Survival Analysis of Traditional Chinese Herbal Medicine Spleen-invigorating Compound in Patients with Pancreatic cancer


 Background

Traditional Chinese herbal medicine (TCHM) is widely used in the treatment of pancreatic cancer in China. In this retrospective study, the authors mainly analyzed the effect of TCHM on the survival time of patients with pancreatic cancer.
Methods

From 2011 to 2018, 121 pancreatic cancer patients were enrolled in this study. All patients were divided into either the TCHM group or non-TCHM group based on received TCHM or not. TCHM group received three months or more of TCHM treatment on the basis of comprehensive treatment. Kaplan-Meier method was used to assess the difference in survival time, and Cox proportional hazards regression analysis was performed to identify independent prognostic factors.
Results

The overall survival was different between all patients with and without TCHM (P = 0.000), COX analysis showed the clinical staging (P = 0.050), surgery (P = 0.000), chemotherapy (P = 0.000) and TCHM (P = 0.000) were independent prognostic factors. In a stratification analysis of stage for patients who received chemotherapy, there was a significant increase in median overall survival from 10.7 (non-TCHM group) to 19.5 (TCHM group) months (hazard ratio [HR] = 3.197, 95% confidence interval [CI] 1.989–5.137, P = 0.000). Patients who did not receive chemotherapy, but best supportive care, there was a significant increase in median overall survival from 4.3 (non-TCHM group) to 15.1 (TCHM group) months (HR = 0.041, 95% CI = 0.005–0.329, P = 0.003).
Conclusions

TCHM was an important independent prognostic factor of pancreatic cancer and have an effect on improving the prognosis of pancreatic cancer patients.


Background
Pancreatic cancer is a common malignant tumor,and it's morbidity and mortality have increased obviously in recent years [1][2] .Research shows that pancreatic cancer ranks the 14th in the global cancer morbidity and the 7th in mortality 3 .pancreatic cancer ranks fth in cancer deaths in China and fourth in the United States 4 .The 5-year survival rate of pancreatic cancer patients was only 8%, and the 5-year survival rate of stage I patients was not more than 14% 5 .Therefore, pancreatic cancer has become the most lethal malignant tumor, seriously threatening the health of people all over the world.Surgery is the only way to cure pancreatic cancer, the onset of pancreatic cancer is insidious, most of the patients were found to be in the advanced stage, only 10-15% of patients have the opportunity for surgery, and most patients will eventually have recurrence and metastasis even after surgical treatment.At present, the treatment methods of pancreatic cancer patients mainly include surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy and Traditional Chinese medicine treatment(TCHM).The combination and individual treatment of various treatments have become a new trend in the treatment of pancreatic cancer 6 .Previous research found that the traditional Chinese herbal medicine (TCHM, a herbal formula for invigorating spleen), which was prescribed by practitioners of traditional Chinese medicine based on clinical experiences and pharmaceutical screening, could signi cantly improve overall survival (OS) in patients with pancreatic cancer 7 .In this retrospective study, the possible survival bene t of TCHM treatment for pancreatic cancer was addressed by using such methods as multivariate analysis while employing OS as the primary endpoint.

Treatment
In this retrospective study, all patients were enrolled to either the TCHM group or the non-TCHM group.
Traditional Chinese herbal medicine formula was taken orally for 3 months or more in the TCHM group.The herbal formula for invigorating spleen (TCHM spleen-invigorating compound) was prescribed by practitioners of traditional Chinese medicine at the Department of Oncology, Longhua Hospital,and Yueyang Hospital.In the TCHM spleen-invigorating compound, herbs with invigorating spleen function were the principal elements.The following primary TCHM spleen-invigorating compound in pancreatic cancer treatment was used:Radix pseudostellariae 12 g, Rhizoma atractylodis macrocephalae 12 g, Green tangerine peel 5 g, Dried tangerine peel 5 g, Poria cocos 15 g, Pinellia ternata 9 g, Concha ostreae 15 g, Sargentodoxa cuneata 15 g, solanum nigrum 15 g, decoction, each dose was 300 mL, One dose per day was taken 2-4 times, and the treatment continued for more than 3 months.The herbal components in the formula had been mainly provided by Chinese herbal medication factories with quality control (certi ed GMP).According to patients' symptoms and syndrome differentiation, herbs were increased or reduced every 2 weeks.
Both groups received Western medicine treatments, including the following: surgery (R0 resection, palliative resection), chemotherapy, Radiotherapy, and targeted therapy.Chemotherapy was based on gemcitabine single drug or two drug combination regimen.The combined regimen was gemcitabine combined with oxaliplatin or Tegafur Gimeracil Oteracil Potassium Capsule or albumin paclitaxel or capecitabine, repeated at an interval of three weeks.All patients received at least two cycles of chemotherapy.

