key: cord-1034921-w018k9zc
authors: Chen, Yue; Xu, Yu-ying; Jiang, Hai-jun; Wang, Lei; Zhai, Jia-wei; Zhang, Tong; Yang, Yu-fei
title: Patients with Metastatic Colorectal Cancer after Failure of Second-Line Treatment May Benefit from Low-Dose Apatinib and S-1 Combined with Jianpi Bushen Jiedu Decoction
date: 2022-05-04
journal: Chin J Integr Med
DOI: 10.1007/s11655-022-3676-7
sha: faa7bab57ddf381f9f5144e8ba29dbddd27d4910
doc_id: 1034921
cord_uid: w018k9zc

OBJECTIVE: To evaluate the effect and safety of low-dose of apatinib and S-1 combined with Jianpi Bushen Jiedu Decoction (JBJD) in patients with metastatic colorectal cancer (mCRC) who have failed second or above lines treatment, in order to provide more treatment option for mCRC patients by integrated medicine. METHODS: Thirteen patients were selected from a single-arm, open-label clinical study from April 2019 to September 2020. The patients were treated with low-dose apatinib (250 mg, once a day) and S-1 (20 mg, twice a day) combined with JBJD for at least one cycle and were followed up to August 2021. The primary endpoint was disease progression-free survival (PFS). Disease control rate (DCR), objective response rate (ORR), and overall survival (OS) of patients were observed as the secondary endpoints. Adverse events were recorded as well. RESULTS: The average age of the 13 patients was 56.5 ±13.0 years and 76.9% were male. The median PFS and median OS were 4.6 and 8.3 months, respectively. The ORR was 7.7% (1/13) while the DCR was 61.5% (8/13). The common adverse events were hypertension, proteinuria, elevated transaminase, and thrombocytopenia. One patient experienced thrombocytopenia of grade 3. CONCLUSIONS: Patients with mCRC after failure of the second or above lines of treatment may potentially benefit from the treatment of low-dose apatinib and S-1 combined with JBJD because of its similar effect as the standard dose of target therapy and relatively better safety. (Registration No. ChiCTR1900022673) ELECTRONIC SUPPLEMENTARY MATERIAL: Supplementary material (Appendices 1–2) is available in the online version of this article at 10.1007/s11655-022-3676-7.

performance status only and the incidence of adverse events (AEs) remained high. How to reduce the risk of that AE occurring without compromising clinical effectiveness? A number of studies have shown that Chinese medicine (CM) has unique advantages in the treatment of mCRC, such as relieving clinical symptoms, improving quality of life, and prolonging survival of patients. (14) (15) (16) Prof. YANG Yu-fei has focused on CM treatment in patients with mCRC for many years. Prof. Yang put forward the concept of Jianpi Bushen Jiedu [invigorating Pi (Spleen), tonifying Shen (Kidney), and detoxifying] treatment for mCRC, which has been proven to have good clinical effects. (17) In light of this, the treatment that low-dose apatinib (250 mg, once a day) and S-1 (20 mg, twice a day) combined with Jianpi Bushen Jiedu Decoction (健脾补肾解毒方, JBJD) was proposed for patients with mCRC who have failed in the second or above lines of treatment and were unwilling or intolerant to the standard treatment. This prospective interventional study in patients with mCRC aimed to confi rm the effi cacy and safety of JBJD combined with apatinib and S-1.

The inclusion criteria were as follows: (1) patients were 18 and 80 years of age, either gender;

(2) all were histologically diagnosed and staged as clinically metastatic (stage Ⅳ) CRC; (18) (3) previous administration of first-and second-line treatment for mCRC (patients who received prior two or more chemotherapy regimens with or without targeted therapy were eligible); (4) all treated patients were either ineligible for or had refused conventional therapy that are recommended by the National Comprehensive Cancer Network (NCCN) (19) and the Chinese Society of Clinical Oncology (CSCO) guidelines, (20) such as surgery, chemotherapy and radiotherapy; (5) Eastern Cooperative Oncology Group Performance Status (ECOG) of 0-2; (6) life expectancy of at least 3 months; (7) measurable lesions based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; (8) adequate heart, lung, liver and renal functions; (9) adequate coagulation function and no history of abnormal bleeding, thrombosis, or active infl ammatory disease; (10) the investigator considered the patients would be benefi ted clinically.

Patients with any of the following conditions were excluded: (1) presence of other cancers;

(2) uncontrollable hypertension (systolic blood pressure 140 mm Hg or diastolic blood pressure 90 mm Hg, even when taking oral antihypertensives); (3) patients with uncontrolled or symptomatic cardiovascular diseases; (4) any factors affecting absorption of oral medications, such as unable to take oral medication and intestinal obstruction; (5) patients experienced major surgical procedure, open biopsy or significant traumatic injury within 28 days. 

