Clinical Features Of Reactive Cutaneous Capillary Endothelial Proliferation And Association With Clinical Outcomes Following Treatment With Camrelizumab Therapy In Tumors And Explore The Value Of Therapy Of Traditional Chinese Medicine

Background:In recent years,Western medicine has made revolutionary advances in the treatment of malignant tumors with new immune methods and drugs,which have excellent therapeutic effects for most tumors.In particular,immune checkpoint inhibitors(ICIs)have played an important role as broad-spectrum and potent drugs,which coincides with the concept of Chinese medicine of "strengthening the body’s resistance to eliminate pathogenic factors" for preventing and treating malignant tumors through differentiated treatment based on syndrome differentiation,involving aspects of tonifying the kidney,strengthening yang,and regulating spleen and stomach functions.However,immune therapy,including ICIs,often causes immune-related adverse events(irAEs),with skin adverse reactions being the most common.Traditional Chinese medicine believes that such reactions belong to the category of "drug rash."These skin adverse events often affect patients’ tolerance or compliance to immune therapy,quality of life,and the smooth progress of immune therapy.However,multiple studies have shown that the occurrence of skin irAEs is closely related to the clinical efficacy of ICIs(including PD-1/PD-L1 and CTLA4 inhibitors).Therefore,it is highly important and necessary to comprehensively understand,prevent,and manage skin irAEs.As a domestically-produced anti-PD-1 monoclonal antibody,Camrelizumab has been approved by the National Medical Products Administration for the treatment of various cancers including lymphoma,liver cancer,lung cancer,esophageal cancer,and nasopharyngeal carcinoma.It has been widely used and proven to be effective,and is included in the national medical insurance reimbursement scope.However,when used as a monotherapy for cancer treatment,it can cause a common skin irAE known as reactive cutaneous capillary endothelial proliferation(RCCEP).RCCEP has unique clinical manifestations and pathological features,but does not pose a life-threatening risk.Western medicine believes that the mechanism of RCCEP is mainly due to the disorder of the skin’s immune microenvironment,which leads to an imbalance in the expression of factors related to epidermal vascular generation.However,as there is no relevant record in traditional Chinese medicine,the pathogenesis and pattern of symptoms of RCCEP still need to be further explored.The occurrence of RCCEP may be related to the efficacy of camrelizumab as a monotherapy,but whether it is related to the efficacy of combined therapy with camrelizumab is still unknown.Therefore,it is necessary to systematically collect data on the occurrence of RCCEP with camrelizumab in multi-tumor types and large sample studies,to understand the correlation with therapeutic efficacy and influencing factors.Methods:A We collected data from a key registered clinical trial database for the treatment of various malignant tumors using Camrelizumab.We comprehensively analyzed the situation of subjects receiving Camrelizumab monotherapy or combination therapy,including the incidence,onset time,clinical features,treatment,and outcome of RCCEP.We carefully compared the efficacy of Camrelizumab monotherapy or combination therapy in patients who developed RCCEP with those who did not,mainly focusing on differences in objective response rate(ORR),progression-free survival(PFS),and overall survival(OS).At the same time,we conducted a single-center cross-sectional study to collect traditional Chinese medicine(TCM)"four diagnostic" data from patients with induced RCCEP after receiving Camrelizumab.We used clustering analysis and the principles of TCM syndrome differentiation to summarize the distribution patterns of TCM syndromes in patients,and explored the potential TCM mechanisms and treatments for RCCEP.Results:A total of 17 key phase Ⅰ,Ⅱ,and Ⅲ multicenter registered clinical trials involving Camrelizumab were included in this study,with a total of 2016 cases.The overall median exposure time to Camrelizumab for tumor treatment(including monotherapy and combination therapy)was 4.7 months(0.7 to 39.3 months),and the overall median time to RCCEP occurrence was 1.0 month(<0.1 to 11.5 months).The overall incidence of RCCEP was 58.0%(1170/2016 cases),with the highest incidence in the monotherapy group(78.8%,834/1059)and the lowest in the combination of vascular-targeting drugs group(15.2%,95/626).The most common site of RCCEP occurrence was the skin(1169 cases out of 2016),with only a few cases occurring in other sites such as the oral mucosa.The majority of patients(99.3%,2001/2016 cases)had RCCEP of grade 