Clinical And Experimental Research On The Treatment Of EGFRIs-related Adverse Skin Reactions With Traditional Chinese Medicine

Molecularly targeted therapies have been main treatment for cancer,among which the epidermal growth factor receptor inhibitors(EGFRIs)are the most widely used.Dermatologic toxicities are the most common side effects associated with EGFRIs,usually manifested as rash(47-100%),pruritus(8-57%),xerosis(10-49%),which are important issues for they may affect patients' quality of life(QOL)and still be a cause for dose reduction or discontinuation of targeted therapies in severe condition.In clinical practice,we find the standard western medicine have some limit.Our team summarized the change rule of syndrome in patients with EGFRIs treatment,and found syndrome characteristics showed to be wind-heat syndrome in early stage,dampness-heat syndrome in medium stage,and yin-deficiency syndrome in later period.For this reason,we created the "Zhiyang Pingfu decoction"in the treatment of EGFRIs-related rash and pruritus in early and medium stage."Zhiyang Pingfu decoction"was composed of Scutellaria baicalensis Georgi(Huangqin),Radix Sophorae Flavescentis(Kushen),Herba Portulacae(Machixian),Dictamni Radicis Cortex(Baixianpi),Herba Taraxaci(Pugongying),which had the effect of clearing heat-toxin,eliminating dampness,and relieving itch.During 2013 and 2015,we were supported by Beijing Municipal Science and Technology Commission to observe the efficacy and safety of Zhiyang Pingfu decoction.The study enrolled 201 patients.The effective rates in the treatment of rash and pruritus were 90.1%and 57.9%in experiment group,while 12.9%and 28.6%in control group.We searched Zizao Yangrong formula from Chishui Xuanzhu,which may be appropriate for EGFRIs-related xerosis in later period.We used the formula in a few patients and showed satisfied effect.Therefore,this study was to evaluate the curative effect and safety of Zizao Yangrong formula in the treatment of EGFRIs-related xerosis by double-blind,randomized,controlled trial(RCT).Zizao Yangrong formula was mainly consisted of five traditional Chinese medicine herbal,Radix Radix angelicae sinensis(Danggui),Rehmanniae Preparata(Shudi),Scutellaria baicalensis Georgi(Huangqin),Gentiana macrophylla Pall.(Qinjiao),Divaricate Saposhnikovia Root(Fangfeng),which had the effect of nourishing yin and blood,moistening dryness and relieving itch.Meanwhile,this study searched the possible treatment targets of traditional Chinese medicine(TCM)based on previous study results.The experimental study was conducted to explore the molecular mechanism of TCM for drug-related pruritus,which provides theoretical basis and new ideas for the prevention and treatment of TCM.Objective1. To observe the curative effect of"Zizao Yangrong Granules"in the treatment of EGFRIs-related xerosis,as well as to evaluate the decoction's safety by RCT,providing reference for TCM treating EGFRIs-related xerosis.2.To compare the differences in serological indexes between patients with EGFRIs-related pruritus and normal skin patients,and to observe the changes of serum markers before and after application of "Zhiyang Pingfu decoction",providing ideas for exploring the mechanism of action of TCM.3.The method of network pharmacology was used to enrich the target of EGFRIs-related rash and pruritus in the treatment of "Zhiyang Pingfu decoction" and explore the possible mechanism of TCM.4.To observe the effect of "Zhiyang Pingfu decoction"on the behavior of pruritus animal model,and observe the effect of TCM on the pathological morphology of skin,and the intervention of inflammatory signaling pathways related to EGFRIs-related pruritus.Method1."Zizao Yangrong Granule"for the treatment of EGFRIs-associated skin xerosis in a double-bl nd RCTCancer patients with EGFRIs-associated skin xerosis were enrolled in the study.They were randomly assigned to the experimental group and the control group,respectively.They were given oral "Zizao Yangrong granules" combined with topical vitamin E cream or placebo combined with topical vitamin E cream.Skin dryness and series of symptoms were evaluated before and after application every two weeks.The skin test was used to evaluate the improvement of skin dryness,and the dermatology life quality index was used to evaluate the improvement of patients' quality of life.At the same time,monitor safety indicators during treatment.2.Study on the mechanism of EGFRIs-associated pruritus initiallyThe patients included in the early and middle stages of EGFRIs were divided into 3 groups.The normal group was the patients without skin reaction.The control group was the patients with pruritus,who were not treated.The experimental group was the patients with pruritus,who were treated with "Zhiyang Pingfu decoction".At the time of enrollment,medical history data and venous blood were collected.The experimental group was followed up for 7 and 14 days by TCM to evaluate the skin condition and retain venous blood.The concentrations of serum TNF-a,substance P,histamine,IL-31,IL-33,leukotriene B4,IL-1 and PGE were detected by ELISA.The differences of serum markers between the groups were compared and the effect of TCM.3.Mechanism of "Zhiyang Pingfu decoction" based on network pharmacologyIn this study,the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP)and Bioinformatics Analysis Tool for Molecular mechANism of TCM(BATMAN-TCM)were used to query the composition and target information of "Zhiyang Pingfu decoction",and the drug target was selected by the absorption and distribution and metabolism and excretion(ADME)and correlation scores of the components.The target of rash and pruritus was found by using the Adverse Drug Reaction Classification System-Target Profile(ADReCS-Target),Therapeutic Target Database database(TTD),Drugbank