| Part Ⅰ: Transarterial Chemoembolization Plus Radiotherapy versus Radiotherapy alone for Hepatocellular Carcinoma with Macroscopic Vascular InvasionBackground: Primary hepatocellular carcinoma complicated with macrovascular invasion(HCC+MVI)is a kind of advanced tumor,which confers poor survival prognosis.Transcatheter arterial chemoembolization or/and radiotherapy are recommended as local treatment for HCC + MVI in relevant guidelines in China and Korea.However,it is not clear whether TACE + RT is more effective than RT alone in treating such patients.This study intends to retrospectively compare the efficacy of TACE + RT and RT alone in patients with HCC + MVI.Methods: Totally,148 patients with HCC + MVI were included in this study,including 49 patients underwent TACE + RT and 99 patients received RT alone.Propensity score matching analysis was used to control for confounding factors and compare the overall survival,progression-free survival,and intrahepatic control(IC)between the TACE + RT group and RT group.Results: A total of 126 patients(85.1%)died during the follow-up period.Both OS and PFS were better in the TACE + RT group than in the RT group before propensity score matching,but the intrahepatic control rate was not statistically different between the two groups.Of the 41 matched pairs screened by propensity score matching,the TACE + RT group still had better OS and PFS than the RT group(15.0:8.0 months,8.0:4.0 months,all P < 0.05).The 1-,2-,3-,and 5-year OS was 56.1%,28.6%,20.8%,and 15.7% in the TACE + RT group and 31.5%,13.1%,9.8%,and 6.7% in the RT group,respectively(P = 0.017).The 6-,12-,and 24-month PFS was 51.2%,39.0%,and 23.1% in the TACE + RT group and 36.6%,13.9%,and 11.1% in the RT group,respectively(P = 0.04).Two patients(4.1%)experienced radiation-induced liver disease(RILD)and 1 patient(2.0%)experienced RT-related gastrointestinal bleeding in the TACE + RT group,while 9 patients(9.1%)suffered RILD and 2 patients(2.0%)experienced RT-related gastrointestinal bleeding in in the RT group.Conclusion: TACE+RT was well complementarity with no more complications,providing a better PFS and OS compared with RT alone treatment for HCC+ MVI.Part Ⅱ: Transarterial Chemoembolization plus Radiotherapy vs.Surgery for Hepatocellular Carcinoma with Portal Vein Tumor ThrombosisBackground: This study aimed to retrospectively compare the efficacy of transarterial chemoembolization plus radiotherapy or surgery in the treatment of hepatocellular carcinoma with portal vein tumor thrombosis.Methods: From 2010 to 2017,162 patients,accompanying HCC with PVTT,undergoing surgery or TACE+RT were retrospectively analyzed.Overall survival was evaluated in univariable and propensity-score matched analyses by using the Kaplan-Meier method with log-rank test.Results: 125 patients received surgery,and 37 patients treated with TACE+RT.Before propensity score matching,the median OS was comparable between the TACE+RT group and surgery group(14.0 months: 13.9 months,P =0.81).The 1-,2-,3-,and 5-year accumulative OS were 56.3%,33.4%,27.3%,and 17.7% in the TACE+RT group,and 52.8%,33.3%,27.9%,and 16.2% in the surgery group,respectively.After matching,27 well-paired patients were selected.There was also no statistically significant difference in OS between the TACE+RT group and surgery group(median 13.0 vs.10.0 months,P =0.52).The 1-,2-,3-and 5-years OS were 51.6%,31.3%,22.3% and 17.9% in TACE+RT group,and 48.1%,33.3%,16.7% and 11.1% in the surgery group,respectively.We also found no statistically significant difference in OS among Cheng’s type of PVTT(I,II,III).Subgroup analysis showed Cheng’s type of PVTT has a great influence on surgery,with median OS of 19.1months in type Ⅰ PVTT and 11.8 months in type Ⅱ/Ⅲ(P =0.028).Conclusion: In patients with HCC with PVTT,surgical resection was similar to TACE+RT.Surgery appears to be a first-line treatment for patients with type Ⅰ PVTT,while TACE+RT may be an effective first-line treatment for patients with type Ⅱ/Ⅲ.Further prospective randomized controlled trials are recommended to evaluate the actual effects of these regimens.Part Ⅲ: Downstaging Efficacy of