Efficacy of stereotactic ablative radiotherapy in patients with oligometastatic hepatocellular carcinoma: A phase II study.

BACKGROUND & AIMS: Stereotactic ablative radiotherapy (SABR) can extend survival and offers the potential for cure in some patients with oligometastatic disease (OMD). However, limited evidence exists regarding its use in oligometastatic hepatocellular carcinoma (HCC). We aimed to prospectively investigate the efficacy and safety of SABR in patients with oligometastatic HCC. METHODS: We enrolled patients with controlled primary HCC and one to five metastatic lesions amenable to SABR. The primary endpoint was treatment efficacy defined as overall survival (OS) and progression-free survival (PFS). The secondary endpoints included time to local progression, objective response rate, disease control rate, toxicities, and quality of life (QOL), assessed using the EORTC QLQ-C30 before, and 0, 1, and 3 months after SABR. RESULTS: Overall, 40 consecutive patients received SABR on 62 lesions between 2021 and 2022. The most common locations for OMD were the lungs (48.4%), lymph nodes (22.6%), and bone (17.7%). After a median follow-up of 15.5 months, the 2-year OS was 80%. Median PFS was 5.3 months, with 1- and 2-year PFS rates of 21.2% and 0%, respectively. A shorter time to OMD from the controlled primary independently correlated with PFS (p = 0.039, hazard ratio 2.127) alongside age, Child-Pugh class, and alpha-fetoprotein (p = 0.002, 0.004, 0.019, respectively). The 2-year time to local progression, objective response rate, and disease control rate were 91.1%, 75.8%, and 98.4%, respectively. Overall, 10% of patients experienced acute toxicity, and 7.5% experienced late toxicity, with no grade 3+ toxicity. All QOL scores remained stable, whereas the patients without systemic treatments had improved insomnia and social functioning scores. CONCLUSIONS: SABR is an effective and feasible option for oligometastatic HCC that leads to excellent local tumor control and improves survival without adversely affecting QOL. IMPACT AND IMPLICATIONS: Stereotactic ablative radiotherapy (SABR) is a non-invasive treatment approach capable of efficiently ablating the target lesion; however, neither the oligometastatic disease concept nor the potential benefits of SABR have been well-defined in hepatocellular carcinoma (HCC). According to this study, SABR is an effective and safe treatment option for oligometastatic HCC, yielding excellent local tumor control and survival improvement without worsening patients' quality of life, regardless of tumor sites. We also demonstrated that patients with a later presentation of OMD from the controlled primary and lower alpha-fetoprotein levels achieved better survival outcomes. This is the first prospective study of SABR in oligometastatic HCC, providing insights for the development of novel strategies to improve oncologic outcomes. CLINICAL TRIAL NUMBER: NCT05173610.

Stereotactic ablative radiotherapy for pulmonary oligometastases from primary hepatocellular carcinoma: a multicenter and retrospective analysis (KROG 17-08).

OBJECTIVE: Hypofractionated radiotherapy has recently been applied to treat pulmonary metastases of hepatocellular carcinoma. However, there is no definite evidence on its safety and efficacy. We evaluate the clinical outcomes of hypofractionated radiotherapy for oligo pulmonary metastases of hepatocellular carcinoma in the multicenter and retrospective study. METHODS: From March 2011 to February 2018, 58 patients with fewer than five pulmonary metastases of hepatocellular carcinoma who underwent hypofractionated radiotherapy in nine tertiary university hospitals were analyzed retrospectively. The primary endpoint was the local control rate. The secondary endpoints were overall survival, progression-free survival, prognostic factors affecting the treatment outcomes and treatment-related side effects. RESULTS: The local tumor response rate including complete and partial response was 77.6% at 3 months after hypofractionated radiotherapy. The median survival and progression-free survival times were 20.9 and 5.3 months, respectively. The 1-year overall survival and progression-free survival rates were 65.5 and 22.4%, respectively. The good treatment response after hypofractionated radiotherapy (P = 0.001), the absence of intrahepatic tumor (P = 0.004) and Child-Pugh class A (P = 0.010) were revealed as significant prognostic factors for overall survival in the multivariate analysis. A progression-free interval of <6 months (P = 0.009) was a negative prognostic factor for overall survival in the multivariate analysis. Of 58 patients, five (8.6%) had grade 2 or higher radiation pneumonitis after hypofractionated radiotherapy. CONCLUSIONS: The favorable local control rate and acceptable toxicity indicate the clinical usefulness of hypofractionated radiotherapy for hepatocellular carcinoma patients who have less than five pulmonary metastases.

