A Multicenter Trial of YSQTG vs. Simulated Agents With Neoadjuvant Chemoradiotherapy or Chemoimmunotherapy for EC

Yishen Qutong Granules vs. Simulant Combined With Neoadjuvant Chemoradiotherapy or Chemoimmunotherapy in the Treatment of Locally Advanced Esophageal Cancer: A Multicenter, Prospective, Double-Blind, Randomized Controlled Trial Protocol

Esophageal cancer is a high - incidence cancer type in China, characterized by high incidence, high mortality, and low survival rates. Over 90% of esophageal cancer cases in China are squamous cell carcinoma, while in Western countries, approximately 80% are adenocarcinomas. Current international guidelines, including those of the NCCN and CSCO, are not entirely suitable for the diagnosis and treatment of esophageal cancer in the Chinese context. In recent years, although the 5 - year survival rate for esophageal cancer has improved, significant challenges remain, such as severe side effects during chemoradiotherapy and targeted - immunotherapy, decreased patient tolerance and quality of life, and even interruption of treatment.

To leverage the synergistic role of traditional Chinese medicine (TCM) in the treatment of major diseases, this study, which builds on previous research, is founded on the theory of "reinforcing healthy qi to strengthen the body, removing toxins, and resolving stasis." It aims to conduct a multicenter, randomized, controlled clinical trial of the TCM formula Yishen Qutong Granules, designed to reinforce healthy qi to strengthen the body and remove toxins, in combination with neoadjuvant concurrent therapy for locally advanced esophageal squamous cell carcinoma. The study will enroll 268 patients (1:1 ratio) with locally advanced esophageal squamous cell carcinoma (cTNM stage III - IVa) who are expected to undergo neoadjuvant concurrent therapy and are potentially resectable. On the basis of conventional Western medical treatment, the treatment group will be administered the patented TCM formula Yishen Qutong Granules orally, while the control group will receive a Yishen Qutong Simulated Granules orally.

The primary outcome measure will be the clinical benefit rate (CBR, CBR = CR + PR + SD), with secondary outcomes including pathological response rate (mPR), R0 resection rate, and TCM syndrome symptom score. The study aims to establish an objective evaluation system for the efficacy and safety of combined treatment based on the integration of disease and syndrome differentiation. It will also elucidate the mechanisms underlying the therapeutic effects of Yishen Qutong Granules.

This study is a randomized, double-blind, placebo-controlled clinical trial. The objective is to verify the efficacy and safety of Yishen Qutong Granules, a traditional Chinese medicine (TCM) for reinforcing healthy qi to strengthen the body and remove toxins, in combination with neoadjuvant concurrent chemoradiotherapy or neoadjuvant concurrent chemoimmunotherapy for locally advanced esophageal cancer that is expected to be resectable.

Patients will be recruited from the Cancer Hospital of the Chinese Academy of Medical Sciences and other collaborating clinical units involved in this project. The study will include two cohorts:

1. Patients undergoing neoadjuvant concurrent chemoradiotherapy:

1. A total of 268 patients with locally advanced esophageal cancer who are expected to undergo neoadjuvant concurrent chemoradiotherapy will be recruited. They will be randomly assigned in a 1:1 ratio to the treatment group and the control group, with 134 patients in each group.
2. The treatment group will receive neoadjuvant concurrent chemoradiotherapy (radiotherapy + albumin-bound paclitaxel + cisplatin) and will be administered Yishen Qutong Granules concurrently with the chemoradiotherapy, at a dose of 10g per dose, three times daily (Tid).
3. The control group will receive neoadjuvant concurrent chemoradiotherapy combined with a placebo (1/10 the dose of Yishen Qutong Granules), with the same timing, dosage, and duration of administration.
4. The primary efficacy endpoint is the clinical benefit rate (CBR = CR + PR + SD) after neoadjuvant treatment.
5. Secondary endpoints include the pathological response rate (mPR), R0 resection rate, incidence of radiation esophagitis, pain levels caused by radiation esophagitis, and TCM syndrome symptom scores.
6. Follow-up will be conducted every three months for a total of eight times (over two years), during which the progression-free survival (PFS) of patients will be recorded.

