Abstract
Background/Aim: Niraparib is effective against epithelial ovarian cancer (EOC), but with adverse effects. In this study, we retrospectively investigated niraparib maintenance treatment feasibility in Korean patients newly diagnosed with EOC. Patients and Methods: The medical records of 35 patients were reviewed. Data on the baseline clinical characteristics were collected, and adverse effects were described. Results: Sixteen patients underwent treatment suspension or dose reduction. There was no significant difference in adverse effects (A/E) due to the interval between adjuvant chemotherapy conclusion and niraparib initiation. The two groups had similar International Federation of Gynaecology and Obstetrics (FIGO) stages. The number of patients with a history of bevacizumab use was higher in the dose modification group than in the standard dose group. Conclusion: Niraparib use must be considered in those previously treated with bevacizumab. There is a need for prospective research on lower dose (<200 mg) treatments in patients with risk factors.
- Epithelial ovarian cancer
- niraparib
- haematological problems
The diagnosis of epithelial ovarian cancer (EOC) in Korea is steadily increasing (1). However, treatment outcomes have not improved for decades. Standard treatment includes surgical staging through cytoreductive surgery and adjuvant chemotherapy, or neo-adjuvant chemotherapy before cytoreductive surgery to reduce the tumour burden, interval cytoreductive surgery, and additional chemotherapy (2, 3).
Ovarian cancer has since long been known as a sporadic cancer. However, due to advances in genetics in the last decade, it has been confirmed that approximately 15-20% of ovarian cancer patients have either a BRCA mutation or another genetic mutation. BRCA is a gene that repairs injuries in double stranded DNA caused by various factors. Pathologic BRCA mutation causes cancers such as ovarian and breast cancers. Poly (ADP-ribose) polymerase (PARP) proteins repair injuries in the single stranded DNA. Therefore, PARP inhibition in patients with BRCA mutation induces a deficiency of the DNA repair system, referred to as synthetic lethality (4), such that cancer cells can be eliminated. In the last two decades, many treatments targeting PARP have been developed (5-7). PARP inhibitors (PARPi) were mainly used in patients with BRCA mutations, but the introduction of the concept of homologous recombination deficiency (HRD) led to the expectation of a therapeutic effect of PARPi even without BRCA; niraparib, one of the treatments, showed a meaningful therapeutic effect, even in the case of HRD-negative patients (8, 9). According to a previous study on niraparib, treatment can be discontinued due to occurrence of adverse effects (A/E) depending on body weight and platelet count at the beginning of treatment. Therefore, the initial niraparib dose is administered differently by various authorities. In Korea, the license for first-line maintenance was obtained in the mid-2020s, and 200 mg is used as the starting dose in most patients. Therefore, in the present study, we analysed the feasibility and safety of niraparib maintenance therapy in Korean patients newly diagnosed with EOC.
Patients and Methods
The medical records of 35 patients with EOC who were treated with niraparib followed by platinum-based chemotherapy at two hospitals in South Korea between July 2020 and January 2021 were retrospectively reviewed. Patients with other concurrent malignancies, Eastern Cooperative Oncology Group (ECOG) performance status score of >3, or abnormal end-organ function were excluded. Adverse events caused by niraparib were assessed via laboratory blood serum tests and physical examinations based on CTCAE 5.0 criteria (10). All patients visited outpatient clinics every week in the first 3 weeks, after which a 1-month follow-up was performed. All patients received 200 mg of niraparib twice a day as the starting dose. If there was an A/E of grade ≥3 based on CTCAE 5.0, the dose was lowered to 100 mg or discontinued. Dose modification was entirely decided by the individual clinician. If the disease was categorized to have progressed, the dose was discontinued. If the patient did not want to take the drug owing to personal reasons, the treatment was discontinued. Baseline characteristics were analysed to determine the risk factors for dose modification. p-Values <0.05 were considered to be significant. This retrospective study was approved by the institutional review boards of each institution who waived the need for informed consent (IRB No. NCC2021-0049).