Statistical Analysis
The primary endpoint was OS, de ned as time from the day of histologically proven pancreatic ductal adenocarcinoma until death from any cause or the day of lost follow-up or end date of follow-up, which is calculated on a monthly basis.Follow-ups based on telephone survey, were carried out till the study termination date of February 1, 2019.Data analysis was done using SPSS version 19.0.The baseline comparison was analyzed by using Chi square test between the TCHM and non-TCHM groups.
Kaplan-Meier method were used to assess the differences in survival time based on the baseline comparison results.The differences of the clinical and demographic factors were analyzed by log-rank test.The Cox proportional hazards regression analysis of survival includes gender, age, karnofsky performance status (KPS), primary tumor location,metastasis,clinical staging,surgery,chemotherapy, CA199,and CEA.Differences were assumed to be signi cant when the P value was less than 0.05.

Patients
A total of 121 patients were included,65 received the TCHM treatment.In the patients with TCHM, 47 patients (72.3%)died of cancer, 18 patients (27.7%)were alive.And in the patients without TCHM, the numbers were 53 (94.6%), and 3 (5.4%),respectively.We compared the baseline between patients according to the treatment provided.There were no differences between any two groups.See details of baseline characteristics in Table 1.

Survival Analysis Of Overall Group
The median OS was 13.0 months for the overall group.The longest overall survival time was 93.1 months, and the shortest overall survival time was 3.1 months.The median OS was 19.5 months for TCHM and the median OS was 9.2 months for non-TCHM (Fig. 1).
After adjusted the gender and age of pancreatic cancer patients, clinical staging, surgery, chemotherapy, radiotherapy, TCHM,CA199, and CEA expression were included in Multivariate COX regression analysis according to inclusion criteria for 0.05.We found that clinical staging (P = 0.050), surgery (P = 0.000), TCHM (P = 0.000), were independent protective factor for pancreatic cancer patients.See details in Table 2. months for non-TCHM ( Fig. 2).After adjusted the gender and age of pancreatic cancer patients, clinical staging, surgery, and TCHM were included in Multivariate COX regression analysis according to inclusion criteria for 0.05.We found that surgery (P = 0.001), TCHM (P = 0.000), were independent protective factor for pancreatic cancer patients.See details in Table 4. Survival Analysis of Patients Without Chemotherapy The median OS was 7.9 months for the Subgroup of Patients Without Chemotherapy.The median OS was 15.1 months for TCHM and the median OS was 4.3 months for non-TCHM ( Fig. 3).
After adjusted the gender and age of pancreatic cancer patients, clinical staging, surgery, and TCHM were included in Multivariate COX regression analysis according to inclusion criteria for 0.05.We found that surgery (P = 0.027), TCHM (P = 0.003), were independent protective factor for pancreatic cancer patients.
See details in Table 6.

Safety And Toxicity
The treatment was generally well tolerated.there were no TCHM treatment related adverse events observed.No patient died related to TCHM treatment.

