Background

With the increasing number of tumor patients, Chemotherapy is still the main treatment for patients with advanced or recurrent cancer. At the same time, chemotherapy can cause a series of adverse reactions such as myelosuppression, nausea, vomiting, renal or hepatic impairment, cardiotoxicity and so on [1-3]. As these adverse reactions are gradually controlled, CIPN (ChemotherapyInduced Peripheral Neuropathy, CIPN) has become another major challenge that needs to be faced during chemotherapy.

The symptoms of CIPN include pain, tingling, cold-sensitivity and numbness that typically presents in a stocking glove distribution [4,5], which are needed to be treated with drugs for mild cases, and chemotherapy may even be interrupted for severe cases, which affects the effect of treatment. The main drugs that are likely to cause peripheral neurotoxicity include taxanes, platinum, vincristine and so on. According to reports, the clinical incidence of peripheral neurotoxicity caused by paclitaxel (Paclitaxelinduced Peripheral Neuropathy, PIPN) is 59%-80%, and the clinical incidence of peripheral neurotoxicity caused by oxaliplatin (Oxaliplatin-induced Peripheral Neuropathy, OIPN) is 85%-95% [6-8].

CIPN is a challenging and complex pain syndrome that we have no effective preventive and limited treatment options for currently [9]. Although nutritional nerves (such as mecobalamin), antiepileptic (such as gabapentin) and antidepressant (such as Duloxetine [10]. drugs have been shown in clinical trials to reduce the incidence of CIPN, the uncertain efficacy, serious adverse reactions and high price still keep us from choosing these drugs.

The clinical manifestations of CIPN are consistent with the arthralgia of Traditional Chinese Medicine (TCM). In this regard, the main treatment principles should be warming yang and replenishing qi, dispelling cold and eliminating maladies. Shenfu injection is a representative prescription in Chinese medicine that have the effect of warming Yang and replenishing Qi.

Shenfu injection is derived from Shenfu Decoction which confirmed by clinical and basic experiments to have the effect of preventing and treating CIPN. Our previous small sample clinical trial confirmed the efficacy of Shenfu injection in reducing CIPN. The incidence of CIPN in patients treated with oxaliplatin or paclitaxel chemotherapy was 66.66% and the incidence of CIPN in the combined Shenfu injection group was only 32.43% [11]. Moreover, basic experiments also confirmed that Shenfu Injection can reduce the peripheral neurotoxicity of paclitaxel by promoting the expression of NGF in serum [12,13]. Therefore, we designed this study by expanding the sample size to explore whether chemotherapy combined with Shenfu injection is of significance in the prevention and treatment of CIPN and whether the use time of Shenfu injection can affect the curative effect.

Material and methods

Diagnostic

Patients who were diagnosed as malignant tumor (lung cancer, colon cancer, cervical cancer, ovarian cancer and gastric cancer) which pathological stage was stage II-IV by histopathology or pathology cytology. The diagnostic criteria] and the staging criteria refers to National Comprehensive Cancer Network, NCCN [14-18].

Inclusion criteria

1) Pathologically diagnosed as patients with malignant tumors such as lung cancer, grastric cancer, colorectal cancer, ovarian cancer, and cervical cancer; 2) the pathological diagnosis of stage IIIV; 3) The disease state is postoperative adjuvant treatment, such as postoperative recurrence or late progression, it belongs to first-line chemotherapy; 4) Eastern Cooperative Oncology Group Performance Status Scale (ECOG-PS) 0-2 points; 5) Age: between 18 and 70 years old; 6) The chemotherapy regimen contains oxaliplatin or paclitaxel for 2-6 cycles; 7) All enrolled patients signed an informed consent form.

Exclusion criteria

1) Patients with neurological symptoms due to tumor brain metastasis or spinal cord metastasis; 2) There are other diseases that cause peripheral nerve damage, such as electrolyte disorders, diabetes; 3) Patients with skin lesions in the hand and foot parts (such as hand-foot syndrome caused by chemotherapy); 4) Patients who have caused peripheral neuropathy such as radiotherapy, or are undergoing other treatments that can cause neurotoxicity; 5) Patients who have been using antidepressants, antiepileptic drugs, and analgesics within one week of the efficacy evaluation.

Study design

This is a cohort study that included a total of 162 patients who had undergone chemotherapy with paclitaxel or oxaliplatin regimens. Eligible patients were recruited from First Hospital Affiliated Hospital of Chongqing Medical University and Affiliated Hospital of Chengdu University of Traditional Chinese Medicine. Patients were divided into chemotherapy group (74 cases), combined group (79 cases). Patients in the chemotherapy group were administered the whole course of treatment for 2-6 cycles, the combined group were administered Shenfu injection during the same period of chemotherapy. By calculating the long-term and short-term incidence of CIPN and analyzing the side effects as evaluation criteria.