Combination therapy with anti-T-cell immunoglobulin and mucin-domain containing molecule 3 and radiation improves antitumor efficacy in murine hepatocellular carcinoma.

BACKGROUND AND AIM: T-cell immunoglobulin and mucin-domain containing molecule 3 (TIM3) has emerged as a promising immune checkpoint inhibitor target; however, immune checkpoint inhibitor monotherapy does not benefit a substantial percentage of patients. Therefore, this study investigated the antitumor effect of anti-TIM3 therapy combined with radiation in a murine hepatocellular carcinoma (HCC) model. METHODS: The effect of radiation on TIM3 expression was determined in murine and human HCC cells using western blotting, immunohistochemistry, and flow cytometry. Tumor growth and survival rate were measured to evaluate the antitumor effect of this combination therapy. Tumor immunological parameters were assessed using flow cytometry and histology. RESULTS: TIM3 was upregulated in tumor-infiltrating CD8+ and CD4+ T cells in radiation-treated HCa-1-implanted mice. Combination treatment significantly delayed tumor growth compared with monotherapy (P < 0.01). Overall survival was improved in the combination group compared with that in the anti-TIM3 or radiation monotherapy groups (median survival time: 52 days vs 26 or 38 days, respectively, P < 0.001). The antitumor effect of the combination treatment was associated with increased apoptosis and decreased proliferation of tumor cells and reinvigorated CD8+ T-cell activation. CD8+ T-cell depletion reversed the antitumor efficacy of the combination treatment. These findings suggest that CD8+ T cells play key roles in the therapeutic effect of the combination treatment. CONCLUSION: Anti-TIM3 and radiation combination therapy significantly improved the antitumor effect in a murine HCC model, as evidenced by inhibited tumor growth and increased overall survival. This approach could be a novel combined immune-radiotherapy strategy for HCC.

Stereotactic body radiation therapy vs. radiofrequency ablation in Asian patients with hepatocellular carcinoma.

BACKGROUND & AIMS: Few studies have been conducted to compare the efficacies of stereotactic body radiation therapy (SBRT) and radiofrequency ablation (RFA). Thus, in this multinational study, we compared the effectiveness of SBRT and RFA in patients with unresectable HCC. METHODS: The retrospective study cohort included 2,064 patients treated in 7 hospitals: 1,568 and 496 in the RFA and SBRT groups, respectively. More than half of the patients (56.5%) developed recurrent tumors, mainly after transarterial chemoembolization (44.8%). Propensity score matching was performed to adjust for clinical factors (n = 313 in each group). RESULTS: At baseline, the SBRT group had unfavorable clinical features compared to the RFA group, including BCLC stage (B-C 65% vs. 16%), tumor size (median 3.0 cm vs. 1.9 cm), and frequent history of liver-directed treatment (81% vs. 49%, all p <0.001). With a median follow-up of 27.7 months, the 3-year cumulative local recurrence rates in the SBRT and RFA groups were 21.2% and 27.9%, respectively (p <0.001). After adjusting for clinical factors, SBRT was related to a significantly lower risk of local recurrence than RFA in both the entire (hazard ratio [HR] 0.45, p <0.001) and matched (HR 0.36, p <0.001) cohorts. In subgroup analysis, SBRT was associated with superior local control in small tumors (≤3 cm) irrespective of location, large tumors located in the subphrenic region, and those that progressed after transarterial chemoembolization. Acute grade ≥3 toxicities occurred in 1.6% and 2.6% of the SBRT and RFA patients, respectively (p = 0.268). CONCLUSIONS: SBRT could be an effective alternative to RFA for unresectable HCC, particularly for larger tumors (>3 cm) in a subphrenic location and tumors that have progressed after transarterial chemoembolization. LAY SUMMARY: It is currently not known what the best treatment option is for patients with unresectable hepatocellular carcinoma. Here, we show that stereotactic body radiation therapy provides better local control than radiofrequency ablation, with comparable toxicities. Stereotactic body radiation therapy appears to be an effective alternative to radiofrequency ablation that should be considered when there is a higher risk of local recurrence or toxicity after radiofrequency ablation.