Discussion
Pancreatic cancer has a high degree of malignancy, rapid development and poor prognosis.Therefore, pancreatic cancer was a di cult problem in the treatment of malignant tumors.In the present study, Clinical staging was an independent prognostic factor of OS in pancreatic cancer; surgery was an independent prognostic factor of OS in overall group, chemotherapy group and non-chemotherapy group of pancreatic cancer.Therefore, early diagnosis and surgical treatment are crucial for pancreatic cancer patients.Surgery remains the only ways of radical cure for pancreatic cancer.Because pancreatic cancer can be a di cult imaging diagnosis early in its course 8 , most patients are diagnosed at an advanced stage and lose the opportunity for surgery.At present, the overall resection rate of pancreatic cancer is only 10%-15%,with a median survival of 15-17 months and a 5-year survival rate of 5%-7% 9-10 , similar to that of 40 years ago 11 .
For patients with locally advanced or metastatic pancreatic cancer, chemotherapy is the main treatment, gemcitabine has been established as providing clinical bene t and a modest survival advantage over treatment with bolus 5-FU 12 .Therefore, gemcitabine-based chemotherapy is the basis of chemotherapy for pancreatic cancer.It is now often combined with other chemotherapeutic agents (such as cisplatin, oxaliplatin, capecitabine, 5-FU, and irinotecan) for patients with good performance status [13][14][15][16] .MPACT trial show that long-term survival is possible with gemcitabine plus albumin-bound paclitaxel versus gemcitabine only 17 .PRODIGE trial evaluating FOLFIRINOX ( a combination therapy consisting of 5-FU/leucovorin plus oxaliplatin and irinotecan ) versus gemcitabine in patients with metastatic pancreatic cancer,the results showed that patients in the group receiving FOLFIRINOX had longer OS 18 .Eligibility criteria for this trial, however, were stringent,the patient was required to have a good performance status, limiting real-world generalizability 19 .In China, the number of patients receiving FOLFIRINOX chemotherapy is relatively small.In our study, most patients adopt gemcitabine-based chemotherapy.We nd that Chemotherapy can prolong the OS of patients and is an independent prognostic factor of pancreatic cancer.At present, chemotherapy is still the cornerstone of pancreatic cancer treatment.
A meta-analysis identi ed The majority of the data comparing chemoradiation to chemotherapy do not generally show an advantage to the addition of survival 20 .Radiotherapy is often used to relieve local pain symptoms.Poly (ADP-ribose) polymerase (PARP) inhibitors provide a promising avenue of targeted therapy for pancreatic cancers associated with BRCA1/2 mutations.However, there are few patients with BRCA1/2 mutation, and targeted therapy is expensive.Therefore, the number of patients who can bene t from radiotherapy and targeted therapy is still small.Traditional Chinese medicine developed from a totally different background from Western medicine.According to the theory of TCM,the spleen is believed to be responsible for governing transformation and transportation as well as the root of after-birth and the source of Qi ( the fundamental theory of TCM holds that Qi is often translated as vital energy) and blood.In terms of function, the function of spleen in TCM is similar to that of pancreas in anatomy.Based on the symptoms and characteristics of patients and guided by the theories of TCM, we believe that the main cause of pancreatic cancer is the insu ciency of the spleen, so we designed a formula which contain a combination of different kinds of plants or minerals to improve clinical e cacy.In this compound formula, invigorating spleen herbs are the principal elements, whereas heat-clearing and detoxicating herbs as well as blood stasis removing herbs are adjuvant components to assist the effects of invigorating spleen.The major ingredients in this formula were Radix pseudostellariae 12 g, Rhizoma atractylodis macrocephalae 12 g, Green tangerine peel 5 g, Dried tangerine peel 5 g, Poria cocos 30 g, Pinellia ternata 9 g, Concha ostreae 15 g, Sargentodoxa cuneata 15 g, solanum nigrum 15 g.And the attributes of the constituents of this compound formula are as follows: Radix pseudostellariae and Rhizoma atractylodis macrocephalae are used to replenish Qi and invigorate the spleen function; Poria cocos is used for invigorating the spleen function, promoting diuresis and reducing swelling, calming the heart and calming the nerves; the action of Green tangerine peel and Dried tangerine peel is used to promote the circulation of Qi and blood; Pinellia ternata and Concha ostreae are used to resolving hard lump and to dissolve phlegm; the action of Sargentodoxa cuneata and solanum nigrum are heat-clearing and detoxifying.In our previous studies, it was found that TCHM spleen-invigorating compound adopted in this study has effects on improving the survival rate and quality of life of pancreatic cancer patients 21 .Furthermore, it can signi cantly inhibit the growth of human pancreatic cancer BxPC−3 cell line subcutaneous xenografts in nude mice.
In the present study, the TCHM spleen-invigorating compound had a positive effect on pancreatic cancer patients.Clinical staging, surgery, Chemotherapy and the TCHM treatment were independent prognostic factors for pancreatic cancer patients.The TCHM spleen-invigorating compound could prolong OS of pancreatic cancer in chemotherapy group, suggesting that the combination may be a feasible clinical treatment.The TCHM spleen-invigorating compound could also prolong OS of pancreatic cancer in nonchemotherapy group.This suggests that the simple TCHM spleen-invigorating compound has a certain curative effect, however, the number of cases in non-chemotherapy group was too small, so it is necessary to expand the sample size for further study.
Prospective clinical and randomized controlled studies are considered the best evidence.Though there is limitation associated with retrospective study in providing robust evidence, but it is closer to the actual situation of the patient's clinical treatment.In this retrospective study, patients were equally at baseline.Our results suggest that TCHM may be an effective treatment option for pancreatic cancer.
January 1, 2011, and April 30, 2018, patients were enrolled at the Department of Oncology, Longhua Hospital a liated to Shanghai University of Traditional Chinese Medicine and the Department of Oncology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine a liated to Shanghai University of Traditional Chinese Medicine.Major inclusion criteria were as follows: age 18 years or older; histologically proven pancreatic ductal adenocarcinoma; estimated survival time of 3 months or more; the patients' characteristics, pathological ndings, and treating processes were collected retrospectively from individual patient records.Major exclusion criteria were the follows: incomplete clinical staging information; Pregnant and lactating women; multiple malignant tumours; and mentally ill patients and those who had severe acute and chronic diseases that could signi cantly affect treatment and prognosis.Diagnoses were made by surgical pathology or cytology according to the Guidelines for Diagnosis and Treatment of pancreatic cancer developed by the Ministry of Health (2011) and Clinical Practice Guidelines for pancreatic cancer developed by National Comprehensive Cancer Network (2013), and TNM staging was performed according to the guidelines of American Joint Committee on Cancer (2018).The diagnosis of Chinese Medical Differentiation was splenic de ciency, according to the"National Standard Terminology/Chinese Medicine Clinical Diagnosis and Treatment Terminology GB/T16751.2-1997". Figures