Drug administration

Patients in the all groups were administered guidelines standard regimen chemotherapy according to the National Comprehensive Cancer Network (NCCN). Combined group and sequential group were administered Shenfu injection (Shenfu injection production company: Ya’an Sanjiu Pharmaceutical Co., Ltd. Production batch number: 071115 Specification: 50 ml/bottle) which requires Shenfu injection 50-100 ml and 0.5% glucose injection 250 ml to prepare for intravenous injection once a day.

Evaluation index

Peripheral neurotoxicity was graded according to the WHO Anticancer Drug Peripheral Neurotoxicity Grading Criteria Evaluation [19], which divided into 5 levels to evaluate the severity of neuropathy symptoms. (Grade 0: no symptoms; Grade I: paraesthesia and/or decreased tendon reflexes; Grade II; severe paraesthesia and/or mild weakness; Grade III: intolerable paraesthesia and/ or marked motor loss; Grade IV: paralysis). The incidence of CIPN is the main evaluation index of this study, which is divided into short-term curative effect and long-term curative effect.

Short-term efficacy: 1 to 2 months after the last chemotherapy in the chemotherapy group and the combined group, the incidence of CIPN in the two groups.

Long-term efficacy: 11 to 12 months after the last chemotherapy, the incidence of CIPN in each group. The secondary evaluation index is side effects. In this study, common toxic and side effects of Shenfu injection were evaluated for the combined group and chemotherapy group, including gastrointestinal adverse reactions (nausea and vomiting); severity of bone marrow suppression (white blood cells, platelets, hemoglobin); Liver and kidney function damage (Alanine aminotransferase, creatinine).

Refer to the WHO’s adverse reaction classification as follows:

Table 1: WHO patient chemotherapy adverse reaction score table.

Table 2: Characteristics of patients (n(%)).

Statistical analysis

The SPSS 26.0 software was used for analysis, the measurement data was compared by the chi-square test, and the grade data was compared by the rank sum test. P<0.05 means that there is a statistical difference.

Results

Characteristics of study participants

From February 2015 and February 2018, 161 patients who have undergone chemotherapy with paclitaxel or oxaliplatin regimens were included in the study. Among them, 3 patients were excluded because they did not meet the criteria, 5 patients were excluded because they were unwilling to participate in the trial and 2 patients were excluded due to personal reasons. Finally, they were randomly divided into divided into chemotherapy group (78 cases) and combined group (79 cases) according to the ratio of 1:1. During the follow-up period, 2 cases were lost in the combined group, 2 case was lost and 4 case was withdrawn due to severe chemotherapy reaction in the chemotherapy group. There was no significant difference in age, gender, clinical, stage, PS score, tumor type, average chemotherapy cycle, and average Shenfu injection days between the three groups (P>0.05). The baseline conditions of the enrolled patients are shown in Table 2.

CIPN incidence

Comparison of short-term and long-term incidence rates of CIPN by combined group and chemotherapy group

The short-term incidence rates of CIPN: The incidence rates of CIPN in the combined group and chemotherapy group were 27.85% and 66.21% (Z=-4.863, P=0.000). The patients of grade IIIIV CIPN in the combined group and chemotherapy group were 2 cases (2.53%) and 10 cases (13.51%).

Table 3: Comparison of short-term incidence rates of CIPN by combined group and chemotherapy group.

The long-term incidence rates of CIPN: The incidence rates of CIPN in the combined group and chemotherapy group were 17.72% and 45.95% (Z=-4.863, P=0.000). The incidence of grade III-IV CIPN in the combined group and chemotherapy group were 0% (0) and 6.76% (5 cases).

Table 4: Comparison of long-term incidence rates of CIPN by combined group and chemotherapy group.

Subgroup efficacy analysis

Whether different usage time (more or less than 3 weeks) of Shenfu injection will interfere with the short-term and long-term efficacy in the combined group during long-term chemotherapy (5-6 cycles).

Table 5: Comparison of short-term incidence rates of CIPN by the group which cumulative use time of Shenfu injection more than 3 weeks and the group which cumulative use time of Shenfu injection less than 3 weeks.

The short-term incidence rates of CIPN

The incidence rates of CIPN in the group which cumulative use time of Shenfu injection more than 3 weeks and the group which cumulative use time of Shenfu injection less than 3 weeks were 28.57% and 69.23%(Z=-2.128,P=0.029). The incidence of grade IIIIV CIPN in the group which cumulative use time of Shenfu injection more than 3 weeks and the group which cumulative use time of Shenfu injection less than 3 weeks were 0% (0) and 7.69% (1 cases).

Table 6: Comparison of long-term incidence rates of CIPN by the group which cumulative use time of Shenfu injection more than 3 weeks and the group which cumulative use time of Shenfu injection less than 3 weeks.