JBJD is composed of Radix pseudostellariae 30 g, Atractylodis macrocephalae Rhizoma 10 g, Poria cocos 10 g, Radix glycyrrhizae 6 g, Ligustrum lucidum Ait 10 g, Eclipta prostrata L. 10 g, Gastrodia elata Blume 10 g, Uncaria rhynchophylla (Miq.) Jacks. 10 g, Hedyotis diffusa Willd 15 g, and Rhizoma Smilacis glabrae 15 g. JBJD were manufactured by the Department of Pharmaceutics of Xiyuan Hospital, China Academy of Chinese Medical Sciences. The decoction was administered orally twice daily, in the morning and evening after meal. All eligible patients were also scheduled to receive oral treatment of apatinib, 250 mg, once a day and S-1, 20 mg, twice a day (both from Jiangsu HengRui Medicine Co., Ltd., China). Interruption happened until objective disease progression, intolerable toxicity, or occurrence of another discontinuation criterion.

Objective response criteria of the tumors, including complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD), were evaluated according to the RECIST version 1.1 criteria. The primary endpoint was progression-free survival (PFS). Disease control rate (DCR), objective response rate (ORR), and overall survival (OS) of patients were observed as the secondary endpoints. The Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 was used to grade treatmentemergent AEs. AEs were recorded from enrollment to 30 days following the end of therapy.

Data entry was double entered by members of the study team, and the data entered were then reconciled. Descriptive statistics were used to summarize the clinical characteristics of the patients. The OS and PFS were reported as medians and 2-sided 95% confi dence intervals (CI), which were estimated using the Kaplan-Meier method. The proportions of patients with CR, PR, SD and PD were calculated. The ORR was calculated as CR + PR, while DCR as CR+PR+SD. GraphPad Prism software (version 7, LaJolla, CA) and SPSS version 20.0 (IBM Corp., Armonk, USA) were used for the statistical analysis. P<0.05 was considered statistical signifi cance.

From April 2019 to September 2020, a total of 150 patients were screened and 13 patients were enrolled in the study (Appendix 1). All patients received at least one cycle of JBJD combined with low-dose apatinib and S-1 and were followed up to August 30th, 2021. The demographic and clinical characteristics of the patients are shown in Table 1 .

The profi le of treatment administration and dose modifi cation is shown in Appendix 2. All patients were treated with JBJD combined with low-dose apatinib and S-1. Among them, one patient discontinued all medications due to the pandemic of COVID-19. One patient suspended all medications due to external infections and received treatment again after 6 days. And the other patient due to personal reasons discontinued apatinib and S-1 and received treatment again after 1 month. The rest were due to side effects. Overall, the median time of treatment was 4.6 months.

Among the 13 available patients, only 1 (7.7%) achieved PR. The tumor responses of the 13 patients are shown in Figure 1 . The patients who achieved SD and PD were 7 (53.8%) and 5 (38.5%), respectively, with an ORR of 7.7% (95% CI, 0%-24.5%) and DCR of 61.5% (95% CI, 30.9%-92.1%). The median PFS and median OS were 4.6 and 8.3 months, respectively ( Figure 2 ). Overall survival (%)

The incidence of AEs is summarized in Table 2 . There were no treatment-related deaths. The most common AEs were hypertension with an incidence of more than 60% (8 cases), followed by proteinuria, elevated transaminase, and thrombocytopenia, with incidences of 38.5%, 30.8%, and 30.8%, respectively. Only 1 patient experienced thrombocytopenia of grade 3. The most common causes for dose reduction were thrombocytopenia, neutropenia, and proteinuria.

Apatinib is a new type of tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor 2. Clinical studies showed that the median PFS and OS of mCRC who failed the second-line treatment treated with apatinib 500 mg were 4.8 and 9.1 months, respectively. The common grade 3-4 AEs were hypertension (12.5%), hand-foot syndrome (10.4%), thrombocytopenia (10.4%) and proteinuria (8.3%). (25, 26) Among 167 patients with refractory mCRC treated with apatinib and S-1, thrombocytopenia (37.93%), leukopenia (27.59%) and elevated transaminase (27.59%) were the most frequent severe AE according to Li, et al (12) and a total of 10 cases with grade 3 AEs were reported as well. (12) Dai, et al (13) retrospectively analyzed patients of mCRC treated with apatinib and S-1. The median PFS and median OS were 3.93 and 7.77 months, respectively. The major AEs and the incidences were fatigue (52.3%), hypertension (45.0%), hand-foot syndrome (22.7%), leukopenia (15.9%), neutropenia (15.9%), thrombocytopenia (22.7%), elevated transaminase levels (13.6%), and diarrhea (15.9%).