Dose escalation in radiotherapy for incomplete transarterial chemoembolization of hepatocellular carcinoma.

PURPOSE: To investigate the efficacy of radiation dose escalation in patients with hepatocellular carcinoma (HCC) after incomplete transarterial chemoembolization (TACE). METHODS: This study evaluated retrospective data of 323 HCC patients who received radiotherapy after incomplete TACE from 2001-2016. Radiation dose in biologically effective dose (BED) (α/ß = 10) was categorized as <72 Gy (261 patients) and ≥72 Gy (62 patients). Simultaneous integrated boost-intensity modulated radiation therapy (SIB-IMRT) was used significantly more frequently in the high-dose group (64.5% vs. 12.9%; P < 0.001). Local failure-free rate (LFFR), progression-free rate (PFR), and toxicities were compared between the two groups. Additionally, propensity score matching was performed. RESULTS: Median follow-up time for patients who were alive at the time of analysis was 47 months (range 18-189 months). Median overall survival after radiotherapy was 14 months. In multivariate analysis, BED ≥72 Gy was an independent predictor of favorable LFFR (hazard ratio [HR] 0.32; 95% confidence interval [CI] 0.14-0.72; P = 0.006) and PFR (HR 0.67; 95% CI 0.45-0.98; P = 0.04). In the propensity score-matched cohort (62 pairs), 1­year LFFR (94% vs. 81%; P = 0.002), and 1­year PFR (49% vs. 42%; P = 0.01) were significantly higher in the high-dose group. Treatment-related toxicities were comparable between the high-dose and low-dose groups (classic radiation-induced liver disease: 5.3% [3/57] vs. 13.8% [29/210], P = 0.08; grade 2-4 gastrointestinal bleeding: 3.2% [2/62] vs. 7.3% [19/261], P = 0.39). CONCLUSION: Radiation dose with BED ≥72 Gy improved LFFR and PFR without increasing toxicity. In radiotherapy for incomplete TACE of HCC, dose escalation using SIB-IMRT should be actively considered to improve oncologic outcome.

Prognostic factors and patterns of loco-regional failure in patients with R0 resected gallbladder cancer.

BACKGROUND: In this study, risk factors for loco-regional recurrence in curative R0 resected gallbladder adenocarcinoma were investigated. METHODS: Patients with gallbladder adenocarcinoma with curative R0 resections between 2000 and 2016 were retrospectively reviewed. Loco-regional failure-free survival (LRFFS) and overall survival (OS) were analyzed using the Kaplan-Meier method; prognostic factors were analyzed using the Cox proportional hazards model. Based on the identified risk factors, patients were grouped for further analysis. RESULTS: A total of 272 patients were included for analysis; overall, 5-year LRFFS and OS were 83% and 81%, respectively. On multivariate analysis, 3 risk factors for LRFFS were identified; lymphovascular invasion, T3, and N1, by which patients were grouped; group 1 for 0 factor, group 2 for 1 factor and group 3 for 2 to 3 factors. The 5-year LRFFS in groups 1, 2, and 3 were 94%, 73%, and 40%, and the 5-year OS in groups 1, 2, and 3 were 90%, 75%, and 47%, respectively. LRFFS and OS differed significantly among groups (p < 0.05). CONCLUSION: In patients with R0 resected gallbladder cancer, the presence of >1 risk factor increased the risk of loco-regional recurrence. Additional therapeutic strategy for these patients needs further consideration.

Acute severe lymphopenia by radiotherapy is associated with reduced overall survival in hepatocellular carcinoma.