2. Patients undergoing neoadjuvant chemotherapy combined with immunotherapy:

1. A total of 268 patients with locally advanced esophageal squamous cell carcinoma who are expected to undergo neoadjuvant chemoimmunotherapy will be recruited. They will be randomly assigned in a 1:1 ratio to the treatment group and the control group, with 134 patients in each group.
2. The treatment group will receive neoadjuvant chemotherapy combined with immunotherapy (PD1 immunotherapy + albumin-bound paclitaxel + cisplatin) and will be administered Yishen Qutong Granules concurrently, at a dose of 10g per dose, three times daily (Tid).
3. The control group will receive neoadjuvant chemotherapy combined with immunotherapy and a placebo (1/10 the dose of Yishen Qutong Granules), with the same timing, dosage, and duration of administration.
4. The primary efficacy endpoints are the clinical benefit rate (CBR = CR + PR + SD) and symptom scores after neoadjuvant treatment.
5. Secondary endpoints include the pathological response rate (mPR), R0 resection rate, TCM syndrome scores, changes in tongue and pulse, and Numeric Rating Scale (NRS) scores.
6. Follow-up will be conducted every three months for a total of eight times (over two years), during which the progression-free survival (PFS) of patients will be recorded.

Yishen Qutong Granules have been approved as an in-house preparation by the Beijing Municipal Drug Administration (Beijing Drug Preparation No. Z20200072000). The formula consists of the following ingredients: Rehmannia glutinosa (20 g), Drynaria fortunei (10 g), Oldenlandia diffusa (10 g), Scutellaria barbata (10 g), Pheretima aspergillum (10 g), Dioscorea opposita (15 g), Cornus officinalis (15 g), Moutan cortex (10 g), Alisma plantago-aquatica (10 g), and Poria cocos (10 g). In this formula, Rehmannia glutinosa serves as the principal herb, nourishing yin and kidney essence, and enriching marrow. Cornus officinalis and Dioscorea opposita act as secondary herbs, with the former nourishing liver and kidney and the latter benefiting spleen yin. Oldenlandia diffusa and Scutellaria barbata detoxify, remove blood stasis, relieve pain, and inhibit cancer, while Pheretima aspergillum resolves blood stasis, unblocks meridians, and alleviates pain. Alisma plantago-aquatica drains dampness and purges turbidity, Moutan cortex clears fire and promotes blood circulation to remove blood stasis, and Poria cocos drains dampness from the spleen, all serving as adjuvant herbs. Drynaria fortunei, acting as a guiding herb, tonifies kidney, strengthens bones, and directs the other herbs to the affected area. Together, these herbs work synergistically to tonify the kidney, support healthy qi, resolve blood stasis, disperse nodules, detoxify, and relieve pain.

The Yishen Qutong Granules (Yishen Gu Kang Formula) were granted a patent prescription in 2017 (Patent No.: ZL201310582907.9). In 2020, the research team completed preclinical pharmaceutical studies and obtained approval for the in-house preparation (Beijing Drug Preparation No. Z20200072000). In September 2022, the technology was successfully transferred for a value of 20 million yuan, and the related achievements were awarded the Second Prize of the Beijing Science and Technology Progress Award in the same year. A total of 13 clinical and basic research projects have been conducted around the Yishen Gu Kang Formula, which has also been included in three guidelines, such as the "Guidelines for Integrated Traditional Chinese and Western Medicine Diagnosis and Treatment of Cancer Pain" by the China Association of Chinese Medicine. The preparation process and quality control standards of Yishen Qutong Granules were established by the Department of Pharmacy at the Cancer Hospital, Chinese Academy of Medical Sciences.