database,and DisGeNET database.PPI analysis was performed on common targets of TCM and disease,thereby obtaining direct and indirect effects of common targets.Cytoscape software was used for network construction and topology screening of core targets.The DAVID online tool was used to enrich the pathways of the core target of the "Zhiyang Pingfu decoction",and to predict the signal pathway regulated by the decoction.4.Experimental study on animal model of skin itchingA total of 36 male ICR mice were equally divided into blank control group,model control group,positive control group,TCM high-dose group,TCM middle-dose group,and TCM low-dose group.The blank control group did not intervene.The model group received 100ul of normal saline for external use.The positive control group was given aprepitant 40 mg/kg.The high,medium and low doses of Chinese medicine were given 200ul,100ul,50ul of "Zhiyang Pingfu decoction" for external use.They were administered once a day for 14 days.Then SP or physiological saline was injected i.d.into the rostral part of the back to induce itch within 30 minutes of the last administration.The behavioral behavior of the mice after 1 hour of inducing itch,the pathological morphology of the skin,the morphology and density of the mast cells were observed.The expression of NK-1R in the skin was detected by immunohistochemistry and real-time quantitative PCR.The changes of serum TNF-a,IL-1?,histamine,IL-8,IL-31,IL-33,leukotriene B4,PGE2 related to inflammation and pruritus were determined by ELISA.Result1.A total of 68 patients with lung cancer were enrolled in the study,of which 66 completed the study.One patient in the experimental group was decommissioned due to adverse reactions,and one patient in the control group was lost to follow-up.The overall mean age of the patients was 68 years,with 23(33.8%)males and 45(66.2%)females,respectively.The median time from applying the targeted drug to the onset of dryness was 90 days.The effective rate of skin dry treatment for 14 days in the experimental group and the control group was 84.8%and 69.7%,respectively(P<0.05),and the effective rate at 28 days was 84.8%and 75.8%,respectively(P<0.05).Among the enrolled patients,29 patients and 31 patients with pruritus in the experimental group and the control group,respectively.The effective rate of skin pruritus for 14 days in the experimental group and the control group was 72.4%and 58.1%(P<0.05),and the effective rate at 28 days was 79.3%and 61.3%(P>0.05).The patients in experimental group had better quality of life than that in control group.There was no difference in the improvement of skin water content between the two groups.2.A total of 29 patients were enrolled in the study,10 in the normal group,10 in the control group,and 9 in the experimental group.There were no differences in age,gender,and distribution of primary disease among the three groups of patients.There was no significant difference in skin pruritus and accompanying symptoms between the experimental group and the control group.By analyzing the serological indexes of the three groups of patients,the serum SP of patients with pruritus was higher than that of the control group.The pruritus severity scores of the experimental group were gradually decreased after 7 days and 14 days of treatment with TCM.Serological analysis before treatment,7 days of treatment,and 14 days of treatment showed that serum SP levels gradually decreased with the treatment of TCM.The concentrations of serum histamine,IL-8 and LTB4 also varied during the course of treatment.3.A total of 4,355 targets were screened by the active ingredient of "Zhiyang Pingfu decoction",and 763 disease targets were screened by targeted drug-related rash and pruritus targets.A total of 62 key targets shared by drugs and diseases were analyzed.After the PPI database was used to analyze the interaction of the targets,2221 correspondences were obtained.Then Cytoscape software was used to analyze the network topology and cluster analysis,and 11 key targets were obtained.Pathway enrichment results show that TNF pathway may be a signaling pathway regulated by TCM.4.Chinese medicine can down-regulate the expression of NK-1R in the skin of SP induced itching mice,but had no effect on the morphology and density of mast cells.SP induced an increase in the release of LTB4 and TNF-a in mouse skin tissue,and TCM can reduce their release.SP can induce the release of LTB4,TNF-?,IL-1? in the serum of mice,and the serum content is higher than that of skin tissue.TCM can reduce the release of TNF-a from skin tissue and serum.Conclusion1."Zizao Yangrong granule" can effectively improve the skin dryness associated with EGFRIs and other skin manifestations,and significantly improve the quality of life of patients with good safety.2.The occurrence and severity of EGFRIs-related skin pruritus are closely related to serum SP concentration.Serum SP may be a reliable biomarker for EGFRIs-related skin pruritus.At the same time,IL-1?,IL-33,TNF-a may also be involved in the production of itching.3."Zhiyang Pingfu decoction" can improve the symptoms of pruritus caused by EGFRIs.Serum SP concentration is positively correlated with its efficacy,which may be a factor in its anti-itch mechanism.TCM also has a certain effect on the concentration of serum histamine,IL-8 and LTB4.4."Zhiyang Pingfu decoction"may inhibit inflammatory response induced by TNF signaling pathway by inhibiting SP/NK-1R effect,thereby reducing skin pruritus.TCM can improve the pruritus of SP-induced itching mice.TCM may relieve the itching effect by down-regulating the expression of NK-1R and inhibiting the activation of TNF signaling pathway induced by SP/NK-1R binding.The mechanism of itching induced by TCM may not be related to the release of histamine by mast cell degranulation.