition, independent prognostic factors were investigated using univariate and multivariate analyses of seven factors: age, clinical diagnosis, histological type, PFI, number of previous platinum dose, previous dose of BEV, and recurrence site. Statistical analyses were performed using SAS version 9.4, with the significance set at p<0.05.
Results
Patient characteristics. Table II summarizes the background characteristics of the 23 patients enrolled in this study. The median age of the 23 patients was 64 years (range=48-76 years). The performance status was 0 in all patients. The histological type was serous carcinoma in 20 patients (87.0%) and clear cell carcinoma in 3 (13.0%). Overall, 6 patients (26.1%) received one regimen of prior chemotherapy, 15 patients (65.2%) received two regimens, and 1 patient (4.3%) each received three and four regimens, respectively. BEV was administered prior to this treatment in 15 patients (65.2%), while 8 patients (34.8%) did not receive BEV. The most recently administered PARP inhibitors in this treatment were olaparib in 17 (73.9%), niraparib in 4 (17.4%), and rucaparib in 2 patients (8.7%). The PFI was <12 months in 13 patients (56.5%) and ≥12 months in 10 patients (33.3%). The site of recurrence was intraperitoneal in 15 patients (65.2%), distant metastasis in 5 patients (21.7%), and both intraperitoneal and distant metastases in 3 patients (13.0%). Platinum-based chemotherapy with BEV administered to the enrolled patients included TC therapy in 18 patients (78.2%), TP and DC therapy in 1 patient (4.3%), and PLDC therapy in 3 patients (13.0%).
Characteristics of patients included in the study (N=23).
Antitumor response. Table III summarizes the antitumor effects observed in 23 patients. The median number of cycles of platinum-based chemotherapy and BEV was 6 (range=3-11) and 8 (range=3-21), respectively. Complete response was observed in 4 patients (17.4%), partial response in 15 (65.2%), stable disease in 2 (8.7%), and progressive disease in 2 (8.7%). Objective response and disease control rates were 82.6% [95% confidence interval (CI)=61.2-95.1%] and 91.3% (95% CI=72.0-98.9%), respectively.
Anti-tumor response of patients after platinum-based chemotherapy with bevacizumab (N=23).
Survival analysis. Figure 1 shows the PFS (A) and OS (B) of all the patients. The median follow-up period was 11 months (range=2-37 months), and the median PFS and OS were 8 months (95% CI=6.0-13.0) and 25 months (95% CI=16.0-37.0), respectively.
Kaplan–Meier curves for progression-free survival (A) and overall survival (B). The median PFS for all patients was 8 months (95 % CI=6.0-13.0), and the median OS was 25 months (95 % CI=16.0-37.0).
Univariate and multivariate analyses of PFS and OS were performed for the background factors listed in Table II. No independent prognostic factor was found for OS, while age and recurrence site were independent prognostic factors for PFS (Table IV).
Univariate and multivariate analyses of PFS.
Adverse events. The AEs that developed in this study are presented in Table V. Grade 3 or higher hematologic toxicities occurred in 8 patients (34.8%), neutropenia in 14 (60.9%), anemia in 5 (21.7%), and thrombocytopenia in 4 (17.4%). Febrile neutropenia occurred in 1 patient (4.3%). One case (4.3%) of carboplatin dose reduction in the next cycle due to hematologic toxicity was observed. In contrast, non-hematological toxicities of grade 3 or higher were hypertension in 3 patients (13.0%), proteinuria in 2 patients (8.7%), and constipation in 1 patient (4.3%). Additionally, carboplatin hypersensitivity in 8 patients (34.8%) included 4 patients (17.4%) with grade 3 AEs. Patients with carboplatin hypersensitivity were administered desensitization therapy according to a previously published protocol (16). However, 4 patients with grade 3 carboplatin hypersensitivity were switched to paclitaxel with BEV and continued chemotherapy. Of all patients, 1 patient with grade 3 proteinuria discontinued BEV maintenance therapy after six cycles. In addition, no treatment-related deaths occurred.
Adverse events of patients during platinum-based chemotherapy with bevacizumab followed by bevacizumab maintenance therapy (N=23).
Discussion
Recently, PARP inhibitors have been introduced as maintenance therapy for platinum-sensitive recurrent ovarian cancer, although reports on the treatment of recurrence during maintenance therapy are limited. Some studies report that platinum-based chemotherapy for platinum-sensitive recurrent ovarian cancer during PARP inhibitor treatment has a poor RR and short PFS (9-12). In the present study, we aimed to examine the benefit of adding BEV to platinum-based chemotherapy for these patients.