Table 2
Multivariate Analysis of Factors In uencing Survival of Patients With Pancreatic Cancer of Patients With Chemotherapy In a strati cation analysis of stage for 94 patients who received chemotherapy, 53cases in the TCHM group and 41 cases in the non-TCHM group, 36 patients (67.9%) in the TCHM group and 38 patients (92.7%) in the non-TCHM group died.See details of baseline characteristics in Table3. Subgroup

Table 3 The
Details of Baseline Characteristics of Patients With Pancreatic Ductal Adenocarcinoma in The Subgroup of Patients With Chemotherapy.
Abbreviation: TCHM, traditional Chinese herbal medicine; KPS, Karnofsky Performance Scale; CA199,Cancer-associated antigen 19 − 9 ; CEA,carcino-embryonic antigen.Survival Analysis of Patients With Chemotherapy The median OS was 13.7 months for the Subgroup of Patients With Chemotherapy.The median OS was 19.5 months for TCHM and the median OS was 10.7

Table 4
Multivariate Analysis of Factors In uencing Survival of Patients With Pancreatic Cancer in The Subgroup of Patients With Chemotherapy.Subgroup of Patients Without Chemotherapy In a strati cation analysis of stage for 27 patients who did not received chemotherapy, 12 cases in the TCHM group and 15 cases in the non-TCHM group, 11 patients (91.7%) in the TCHM group and 15 patients (100%) in the non-TCHM group died.See details of baseline characteristics in Table5.

Table 5 The
Details of Baseline Characteristics of Patients With Pancreatic Ductal Adenocarcinoma in The Subgroup of Patients Without Chemotherapy.

Table 6
Multivariate Analysis of Factors In uencing Survival of Patients With Pancreatic Cancer in The Subgroup of Patients Without Chemotherapy.