Carcinoma Radiotherapy - Laboratory Research And Clinical Practice

Part Ⅰ: DNA-PKcs subunits in radiosensitization by hyperthermia on hepatocellular carcinoma hepG2 cell lineBackground: Historically, hepatocellular carcinoma (HCC) was regarded as radioresistance, however, no evidence that HCC have an inherent radioresistance.Purpose: To investigate the radiosensitive to radiation and the ability of DNA repair after exposure to radiation, as well as the role of DNA-PKcs subunits in radiosensitization by hyperthermia on HCC HepG2 cell lines.Methods: Hep G2 cells were exposed to hyperthermia and irradiation. Hyperthermia was given at 45.5 ℃. Cell survival was determined by an in vitro clonogenic assay for the cells irradiated with or without hyperthermia at various time points. DNA DSB (double strand break) rejoining was measured using asymmetric field inversion gel electrophoresis (AFIGE). The DNA-PKcs activities were measured using DNA-PKcs enzyme assay system.Results: HepG2 HCC cell line is sensitive to radiation due to their α/β higher than 11 Gy. Hyperthermia can significantly enhance irradiation-killing cells. Thermal enhancement ratio as calculated at 10% survival was 2.02. The difference in radiosensitivity between two treatment modes manifested as a difference in the a components, which a value was considerably higher in the cells of combined radiation and hyperthermia as compared with irradiating cells. Survival fraction showed 1 logarithm increase after an 8-hour interval between heat and irradiation, whereas DNA-PKcs activity did not show any recovery. The cells were exposed to heat 5 minutes only, DNA-PKcs activity was inhibited at the nadir, even though the exposure time was lengthened. Whereas the ability of DNA DSB rejoining was inhibited with the increase length of hyperthermic time. The repair kinetics of DNA DSB rejoining after treatment with Wortmannin is different from the hyperthermic group due to the striking high slow rejoining component. Conclusion: HCC is radiosensitive. Determination with the cell extracts and the peptide phosphorylation assay, DNA-PKcs activity was inactivated by heat treatment at 45.5 ℃, and could not restore. Cell survival is not associated with the DNA-PKcs inactivity after heat. DNA-PKcs is not a unique factor affecting the DNA DSB repair. This suggests that DNA-PKcs do not play a crucial role in the enhancement of cellular radiosensitivity by hyperthermia. Part Ⅱ: A comparison of chemoembolization combination with and without radiotherapyfor unresectable hepatocellular carcinomaBackground: Transcatheter arterial chemoembolization is frequently used for the treatment ofthis cancer, but complete or massive necrosis is seldom observed. Historically, radiotherapy forhepatocellular carcinoma has yielded poor long-term survival. Multimodality therapy has beeninitiated in an effort to improve survival statistics.Purpose: This study evaluated the effect of transcatheter arterial chemoembolization combinedwith external beam radiotherapy on the response rates and survival of patients with unresectablehepatocellular carcinoma.Patients and Methods: We retrospectively studied 203 patients with unresectable hepatocellularcarcinoma, who were free of tumor thrombus, lymph node involvement, or extrahepaticmetastasis based on computed tomography scans of the chest and abdomen. Among the 203patients who received transcatheter arterial chemoembolization as initial therapy, 54 alsoreceived combination therapy with external beam radiotherapy. Tumor response rate, survival,and failure patterns were analyzed and compared between the two groups.Results: Objective responses (complete and partial responses) on computed tomography studywere observed in 31% and 76% of patients in the non-radiotherapy and radiotherapy groups,respectively. Overall survival rates in the patients in the radiotherapy group were 71.5%, 42.3%,and 24.0% at 1, 2, and 3 years, respectively, improved over the non-radiotherapy group rates of59.6%, 26.5%, and 11.1% at 1, 2. and 3 years, respectively. Intrahepatic failure was lower in theradiotherapy group than in the non-radiotherapy group, but the difference was not significant.Side effects from radiotherapy were common, but rarely severe.Conclusions: This retrospective study suggests that the outcome of unresectable hepatocellularcarcinoma can be influenced by radiation therapy, but a prospective randomized trial would benecessary to draw definitive conclusions.Part Ⅲ: A comparison of treatment combinations with and without radiotherapy for thehepatocellular carcinoma with portal vein and/or inferior vena cava tumor thrombusBackground: The incidence of tumor thrombi is higher in patients with HCC. However. TACEand surgical resection are not indicated for HCC with PV trunk occlusion by tumor thrombibecause of a lack, of efficacy and possible complications.Purpose: We evaluated the potential role of external beam radiation therapy (EBRT) in thetreatment of hepatocellular carcinoma (HCC) patients with portal vein (PV) and/or inferior venacava (IVC) tumor thrombi.Methods and Materials: One hundred fifty-eight HCC patients with PV and/or IVC tumorthrombus were reviewed and analyzed by Kaplan-Meier and Cox regression analysis. Forty-fourHCC patients who received local limited EBRT (in addition to other treatment modalities) wereclassified as the EBRT group. The