PURPOSE: Radiotherapy (RT) for peripheral organs can affect circulating lymphocytes and cause lymphopenia. We aimed to investigate RT-related lymphopenia in patients with hepatocellular carcinoma (HCC). METHODS: Medical records of 920 patients who received RT for HCC during 2001-2016 were reviewed. Total lymphocyte count (TLC) were obtained and analyzed for clinical outcome. Acute severe lymphopenia (ASL) was defined as TLC <500/µL within the first 3 months of the start of RT. RESULTS: The median TLCs before and 1 month after the start of RT were 1120 and 310/µl, respectively, and the TLCs did not recover to their initial level after 1 year. Overall, 87.4% of patients developed ASL. The median overall survival was 13.6 and 46.7 months for patients with and without ASL, respectively (p < 0.001). ASL was independently associated with poor overall survival with a hazard ratio (HR) of 1.40; 95% confidence interval (CI), 1.02-1.91 (p = 0.035). In the multivariate analysis, larger planning target volume (HR, 1.02; 95% CI, 1.01-1.03; p < 0.001) and lower baseline TLC (HR, 0.86; 95% CI, 0.82-0.91; p < 0.001) were significantly associated with an increased risk of ASL, while hypofractionation (stereotactic body RT: HR, 0.19; 95% CI, 0.07-0.49; p = 0.001) was significantly associated with a reduced risk of ASL. CONCLUSION: Acute severe lymphopenia after RT was associated with poor overall survival in patients with HCC. Stereotactic body RT may reduce the risk of ASL. Further attention to and research on the cause, prevention, and reversal of this phenomenon are needed.

Clinical safety and efficacy of salvage reirradiation for upper abdominal malignancies.

PURPOSE: Reirradiation has the potential to provide effective local control of upper abdominal malignancies. This study aimed to evaluate the safety and efficacy of reirradiation for upper abdominal malignancies. METHODS: A total of 42 patients with a history of prior radiotherapy (RT) received reirradiation for abdominal malignancies between 2005 and 2017. Each patient's medical records, contours, and dose distribution for both RT courses were reviewed. The median dose of the prior RT was 50.0 Gy (range, 30.0-60.0 Gy) and the median dose of reirradiation was 45.0 Gy (range, 15.0-75.0 Gy). RESULTS: With a median follow-up of 10.9 months, the median infield-failure-free survival (IFFS) rate was 9.2 months. Gross tumor volume (GTV) significantly related to IFFS in both the univariate (p = 0.009) and multivariate analyses (p = 0.024), and patients with a GTV of <60.0 mL had an improved IFFS (p = 0.001). Four patients experienced ≥grade 3 late toxicities. In the retrospective dose reconstruction analysis in these patients, the cumulative dose to the most exposed 2 cc (D2cc) of the duodenum was >60.0 Gy (range, 60.1-73.7 Gy). In the univariate analysis, the D2cc of the duodenum and a preexisting duodenal ulcer identified using endoscopy prior to reirradiation significantly correlated with late severe toxicity (p = 0.021 and 0.017, respectively). CONCLUSIONS: Reirradiation for upper abdominal malignancies could be safely performed for patients without preexisting gastrointestinal morbidity unless the duodenum received excessive radiation doses. Reirradiation could also provide substantial IFFS, especially for patients with a GTV of <60.0 mL.

Downstaging with Localized Concurrent Chemoradiotherapy Can Identify Optimal Surgical Candidates in Hepatocellular Carcinoma with Portal Vein Tumor Thrombus.

BACKGROUND: Locally advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) has a poor oncological outcome. This study evaluated the oncological outcomes and prognostic factors of surgical resection after downstaging with localized concurrent chemoradiotherapy (CCRT) followed by hepatic arterial infusion chemotherapy (HAIC). METHODS: From 2005 to 2014, 354 patients with locally advanced HCC underwent CCRT followed by HAIC. Among these patients, 149 patients with PVTT were analyzed. Exclusion criteria included a total bilirubin ≥ 2 mg/dL, platelet count < 100,000/µL, and indocyanine green retention test (ICG R15) > 20%. During the same study period, 18 patients with PVTT underwent surgical resection as the first treatment. Clinicopathological characteristics and oncological outcomes between groups were compared. RESULTS: Among 98 patients in the CCRT group, 26 patients (26.5%) underwent subsequent curative resection. The median follow-up period was 13 months (range 1-131 months). Disease-specific survival differed significantly between the resection after localized CCRT group and the resection-first group {median 62 months (95% confidence interval [CI] 22.99-101.01) versus 15 months (95% CI 10.84-19.16), respectively; P = 0.006}. Multivariate analyses showed that achievement of radiologic response was an independently good prognostic factor for both disease-specific survival (P = 0.039) and disease-free survival (P = 0.001) CONCLUSIONS: Localized CCRT could be an effective tool for identifying optimal candidates for surgical treatment with favorable tumor biology. Furthermore, with a 26.5% resection rate and 100% response in PVTT for resection after CCRT, our localized CCRT protocol may be ideal for PVTT.