Sample Size Calculation

1. Chemoradiotherapy Group: The clinical benefit rate (CBR), defined as the proportion of patients achieving complete response (CR), partial response (PR), or stable disease (SD), was selected as the primary endpoint. Based on literature review and preliminary results of Yishen Qutong Granules, the estimated CBR for the treatment group was 0.88, while that for the neoadjuvant concurrent chemoradiotherapy group (paclitaxel + platinum-based chemotherapy with radiotherapy) was 0.73. With a two-sided α of 0.05 (one-sided α = 0.025) and a 1:1 allocation ratio between the treatment and control groups, the sample size was calculated using PASS software. The results indicated that 122 participants were required for each group. Accounting for a 10% dropout rate due to loss to follow-up or refusal, the final sample size was determined to be at least 134 participants per group, totaling 268 participants.
2. Chemoimmunotherapy Group: The primary efficacy endpoints included the clinical benefit rate (CBR) after neoadjuvant therapy and symptom improvement scores, with the latter used for sample size calculation. Based on literature review and preliminary data from Yishen Qutong Granules, the estimated symptom improvement rate was 0.799 for the treatment group and 0.6 for the control group. A non-inferiority margin of 0 (control group minus treatment group) was set, with a one-sided α of 0.025 and a β of 0.1. With a 1:1 allocation ratio, the calculated sample size was 107 participants per group, totaling 214 participants. Considering a 20% dropout rate, the final sample size was adjusted to 268 participants, with 134 participants in each group.

In this study, the following categorical variables were described using frequencies or percentages, and comparisons between groups were performed using the chi-square test or Fisher's exact test:

1. Clinical Benefit Rate (CBR): Defined as the percentage of evaluable cases achieving complete response (CR), partial response (PR), or stable disease (SD) after treatment.
2. Major Pathological Response (mPR): Defined as the proportion of patients with ≤10% viable tumor cells in the resected tissue specimens following neoadjuvant therapy.
3. R0 Resection Rate: Refers to the percentage of cases where the tumor was completely removed with no residual cancer cells detected at the surgical margins.
4. Incidence of Radiation Esophagitis: Defined as the proportion of enrolled patients diagnosed with radiation esophagitis, confirmed through medical history, symptoms, esophageal barium X-ray, and endoscopy.
5. Safety Indicators: Including routine blood, urine, and stool tests, liver and kidney function tests, and electrocardiogram results, analyzed statistically based on the presence or absence of abnormalities.

For continuous variables in this study, the Shapiro-Wilk test was used to assess normality. If the data followed a normal distribution, they were expressed as mean ± standard deviation, and comparisons between two groups were conducted using the independent samples t-test, while comparisons among multiple groups were performed using one-way ANOVA. If the data did not follow a normal distribution, they were expressed as median (interquartile range), and comparisons between two groups were conducted using the Mann-Whitney U test, while comparisons among multiple groups were performed using the Kruskal-Wallis rank-sum test. The continuous variables included:

1. Quality of Life (QLQ-C30) Score: Assessed using the EORTC Quality of Life Questionnaire Core 30 (QLQ-C30) to evaluate patients' quality of life.
2. Symptom Scores After Neoadjuvant Therapy: Comprising the sum of patient-reported symptom improvement scores and scores for tongue and pulse condition improvements.
3. Traditional Chinese Medicine (TCM) Syndrome Scores: Including the sum of scores for kidney deficiency syndrome and blood stasis-toxicity syndrome.
4. Progression-Free Survival (PFS): Defined as the time from randomization to tumor progression or death, with differences in PFS between groups compared using the Log-rank test.

All statistical analyses were performed using R software (version 4.0.3). Two-sided tests were applied, and a P-value <0.05 was considered statistically significant, with a significance level of α=0.05.

Quality Control and Assurance

1. The National Cancer Center/Cancer Hospital of the Chinese Academy of Medical Sciences serves as the leading and implementing institution, establishing a comprehensive organizational management system to ensure the successful completion of the project. The Quality Control Office is located within the Department of Cancer Prevention and Control at the National Cancer Center, overseen by Director Yawei Zhang, a project member and former tenured associate professor at the Yale School of Public Health, who was also selected under the Ministry of Science and Technology's "Thousand Talents Plan." Director Zhang is responsible for overall quality control and supervision. The project has designated one full-time project manager and one assistant to coordinate research activities and ensure the project's progress. They strictly adhere to the project requirements, comply with the management of the overarching project administration and the leading institution, submit regular progress reports, and promptly report any significant issues encountered during implementation.
2. A Project Management Office and an Advisory Committee composed of experts will be established. The Project Management Office, consisting of the principal investigator and full-time project managers, will handle daily operations, including monitoring and supervising the implementation of tasks across participating institutions. The Advisory Committee, organized by the principal investigator, will include technical, economic, and management experts in the field of esophageal cancer collaborative therapy. This committee will provide consultation on research protocols and technical issues, objectively evaluate the prospects of proposed research activities, offer recommendations, and ensure scientific rigor and feasibility through academic decision-making and quality oversight. Regular project coordination meetings will be held to determine the overall plan and technical strategies. In the event of major issues, the leading institution and the principal investigator will coordinate with the Advisory Committee to develop timely solutions and ensure corrective actions are implemented by relevant units, thereby guaranteeing the project's smooth progression.

