Original research••

Efficacy of oral tetra-arsenic tetra-sulfide maintenance therapy for ovarian cancer: a single-center observational study

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Abstract

Objective To investigate firstly Chinese patent medicine Realgar-Indigo Naturalis Formula (RIF), which mainly contains tetra-arsenic tetra-sulfide formula for the maintenance therapy of ovarian cancer.

Methods We recruited all patients with ovarian epithelial cancer who were diagnosed at Peking University People’s Hospital between January 2018 and January 2021. All these patients received standard chemotherapy and achieved complete remission. The patients took RIF (60 mg/kg daily in an oral divided dose) in a 4-week-on and 4-week-off regimen. The main efficacy indicators, including progression-free interval (PFI) and overall survival (OS), were measured and evaluated regularly. Additionally, the safety and side effects were closely monitored.

Results A total of 20 patients were included in this study. Regarding the treatment, patients received oral arsenic for 3–18 courses (the longest treatment interval was equivalent to 3 years). The median follow-up time was 43 months. Subsequently, data analysis was conducted, revealing that the median PFI was 23 months. P53 mutations were worse than P53 wild-type PFI, and the median PFI was 19.2 months (p=0.03). Regarding P53 wt status, the HR for disease progression or death was 0.25 (95% CI 0.07 to 0.91). The 3-year OS was 89%, and the 5-year OS was 77%. The common side effects were abdominal pain and diarrhoea.

Conclusions RIF compound proved to be an effective Chinese patent medicine maintenance therapy for ovarian cancer, thus prolonging the PFI of patients and controllable side effects, in particular simple and convenient for the method of administration and better potency ratio. These findings need to be validated in multicentre research studies with large sample sizes.

Trial registration number ChiCTR2400090349.

What is already known on this topic

Advanced epithelial ovarian cancer is predominantly relapsed and has a poor prognosis. Maintenance treatment prolonged the progression-free interval with controlled side effects for ovarian cancer.

What this study adds

Realgar-Indigo Naturalis Formula (RIF) compound is a traditional Chinese medicine patent prescription with specific antitumour effects. We used RIF to investigate the maintenance treatment of patients with ovarian cancer. RIF proved to be an effective traditional Chinese Medicine Patent Prescription maintenance treatment for ovarian cancer. The method of administration was simple and had a better potency ratio.

How this study might affect research, practice, or policy

It is suggested that the RIF compound may prove to be an effective maintenance therapy for ovarian cancer, thus prolonging the progression-free interval of patients and controllable side effects.

Introduction

Epithelial ovarian cancer (EOC) is predominantly detected in advanced stages. Following cytoreductive surgery and platinum-based adjuvant chemotherapy, approximately 75% of patients relapsed at around 18 months; furthermore, 25% of patients are resistant to primary chemotherapy and have a poor prognosis.1 The distinction between platinum-sensitive and platinum-resistant recurrence has been thoroughly explored; a platinum-free interval of 6 months or longer is now used to define ‘platinum-sensitive’ malignancies, while those with a platinum-free interval of less than 6 months are used to define ‘platinum-resistant’ cancers. A major therapeutic concern is identifying methods to prolong the platinum-free interval in clinics.

Currently, the maintenance treatment for EOC involves diverse mechanisms of action. It includes the use of single drugs and combinations of various agents. These agents comprise antivascular inhibitors, tyrosine kinase inhibitors, poly ADP-ribose polymerase inhibitors, immune checkpoint inhibitors, monoclonal or bispecific antibodies, multitarget tyrosine kinase inhibitors and others. However, although different treatment schemes have achieved good curative effects, patients need to take these drugs orally for a long period; furthermore, this strategy is associated with several side effects, including insomnia, bone marrow suppression, gastrointestinal adverse reactions, fatigue and other adverse reactions. Furthermore, these schemes are expensive and could influence a patient’s quality of life and treatment compliance. Considering the limitations of current maintenance treatments for EOC, researchers have been exploring alternative therapies. In recent years, arsenic-containing compounds have emerged as a promising option.2 Recall that EOC patients face challenges such as high recurrence rates and significant side effects from current treatments. In this context, Realgar-Indigo Naturalis Formula (RIF) has shown remarkable potential.

