Malignant tumors represent a major global public health challenge. According to the latest World Health Organization (WHO) statistics, cancer is the second leading cause of death worldwide. The global burden of cancer continues to rise [1], with gynecological malignancies—such as ovarian cancer and cervical cancer—constituting a substantial proportion of cancer-related incidence and mortality among women. Although current comprehensive treatment strategies have significantly improved patient survival, multiple symptoms resulting from both the disease and antitumor therapies continue to severely affect patients’ quality of life, treatment compliance, and long-term prognosis [2,3].

Since the initial description of symptom co-occurrence in patients with cancer [4], the concept has evolved into the “symptom cluster,” defined as a stable group of 2 or more interrelated symptoms that often share underlying mechanisms and result in clinical outcomes more severe than the sum of individual symptoms [5-9]. Despite the lack of a singular consensus on its definition, it is widely recognized that symptom clusters are complex and heterogeneous. Their presence is strongly associated with diminished quality of life, increased risk of treatment interruption, and poorer prognosis, necessitating a shift from single-symptom management to a more holistic, cluster-based intervention approach.

Currently, intervention strategies for symptom clusters primarily fall into 2 categories: pharmacological and nonpharmacological treatments. Pharmacological management follows the principle of symptomatic support, wherein specific medications are selected based on the patient’s predominant symptoms—for instance, analgesics for pain relief or anxiolytic and antidepressant agents for alleviating anxiety and depression. Nonpharmacological interventions include a variety of approaches such as structured exercise, mindfulness meditation, professional psychological support, and music therapy, among others [10-12]. Although these interventions have become integral to comprehensive symptom management, they tend to emphasize general applicability and have yet to evolve into systematic protocols tailored to specific cancer types. This lack of personalized and structured approaches may limit further improvement in therapeutic outcomes.

Surgery remains the cornerstone of treatment for ovarian cancer. However, bilateral oophorectomy induces a precipitous decline in estrogen levels, leading to a constellation of sequelae, such as premature menopausal symptoms, sexual dysfunction, and altered body image [13,14]. The loss of reproductive organs can profoundly affect a woman’s self-identity, body perception, and gender identity [15], often resulting in significant psychological distress [16]. This internal conflict is frequently exacerbated by a discrepancy between societal stereotypes of femininity and the patients’ lived experiences, which can contribute to social withdrawal and strained family relationships [17].

Furthermore, the clinical prognosis adds another layer of complexity. Approximately 80% of patients with ovarian cancer are diagnosed at an advanced stage, with approximately 75% experiencing disease recurrence within 2 years. The 5-year overall survival (OS) rate for advanced-stage disease remains dismally low, ranging from 10% to 40% [18]. This stark clinical reality imposes a substantial psychological burden on patients. Compounding this are therapeutic challenges—including platinum resistance, limited targetable mutations in homologous recombination repair pathways, and an immunologically inert tumor microenvironment—which further intensify psychological distress in patients from a prognostic standpoint [19].

In summary, the interplay of surgical, psychological, social, and prognostic factors creates a complex web of stressors that collectively contribute to the high prevalence of psychoneurological symptom clusters (PNSCs) in patients with ovarian cancer.

Traditional Chinese medicine (TCM) emphasizes holistic regulation, with accumulating evidence demonstrating its efficacy in managing cancer-related symptom clusters. For instance, acupuncture significantly alleviates chemotherapy-induced nausea and vomiting [20] while also improving clusters comprising pain, fatigue, and sleep disturbances [21]. Furthermore, TCM interventions effectively relieve menopausal-like symptoms—such as hot flashes and insomnia—arising from treatment-induced endocrine deficiencies [22]. Mind-body exercises such as Tai Chi have even exhibited therapeutic effects comparable to cognitive behavioral therapy (CBT) for insomnia [23].

Building on these foundations, together with insights from our team’s clinical experience and preliminary small-scale studies, we have developed an integrative interventional protocol named the “TiaoShenZhiAi” (TSZA) regimen. Rooted in the TCM philosophy of “Regulating the Spirit to Treat Cancer,” the TSZA regimen is designed as an interdisciplinary oncological approach targeting psychoneurological symptoms associated with cancer, with the aim of improving patient survival and quality of life. In this study, the TSZA regimen specifically refers to a combination of standard-dose Compound Ciwujia Granules and a structured psychological intervention.

We have initiated this multicenter randomized controlled trial to rigorously evaluate the efficacy of the TSZA regimen in patients with ovarian cancer and PNSCs. Beyond clinical symptom remission, this study aims to enhance treatment adherence and potentially extend survival. Crucially, by integrating multimodal neuroimaging (functional magnetic resonance imaging [fMRI]) and targeted proteomics, we seek to elucidate the underlying biological signatures of PNSCs and the restorative mechanisms of the TSZA regimen, thereby advancing precision intervention strategies in integrative oncology.

The primary objective of this study is to evaluate the efficacy and safety of the TSZA regimen in alleviating PNSCs among patients with ovarian cancer. The secondary objectives include assessing its impact on patients’ quality of life and survival outcomes. Furthermore, the study aims to explore the characteristics of the patient population that derives benefit from the TSZA regimen for these symptoms.