Compensatory hypertrophy of the liver after external beam radiotherapy for primary liver cancer.

PURPOSE: We investigated whether external beam radiotherapy (EBRT) could induce compensatory liver hypertrophy in liver cancers and assessed related clinical factors. METHODS: A total of 82 consecutive patients receiving EBRT for hepatocellular carcinoma (n = 77) or cholangiocarcinoma (n = 5) from April 2012 to June 2014 were recruited and divided into two subgroups according to tumor location in the right or left lobe. The left lateral and right lobes were considered as unirradiated volumes accordingly. Total liver volume (TLV), nontumor liver volume (NLV), left and right lobe whole volume (LLWV and RLWV, respectively), volume of liver irradiated < 30 Gy (V< 30 Gy), Child-Pugh (CPS) score, future liver remnant (FLR) ratio, and percentage of FLR hypertrophy from baseline (%FLR) were assessed. RESULTS: In the right lobe group, %FLR hypertrophy and LLWV increased significantly at all follow-ups (p < 0.001). %FLR hypertrophy steadily increased until the fourth follow-up. Multivariate analysis showed that the factor associated with maximum %FLR hypertrophy was tumor extent (upper or lower lobe vs. both lobes; p = 0.022). Post-RT treatments including transarterial chemoembolization or hepatic arterial infusion chemotherapy were associated with a CPS increase ≥ 2 (p = 0.002). Analysis of the RT only subgroup also showed a significant increase of %FLR until the fourth follow-up (p < 0.001). In the left lobe group, %FLR hypertrophy and RLWV showed no significant changes during follow-up. CONCLUSION: Significant compensatory hypertrophy of the liver was observed, with a steady increase of %FLR hypertrophy until the fourth follow-up (median: 396 days). Locally advanced tumors extending across the upper and lower right lobe were a significant factor for compensating hypertrophy after EBRT.

Improved oncologic outcome with chemoradiotherapy followed by surgery in unresectable intrahepatic cholangiocarcinoma.

PURPOSE: To investigate the ability of chemoradiotherapy (CRT) to down-stage unresectable intrahepatic cholangiocarcinoma (IHCC) to resectable lesions, as well as the factors associated with achieving such down-staging. METHODS: The study cohort comprised 120 patients diagnosed with stage I-IVA IHCC between 2001 and 2012. Of these patients, 56 underwent surgery and 64 received CRT as their initial treatment. The rate of curative resections for patients who received CRT was assessed, and the locoregional failure-free survival (LRFFS) and overall survival (OS) rates of these patients were compared to those of patients who underwent CRT alone. RESULTS: Median follow-up was 36 months. A partial response after CRT was observed in 25% of patients, whereas a biologic response (a >70% decrease of CA19-9) was observed in 35%. Eight patients (12.5%) received curative resection after CRT and showed significantly improved LRFFS and OS compared to those treated with CRT alone (3-year LRFFS: 50 vs. 15.7%, respectively, p = 0.03; 3­year OS: 50 vs. 11.2%, respectively, p = 0.012); these rates were comparable to those of patients who received initial surgery. Factors associated with curative surgery after CRT were gemcitabine administration, higher radiotherapy dose (biological effective dose ≥55 Gy with α/ß = 10), and a >70% reduction of CA19-9. CONCLUSION: Upfront CRT could produce favorable outcomes by converting unresectable lesions to resectable tumors in selected patients. Higher radiotherapy doses and gemcitabine-based chemotherapy yielded a significant reduction of CA19-9 after CRT; patients with these characteristics had a greater chance of curative resection and improved OS.

Risk stratification for locally advanced hepatocellular carcinoma using pretreatment alpha-foetoprotein and 18 F-fluoro-2-deoxyglucose positron emission tomography.

