Clinical Efficacy of QYHJ and Standard Chemotherapy in the Treatment of Advanced Pancreatic Cancer

Our study is a prospective, multicenter, randomized controlled clinical study included patients with stage IV pancreatic ductal adenocarcinoma receiving gemcitabine-based first-line combination therapy according to the 2022 NCCN guidelines and with an estimated survival of \> 3 months. According to reports and previous research results, we plan to include 306 subjects, and the subjects will divide into experimental group and the control group by a ratio of 1:1. All patients in the treatment group will receive QingyiHuaji optimized formula and standard treatment, and patients in the control group will receive placebo combined with standard treatment. Overall survival (OS) is defined as the primary endpoint, and progression-free survival (DFS), quality of life of cancer patients, and relief rate of TCM symptoms are considered as the secondary endpoint to observe the clinical efficacy of Qingyihuaji optimized formula combined with standard chemotherapy for stage IV pancreatic ductal adenocarcinoma. It will provide high-level evidence-based medical basis for the clinical effect of Qingyihuayi optimization prescription on pancreatic cancer with damp-heat accumulation syndrome. The hypothesis of this study is that the combination of Qingyihuaji optimized prescription with standard chemotherapy has the advantage of significantly prolonging the overall survival time, and is feasible and safe for the subjects diagnosed with stage IV pancreatic ductal adenocarcinoma by cytology or histology. The study lasted for 32 months, from 2023 April to December 2025.

Pancreatic cancer is a digestive tract tumor with high malignancy and poor prognosis. The overall 5-year survival rate of early stage patients after surgery is less than 9%, while the median survival time of advanced stage patients is only 3-6 months. According to statistics, in 2020, there were about 420,000 new cases of pancreatic cancer worldwide, and about 410,000 deaths. In China, with the improvement of people's living standards and the progress of population aging, the incidence of pancreatic cancer is rising year by year, ranking 7th among men, and the mortality rate is 6th among men and 8th among women.

Due to its deep anatomical location, lack of typical clinical symptoms, and easy invasion and metastasis of tumors, pancreatic cancer is difficult to be detected in the early stage. More than 80% of patients are in local advanced stage or have distant metastasis at the time of diagnosis, thus losing the opportunity for radical surgery. Currently gemcitabine combined with albumin-binding paclitaxel regimen or FOLFIRINOX (fluorouracil, calcium leucovorin, irinotecan, oxaliplatin) regimen is the first-line chemotherapy regimen for pancreatic cancer.

However, pancreatic cancer has poor sensitivity to chemical and radiotherapy, and there has been little progress in targeted therapy and immunotherapy, resulting in no significant improvement in the survival rate of pancreatic cancer in recent decades. Meanwhile, the curative effect of other common tumors has made rapid progress. It is estimated by the NCI in the United States that if there is no breakthrough in the treatment of pancreatic cancer, pancreatic cancer will become the second largest tumor killer in human by 2030.

After nearly 20 years of dedicated research, the research team of Fudan University Shanghai cancer center, has carried out the integrated treatment mode of traditional Chinese and Western medicine to improve the survival of advanced pancreatic cancer patients, making the median OS of advanced pancreatic cancer patients reach the world leading level by 45% longer than that of chemotherapy alone, and the 3-year, 5-year survival rate reaches 15% and 6.2%, respectively. However, for patients with locally advanced unresectable pancreatic cancer without metastasis, how to improve their survival rate and quality of life is worth further researching.

The results suggest that QingyiHuayi formula has certain anti-tumor effect in advanced pancreatic cancer, and the combination of Qingyi Huayi formula with chemotherapy can prolong the survival period of patients, improve the clinical benefit rate, and may improve the therapeutic effective rate, without increasing the adverse reaction of radiotherapy and chemotherapy. The pathogenesis theory of cancer toxins puts forward that the pathogenesis of cancer toxins should be the core of syndrome differentiation, which solves the complicated and difficult problem of TCM tumor classification by disease differentiation. Four key points of clinical identification of cancer toxins pathogenesis were put forward to achieve the breakthrough of cancer virus identification and diagnosis technology bottleneck. To establish anti-cancer and detoxification treatment methods and classification of anti-cancer and detoxification Chinese medicines, and promote the clinical precision treatment and drug use of TCM tumors. Therefore, Qingyihuayi formula is a safe and effective treatment plan for advanced pancreatic cancer. After optimization, more clinical studies are needed to clarify the value of Qingyihuayi formula in the treatment of advanced pancreatic cancer and find more target groups of benefits.

In order to control random allocation and allocation hiding and ensure the science and standardization of randomized controlled trials, IWRS system of Beijing Biaoji Information Technology Co., Ltd. was used for randomization.

