Efficacy of Aidi Injection and Brucea javanica Oil Emulsion Injection in Rectal Cancer during CapeOX Adjuvant Chemotherapy.

BACKGROUND: Adjuvant chemotherapy with CapeOX regimen is widely used in resected rectal cancer, which brings benefits to patients. But drug-related toxicities are severe during this process; thus, survival outcomes may potentially be affected. This study explored the efficacy of two Chinese herbal injections, Aidi injection (ADI) and Brucea javanica oil emulsion injection (BJOEI), as adjuvant drugs in CapeOX adjuvant chemotherapy on rectal cancer patients.
METHODS: A total of 240 cases were enrolled in this retrospective study. 80 cases received CapeOX with ADI (the ADI group), 80 cases received CapeOX with BJOEI (the BJOEI group), and the rest 80 cases received CapeOX alone (the control group). After four cycles' chemotherapy, adverse reactions (ADRs) and quality of life (QOL) were analyzed. Then, patients received follow-up for at least one year, and the endpoint was disease-free survival (DFS).
RESULTS: All patients completed at least four cycles' adjuvant chemotherapy. The incidence of leukopenia and thrombocytopenia was significantly lower in the ADI group; the incidence of nausea was significantly lower in the BJOEI group; the incidence of hand-foot syndrome was significantly lower in both the ADI group and BJOEI group. Significant difference was found in the control group regarding the Karnofsky Performance Status (KPS) scores prior and posttreatment. No difference was found among three groups regarding one-year DFS.
CONCLUSION: As adjuvant drugs for rectal cancer during CapeOX chemotherapy, ADI shows advantages in decreasing leukopenia and thrombocytopenia, while BJOEI results better in remitting nausea. Both two CHIs had positive impacts on decreasing hand-foot syndrome and the maintenance of patients' QOL. It is worthy of further study and promotion for CHIs.

1. Introduction

Colorectal cancer (CRC) is the most common malignant tumor in the digestive system. Globally, its incidence and mortality rank third and second, respectively [1]. Currently, CRC becomes an increasing cancer burden to Chinese society due to westernization in lifestyles; thus, its incidence has risen to the second [2]. In China, the incidence of rectal cancer is much higher than colon cancer, and the number of which also accounts for nearly half of the total CRC patients [3, 4]. They suffer from a worse quality of life (QOL) and a poorer prognosis. Currently, radical surgery followed by adjuvant chemotherapy is still the standard treatment of resectable rectal cancer [5]. Unfortunately, quite a few patients are undergoing complications from sphincter excision and chemotherapeutic toxicity. CapeOX (XELOX) is a first-line adjuvant regimen that brings convenient use and lowers toxicity to rectal cancer patients [6]. However, adverse reactions (ADRs) are unavoidable after long-range chemotherapy.

The Chinese herbal injection (CHI) is based on the theories of traditional Chinese medicine (TCM), and the application of which is a symbol of the modernization of TCM. Currently, over a dozen CHIs are frequently used in treating human cancer: Aidi, Astragalus polysaccharides, Brucea javanica oil emulsion, Cinobufacini, compound matrine, Delisheng, ginseng polysugar, Kangai, Kanglaite, and Shenqifuzheng [7] The majority studies of these anticancer CHIs are related to lung cancer, and it is concluded that CHIs can reduce ADRs during chemotherapy and promote patients' QOL, which has been demonstrated by evidence-based medicine [8]. Most of the reports published in English were reviews or meta-analyses, which were based on similar studies previously published in Chinese. However, among these articles, few researchers directly compared and evaluated different CHIs in one same study. Due to the limitations of current clinical researches and meta-analyses, higher-level evidences are needed.

Aidi injection (ADI) and Brucea javanica oil emulsion injection (BJOEI; Yadanziyouru injection) are both common CHIs for many malignant tumors. It is generally accepted in TCM that CRC, a disease with deficiency of both spleen and kidney, can result better in survival outcome by regulating the immune microenvironment from these TCM drugs [8]. For advanced CRC patients, the two CHIs also show survival benefits as the palliative treatments. But there is a lack of researches concerning their applications after radical surgery. This study focuses on the safety and efficacy of the two CHIs combined with CapeOX adjuvant chemotherapy in patients with resected rectal cancer.

2. Materials and Methods

2.1. Study Design

From August 2017 to May 2020, a total of 240 patients with rectal cancer were enrolled in this study. All patients have undergone laparoscopic radical surgery by our experienced surgeons and received adjuvant chemotherapy. They were divided into three groups: the group with CapeOX regimen plus ADI (the ADI group), the group with CapeOX plus BJOEI (the BJOEI group), and the group with CapeOX alone (the control group).