Radiotherapy-based Treatment of Hepatocellular Carcinoma with Macroscopic Vascular Invasion: A Prospective Cohort StudyBackground: In the treatment of HCC + MVI,downstaging of tumor thrombus and/or primary HCC is expected to provide patients with the opportunity for radical hepatectomy.This study intends to prospectively evaluate the clinical efficacy and toxic side effects of TACE + RT/RT downstaging translational therapy for HCC + MVI.Methods: From March 2018 to May 2020,30 patients with primary HCC + MVI were prospectively treated with TACE + RT(n = 24)or RT alone(n=6).The primary study endpoint was OS;the secondary study endpoints were PFS,downstaging success rate,and surgical conversion rate.Adverse events were assessed using the Common Terminology Criteria for Adverse Events(CTCAE 4.0).Results: The follow-up time of the entire cohort was 24 months.The median OS of the entire cohort was 22.0 months,12-,24-months OS was 60.0% and 47.8%,respectively.The median PFS was 13.0 months,12-,24-months PFS was 53.3% and 27.0%,respectively.During downstaging window phase within 3-6 months,22 patients were evaluated as downstaging success by clinical imaging.Among them,9 patients underwent R0 radical hepatectomy and 13 patients refused surgical treatment due to personal reasons,yielding a downstaging success rate of 73.3%(22/30 cases)and a surgical conversion rate of 30.0%(9/30 cases).Of the patients who underwent surgery,4 had postoperative complications of grade 4 or higher(2 gastrointestinal bleeding and 4 bile leakage).Conclusion: Radiation-based downstaging provides a considerable downstaging success rate and surgical conversion rate in patients with HCC + MVI.Part Ⅳ: Development and Validation of Nomogram for Liver Regeneration after Radiotherapy in Patients with Hepatocellular CarcinomaBackground: In the clinical practice of previous RT for liver cancer,more attention has been paid to the prevention and treatment of RILD,without in-depth exploration of liver regeneration after radiotherapy.Liver regeneration is beneficial to the prevention and recovery of RILD,which will become a new hotspot of clinical attention.In this study,we analyzed the changes of liver regeneration after radiotherapy for HCC based on the data of two prospective studies and established and validated a predictive model for the probability of liver regeneration after radiotherapy for HCC.Methods: The training cohort included 30 HCC patients with MVI who received downstaging radiotherapy;the validation cohort included 21 HCC patients with microvascular tumor thrombus who received postoperative adjuvant radiotherapy.Liver regeneration was defined as absolute normal liver volume increased by more than 10%,without Child-Pugh(CP)classification decline and intrahepatic tumor progression.Models and nomograms for liver regeneration after radiation therapy were developed and validated using logistic regression methods.Receiver operating characteristic curve(ROC)analysis was used to obtain the optimal cutoff point of the predictor,and risk stratification was performed according to the optimal cutoff point to compare the probability of liver regeneration in different patients.Results: After radiotherapy,12(40%)in the training cohort and 13(61.9%)patients in the validation cohort experienced liver regeneration.Standard residual liver volume spared from at least 20 Gy(SVs20)and ALT were the best predictors of liver regeneration model.The liver regeneration model established based on SVs20 and ALT showed good predictive power in both training cohort(AUC = 0.759)and validation cohort(AUC = 0.808).SVs20 = 303.4 m L and ALT = 43 U/L were the optimal cut-off points for risk stratification of patients.In the entire study cohort,the probability of liver regeneration decreased sequentially in the liver regeneration-high probability group(ALT < 43 U/L and SVs20 < 303.4 m L),liver regeneration-medium high probability group(ALT ≥ 43 U/L and SVs20 < 303.4 m L),liver regeneration-medium low probability group(ALT < 43 U/L and SVs20 ≥ 303.4 m L),and liver regeneration-low probability group(ALT ≥ 43 U/L and SVs20 ≥ 303.4 m L),which were 