The long-term incidence rates of CIPN

The incidence rates of CIPN in the group which cumulative use time of Shenfu injection more than 3 weeks and the group which cumulative use time of Shenfu injection less than 3 weeks were 14.29% and 53.85% (Z=-2.122,P=0.034). No grade III to IV neurotoxicity in both group. Only 2 cases (14.29%) of grade I neurotoxicity in the group which cumulative use time of Shenfu injection more than 3 weeks and 3 cases (23.08%) of grade II neurotoxicity and 4 cases (30.77%) of grade I neurotoxicity in the group which cumulative use time of Shenfu injection less than 3 weeks.

Table 7: Comparison of the incidence of adverse reactions in the combined group and chemotherapy group.

Comparison of the incidence of adverse reactions

No significant difference in the nausea, vomiting, liver function damage, and renal function damage between combined group and chemotherapy group (P>0.05). The incidence rate of leukopenia, thrombocytopenia and hemoglobin reduction in the combined group was less than in the chemotherapy group (P<0.05).

Discussion

Chemotherapy is still the mainstream method of medical oncology treatment. In addition to gastrointestinal reactions and bone marrow suppression, peripheral neurotoxicity is also a common side effect of chemotherapy whose incidence is next to blood toxicity caused by chemotherapy. The clinical incidence of Chemotherapy-Induced Peripheral Neuropathy (CIPN) is about 59-90%. Reducing the chemotherapy dose, changing the chemotherapy regimen and even being forced to interrupt chemotherapy when CIPN occurs [20]. Obviously, CIPN has become the main factor which affects the progress of chemotherapy. Interrupting chemotherapy or reducing the dose will seriously reduce the efficacy and cause tumor progression.

Among all the chemotherapeutic agents, oxaliplatin and paclitaxel which have been widely used in lung cancer, esophageal cancer, breast cancer, gynecological tumors, lymphomas and so on are most likely to cause CIPN. The main clinical manifestations of CIPN are numbness of the extremities, hypoesthesia, movement disorders, blurred vision. Proprioceptive disorders such as vibration and position perception, muscle or joints pain can appear in severe cases [4,5].

At present, no well-established drug are used in the prevention and treatment of CIPN. The antiepileptic drug gabapentin, the antidepressant duloxetine, gabapentin, nortriptyline, vitamins and topical ketamine/amitriptyline cream are often used to relieve some CIPN symptoms in clinical [21]. Although some drugs have been proven to be effective in preventing CIPN, they are not widely recognized because of conflicting conclusions from different trials with the same drugs and obvious side effects. For example, glutathione can be used to prevent CIPN in receiving cisplatin chemotherapy, but glutathione can also reduce the antitumor activity of cisplatin by increasing the elimination of cisplatin from the kidneys [22]. Duloxetine, gabapentin relieve pain caused by CIPN through central analgesic, but these drugs have no effect on other symptoms such as numbness and sensory disturbances. The NCCN guidelines recommend to use the antidepressant duloxetine for CIPN that has occurred and describe that duloxetine has the moderate degree of effectiveness, evidence and recommendation and the low degree of safety [7]. For CIPN that has not occurred, the current guidelines do not recommend any drugs for prevention and treatment.

Traditional Chinese medicine has its unique advantages in the treatment of tumors. It is a unique treatment method with obvious advantages in cancer treatment in China. Chinese medicine has a very early understanding of tumors. As early as 3,500 years ago, there was a record of «tumor» in the oracle bone inscriptions of the Shang Dynasty. With the development of medicine, TCM has changed from the past macro differentiation to the use of modern medical technology to use micro syndrome differentiation to unify prevention and treatment, formed a model of integrated Chinese and Western medicine treatment of tumors with Chinese characteristics. By reviewing many domestic and foreign experimental studies on the treatment of tumors with TCM, we found that TCM can effectively improve the sensitivity of radiotherapy and chemotherapy, minimize the toxic and side effects of radiotherapy and chemotherapy, reduce the recurrence and metastasis of tumor, completely cure the patients with tumors who have received radical treatment, improve the quality of life of patients with advanced tumors, and prolong the survival of patients to achieve «survival with tumors» [23]. As for the reports on the treatment of CIPN with Traditional Chinese Medicine, we have consulted related literatures that some kinds of decoctions can reduce the incidence of CIPN caused by oxaliplatin [7,24,25] for example, Huangqi Guizhi Wu Decoction. Modified Lizhong Decoction which composed of dried ginger and ginseng can reduce the severity and incidence of CIPN [26]. Tongmai Sini Decoction which composed of Aconite, Licorice can reduce the incidence of oxaliplatin CIPN [11]. Chinese medicine compatible with astragalus can reduce the neurotoxicity of paclitaxel chemotherapy [7]. Although many scholars have begun to pay attention to the prevention and treatment of CIPN with traditional Chinese medicine, the enthusiasm of research CIPN is still not high enough. Although the search is not limited to years, only 43 documents related to traditional Chinese medicine have been found so far. The focus is much lower than other chemotherapy toxicities such as gastrointestinal reactions and bone marrow suppression.