Results
Among the 35 patients, 3 were excluded as they experienced disease progression. Among the remaining 32 patients, 16 experienced treatment suspension or dose reduction. The baseline characteristics of patients with a reduced or suspended niraparib dose were compared with those of patients with no change in niraparib administration (Table I). There was no significant difference in the occurrence of A/Es due to the interval between adjuvant chemotherapy conclusion and niraparib initiation. The FIGO stages of the two groups were similar. The number of patients with a history of bevacizumab use was more in the dose modification group than in the standard dose group. The reasons for discontinuation or dose reduction were leukopenia (4), thrombocytopenia (6), and anaemia (4); among patients undergoing dose modification, 82.3% experienced hematologic A/Es. Other A/Es included fatigue (1), nausea (1), and dermatologic problem (1) (Figure 1). Dose modification was mostly required within 2 months of treatment initiation (76.5%) (Figure 2). The dosage of four patients experiencing A/Es was reduced to 100 mg without any interval in administration. The A/Es disappeared after around 14 days of dose modification (median=14 days, mean=7.66 days). No specific side-effects were observed after restarting niraparib.
Discussion
To the best of our knowledge, this is the first study in the Asian population on first-line maintenance treatment with niraparib. During the initial dose of 200 mg, side effects occurred in more than 50% of patients, which resulted in reducing the dose to 100 mg. Most side effects occurred within 2 months of administration. When patients recovered from A/Es after dose reduction or discontinuation, the dose was either increased back to 200 mg or maintained at 100 mg.
In the first clinical study of niraparib, the initial dose was 300 mg (8). In the same study, the dosage was adjusted to 200 mg for patients with platelet count <150 k and weight <77 kg; no difference in treatment effect was observed in these patients compared with those administered 300 mg niraparib. In Korea, most patients weigh ≤77 kg. Therefore, 200 mg niraparib was administered as the starting dose, but A/Es occurred in 50% of patients. In the case of a recurrent study with 300 mg as the starting dose (11, 12), Asian patients did not show any significant differences in A/Es from patients in Western populations.
We can consider a difference between the first- and second-line treatments because there would be a large difference after performing surgery and chemotherapy sequentially in newly diagnosed patients. Although absolute comparisons are not possible, the tumour burden in newly diagnosed patients is more than that in patients with recurrent disease.
There are many considerations on when to plan treatment for epithelial ovarian cancer. Although standard chemotherapeutic regimens have been established, a multimodal consideration was absolutely necessary, such as additional therapeutic agents, neo-adjuvant chemotherapy, intravenous or intraperitoneal infusion route, tumour histology (13).
The interval between the last chemotherapy session date and the PARPi initiation date, the experience of neo-adjuvant chemotherapy, and the total number of chemotherapy cycles did not significantly affect the occurrence of A/Es. However, there were many patients with a history of bevacizumab use. Hypertension, proteinuria, and bowel perforation are well-known side-effects of bevacizumab, an anti-VEGF receptor; however, hematological A/Es are not common. In addition, the estimated half-life of bevacizumab is 19.9 days. At the time of niraparib administration, bevacizumab concentration in patients’ systemic circulation was low; hence, it would not cause interference with niraparib (14). Nevertheless, it was difficult to decipher an exact reason for the occurrence of A/Es. However, in the case of patients with a history of bevacizumab use, stage IV cancer or suboptimal surgery (macroscopic residual tumours) was common considering their clinical factors (15, 16). Notably, the patients’ tumour burden was relatively high; thus, there may be more patients with a poor general health status and various underlying diseases. The results of the PAOLA study using other PARPi (olaparib and bevacizumab) did not indicate any increase in complications over the single use of PARPi (17).
In this study, many side-effects were observed within 2 months of initial niraparib dose administration; therefore, the subsequent dose was reduced. However, after the A/Es were controlled by either dose reduction or suspension, the administration continued without major problems. The actual effects of niraparib on patient survival will be revealed over the course of time.
The strength of this study was that this is the first study on niraparib use in Asian populations. Unlike other PARPi, niraparib can be used in those without genetic mutations; thus, the demand for its use by patients may increase in the future. This study, therefore, provides guidance on management of such patients. This study has certain limitations; the sample size was relatively small, and the follow-up period for evaluating the response to PARPi was short.
Prospective research is warranted for determining a safe dose before adjustment in Asian populations. With the determination of the efficacy of a reduced dose, it will be possible to proceed with treatment more safely.
Footnotes
Authors’ Contributions
Each Author participated sufficiently in the work to take responsibility for the appropriate portions of the content. Study concept and design: WKS and SYP; Data analysis: WKS, SHB, and JJN; Drafting of the manuscript: WS and JJN; Revision and review of manuscript: WKS, SHB, SYP, MCL, and BGK. Approval of the final manuscript: all Authors.
Conflicts of Interest
The Authors declare no competing interests.
- Received June 14, 2021.
- Revision received July 17, 2021.
- Accepted July 21, 2021.
- Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.