JBJD is a prescription for strengthening the body resistance to eliminate pathogenic factors. In this prescription, Radix pseudostellaria, Atractylodis macrocephalae Rhizoma, Poria cocos, Radix glycyrrhizae can invigorate Pi and replenish qi. They were useful for treating hypofunction of Pi, a symptom that is partially equivalent to that of gastrointestinal motility disorders, such as fatigue, diarrhea, and nausea. (27, 28) Ligustrum lucidum Ait, Eclipta prostrata L. can nourish Gan and Shen, which have an impact on promoting hematopoiesis, and prevents myelosuppression in patients treated with chemotherapy and targeted therapy. (29) Gastrodia elata Blume and Uncaria rhynchophylla (Miq.) Jacks. can calm Gan and suppress yang, and experimental studies show that they have blood pressure-lowering activity. (30) (31) (32) Hedyotis diffusa Willd and Rhizoma smilacis glabrae could enhance host anti-tumor immunity and antitumor effects. (33, 34) The results of this study showed that the combination of JBJD with low-dose apatinib and S-1 had comparable effi cacy with better tolerability in mCRC patients after second-line treatment. However, patients enrolled in this study demonstrated worse ECOG-PS and fewer AEs of grade 3 and 4. On the basis of symptomatic treatment, drug reduction, or short-term withdrawal, most of the AEs would be tolerated, predictable, controllable, and reversible. Therefore, the combination of JBJD with 

In China, regorafenib, fruquintinib, and trifl uridinetipiracil were approved for patients with mCRC in the third-line setting, which showed that the median PFS of patients with mCRC treated by third-line and above was only 2.0-3.7 months, and the median OS was 7.8-9.0 months. (21, 22) The results of the ALTER0703 trial recently published showed that the median PFS of patients with mCRC treated with anlotinib was 4.1 months, but it has not been approved for third-line treatment of mCRC. (23, 24) Meanwhile, some patients cannot receive standard treatment for various reasons, such as intolerable side effects, poor physical condition, and old age. In all, the efficacy of later-line treatment of mCRC patients still faces big challenges. Thus, our study fully respected for the patients' willingness and took the advantages of CM. Patients who had failed second-line treatment and were either ineligible for or had refused the standard treatments were enrolled. Our study adopted a treatment model of integrated Chinese and Western medicine to provide mCRC patients with a treatment option of CM combined with low-dose antiangiogenic drugs and chemotherapeutic drugs. apatinib and S-1 might be safe and effective for mCRC patients in the third-line or higher setting. Patients with mCRC who are elderly, poor in physical and economic conditions, or unable to tolerate conventional therapy are likely to be benefi t from the treatment. However, this study was an open-label, single-arm clinical trial. The limitation of our study included the small sample size without a control group, the efficacy was lack of comparison, and the description of clinical characteristics is statistically weak. Because of the epidemic of COVID-19, it was diffi cult to enroll as many participants as originally planned, although we had already extended the enrollment period. Thus, the duration of the study reported in this article was longer than that in the trial registration and the protocol, and the sample was smaller. And it was also a signifi cant reason for treatment interruption. Therefore, further prospective randomized controlled clinical trials are urgently needed to verify the effi cacy and safety of this treatment.

The treatment of integrated Chinese and Western medicine in this study was not simply CM plus Western medicine. It is a treatment for the patient who is unable or unwilling to receive conventional Western medicine and diffi cult to benefi t from pure CM treatment. On the basis of understanding the principles and programs of Western medicine, medicinal properties and drugs were used as sharp tools for removing pathogens in CM and increasing the treatment efficacy. This treatment in this study has many strengths. Firstly, all drugs were taken orally, and patients did not need to be hospitalized. They could be treated in outpatient clinics, which was convenient for patients and relieved hospitalization pressure. Secondly, the dosage of drugs can be adjusted fl exibly, and can be increased or decreased in time according to the patient's responses, side effects, clinical symptoms, etc. noreover, the risk of AEs was low. The control of side effects can significantly extension of the frontiers of the treatment, thereby enhancing the efficacy of mCRC patients. It is hoped that this study could provide new horizons for the clinical trials of integrated Chinese and Western medicine in treating mCRC, so as to explore a way of integrated treatment suitable for mCRC patients.

In conclusion, this clinical trial demonstrated that the combination of JBJD with low-dose apatinib and S-1 may have similar efficacy and comparably better safety profi le for use after failure of the second line for patients with mCRC, especially for patients who were at advanced age, poor in physical and economic conditions, or unable to tolerate conventional therapy. Our study was a single-center open-label, single-arm clinical trial with small number of patients and more prospective randomized controlled clinical trials are urgently needed.

The authors declare that there are no confl icts of interest regarding the publication of this paper.

Chen Y wrote the manuscript and was involved in the extraction of data, the statistical analysis of data and the follow- 

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