The inclusion criteria of cases were listed as follows: (I) aged 18 to 75 years; (II) diagnosed as primary rectal adenocarcinoma with clinical-stage I to III; (III) patients have undergone laparoscopic radical surgery (Dixon, Miles or Hartmann) with R0 resection; (IV) diagnosed and confirmed again by postoperative pathological examination; (V) expected survival was longer than three months; and (VI) Eastern Cooperative Oncology Group (ECOG) score was 0 or 1. The exclusion criteria were listed as follows: (I) history of neoadjuvant therapy; (II) severe cardiac, liver, or renal insufficiency that could not endure postoperative treatment; (III) combined with other primary tumors; and (IV) patients with any contraindication mentioned in the instructions of the two CHIs. The procedures were conducted following the principles of the Declaration of Helsinki (as revised in 2013) and in accordance with the ethical standards of our hospital. All patients have signed informed consent.

Radical surgery was performed among the patients. Three to four weeks after surgery, they started to receive adjuvant chemotherapy with CapeOX regimen, or plus respective CHI. Before the postoperative treatment, patients' QOL was scored using the Karnofsky Performance Status (KPS; scored 100 to 0) scale [9]. KPS scale is commonly applied in cancer patients, which is regarded as an evaluator for the feasibility of chemotherapy, and its detailed criteria are listed in Table 1.

Table 1

Karnofsky Performance Status scoring scale.

Score	Definition
100	Normal, no complaints; no evidence of disease
90	Able to carry on normal activity; minor signs or symptoms of disease
80	Normal activity with effort; some signs or symptoms of disease
70	Cares for self; unable to carry on normal activity or to do active work
60	Requires occasional assistance, but is able to care for most personal needs
50	Requires considerable assistance and frequent medical care
40	Disabled; requires special care and assistance
30	Severely disabled; hospital admission is indicated although death not imminent
20	Very sick; hospital admission or active supportive treatment necessary
10	Moribund; fatal processes progressing rapidly
0	Dead

2.2. Treatment Regimen

For the ADI group, 50 mL ADI (Guizhou Yibai Pharmaceutical Co. Ltd., Guizhou, China) diluted into 250 mL normal saline was intravenously infused from day 1 to day 14, once a day. After ADI given on day 1, oxaliplatin (Shandong Xinshidai Pharmaceutical Co. Ltd., Shandong, China) diluted into 500 mL 5% glucose was intravenously infused from day 1 to day 14. The dose of oxaliplatin was calculated on the basis of body surface area (BSA; 130 mg/m2). Meanwhile, capecitabine (Jiangsu Hengrui Medicine Co. Ltd., Nanjing, China) was taken orally twice a day from day 1 to day 14, and its dose was based on BSA (1000 mg/m2). Then, drugs were stopped for 7 days. The expected treatment time ranged from three to six months.

For the BJOEI group, 10 mL BJOEI (Shenyang Yaoda Leiyunshang Pharmaceutical Co. Ltd., Shenyang, China) diluted into 250 mL normal saline was intravenously given from day 1 to day 14, once a day. Then, the administration of oxaliplatin and capecitabine was equal to the ADI group. For the control group, only CapeOX regimen was given. The frame of the study is presented in Figure 1.

Figure 1

The treatment process and study design. ECOG: Eastern Cooperative Oncology Group; ADI: Aidi injection; BJOEI: Brucea javanica oil emulsion injection.

2.3. Evaluation of Drug-Related Adverse Reactions

Common indicators of drug-related ADRs were graded from 0 to V according to the Common Terminology Criteria for Adverse Events (CTCAE; version 5.0), including leukopenia, anemia, thrombocytopenia, nausea, vomiting, diarrhea, constipation, alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, hand-foot syndrome, and peripheral neuropathy [10].

2.4. Quality of Life Assessment

The QOL of the three groups was evaluated three months later by reviewing the QOL score, following the KPS criteria. Comparison of the scores prior and posttreatment can reflect the changes in QOL.

2.5. One-Year Follow-Up

Postoperative follow-up was started after surgical operation. We used telephone and outpatient follow-up to perform data collection. The endpoint of the follow-up was disease-free survival (DFS).