There are several arsenic-containing compounds, including arsenic trioxide (ATO) which is used intravenously, and oral arsenic formulations, such as RIF. These mainly contain arsenic disulfide (As₂S₃) and are derived from traditional Chinese herbal medicines. Arsenic agents and their compounds use different antitumour mechanisms. ATO is commonly used in China and is effective for the treatment of haematological malignancies and also for the treatment of solid tumours, including lymphoma, gastric cancer, liver cancer, breast cancer, pancreatic cancer, lung cancer and osteosarcoma.3–8 Studies have also shown that arsenic can effectively inhibit the growth of various malignant tumours via multiple mechanisms, including the cell cycle, apoptosis, DNA damage repair, telomerase activity and antiangiogenesis.9–14 Tang et al found that the combination of ATO and olaparib activated the AMPK α pathway and suppressed the expression levels of stearoyl-CoA desaturase 1.15 Furthermore, arsenic has been shown to inhibit cell growth and increase apoptosis in ovarian cancer cells and exerts synergistic effects with cisplatin and paclitaxel treatment.16

Previously, we reported the basic and clinical application of ATO for the treatment of resistant uterine malignant tumours and EOC;17 18 preliminary analysis showed that ATO was an effective treatment for patients with endometrial cancer and EOC.19 20 We also reported an ATO-based sequential chemotherapy scheme for recurrent drug-resistant and refractory ovarian cancer which demonstrated key advantages with regard to survival.21 Over recent years, arsenic has attracted increasing levels of attention from gynaecologists because of its specific anti-tumour effects, reduced side effects, and low cost, especially the synergistic antitumour effects of arsenic and other drugs.

The results of a previous multicentre, non-inferiority, randomised, and controlled phase 3 clinical trial showed that RIF achieved good effects for the treatment of malignant tumours, including acute promyelocytic leukaemia (APL) and several solid tumours.3–6 The oral arsenic RIF regimen provides similar efficacy to intravenous ATO for APL in both adults and children and is highly efficient, cost-effective and convenient for outpatient chemotherapy; furthermore, RIF provides a good quality of life for patients.22 23

The purpose of this study was to investigate the efficacy and side effects of RIF-containing oral arsenic in the maintenance treatment of EOC following standard treatment and to provide a new scheme with the characteristics of Chinese patent medicine for the maintenance treatment of patients with EOC.

Methods

Clinical data

Between January 2018 and January 2021, we enrolled 20 patients with EOC who underwent cytoreductive surgery and platinum-based chemotherapy and achieved complete remission.

Eligible patients were at least 18 years of age. All patients had high-grade serous or endometrioid tumours that were classified as stage III or IV, according to the criteria of the International Federation of Gynecology and Obstetrics 2014. The therapeutic effect was evaluated according to RECIST V.1.1 criteria, the measurement of the Gynecologic Cancer Intergroup Cancer Antigen 125 (CA-125 (MUC-16)) and clinical examinations.

The exclusion criteria were as follows: non-ovarian epithelial cancer, ovarian cancer, fallopian tube cancer, and peritoneal cancer that were not diagnosed clinically; patients that were currently receiving other therapies (chemotherapy, antiangiogenic, or immunotherapy); patients who were known allergic to RIF or drug components with similar chemical structures; patients with serious or uncontrolled medical conditions who were not suitable for chemotherapy; and patients undertaking other drug clinical trials at the same time.

This study followed the Declaration of Helsinki. The predesigned review protocol was submitted to ChiCTR with the registration number (iD: ChiCTR2400090349).

Medication scheme

The patients took RIF (60 mg/kg daily in an oral divided dose) in a 4-week-on and 4-week-off regimen. The total treatment period lasted 2 years. If there were no obvious side effects evaluated regularly, some patients were extended to 18 courses of oral administration; this was equivalent to a 3-year treatment interval.

The treatment was continued until the disease progressed or unacceptable side effects were observed. If unacceptable toxicity was directly caused by the study drug, the treatment was reduced by one dose, or drug administration was postponed for 7–10 days. If the drug toxicity or drug interruption lasted for 4 weeks after the last dose was administered, the study treatment was terminated.

Clinical indicators and efficacy evaluation

After the standard treatment of EOC and during the maintenance treatment, we conducted a comprehensive treatment review, including a medical history and physical examination every 2–4 months for 2 years, every 3–6 months for 3 years and every year for 5 years. Every 3 months, we performed blood examinations including routine blood analysis, biochemical markers, tumour markers, and imaging, including ultrasound or regular CT.

Efficacy measures included tumour assessments using CT by the RECIST 1.1 criteria, measurement of the Gynecologic Cancer Intergroup cancer antigen 125 (CA-125 (MUC-16)) and clinical examinations. Other studies (MRI, X-ray, Positron Emission Tomography-Computed Tomography and ultrasound) were also performed if required.