BACKGROUND & AIMS: We investigated the significance of 18 F-fluoro-2-deoxyglucose positron emission tomography (18 F-FDG PET) parameters and alpha-foetoprotein (AFP) levels in patients with locally advanced hepatocellular carcinoma (LA-HCC). METHODS: We retrospectively analysed data of 228 patients with LA-HCC who underwent pretreatment 18 F-FDG PET between January 2003 and December 2013. All patients were treated using liver-directed therapy involving radiotherapy. The maximum standardized uptake values (SUVs) and tumour-to-extratumoural liver SUV ratios were calculated, and pretreatment AFP values were obtained. RESULTS: Patients were divided into high and low maximum SUV (SUVmax) groups according to a SUV cut-off of 4.825 determined via receiver-operating characteristic analysis. High AFP level (>550 ng/mL) and high SUVmax were significant predictors of overall and progression-free survival. Better treatment responses and longer median progression-free and overall survival were observed in the low SUVmax group, compared to the high SUVmax group. Similar results were obtained for SUV ratio-based (cut-off value: 2.355) and AFP-based analyses (cut-off value: 550 ng/mL). Three risk groups were identified using the double biomarkers of SUVmax and AFP value as strong prognosticators predictive of survival outcomes. This risk stratification was identified as a prognosticator of survival outcomes, even after subgroup analyses. Furthermore, in high risk group, significantly high extrahepatic failure was shown while in low risk group, significantly low intrahepatic failure. CONCLUSIONS: Clinical significance of double biomarkers, SUV and AFP, could be translated into risk stratification for LA-HCC. It could be a valuable tool for survival outcome prediction.

Radiotherapeutic strategies for hepatocellular carcinoma with portal vein tumour thrombosis in a hepatitis B endemic area.

BACKGROUND & AIMS: This nationwide, multicenter study investigated treatment outcomes as well as the optimal radiotherapeutic strategy in patients with hepatocellular carcinoma (HCC) and portal vein tumour thrombosis (PVTT). METHODS: We retrospectively reviewed the records of 985 patients who received radiotherapy (RT) for PVTT. The median equivalent RT dose was 48.75 Gy. Combined treatment, defined as liver-directed treatments performed within a month of RT, was administered to 657 patients (66.7%). The PVTT and primary tumour were irradiated in 413 patients (41.9%), and PVTT only was targeted in 572 patients (58.1%). RESULTS: The response rate of the PVTT was 51.8%, and RT responders had a significantly longer survival than non-responders (15.2 vs. 6.9 months). Equivalent RT dose and combined treatment predicted response of PVTT. The median overall survival (OS) was 10.2 months. Multivariate analysis revealed the equivalent RT dose ˃45 Gy and combined treatment as significant positive factors for OS. In the propensity score matching analysis, the combined treatment group had better OS than the no combined treatment group, whereas the OS of the PVTT + primary tumour group did not differ significantly from that of the PVTT only group. CONCLUSION: The equivalent RT dose ˃45 Gy, given in combination with other treatments, provided better PVTT control and OS. The optimal RT volume is suggested for either PVTT + primary or PVTT only. Taken together, multimodal treatment with equivalent RT dose higher than 45 Gy is recommended for patients with HCC and PVTT.

Interobserver variability in gross tumor volume delineation for hepatocellular carcinoma : Results of Korean Radiation Oncology Group 1207 study.

PURPOSE: There has been increasing use of external beam radiotherapy for localized treatment of hepatocellular carcinoma (HCC) with both palliative and curative intent. Quality control of target delineation in primary HCC is essential to deliver adequate doses of radiation to the primary tumor while preserving adjacent healthy organs. We analyzed interobserver variability in gross tumor volume (GTV) delineation for HCC. PATIENTS AND METHODS: Twelve radiation oncologists specializing in liver malignancy participated in a multi-institutional contouring dummy-run study of nine HCC cases and independently delineated GTV on the same set of provided computed tomography images. Quantitative analysis was performed using an expectation maximization algorithm for simultaneous truth and performance level estimation (STAPLE) with kappa statistics calculating agreement between physicians. To quantify the interobserver variability of GTV delineations, the ratio of the actual delineated volume to the estimated consensus volume (STAPLE), the ratio of the common and encompassing volumes, and the coefficient of variation were calculated. RESULTS: The median kappa agreement level was 0.71 (range 0.28-0.86). The ratio of the actual delineated volume to the estimated consensus volume ranged from 0.19 to 1.93 (median 0.94) for all cases. The ratio of the common and encompassing volumes ranged from 0.001 to 0.56 (median 0.25). The coefficient of variation for GTV delineation ranged from 8 to 57 % (median 26 %). CONCLUSION: The interobserver variability in target delineation of HCC GTV in this study is noteworthy. Multi-institution studies involving radiotherapy for HCC require appropriate quality assurance programs for target delineation.