88.9%,60%,43.75%,and 33%,respectively(P = 0.032).Conclusions: SVs20 and ALT were important predictors of liver regeneration after radiotherapy.The established clinical model of liver regeneration based on SVs20 and ALT may provide a reference for dose limitation in normal liver and contribute to the optimization of radiotherapy planning.Part Ⅴ: Animal Models of Liver Regeneration after Radiotherapy in Sprague-Dawley RatsBackground: Due to the limitations of human trials,basic research is an important cornerstone for understanding radiation-induced liver injury-liver regeneration.Previous animal models of liver regeneration have mainly focused on liver regeneration in the context of hepatectomy or chronic injury,while little is known about liver regeneration after radiotherapy.Compensatory regeneration of liver after radiotherapy can promote the recovery of liver injury,and its mechanisms and influencing factors are worthy of study.The current study aimed to establish SD rat models of right liver radiotherapy injury-left liver regeneration by simulating clinical radiotherapy.To lay foundation for future research,we further explored the characteristics of liver regeneration and related evaluation indicators.Methods: Seventy-five 8-week-old male SD rats were cultured in the common animal room,and the rats were randomly divided into 5 groups according to the random number table,with 15 rats in each group.The design of the radiotherapy model in all experimental groups was right liver stereotactic irradiation-left liver protection and regeneration.According to different irradiation doses and irradiation volumes,the animal models were divided into group A(experimental group): 25 Gy/1fx + 2/3 liver volume irradiation,group B(experimental group): 15 Gy/1fx + 2/3 liver volume irradiation,group C(experimental group): 15 Gy/1fx + 1/2 liver volume irradiation,group D(experimental group): 25 Gy/1fx + 1/2 liver volume irradiation,group E(control group): both left and right livers were not irradiated and used as the blank control group.Three randomly selected rats in each group were sacrificed on days 1,8,15,30,and 100 after radiotherapy.The body weight,left liver weight,left liver volume,and liver function index values of the rats were recorded at each dissection,and the liver regeneration activity was assessed by detecting the expression of cell proliferation factor Ki-67 protein using immunohistochemistry.Results: No SD rats died of radiation-induced liver injury during the 100-day experimental observation.(1)The liver function indexes,i.e.,total bilirubin,ALT,and AST,in groups A,B,C,and D of the experimental group increased to the peak value on the first day after radiotherapy,followed by gradual recovery.These liver function indexes were significantly higher than those in the control group E on days 1 and were the same as that in group E on days 8,15,30,and 100.(2)Immunohistochemical detection revealed a similar trend with Ki67 protein expression in the left liver of the experimental groups(A,B,C,and D)began to gradually increase(> 1%)on day 8 after radiotherapy,peaked(3 – 5%)on day 15,and then gradually decreased to normal.There was no significant change in Ki67 protein expression in left liver at each time node in the control E group(all ≤ 1%);(3)On day 100,left liver volume and left liver weight were slightly higher in groups B and D than in groups A and C.Conclusion: Radiation-induced liver injury activated left liver regeneration in all experimental groups(groups A,B,C,and D).The first day after radiotherapy was the best time node to observe the degree of liver injury.Liver regeneration was in an incomplete activation or even inhibition state on days 1 and 8,and the liver regeneration activity was obvious on day 15 after radiotherapy,which was the best time node to observe the changes in Ki67 m RNA and protein expression.More obvious left liver regeneration was observed in the B model(15 Gy/1 fx + 2/3 liver volume irradiation)and D model(25Gy/1fx +1/2 liver volume irradiation),which was very suitable for the basic translational research of radiation-induced liver regeneration. |
PDF Full Text Request