The Shenfu injection introduced in this study can be applied to the treatment of a variety of diseases. The Shenfu injection not only has a protective effect on the cardiovascular system and respiratory system [27], but also can reduce the toxicity of chemotherapy in the treatment of tumors [28]. At the same time, numerous studies have shown that Shenfu injection can reduce bone marrow suppression during chemotherapy. Ginseng is a plant of the Araliaceae family which main components are saponins and carbohydrates, and other components include organic acids, proteins, enzymes, flavonoids, vitamins and so on [29]. The attached piece is the root of Aconitum of the Ranunculaceae plant, the main components are a variety of diterpenoids, aconitine, flavonoids and isoliquiritigenin [30].

The study evaluated the occurrence of CIPN in each group of 1-2 months after the end of chemotherapy. At this time, shortly after the completion of chemotherapy, the result of study reflected the prevention and treatment effect of chemotherapy in the acute phase of nerve injury. The study also evaluated the occurrence of CIPN in each group of 11-12 months after the end of chemotherapy to obtain a comparison of long-term efficacy.

Analyzing the combined group and the chemotherapy group, we found that a total of 22 (27.85%) in the combined group and 49 in the chemotherapy group (66.22%) had neurotoxicity manifestations of varying degrees in the first phase of follow-up. By comparison, the CIPN incidence of the combined group was significantly less than the chemotherapy group (P<0.01). The grade III-IV CIPN occurred in 2 cases (2.53%) in the combined group and 10 cases (13.51%) in the chemotherapy group, which indicates Shenfu injection can significantly reduce the incidence of CIPN during chemotherapy. In the second phase follow-up, a total of 14 (17.72%) in the combined group and 34 people (45.95%) in the chemotherapy group developed CIPN. By comparison, the CIPN incidence of the combined group was significantly less than the chemotherapy group (P<0.01). Moreover, no patients occurred the grade III-IV CIPN in the combined group and 5 cases (6.76%) in the chemotherapy group (P<0.01). In summary, Combined use of Shenfu injection during chemotherapy can significantly reduce the incidence of CIPN.

After comparing the both groups, we found that the effect will be better when the use of Shenfu injection may be used at the same time as chemotherapy. In order to explore the relationship between the dosage of Shenfu injection and the curative effect, we conducted a subgroup analysis in the combined group who received medium and long term of chemotherapy (5-6 cycles). All the patients from combined group were divided into the group with the cumulative dosage of Shenfu injection greater than 3 weeks and the group less than or equal to 3 weeks.

During the first phase of follow-up, the incidence of CIPN was 28.57% (4/14) in the group with the cumulative dosage of Shenfu injection greater than 3 weeks and 67.23% (9/13) in the group with the cumulative dosage of Shenfu injection less than or equal to 3 weeks (P<0.05). During the second phase of follow-up, the incidence of CIPN was 14.29% (2/14) in the group with the cumulative dosage of Shenfu injection greater than 3 weeks and 46.15% (6/13) in the group with the cumulative dosage of Shenfu injection less than or equal to 3 weeks (P<0.05). Regardless of the short-term and long-term effects, the group with the cumulative dosage of Shenfu injection greater than 3 weeks better than the group less than or equal to 3 weeks.

Up to now, no serious adverse reactions have been found innumerous studies of Shenfu injection. The instructions only mention the possibility of allergies. The adverse reactions were analyzed in this study We found that three groups showed no difference in nausea, vomiting, liver and kidney function damage. The incidence of bone marrow suppression in the combined group was lower than the chemotherapy group.

Conclusion

In conclusion, combined use of Shenfu injection during chemotherapy can significantly reduce the incidence of CIPN. In longterm chemotherapy, the longer the combined use of Shenfu injection, the better the prevention and treatment effect of CIPN. Combined use of Shenfu injection during chemotherapy has no obvious side effects and can reduce the incidence of bone marrow suppression.

Declarations

Data availability: The data that support the findings of this study are available upon request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions

Ethical approval: This study involving human participants was reviewed and approved by the Medical Ethics Committee of the Hospital of Chengdu University of Traditional Chinese Medicine (No. 2015BL-003). And this study was performed in accordance with the Declaration of Helsinki. All patients provided his written informed consent to participate in this study.

Description: The material has not been published previously, and will not be submitted for publication elsewhere.

Conflicts of interest: All authors declare that they have no conflicts of interest.

Funding: No funding was obtained for this study.

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