2.6. Statistical Analysis

IBM SPSS Statistics (version 23) software was used for data analysis, and GraphPad Prism (version 8.0.2) for Kaplan-Meier curve drawing. Continuous variables were shown as mean ± standard deviation and analyzed by one-way ANOVA test. Chi-square test was used for enumeration data, Mann-Whitney U test for ranked data between two groups, and Kruskal-Wallis test for ranked data among three groups. When the ranked data were paired, matched samples t-test was performed. Log-rank test was used to compare the DFS among the three groups. P values listed in this article were all derived from two-tailed tests. P < 0.05 was considered statistically significant.

3. Results

3.1. Patient Characteristics

Patients' characteristics are displayed in Table 2. The mean age of the ADI group, the BJOEI group, and the control group was 59.1 ± 9.0, 60.4 ± 9.8, and 57.9 ± 10.1 years, respectively; and the median age was 59, 60.5, and 58 years, respectively. The number of cases with stoma (permanent or protective) in the three groups was 20, 17, and 19, respectively. There were no statistical significances in demographic and disease characteristics among the three groups (all P > 0.05). All patients have finished at least four cycles' adjuvant therapy as planned, and none of them dropped out during this process.

Table 2

Patient characteristics of the three groups.

	ADI group (n = 80)	BJOEI group (n = 80)	Control group (n = 80)	F/χ2	P value
Age (years)	59.1 ± 9.0	60.4 ± 9.8	57.9 ± 10.1	1.270	0.283
Gender (%)				0.742	0.690
Male	53 (66.25)	58 (72.50)	55 (68.75)
Female	27 (33.75)	22 (27.50)	25 (31.25)
BMI (kg/m2)	22.12 ± 2.09	21.83 ± 2.40	21.64 ± 1.76	1.060	0.348
Tumor length (cm)	3.69 ± 1.26	3.73 ± 1.20	3.57 ± 0.96	0.393	0.676
Preoperative clinical stage (%)				4.715	0.318
I	2 (2.50)	0 (0.00)	0 (0.00)
II	22 (27.50)	20 (25.00)	18 (22.50)
III	56 (70.00)	60 (75.00)	62 (77.50)
ECOG performance status (%)				0.870	0.647
0	66 (82.50)	70 (87.50)	69 (86.25)
1	14 (17.50)	10 (12.50)	11 (13.75)
Baseline CEA level (%)				1.363	0.506
≤4.5 ng/mL	24 (30.00)	19 (23.75)	18 (22.50)
>4.5 ng/mL	56 (70.00)	61 (76.25)	62 (77.50)
Surgical method (%)				1.195	0.879
Dixon	60 (75.00)	63 (78.75)	61 (76.25)
Miles	8 (10.00)	9 (11.25)	10 (12.50)
Hartmann	12 (15.00)	8 (10.00)	9 (11.25)
Histological differentiation (%)				2.292	0.682
Well	11 (13.75)	9 (11.25)	13 (16.25)
Moderate	41 (51.25)	43 (53.75)	46 (57.50)
Poor	28 (35.00)	28 (35.00)	21 (26.25)

3.2. Adverse Reactions

Drug-related ADRs were compared after four cycles' adjuvant therapy, and the number of which is shown in Table 3. There were a total of 10 cases (12.50%; 8 with grade 1~2, and 2 with grade 3~4) in the ADI group facing leukopenia, while the number in the control group was 30 (37.50%; 27 with grade 1~2, and 3 with grade 3~4), showing a significantly lower incidence after using ADI (P < 0.001). As for thrombocytopenia, the number of grade 1~4 in the three groups was 3 (3.75%), 10 (12.5%), and 15 (18.75%), respectively, and the incidence of which in the ADI group was significantly lower than that in the BJOEI group (P < 0.05). For the cases of nausea, the BJOEI group (21 cases, 26.25%) was significantly lower than the ADI group (36, 45.00%; P < 0.05). Compared with the control group (22 cases, 27.50%), hand-foot syndrome occurred significantly less in the ADI group (6 cases, 7.50%) and the BJOEI group (8 cases, 10.00%; P < 0.05). The comparison of each adverse reaction was illustrated with Figure 2.

Table 3

Drug-related adverse reactions in the three groups.

