| Background and PurposesIn 2020,the number of newly diagnosed patients with hepatocellular carcinoma in the world is about 900000,and the number of patients who die from hepatocellular carcinoma is as high as 830000,which seriously threatens human life.Liver malignant tumor is one of the most common malignant solid tumors in human beings.Among malignant tumors,primary liver cancer ranks fifth.Because of its high treatment difficulty,it has become the third leading cause of cancer-related death.Nearly 50%of the cases of primary liver cancer in the world occur in China.Liver transplantation is an effective method to cure patients with early hepatocellular carcinoma.The 5-year survival rate can be significantly improved by liver transplantation and long-term follow-up treatment,which is about 60%?75%.However,tumor recurrence or metastasis after liver transplantation is still as high as 8%?20%,which seriously affects the long-term survival of patients with liver cancer.Patients with local recurrence and no distant metastasis after liver transplantation can adopt local treatment methods,such as reoperation,local resection,radiofrequency ablation,TACE,radiotherapy,etc.Unfortunately,some patients have high malignancy,rapid cell proliferation,rapid tumor growth,multifocal growth in the liver,or distant organ or lymph node metastasis along the blood or lymph duct,losing the opportunity of local treatment.For these patients without local treatment indications and/or distant metastasis,there is still a lack of consensus on effective and systematic treatment.Sorafenib is a multi kinase inhibitor with clear targeting effect.The establishment of sorafenib's standard treatment status has achieved basically the same results based on sharp research and Oriental research.These two large,randomized controlled,international multicenter clinical trials are a leap in the history of human liver cancer treatment.For delaying the tumor progression and prolonging the survival time of patients with advanced hepatocellular carcinoma,the conclusions of the two studies are consistent,and sorafenib targeted therapy is well tolerated.Therefore,sorafenib has become a targeted therapeutic drug with breakthrough clinical efficacy for advanced hepatocellular carcinoma.Its clinical application has made the systemic therapeutic drugs for hepatocellular carcinoma from scratch and has epoch-making significance.As a first-line standard treatment,its position in the treatment of liver cancer has continued until now.However,in the field of recurrence and metastasis after liver transplantation,the clinical data on the efficacy of sorafenib are insufficient,and the interaction between sorafenib and immunosuppressants has not been clear.Oxaliplatin is an alkylating agent,belonging to the third generation platinum,which is non cell cycle specific.Its molecular mechanism is related to DNA blocking.Due to the different molecular structure,oxaliplatin does not produce cross resistance with the first generation platinum representative drug cisplatin and the second generation platinum representative drug carboplatin.Compared with bone marrow suppression of carboplatin and nephrotoxicity of cisplatin,oxaliplatin related adverse reactions were significantly reduced.Oxaliplatin and fluorouracil have synergistic and therapeutic effects.In view of its unique advantages and efficacy,oxaliplatin is widely used in clinical practice.Hepatocellular carcinoma has previously been considered to have a poor response to chemotherapeutic drugs.In 2013,the results of each study(a prospective,randomized controlled,multicenter,phase III clinical study of hepatocellular carcinoma)showed that the median OS of patients receiving oxaliplatin based FOLFOX 4 regimen was 6.40months,the RR was 8.15%,and the DCR was 52.17%.Its efficacy was affirmed at home and abroad,and was recommended as the standard treatment regimen for advanced liver cancer by many guidelines at home and abroad,It brings a new choice for the treatment of patients with advanced liver cancer.However,the clinical data on the effectiveness of FOLFOX 4 regimen in patients with tumor recurrence after liver transplantation are insufficient,and the interaction between FOLFOX 4 regimen and immunosuppressants has not been clear.Therefore,for advanced patients with tumor recurrence or metastasis after liver transplantation of hepatocellular carcinoma,to explore the therapeutic effect and clinical safety of sorafenib and FOLFOX 4 regimen chemotherapy,so as to provide more clinical medical evidence for the systematic treatment of such patients,which is of great significance to the choice of clinical treatment decision-making,and is worthy of further in-depth analysis and research.MethodsPatients with pathologically diagnosed hepatocellular carcinoma who are diagnosed with tumor recurrence and/or metastasis after liver transplantation and have no indication of local treatment shall be treated with sorafenib targeted therapy,FOLFOX4 regimen chemotherapy or best supportive therapy with the informed consent of the patient and in combination with the actual situation of the patient.The dosage of sorafenib is:sorafenib(Bayer company,trade name:dojme)400 mg each time,twice a day.Medication until serious adverse events,RECIST standard disease progression or patient death.In case of drug-related side effects,take active symptomatic treatment.If the patient cannot tolerate it,it is allowed to reduce or stop sorafenib according to clinical routine.Sorafenib treatment can be resumed after the adverse reaction returns to grade 1.FOLFOX4 regimen was as follows:oxaliplatin 85mg/m~2on day 1,calcium folate 200mg/m~2on day 1 and 2,fluorouracil 400 mg/m~2on day 1 and 2,fluorouracil 600 mg/m~2intravenously pumped for 22 hours on day 1 and 2,a 14-day cycle.A maximum of 12cycles of chemotherapy followed by optimal supportive treatment.Treatment continues until serious adverse