total radiation dosage ranged from 36 to 60 Gy (median 50 Gy), focused on the tumor thrombi. One hundred and fourteen HCC patients who did not receive EBRT were selected from hospitalized HCC patients with PV and/or IVC thrombi in the same period and were classified as the non-EBRT group; the intrahepatic tumors of these patients were treated with transarterial chemoembolization (TACE) or resection based on the patients' status. Parameters observed include survival rates and the tumor thrombus response to EBRT as seen on CT scan or MRI.Results: Out of the 44 patients who received EBRT, 15 (34.1%) showed complete disappearance of tumor thrombi, 5 (11.4%) were in partial remission, 23 (52.3%) were stable in their tumor thrombi, and 1 (2.3%) patient showed disease progression at the end of the study period. The median survival was 8 months, and the 1-year survival rate was 34.8% in the EBRT group. In the non-EBRT group, the median survival and 1-year survival rate were 4 months and 11.4%, respectively. In stepwise multivariate analysis, EBRT showed a strongly protective value (RR = 0.324, P < .001). Survival was not related to intrahepatic tumor status in the non-EBRT patients. However, in the EBRT group, poorer prognosis was significantly related to intrahepatic multifocal or diffusion lesions, and the most common reason for death was liver failure caused by the uncontrolled intrahepatic diseases.Conclusion: Although EBRT is palliative in intent, it is preferred for prolonging survival in the treatment of tumor thrombi. Part Ⅳ: Consideration of the role of radiotherapy for lymph node metastases in patients with HCC —A retrospective analysis for prognostic factors from 125 patients Background: The patients with LN metastasis from HCC have a poor prognosis, even if they undergo radical resection by experienced surgeons. TACE and PEI are not suitable for HCC patients with LN involvement.Purpose: We evaluated the role of radiotherapy for HCC patients with abdominal LN metastasis at our institution in the past 7 years.Patients and Methods: We identified 125 patients with HCC metastasis to regional LNs treated with or without external beam radiation therapy (EBRT) between 1998 and 2004. Clinical characteristics collected included the alpha-fetoprotein (AFP) status, γ-glutamyltransferase (γ-GT), the status of intrahepatic tumors (size, number), previous therapy for the intrahepatic tumors, metastatic LN status (location, number, and size), tumor thrombi, and Child-Pugh classification. Sixty-two patients who received local limited EBRT were classified as the EBRT group. The patients received locoregional LN irradiation. The tumor dose ranged from 40 to 60Gy in daily 2.0-Gy fractions (Fx), five times a week. Sixty-three patients who did not receive EBRT were selected from hospitalized patients in the same period and were classified as the non-EBRT group. Parameters observed include survival rates and the tumor response to EBRT both as demonstrated by clinical symptoms and as seen on CT scan. The Kaplan-Meier method was used to evaluate survival rates, and the Cox regression model was used to identify predictors of outcome.Results: After EBRT, partial response and complete response were observed in 37.1% and 59.7%, respectively. Median survival was 9.4 months (95% CI: 5.8-13.0) for the EBRT group, and 3.3 months (95% CI: 2.7-3.9) for the non-EBRT group (P < 0.001). Multivariate analysis showed that multiple intrahepatic primary tumors, occurrence of tumor thrombi, without therapy for intrahepatic tumors, higher Child-Pugh classification, were related to poorer prognosis in all patients. In the EBRT group, the survival periods decreased as the distance of LN involvement from the liver increased (following the natural flow of lymph) and was also associated with the intrahepatic primary tumor size. Death resulted from LN-related complications was lower in the EBRT group.Conclusion: LN metastasis from HCC is sensitive to EBRT. EBRT with 25 fractions of 2 Gy is an effective palliative treatment for patients with LN from HCC presenting with good performance status and may prolong overall survival. Part Ⅴ: Radiation therapy for adrenal gland metastases from hepatocellular carcinomaBackground: The adrenal gland is a common site of extrahepatic metastases from hepatocellularcarcinoma. However, it has been the subject of few studies, and the optimal treatment remainsunclear. Methods previously tried for the management of adrenal gland metastasis ofhepatocellular carcinoma included surgical resection, transarterial chemoembolization, orpercutaneous ethanol injection, on the basis of case reports. External beam radiation therapy hasseldom been applied for patients with adrenal gland metastases.Purpose: To study the radiation effects on adrenal gland metastases from HCC.Patients and methods: We retrospectively studied 22 patients with adrenal metastases fromhepatocellular carcinoma who were treated with limited-field external beam radiation therapy.The radiation dose to the adrenal lesion ranged from 36 to 54 (median 50) Gy, while theintrahepatic lesions were treated with either surgical resection or transarterialchemoembolization.Results: Among the 14 patients who had pain related to adrenal metastases, 11 (78.6%) patientshad complete pain relief without medication that lasted until death. Two (14.3%) patients had...