The endpoints included progression-free interval (PFI) and the duration of response and safety. PFI was defined as the interval from the end of adjuvant chemotherapy to the time of disease progression, diagnosis, or death for any cause (whichever occurred first), or until the last PFI assessment for living patients without the progression of cancer. The duration of response was assessed in patients who successfully achieved a response until neoplasm recurrence. The duration was defined as the time from the date of the first registered response until the date of documented cancer progression or death from any cause. Adverse events were assessed according to the common terminology criteria for adverse events defined by the National Cancer Institute. The overall survival (OS), safety and side effects were measured and evaluated regularly.

Statistical methods

We calculated the proportion of patients achieving responses and determined 95% CIs using the Clopper-Pearson method. The Kaplan-Meier method was used to determine survival time, PFI and associated 95% CIs. SPSS (V.22.0) was used for all analyses.

Results

Baseline characteristics of patients with EOC

The general clinical and pathological characteristics, along with the demographic and baseline disease characteristics of the 20 patients, are shown in table 1. The median age was 52 years (ranging from 22 to 69 years). Several histopathological types were present. There were 16 cases involving newly diagnosed advanced EOC and 4 cases of recurrence EOC.

Table 1

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Patient characteristics of the enrolled patients (n=20)

All patients initially received either six 3-weekly cycles of intravenous carboplatin (Area Under the Curve, AUC=5) and paclitaxel (175 mg/m² of body surface area). 11 patients progressed with the carboplatin and paclitaxel chemotherapy regimen and were treated with oxaliplatin (110 mg/m² of body surface area) combined with taxanes chemotherapy. Of these, three patients, who remained insensitive or had progressed, were treated with platinum-free combined chemotherapy (ATO combined with multiple drugs and with sequential combined chemotherapy).

Clinical treatment schemes

All 20 patients were treated with a specific RIF scheme, consisting of 3–6 courses (9 patients), 7–9 courses (5 patients), 10–12 courses (4 patients), 13 courses (1 patient) and 18 courses (1 patient). The patients received a median of 8 courses of treatment (range: 3–18 cycles). A total of five patients stopped taking the drug after three courses of medication, and four patients stopped taking the drug due to disease progression; three of these patients were undergoing initial treatment, one patient experienced recurrence and was receiving maintenance treatment, and one case stopped taking medicine due to personal economic factors.

Efficacy of medication

The follow-up observation ended on 17 June 2023, with a median follow-up time of 43 months (range: 11.8–64.0 months). The median PFI was 23 months (range:7.0–61.4 months) for 20 patients (figure 1).

Figure 1

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Kaplan-Meier graph for progression-free interval (PFI) in patients.

PFI was grouped according to whether P53 mutations existed or not; P53 mutations were worse than P53 wild-type PFI, and the median PFI was 19.2 months (p=0.03) (figure 2). Regarding P53 wt status, the HR for disease progression or death was 0.25 (95% CI: 0.07 to 0.91).

Figure 2

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Kaplan-Meier graph for progression-free interval (PFS) in patients grouped according to the existence of P53 mutation.

Of the five patients with non-high-grade serous ovarian cancer, all of whom were refractory, one case of clear cell carcinoma recurred with a PFI of 9.7 months, the remaining patients did not relapse, and the PFI was 22–61.4 months at follow-up.

The 3-year OS was 89% and the 5-year OS was 77%. The OS ranged from 11.8 to 64.0 months (figure 3). After treatment, 10 cases relapsed and then received further treatment by surgery or combined chemotherapy according to the situation of the recurrent lesions. At the end of follow-up, there had been four deaths, all of which were tumour related.

Figure 3

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Kaplan-Meier graph for OS in patients. OS, overall survival.

Main side effects

The most common adverse events were oedema (11) and weight gain (10). Grade 1–2 side effects included oedema of the face (10), nausea (8), diarrhoea (3) vomiting (2), abdominal pain (2), lower gastrointestinal haemorrhage (2), abdominal pain (2), drug-induced liver injury (1), gastritis (1) and rash (1).