Gadducci et al. studied 103 patients with platinum-sensitive recurrence after PARP inhibitors followed by platinum-based chemotherapy and reported response rates (RRs) of 26.2% and 41.9% for PFI of 6-12 months and >12 months, respectively (9). Cecere et al. also studied 45 patients with platinum-sensitive recurrence after olaparib followed by platinum-based chemotherapy and reported RRs of 11.1% and 22.2% for PFI of 6-12 months and >12 months, respectively (10). In addition, Rose et al. studied PFS in patients with BRCA mutations receiving second- and third-line platinum chemotherapy. Median PFS in the second line with and without PARP inhibitors were 8.0 and 19.1 months, respectively (p=0.005), and in the third line were 7.9 and 18.4 months, respectively (p<0.001) (11). Furthermore, Nakazawa et al. studied 17 patients with platinum-sensitive recurrence after olaparib followed by platinum-based chemotherapy and reported a RR of 23.5%, median PFS was 2.6 months and 9.7 months for 6-12 months and >12 months, respectively. The definition of platinum-sensitive recurrence after PARP inhibitors therapy in this study as PFI >6 months should be reconsidered (12).
In this study, we investigated the efficacy and safety of platinum-based chemotherapy with BEV followed by BEV maintenance for platinum-sensitive recurrence during treatment with PARP inhibitors. Our study results showed that the median PFS and OS were 8 and 25 months, respectively. The RR was 82.6%, and the disease control rate was 91.3% for this treatment.
The GOG213, OCEANS, and MITO16B-MaNGO trials have reported an additive effect of BEV in the treatment of recurrent platinum-sensitive ovarian cancer. RRs of platinum-based chemotherapy with BEV in the GOG213, OCEANS, and MITO16B-MaNGO trials were 78%, 78.5%, and 69.2%, respectively, and median PFS were 13.8, 12.4, and 11.8 months, respectively (13, 17, 18). Tanigawa et al. reported a median PFS of 11.1 months for repeated BEV in Japanese patients with platinum-sensitive recurrence (19). Thus, BEV has an important role in the chemotherapy of platinum- sensitive recurrent ovarian cancer.
It has been reported that olaparib treatment in platinum-sensitive ovarian cancer patients with BRCA mutations causes functional reversion mutations resulting in the development of resistance to olaparib. A loss of PARP expression after olaparib administration was hypothesized to be responsible for this resistance (20, 21). This can also explain the reason behind the failure of usual platinum-based chemotherapy is not effective, but the mechanism remains unclear from past reports.
The concept of resistance to non-platinum drugs, such as BEV and paclitaxel, has not yet been demonstrated. Our results suggest that the addition of BEV can provide a treatment effect equivalent to platinum-based chemotherapy with BEV for platinum-sensitive recurrence, as previously reported.
The study also included 8 cases (34.8%) with carboplatin hypersensitivity. The median number of carboplatin doses that caused hypersensitivity in these patients was 19 (range=15-27). In previous reports of platinum-sensitive ovarian cancer treatment, hypersensitivity to carboplatin was observed in only 4.1-9.1% of patients (17, 22-24), whereas the incidence was high in this study. One of these patients had grade 3 carboplatin hypersensitivity, which was changed to cisplatin, resulting in grade 3 hypersensitivity that recurred in the next cycle. Carboplatin is administered more frequently in most cases; therefore, careful attention should be paid to hypersensitivity.
Although a small number of grade 3 or higher hematologic and non-hematologic toxicities were observed, only one patient resulted in discontinuation of treatment, indicating that this treatment was relatively safe.
Our study has some limitations which can be addressed by future clinical trials. Foremost, this was a retrospective study of patients from only two centers. Additionally, patients’ quality of life was not evaluated our study. We plan to conduct a phase II clinical trial that includes quality of life evaluation to prove its usefulness.
In conclusion, platinum-based chemotherapy with BEV followed by BEV maintenance clearly demonstrates antitumor activity with a manageable toxicity profile in patients with platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer during treatment with PARP inhibitors. To our knowledge, this treatment is the first reported in the world. Further clinical trials should be carried out with this combination to provide therapeutic options for platinum-sensitive recurrent ovarian, fallopian tube, and primary peritoneal cancers post treatment with PARP inhibitors.
Acknowledgements
The Authors thank the patients and large number of clinicians, research nurses, data managers, and other clinical and support staff at participating centers. We would like to thank Honyaku Center Inc. for English language editing.
Footnotes
Authors’ Contributions
Abe M and Shoji T conceived the study. Abe M, Chiba Y, Takatori E, Kaido Y, Nagasawa T, and Kagabu M performed a literature search. Takahashi F performed analysis and interpretation of date. Abe M prepared the original manuscript. Shoji T, Baba T, and Aida T performed drafting and revising the article. All Authors have read and agreed to the published version of the manuscript.
Conflicts of Interest
The Authors declared that there are no conflicts of interest.
- Received January 12, 2023.
- Revision received January 28, 2023.
- Accepted February 3, 2023.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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).
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