events,RECIST-standard progression,or patient death occur.When drug-related side effects occur or patients cannot tolerate them,symptomatic treatment will be given according to clinical routine,and follow-up chemotherapy drugs will be reduced or discontinued as appropriate.During antineoplastic therapy,the patient continued treatment with proto-Immsupuno-pressants(e.g.,tacrolimus,sirolimus,etc.)and optimal supportive therapy.Imaging examination(such as CT,MRI,etc.)was performed every 4 cycles in the chemotherapy group,every 2 months in the sorafenib group and the best supportive treatment group to evaluate the efficacy of antitumor treatment.The main outcome measures were PFS and OS,and the secondary outcome measures were ORR,DCR,1-year survival rate,rejection and AE.The efficacy evaluation was determined as Cr,PR,SD and PD according to RECIST version 1.1.The ORR was calculated as Cr+PR and the DCR was calculated as Cr+PR+SD.Adverse reaction evaluation was recorded according to NCI-CTC version 4.0.Results and ConclusionsWe got the following results in the research:1.A total of 40 patients with recurrent and metastatic hepatocellular carcinoma after liver transplantation were treated with sorafenib.All patients could be evaluated.There were 0 cases of complete remission(CR),3 cases of partial remission(PR),9 cases of disease stability(SD).The recent objective effective rate(ORR)was 7.5%and the disease control rate(DCR)was 30.0%.The median duration of sorafenib treatment was 7.1 months(range:1?36 months).Up to the deadline of follow-up on February 10,2021,25 of the 40patients included died.The median PFS was 7.1 months(95%CI:4.086?10.114 months)and the median OS was 21.1 months(95%CI:10.584?31.616 months);The 1-year survival rate was 57.5%,and the 2-year survival rate was 30.0%.The median OS of the 12patients who relapsed 10 months after liver transplantation was 29.6 months,which was significantly longer than the 14.7 months of the 28 patients who relapsed 10 months after liver transplantation,and the difference was statistically significant(P=0.032).2.22 patients were included in FOLFOX4 chemotherapy group and 24 patients in best supportive care(BSC)group.The efficacy and adverse reactions of the two groups were compared.In the chemotherapy group,each patient completed at least 3 cycles of FOLFOX4 regimen chemotherapy,of which 5 patients completed all 12 cycles of FOLFOX4 regimen chemotherapy.2 patients were stopped after the 8th and 10th cycles of chemotherapy due to grade 3 hand and foot numbness,and were subsequently changed to the best supportive treatment.There were no complete remission cases in both groups,including 3 cases of partial remission(PR),12 cases of stability(SD)and 7 cases of progression(PD)in the chemotherapy group,1 case of PR,8 cases of SD and 15 cases of PD in the BSC group;The RR of chemotherapy group and best supportive treatment group were 13.6%and 4.2%respectively(P>0.05),while the DCR of chemotherapy group was68.2%,which was higher than 37.5%of BSC group(P<0.05).By February 10,2021,46 patients were followed up for a median of 21 months.The median PFS in the chemotherapy group was 7.0(95%CI:2.536?11.464)months,which was longer than 3.0(95%CI:1.895?4.105)months in the BSC group(P=0.004).The median OS of chemotherapy group and BSC group were 16.0(95%CI:9.049?22.951)and 14.0(95%CI 8.620?19.380)months,respectively,with no significant difference(P=0.193).In the BSC group,the median OS of 15 patients who met the Milan standard was15.1(95%CI:13.500?16.700)months,which was better than 6.5(95%CI 3.302?9.698)months of 9 patients who exceeded the Milan standard(P=0.028).In the chemotherapy group,the median OS of 13 patients who met the Milan standard was 20.0(95%CI:9.100?30.900)months,which was not statistically significant compared with 16.0(95%CI:7.702?24.298)months of 9 patients who exceeded the Milan standard(P=0.869).In the BSC group,the median OS of 15 patients without vascular invasion was 15.1(95%CI:13.516?16.684)months,which was better than 6.0(95%CI:3.663?8.337)months in 9patients with vascular invasion(P=0.015).In the chemotherapy group,the median OS of12 patients without vascular invasion was 25.0(95%CI:15.456?34.544)months,which was better than 13.0(95%CI:3.548?22.452)months in 10 patients with vascular invasion(P=0.027).3.The main adverse reactions in sorafenib group were CTCAE grade 1?2,including diarrhea,hand foot skin reaction,hypertension,rash,abnormal liver function,proteinuria,etc.CTCAE grade 3?4 adverse reactions included 1 case of grade 3 and 4 hand foot skin reaction and 1 case of grade 3 diarrhea.After sorafenib reduction or withdrawal,the grade3 adverse reactions recovered to grade 1,and the patients were well tolerated.The adverse reactions in the chemotherapy group were different from those in the sorafenib group,mainly including vomiting,diarrhea,numbness of hands and feet,neutropenia,nausea,thrombocytopenia,elevated transaminase and oxaliplatin allergy,mainly grade 1?2.Grade 3?4 adverse reactions included grade 3 hand and foot skin reactions in 2 cases,grade 4 neutropenia in 1 case and grade 3 neutropenia in 2 cases.After active symptomatic treatment,or reduction or withdrawal of chemotherapy drugs,the above adverse reactions can be alleviated,and the overall tolerance of patients is good.All patients received sorafenib or FOLFOX 4 chemotherapy,and no rejection occurred during antitumor treatment.ConclusionsThis study is the first to demonstrate that sorafenib and FOLFOX 4 regimen have certain efficacy in patients with advanced hepatocellular carcinoma recurrence or metastasis after liver transplantation,without increasing the incidence of rejection reaction and with good safety.Sorafenib and FOLFOX 4 can be used as clinical treatment options in these patients.Due to the small sample size of this study,the sample size can be expanded for further exploration. |
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