	Grade 0 (%)			Grade 1 + grade 2 (%)			Grade 3 + grade 4 (%)			H	P value
	ADI group	BJOEI group	Control group	ADI group	BJOEI group	Control group	ADI group	BJOEI group	Control group
Leukopenia	70 (87.50)	61 (76.25)	50 (62.50)	8 (10.00)	15 (18.75)	27 (33.75)	2 (2.50)	4 (5.00)	3 (3.75)	12.645	0.002
Anemia	46 (57.50)	39 (48.75)	36 (45.00)	33 (41.25)	39 (48.75)	44 (55.00)	1 (1.25)	2 (2.50)	0 (0.00)	2.407	0.300
Thrombocytopenia	77 (96.25)	70 (87.50)	65 (81.25)	3 (3.75)	10 (12.50)	14 (17.50)	0 (0.00)	0 (0.00)	1 (1.25)	8.860	0.012
Nausea	44 (55.00)	59 (73.75)	39 (48.75)	35 (43.75)	20 (25.00)	39 (48.75)	1 (1.25)	1 (1.25)	2 (2.50)	11.023	0.004
Vomiting	69 (86.25)	70 (87.50)	64 (80.00)	11 (13.75)	10 (12.50)	14 (17.50)	0 (0.00)	0 (0.00)	2 (2.50)	2.157	0.340
Diarrhea	54 (67.50)	46 (57.50)	42 (52.50)	25 (31.25)	34 (42.50)	35 (43.75)	1 (1.25)	0 (0.00)	3 (3.75)	4.101	0.129
Constipation	64 (80.00)	62 (77.50)	55 (68.75)	13 (16.25)	16 (20.00)	25 (31.25)	3 (3.75)	2 (2.50)	0 (0.00)	2.416	0.299
ALT increase	63 (78.75)	73 (91.25)	66 (82.50)	13 (16.25)	7 (8.75)	12 (15.00)	4 (5.00)	0 (0.00)	2 (2.50)	5.251	0.072
AST increase	67 (83.75)	72 (90.00)	64 (80.00)	12 (15.00)	6 (7.50)	13 (16.25)	1 (1.25)	2 (2.50)	3 (3.75)	3.043	0.218
Creatinine increase	72 (90.00)	68 (85.00)	68 (85.00)	8 (10.00)	12 (15.00)	12 (15.00)	0 (0.00)	0 (0.00)	0 (0.00)	1.149	0.563
Hand-foot syndrome	74 (92.50)	72 (90.00)	58 (72.50)	6 (7.50)	8 (10.00)	21 (26.25)	0 (0.00)	0 (0.00)	1 (1.25)	14.999	0.001
Peripheral neuropathy	70 (87.50)	71 (88.75)	62 (77.50)	10 (12.50)	9 (11.25)	16 (20.00)	0 (0.00)	0 (0.00)	2 (2.50)	4.898	0.086

Figure 2

The comparison of adverse reactions in the ADI group, the BJOEI group, and the control group. Significant differences were shown concerning leukopenia, thrombocytopenia, nausea, and hand-foot syndrome. (a) The ADI group; (b) the BJOEI group; (c) the control group.

3.3. Quality of Life

The KPS scores of the three groups prior and posttreatment were shown in Table 4. In the ADI group, the mean KPS scores before and after treatment were 76.59 ± 8.51 and 76.32 ± 7.81, respectively, and no significant difference was found (t = −0.705, P = 0.483). The scores in the BJOEI group were 77.35 ± 7.48 and 76.66 ± 6.79, respectively, with no significant difference (t = −1.686, P = 0.096). And the scores in the control group were 78.13 ± 7.48 and 75.00 ± 8.11, respectively, with a significant difference (t = 5.992, P < 0.001). A histogram is also presented in Figure 3 to show the comparison of the KPS scores prior and posttreatment in each group.

Table 4

Karnofsky Performance Status scoring of the three groups.

	ADI group (n = 80)	BJOEI group (n = 80)	Control group (n = 80)	F/χ2	P value
Prior treatment (%)	76.59 ± 8.51	77.35 ± 7.48	78.13 ± 7.48	1.913	0.128
90	10 (12.50)	9 (11.25)	14 (17.50)	8.394	0.211
80	36 (45.00)	40 (50.00)	39 (48.75)
70	24 (30.00)	26 (32.50)	25 (31.25)
60	10 (12.50)	5 (6.25)	2 (2.50)
Posttreatment (%)	76.32 ± 7.81	76.66 ± 6.79	75.00 ± 8.11	0.352	0.788
90	8 (10.00)	6 (7.50)	7 (8.75)	3.681	0.720
80	35 (43.75)	39 (48.75)	35 (43.75)
70	30 (37.50)	32 (40.00)	29 (36.25)
60	7 (8.75)	3 (3.75)	9 (11.25)
t	-0.705	-1.686	5.992
P value	0.483	0.096	<0.001

Figure 3

The comparison of the mean KPS scores prior and posttreatment in the ADI group, the BJOEI group, and the control group. The mean score in the control group showed a significant reduction after chemotherapy treatment.