This study uses a randomized, double-blind, active-controlled (low-dose control), prospective, multicenter design. Eligible participants will be randomized in a 1:1 ratio to either the intervention group or the control group. Prior to enrollment, baseline data—including medical history, physical examination findings, relevant laboratory results, and patient-reported outcomes—will be collected for screening and eligibility confirmation. All enrolled participants will be managed under a unified protocol. The combined drug and psychological intervention will be administered over a 3-month period. On completion of the intervention, participants will undergo 3 subsequent follow-up visits, each spaced 3 months apart, resulting in a total follow-up duration of 12 months. Figure 1 presents the participant flow through the trial.

Participants will be recruited from 6 hospitals in mainland China. Eligible individuals must be patients diagnosed with ovarian cancer accompanied by PNSCs. The diagnosis of ovarian cancer will be based on the 2020 WHO Classification of Female Genital Tumours (5th edition) and will be confirmed by cytological or histopathological examination. Disease staging will follow the 2017 International Federation of Gynecology and Obstetrics staging system (8th edition). The presence of a PNSC will be assessed using the MD Anderson Symptom Inventory for Ovarian Cancer (MDASI-OC) scale, a validated instrument for evaluating symptoms in patients with ovarian cancer. According to the standard definition of symptom clusters, 4 related symptoms—fatigue, sleep disturbance, distress, and sadness—will be evaluated. An average score of ≥4 across these 4 symptoms will be required to define the presence of the PNSCs. Recruitment will be conducted through multiple channels, including physician referrals, patient referrals, and posted advertisements in participating hospitals. Table 1 presents the specific information of participating units.

A superiority design is used for this study. Given the lack of a universally established remission standard for the PNSCs derived from the MDASI-OC scale, parameters are determined based on internal pilot data and expert consensus. The remission rate for the control group at 3 months is estimated at 10%. We posited an absolute increase of 30% in the intervention group, corresponding to an expected remission rate of 40%. To ensure clinical significance, a superiority margin (M) of 15% is prespecified and incorporated into the sample size formula. Assuming a one-sided significance level (α) of .025 and a statistical power (1-β) of .80, calculations performed via PASS software (version 15.0; Superiority by a Margin Tests for the Difference Between Two Proportions) yielded a required sample size of 116 participants per group. Accounting for an anticipated 20% dropout rate, a minimum of 145 participants per group is required. To further enhance the robustness of the findings and to accommodate potential variability in dropout rates or covariate adjustments, the final total sample size is determined to be 316 participants (158 per group). This ensures that the actual statistical power of the final analysis set remains consistently above 80%.

After registration and completion of the baseline assessment, eligible patients who provide written informed consent will be randomly assigned in a 1:1 ratio to either the intervention group or the control group. Randomization will be performed using a centralized system using center-stratified block randomization. An independent statistician, who is not involved in the trial implementation, will generate the allocation sequence. The randomization results will be encrypted and transmitted to an independent third party responsible for the allocation system, where they will be kept confidential until trial completion. The personnel responsible for participant recruitment and intervention delivery will remain blinded to the group assignments.

This study adopts a double-blind design. Drug blinding and distribution packaging are jointly carried out by statisticians who are not directly involved in this clinical trial and the pharmaceutical factory responsible for drug production. The trial drug and the control drug are respectively assigned unique drug packaging numbers and drug blinding codes, which are filled in (or pasted) on the drug labels. The control drug contains 10% of the components of the investigational drug. This active-controlled design provides a more rigorous comparison and addresses the practical challenges of producing an indistinguishable placebo in TCM research.

An independent blind background file will be established for each random number. The content includes key information such as the group to which the subject with the number is assigned (such as group A or group B) and the medication requirements (investigational drug or control drug) in case of emergency unblinding. The third party responsible for the random system is responsible for confidential storage. It is only opened by authorized personnel in accordance with the procedures in emergency situations, such as SAE, where unblinding is necessary.

A 2-step unblinding method will be adopted. After all research data are entered, verified, and have undergone blinded review, the database will be locked. The first unblinding will be performed by the blinding code custodian to identify group A and group B. This information will then be handed over to the biostatistician for statistical analysis. After the statistical analysis is completed, the second unblinding will be conducted to clarify the intervention and control groups.

In this trial, both the intervention and control groups will receive standard-of-care treatment for ovarian cancer as the foundational therapy, in accordance with the 2024 NCCN International Guidelines. This may include platinum-based chemotherapy and/or targeted, antiangiogenic, or hormonal agents, as clinically indicated.