Radiological-pathological correlation study of hepatocellular carcinoma undergoing local chemoradiotherapy and surgery.

BACKGROUND AND AIMS: Optimal response criteria and assessment timing were investigated through radiologic-pathologic correlation in hepatocellular carcinoma (HCC) treated with localized chemoradiotherapy (CRT). METHODS: We reviewed 19 consecutive HCC patients who underwent surgical resection after radiotherapy and concurrent hepatic arterial infusion chemotherapy. Patients who received transarterial chemoembolization before RT or surgery were excluded from evaluation. Tumor diameters and total and enhancing tumor volumes were measured from CT images obtained 1, 3, 6, and 9 months after CRT. Percent changes calculated using size (RECIST and WHO) and enhancement criteria (mRECIST and EASL) were correlated with percent changes in total and enhancing tumor volumes, and with percent viable tumor in surgical specimens. RESULTS: Median time between CRT and resection was 4.1 months (range, 1.5-15.4 months). CR and PR rates were 0 and 68% by RECIST, 0 and 63% by WHO, 53% and 37% by mRECIST, and 53% and 42% by EASL. Pathologic CR (pCR) rate was 52.6%. Radiologic criteria showed strong correlation with tumor volumes at 1 and 3 months after CRT; at 6 months, however, size and enhancement criteria showed strong correlation only with total and enhancing tumor volumes, respectively. Enhancement criteria were better predictors of pathologic response at all times including preoperative evaluation (RECIST: R(2) = 0.303, P = 0.015 and WHO: R(2) = 0.366, P = 0.006 vs. mRECIST: R(2) = 0.760, P < 0.0001 and EASL: R(2) = 0.768, P < 0.0001). Time interval >6 months before resection showed significant correlation with pCR (P = 0.013). CONCLUSIONS: We recommend using enhancement criteria in assessing tumor viability, especially if the tumor was to be resected <6 months after CRT.

Irradiation-induced localization of IL-12-expressing mesenchymal stem cells to enhance the curative effect in murine metastatic hepatoma.

Irradiation in conjunction with gene therapy is considered for efficient cancer treatment. Mesenchymal stem cells (MSCs), due to their irradiation-promotable tumor tropism, are ideal delivery vehicles for gene therapy. In this study, we investigated whether treatment with radiation and interleukin (IL)-12-expressing MSCs (MSCs/IL-12) exerts improved antitumor effects on murine metastatic hepatoma. HCa-I and Hepa 1-6 cells were utilized to generate heterotopic murine hepatoma models. Tumor-bearing mice were treated with irradiation or MSCs/IL-12 alone, or a combination. Monocyte chemoattractant protein-1 (MCP-1/CCL2) expression was assessed in irradiated hepatoma tissues to confirm a chemotactic effect. Combination treatment strategies were established and their therapeutic efficacies were evaluated by monitoring tumor growth, metastasis and survival rate. IL-12 expression was assessed and the apoptotic activity and immunological alterations in the tumor microenvironment were examined. MCP-1/CCL2 expression and localization of MSCs/IL-12 increased in the irradiated murine hepatoma cells. The antitumor effects, including suppression of pulmonary metastasis and survival rate improvements, were increased by the combination treatment with irradiation and MSCs/IL-12. IL-12 expression was increased in tumor cells, causing proliferation of cluster of differentiation 8(+) T-lymphocytes and natural killer cells. The apoptotic activity increased, indicating that the cytotoxicity of immune cells was involved in the antitumor effect of the combined treatment. Treatment with irradiation and MSCs/IL-12 showed effectiveness in treating murine metastatic hepatoma. IL-12-induced proliferation of immune cells played an important role in apoptosis of tumor cells. Our results suggest that treatment with irradiation and MSCs/IL-12 may be a useful strategy for enhancing antitumor activity in metastatic hepatoma.