1 to 2,with only a few cases(0.7%,15/2016 cases)being of grade 3,and no cases of grade 4 or 5.Therefore,most cases of RCCEP do not require special treatment in clinical practice,and only a few cases(345/2016)require local treatment,mainly by laser or surgical excision(188/345 cases).The incidence of local bleeding was 16.8%,which can be treated by local compression and topical application of Yunnan Baiyao(a traditional Chinese medicine);only 1.2%of cases were complicated by local infection,which required the use of topical antibiotic ointment.The overall remission rate of RCCEP after treatment was 52.8%,with a median time to remission of 6.2 months(0.3 to 37.8 months).Among the 10 included phase Ⅰ,Ⅱ,and Ⅲ clinical trials,a total of 1305 cases were included.The monotherapy group had the highest incidence of RCCEP,reaching 77.0%(516/670 cases),followed by the combination of Camrelizumab and cytotoxic chemotherapy drugs group,which was 67.8%(230/339 cases);while the combination of Camrelizumab and vascular-targeting therapy drugs group had the lowest incidence,only 23.6%(70/296 cases).The majority of RCCEP cases were of grade 1 to 2,with only a few cases of grade 3(8/1305 cases).In the groups receiving single-agent therapy,combination therapy with vascular-targeting drugs,and combination therapy with cytotoxic drugs,the median time to occurrence of RCCEP was 0.8 months(IQR:0.6,1.2),5.0 months(IQR:2.7,8.0),and 1.6 months(IQR:1.0,4.2),respectively.The median duration of RCCEP after occurrence was 4.8 months(IQR:2.6,8.8),4.4 months(IQR:1.7,8.9),and 7.2 months(IQR:4.1,14.3),respectively.In the groups receiving single-agent therapy,combination therapy with vascular-targeting drugs,and combination therapy with cytotoxic drugs,the ORR of patients who developed RCCEP was higher than that of those who did not,with ORRs of 23.8%vs.1.9%(p<0.0001),48.6%vs.21.2%(p<0.0001),and 78.7%vs.54.1%(p<0.0001),respectively.The median PFS of patients who developed RCCEP was significantly longer than that of those who did not in all three groups(single-agent therapy:HR=0.36,95%CI,0.30-0.44;combination therapy with vascular-targeting drugs:HR=0.39,95%CI,0.28-0.54;combination therapy with cytotoxic drugs:HR=0.38,95%CI,0.28-0.52;all p<0.0001).The median OS of patients who developed RCCEP was also significantly longer(HR=0.34,95%CI,0.27-0.41;HR=0.46,95%CI,0.31-0.66;HR=0.19,95%CI,0.12-0.30;p<0.0001).In a cross-sectional study conducted at our center,a total of 104 RCCEP patients were included,with the main TCM syndromes being Qi deficiency and blood stasis syndrome,Qi stagnation and blood stasis syndrome,blood heat mania syndrome,and blood dryness and fluid deficiency syndrome.The pathogenesis is that cancer patients are mostly deficient in vital energy and cannot be nourished,and the pharmacological properties of carrelizumab are similar to the tonifying effects of traditional Chinese medicine.Therefore,RCCEP may be a cutaneous manifestation of the disorder of Qi and blood circulation due to excessive tonification.In treatment,Chinese herbal medicines with the effects of promoting Qi circulation,activating blood circulation,resolving blood stasis,and nourishing body fluids can be used.Conclusions:RCCEP is a common irAE when treating tumors with Camrelizumab monotherapy.From the Western medicine perspective,its occurrence mechanism is related to changes in the skin immune microenvironment,leading to epidermal angiogenesis and suppression disorders.From the TCM perspective,it is mainly due to the weakness of tumor patients that cannot be supplemented,which may be a manifestation of skin dysfunction caused by abnormal Qi and blood circulation after excessive tonifying.Most patients with RCCEP have mild symptoms and are self-limiting,and symptomatic treatment with supportive measures is recommended,mainly to prevent and treat local bleeding and infection.If bleeding or infection occurs,local hemostatic agents or antibiotics should be applied.The incidence of RCCEP significantly decreases when Camrelizumab is combined with vascular targeting drugs or cytotoxic chemotherapy drugs,which may be related to highly selective competition for the ATP binding site of VEGFR-2 in cells or inhibition of VEGF expression.Dialectical materialism believes that things are always divided into two parts;under certain conditions,bad things can turn into good things.This study fully demonstrates that the occurrence of RCCEP is closely related to the effectiveness of anti-tumor treatment(including objective efficacy and survival benefits)whether using Camrelizumab monotherapy or combination therapy with vascular targeting drugs or cytotoxic chemotherapy drugs.Therefore,RCCEP can also be used as a clinical biomarker to predict the effectiveness of Camrelizumab in tumor treatment.