Both the intervention and control groups will receive the same psychological intervention. The intervention is based on CBT and mindfulness theory and is adaptively designed to address the characteristics of the PNSC in patients with ovarian cancer. It comprises a total of 12 sessions. The intervention is delivered in an online prerecorded format, once weekly, with each session lasting approximately 30 to 45 minutes. The materials are distributed to participants on schedule by the investigators according to a treatment manual. The session content includes cognitive restructuring of illness perceptions, pain tolerance, understanding and expressing interpersonal needs, family and social support, comorbidity of depression and sleep disturbances, sleep hygiene education, the theoretical basis of insomnia, stimulus control, cognitive restructuring for insomnia, emphasis on long-term coexistence, finding meaning within limitations, and relapse prevention. All sessions will be recorded by qualified mental health professionals from the Shanghai Mental Health Center, China. Prior to release, each session script is independently reviewed by another psychotherapist or the principal investigator to ensure objectivity, avoid leading statements or overpromising, and comply with ethical requirements for psychooncological interventions. To ensure consistency of intervention delivery across centers, standardized prerecorded materials are used at all sites. Investigators at each center receive unified training prior to study initiation, and intervention adherence is centrally monitored and recorded by the study team.

In addition, participants in the intervention group will receive the TSZA regimen, which consists of Compound Ciwujia Granules (containing Acanthopanax senticosus and Schisandra chinensis) combined with psychological intervention. The granules will be administered twice daily, one sachet each time, 30 to 60 minutes after meals, for a continuous period of 3 months.

The control group will receive matching low-dose active control granules (containing 10% of the active ingredients found in Compound Ciwujia Granules), which are identical in appearance, odor, and taste to the investigational drug, following the same dosing schedule.

During the study period, the use of any medications not specified in the study protocol is prohibited. In principle, participants should not take other Chinese herbal medicines, Chinese patent drugs with sedative or sleep-promoting claims, biologics, or any other agents that may potentially affect sleep, fatigue, or mental health. Any use must be reported.

During the 3-month treatment period, follow-up visits will be scheduled once per month. After the completion of treatment, follow-up assessments will be performed every 3 months. The total follow-up duration will be 1 year. Data collection time points are presented in Table 2.

Vital signs (respiration, body temperature, heart rate, and blood pressure) will be monitored at baseline and at 1, 2, 3, 6, 9, and 12 months after enrollment. Laboratory test indicators—including complete blood count (white blood cells, hemoglobin, and platelets), urinalysis (urine protein and urine white blood cells), liver and kidney function (alanine aminotransferase, aspartate aminotransferase, and serum creatinine), and electrocardiogram (ECG [electrocardiography] findings and QT interval)—will be assessed at baseline and at 3 months. All findings will be categorized based on clinical significance as normal, abnormal but not clinically significant, or abnormal and clinically significant.

Adverse events (AEs) are defined as any undesirable or negative experience or outcome that does not have a causal relationship with the treatment. Although the treatment regimens used in clinical research have undergone initial safety evaluations, individual differences may lead to unexpected adverse reactions in some participants. All AEs will be recorded, and appropriate management will be immediately provided. Furthermore, participants are guaranteed by state health insurance and are permitted to withdraw from the study at any stage without any consequences.

Researchers are required to have relevant qualifications or experience in conducting medical clinical research. Before the start of the study, the researchers will receive training to be familiar with the research plan, correctly master the inclusion and exclusion standards and scale evaluation methods, and fill in the Electronic Data Capture (EDC) in a standardized manner. In addition, psychological intervention training will be provided by mental health experts.

One interim analysis is planned when approximately 50% of participants have completed the 3-month primary end point assessment. To control the overall one-sided type I error rate at 0.025, a group sequential approach based on the O’Brien-Fleming alpha-spending function will be applied, allocating one-sided nominal significance levels of 0.0026 and 0.0240 to the interim and final analyses, respectively.

While there is a certain risk of information leakage, we have implemented comprehensive measures to mitigate such risks. EDC system is secured via username and password authentication, with all patient information being encrypted to ensure that only authorized research personnel and regulatory officials can access participant data. Individuals will be identified solely by a unique ID number and initials in all data analyses and publications.

Following the trial, participants who demonstrate a positive response to the investigational product may choose to continue its use at their own discretion. For those with a suboptimal response, other appropriate therapeutic options will be recommended based on their specific clinical presentation.

Additionally, should any participant sustain harm during the trial that is medically determined to be related to the study, the sponsor will provide appropriate compensation.

The findings of this study may be submitted for publication in peer-reviewed medical journals, conference presentations, broadcast media, and presentations to stakeholders. In all publications, participant confidentiality will be strictly protected in accordance with applicable laws and regulations. No personally identifiable information will be disclosed unless mandated by law.

This study will be conducted in accordance with the principles of the Declaration of Helsinki and relevant Chinese laws, regulations, and guidelines pertaining to clinical trials. The study protocol has been approved by the Ethics Committee of Shanghai Hospital of Traditional Chinese Medicine (Approval ID: 2024SHL-KY-108‐02). Any protocol amendments must be submitted to the lead Ethics Committee for approval. Once approved, they shall then be submitted to the ethics committees of all participating sites for filing. After having fully understood the trial’s methodology, objectives, potential benefits, and risks, all eligible participants will provide signed informed consent in person, agreeing to the collection of trial-related subject data and biological specimens.