In order to ensure data multi-channel upload, safe storage, data desensitization and data sharing, as well as the accuracy of data entry and simple cleaning, the EDC system needs to be established. Beijing Biaozhi Information Technology Co., Ltd. is entrusted with the EDC system. It includes: ①EDC system; ②System supporting services: CRF annotation, eCRF establishment and testing, logic verification (logic verification plan, logic verification rule programming, logic verification rule testing), EDC training services; ③ Project management.

The median survival time of locally advanced pancreatic cancer is 4.43 months reported in relevant literatures, and the expected median survival time of the study group is 7.03 months. The test level (α) is set as 0.05, the test efficacy (1-β) as 0.80, and the expected shedding rate is 10%. After calculating by PASS software, a total of 306 patients are expected to be enrolled, and the experimental group and control group were randomly divided by 1:1, with 153 patients in the experimental group and 153 in the control group.

Descriptive statistical analysis will be used in this study. The measurement data are described by mean, standard deviation, median, lower quartile, upper quartile, minimum and maximum. Count data and rank data list frequency (component ratio) and rate. Describe the number of subjects enrolled in each group, and the number of cases dropped and eliminated. The final analysis of the study will be based on data collected by the subjects throughout the study period.

Eligibility Criteria:
Inclusion Criteria:

1. Histologically or cytologically confirmed Stage IV pancreatic ductal adenocarcinoma.
2. The expected survival time is \>3 months;
3. Patients meet the standard treatment of gemcitabine - based first-line combination therapy recommended by the 2022 edition of the NCCN Pancreatic Cancer Guidelines;
4. Age above 18 years old and ≤75 years old;
5. ECOG physical state score 0-1;
6. Patients own adequate organ and bone marrow function, defined as neutrophils ≥1,500/ul, hemoglobin ≥ 8.0gm /dL, platelets ≥80,000/uL, serum creatinine \< 2.0 mg/dL, bilirubin \< 1.5 mg/dL, alanine aminotransferase \< 3 times the upper limit of normal; If obstructive jaundice was allowed to enter the study after desicrin treatment, liver function markers were moderately relaxed to bilirubin \< 2.5 mg/dL and alanine aminotransferase \< 5 times the upper limit of normal.
7. Patients must have measurable lesions that meet the RECIST1.1 evaluation criteria. Bone scan abnormalities alone or osteolytic changes shown on plain radiographs cannot be measurable lesions, but can be evaluated in conjunction with bone scan abnormalities. Simple osteogenic bone metastases, pleural or peritoneal exudation, and radiation injury could not be considered as measurable lesions.
8. Patients who have not received "Qingyi Huayji Optimized formula " before (patients who have taken medicine for less than 2 weeks can be included at the discretion of the researchers) and who have received other traditional Chinese medicine treatment before must stop taking medicine 1 week before this study.
9. Female subjects of reproductive age must undergo a negative pregnancy test within 2 weeks prior to study drug initiation and be willing to use a medically approved highly effective contraceptive (e.g., intrauterine device, contraceptive or condom) during the study period and within 3 months after the last study drug administration; Male subjects with partners of women of reproductive age should agree to use effective contraceptive methods during the study period and within 3 months after the last study administration;
10. Patients is expected to possess good compliance, can understand and sign written informed consent, and willing to cooperate with the collection of TCM syndrome information;
11. SIRI value ≥0.8; SIRI = N × M/L, N, M, and L represent peripheral blood neutrophil, monocyte, and lymphocyte counts, respectively.

Exclusion Criteria:

1. Patients with ECOG score ≥2, who could not tolerate any antitumor therapy, or who could only receive the best supportive treatment were not considered for inclusion in this study.
2. The expected survival time \< 3 months.
3. Other serious diseases or conditions, including deep vein thrombosis of the lower extremities, congestive heart failure (New York Heart Association Grade III or IV), unstable angina, etc.
4. Patients with co-infection requiring intravenous antibiotic treatment.
5. Pregnant or lactating women. Women of childbearing age who were unwilling or unable to use an acceptable method of contraception throughout the treatment period of this trial and within 12 weeks after the final administration of the study drug.
6. Known pancreatic neuroendocrine tumors, acinar cell carcinoma, intraductal papillary tumors and other types of pancreatic tumors.
7. Past or concurrent cancers with a primary focus or histologically distinct from pancreatic cancer, except cervical carcinoma in situ, treated basal cell carcinoma, and superficial bladder tumors (Ta, Tis \& T1). Any cancer that had been cured for more than 3 years prior to inclusion was admitted.
8. Those who are known to be allergic to components of Qingyihuaji optimized formula.
9. Unable to swallow Traditional Chinese medicine or untreated malabsorption syndrome, or unwilling to take Traditional Chinese medicine.