3.4. One-Year Prognosis

All patients received at least one-year follow-up, and the DFS was evaluated by computed tomography examination. Among them, 12, 14, and 17 cases had local recurrence or distant metastasis in the ADI group, the BJOEI group, and the control group, respectively. The DFS rate was 85.0%, 82.5%, and 78.8%, respectively. There was no significant difference among the three groups (P = 0.289). The Kaplan-Meier curve of DFS is shown in Figure 4.

Figure 4

The comparison of disease-free survival rate among the three groups. There was no significant difference in disease-free survival rate among them (P = 0.289).

4. Discussion

Adjuvant chemotherapy forms an important part in the treatment of rectal cancer. Via systemic administration, long-term benefits are brought to most patients undergone surgical resection [11]. However, drug-related ADRs frequently occur in postoperative treatments; thus, patients' QOL and compliance to adjuvant chemotherapy are accordingly lowered. These negative impacts can potentially limit survival outcomes.

In the theories of TCM, the causes of rectal cancer include excessive fatigue, improper diet, and deficiency of Zheng-Qi (Qi; body energy); thus, the symptom of damp and poison stasis is emerged [12]. Meanwhile, side effects of chemotherapy, especially peripheral neurotoxicity, are also derived from the damage of Qi. The loss of Qi aggravates the imbalance between Yin and Yang, insufficiency of the liver and kidney, and decrease in immunity. As a result, tumor progression is frequently promoted [13]. ADI and BJOEI are both TCM preparations that are extracted and purified from active ingredients of Chinese herbs [14]. Serving as anticancer CHIs, they are generally accepted in TCM hospitals. Multiple studies in China concluded that different CHIs have similar but uneven positive impacts on cancer patients [8]. However, the usage of anticancer CHIs has not been unified, which limits the development of these TCM injections. The compatibility and dosage need to be standardized consequently.

In this study, the efficacy of ADI and BJOEI was directly compared in rectal cancer patients after their surgical operations. Also, the usage of CHIs was in strict accordance with the instructions. The results showed that the two CHIs have respective advantages in preventing different ADRs in CapeOX chemotherapy. There were no significant differences among the three groups including anemia, vomiting, diarrhea, constipation, ALT, AST, creatinine, and peripheral neuropathy (P > 0.05). For patients in the ADI group, the risk of leukopenia was much lower than that in the control group (P < 0.05), and the risk of thrombocytopenia was much lower than that in the BJOEI group (P < 0.05), indicating that ADI may offset the suppressive effect of chemotherapeutic agents on bone marrow to a certain extent; hence, the coagulation function was also sustained. This result can be attributed to cantharides (Banmao), the main component of ADI. As an antitumor agent, cantharides serves for antiangiogenesis, tumor cells apoptosis induction, and multidrug resistance reversal [15, 16]. For the BJOEI group, we found the toxicity grade of nausea was significantly lower compared to the ADI group (P < 0.05). Since gastrointestinal reactions are the main side effects during chemotherapy, BJOEI can be commonly used as an adjuvant drug to prevent nausea or vomiting. Also, both ADI and BJOEI showed significant advantages in decreasing the incidence of hand-foot syndrome. Furthermore, the QOL scores posttreatment were compared pairwise with the initial values in respective groups, and neither of groups using CHIs showed significant difference (P > 0.05); comparatively, a statistical significance was found in the control group between the scores prior and posttreatment (P < 0.05). These results indicated that both two CHIs did not downgrade the living ability; moreover, they may have potential effects on the maintenance of patients' QOL. In addition, we also compared the DFS in the first year, and the results indicated that the one-year prognoses were similar among the three groups. The cases and follow-up time should be expanded.

Some limitations remained in this study. Potential biases were inevitable because of the small sample size, and some of the outcome measures were subjective. Also, there is the absence of more different chemotherapy regimens or CHIs in the study, so the efficacy of CHIs cannot be comprehensively evaluated. In addition, since this is a retrospective study, large-scaled randomized controlled trials should be performed, and long-term QOL and survival assessments are required in the future.

5. Conclusions

As the adjuvant drug for rectal cancer in CapeOX chemotherapy, ADI shows advantages in decreasing leukopenia and thrombocytopenia, and BJOEI results better in remitting nausea. Both two CHIs showed potential effects on decreasing the incidence of hand-foot syndrome, and the maintenance of patients' QOL. For different symptoms during chemotherapy, appropriate CHIs should be accordingly selected.