Discussion and conclusions

The rate of recurrence for ovarian cancer remains high after first-line chemotherapy. Therefore, we must identify antivascular targeted therapies, immune checkpoint inhibitors, combinations of PARP inhibitors with immunotherapies and other measures for maintenance treatment to prolong PFI and delay tumour recurrence. Many clinical trials have shown that PARP inhibitors are one of the important maintenance treatment schemes for ovarian cancer. The third phase of the SOLO1 trial showed that patients with BRCA gene mutation had a median PFI of 56 months and 14 months.24 In the PRIMA trial, a subgroup of patients who were BRCA-positive showed a PFI of 22.1 months and 10.9 months in the placebo and experimental groups, respectively. In the subgroup of homologous recombination deficiency patients without BRCA mutation, the median PFI in the experimental and placebo treatments was 19.6 months and 8.2 months, respectively.25 In patients with homologous recombination defects, the PFI of the experimental group and the placebo group was 29 months and 11 months, respectively; the PFI of the overall patient population was 20 months vs 9.2 months.26 The phase III PRIMA/ENGOT-OV26/GOG-3012 trial showed that the overall population of patients had a median PFI of 13.8 months.27

Collectively, these findings suggested that maintenance therapy under the guidance of genetic testing has become a significant clinical strategy. These data also suggest that when based on differences in gene status, the entire population will benefit from PARP inhibitor maintenance treatment, although this strategy takes a long time and is linked to high costs and significant side effects. Furthermore, these treatments are inconvenient for patients over long periods. Consequently, there is a significant need to develop a new maintenance treatment scheme.

RIF is a Chinese patent medicine mainly containing tetra-arsenic tetra-sulfide formula. Previous multicentre clinical trials demonstrated the efficacy and safety of RIF for the treatment of patients with leukaemia. Many clinical RCT studies of leukaemia have confirmed that when compared with intravenous ATO, oral RIF improved the prognosis of patients with high oral compliance; furthermore, this treatment saved hospitalisation expenses and improved the quality of life. However, few studies have investigated the use of RIF for the treatment and maintenance treatment of ovarian cancer.

In our research centre, we used the Chinese patent medicine Compound Huangdai Tablets to investigate the treatment of recurrent ovarian cancer.18 Analysis showed that these tablets had a good curative effect improved the patient’s quality of life and could permit oral chemotherapy at home in the future. On this basis, we used compound Huangdai tablets to investigate the maintenance treatment of patients with ovarian cancer. When compared with previous studies, the PFI of the treated patients was significantly different. The main adverse reactions were reactions in the gastrointestinal tract and the skin. The side effects were relatively mild and controllable.

Our analysis showed that the median PFI of patients with P53 mutations and wild-type P53 were 61.4 months and 19.2 months, respectively. Consequently, patients with P53 mutations can benefit more from the oral administration of RIF, and the expression levels of P53 can be used to predict prognosis. Analysis of the five patients with non-high-grade serous ovarian cancer suggested that patients had long-term benefits after treatment with this drug, although the sample size needs to be expanded to validate this.

At present, in China, the average cost of each course of RIF treatment for patients is no more than US$900, which is equivalent to an average of no more than US$15 per day since the interval between each course of treatment is 1 month. Therefore, this scheme can be considered for the maintenance treatment of ovarian cancer in the future. This medicine is convenient for patients, has a better potency ratio and good potency ratio and leads to a significant improvement in quality of life.

This study has limitations that need to be considered, it was only for a single centre and single arm and involved a small number of cases. In the next step, multicentre, randomised and controlled clinical studies need to be performed to confirm RIF as the Chinese patent medicine of maintenance treatment and provide new clinical options for ovarian cancer.

Contributors: Conception and design of the work: YY and XL; Analysis and interpretation of the data: YY; Drafting of the paper: YY; Data collection and critical revision for intellectual content: XS, LZ, YWa, YWu and LW; Final approval of the version to be published: YY and XL. All authors agreed to be accountable for all aspects of this study. XL from Peking University People’s Hospital is the guarantor.
Funding: This study was supported by the the horizontal project: Antitumor effects of Realgar-Indigo naturalis formula (RIF) combined with Apatinib on platinum-resistant ovarian cancer Research (Project No. 2022-Z-23).
Competing interests: LW has served as an advisory committee member of GOCM. There are no competing interests for other authors
Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review: Not commissioned; externally peer reviewed.

Data availability statement

Data may be obtained from a third party and are not publicly available.

Ethics statements

Patient consent for publication:

Ethics approval:

This study involves human participants and was approved by the Ethics Committee of Peking University People’s Hospital (protocol number 2023PHB278-001). Participants gave informed consent to participate in the study before taking part.

Acknowledgements

The authors would like to acknowledge the help provided by the Peking University People's Hospital.

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Received: 21 November 2024
Accepted: 1 February 2025
First published: 26 February 2025

Pre-publication versions •Review history

Efficacy of oral tetra-arsenic tetra-sulfide maintenance therapy for ovarian cancer: a single-center observational study