Quality Assurance Plan: We will conduct regular data audits that encompass both automated data validation and manual review processes. The automated validation will utilize specialized software designed to assess data consistency and completeness, ensuring that all entered data adheres to predefined formats and ranges. Furthermore, annual on-site audits will be scheduled by an independent third-party entity to verify the compliance of data collection and processing procedures. Any discrepancies or errors identified will be documented, and corrective actions will be implemented promptly.

Data Checks: All data inputs will undergo a two-tier verification process. Initially, an automated system will perform a preliminary check based on predefined criteria such as data range, format, and logical relationships to identify potential errors or inconsistencies. Subsequently, research team members will conduct a manual review focusing on data flagged by the automated system and randomly selected additional data entries to ensure the accuracy and reliability of the data.

Source Data Verification: To ensure the accuracy of source data, we will implement a rigorous source data verification procedure. This involves comparing the data in the registry with the original data sources, such as medical records and laboratory reports. We will employ an electronic data capture system to minimize data entry errors and conduct regular checks for data consistency. Moreover, a 100% source data verification will be performed for key variables to guarantee the representativeness and accuracy of the data.

Data Dictionary: Patient ages will be extracted from electronic health records and encoded using WHO standards. All laboratory results will be retrieved from the central laboratory database and encoded according to MedDRA standards. The data dictionary will provide clear guidelines for each variable, ensuring data consistency and comparability.

Standard Operating Procedures (SOPs): We will establish Standard Operating Procedures (SOPs) for all critical operations within the study, including patient recruitment, data collection, data management, data analysis, and adverse event reporting. Each SOP will detail the steps to be taken, the responsible parties, and the timelines, ensuring consistency and reproducibility in all operations. For instance, the patient recruitment SOP will outline the recruitment process, screening criteria, and the informed consent procedure. The data collection SOP will specify the format and timing of data entry, as well as measures for data quality control.

Inclusion Criteria:

1. Patients met the diagnostic criteria of expected resectable stage III-IVa esophageal cancer, and esophageal squamous cell carcinoma was confirmed by pathology. The diagnostic criteria refered to the guidelines for the diagnosis and treatment of esophageal cancer (2018 edition). Staging criteria: UICC/AJCC TNM staging system (8th edition, 2017) was used.
2. patients had not received previous treatment and planned to receive neoadjuvant simultaneous radiotherapy (radiotherapy + platinum in combination with albumin-paclitaxel), or proposed neoadjuvant chemotherapy in combination with immunopharmaceuticals (Immunotherapy reference 2024 CSCO Esophageal Cancer Diagnosis and Treatment Guidelines + platinum in combination with albumin-paclitaxel)
3. In accordance with the syndrome type of positive deficiency and toxin stasis (kidney deficiency and deficiency syndrome + blood stasis and toxin stagnation syndrome), that is, at least one main symptom + two secondary symptoms in each syndrome scale;
4. Karnofsky Performance Scale (KPS) ≥70; (5)18 ≤ age ≤ 80 ;

(6) Patients who agreeed to participate in this study and sign the informed consent form.

Exclusion Criteria:

1. ①Yishen Qutong Granules Comparison Simulator Cooperative Neoadjuvant Synchronized Radiotherapy Group: those who have contraindications to radiotherapy such as esophageal fistula or those who are allergic to chemotherapeutic drugs; ②Yishen Qutong Granules Comparison Simulator Cooperative Neoadjuvant Chemotherapy Combined with Immunotherapy Drugs Group: those who have contraindications to chemotherapy and immunotherapy or those who are allergic to the drugs;
2. patients with a history of other tumors, cardiovascular and cerebrovascular diseases, liver and kidney function damage, hematopoietic system diseases, and other serious diseases;
3. patients with mental disorders;
4. patients during pregnancy and lactation;
5. patients allergic to traditional Chinese medicine used in this study.