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This systematic review and meta-analysis reports on outcomes and hepatic toxicity rates after stereotactic body radiation therapy (SBRT) for liver-confined hepatocellular carcinoma (HCC) and presents consensus guidelines regarding appropriate patient management. Using the Preferred Reporting Items for Systemic Review and Meta-Analyses guidelines, a systematic review was performed from articles reporting outcomes at ≥5 years published before October 2022 from the Embase, MEDLINE, Cochrane, and Scopus databases with the following search terms: ("stereotactic body radiotherapy" OR "SBRT" OR "SABR" OR "stereotactic ablative radiotherapy") AND ("hepatocellular carcinoma" OR "HCC"). An aggregated data meta-analysis was conducted to assess overall survival (OS) and local control (LC) using weighted random effects models. In addition, individual patient data analyses incorporating data from 6 institutions were conducted as their own subgroup analyses. Seventeen observational studies, comprising 1889 patients with HCC treated with ≤9 SBRT fractions, between 2003 and 2019, were included in the aggregated data meta-analysis. The 3- and 5-year OS rates after SBRT were 57% (95% confidence interval [CI], 47%-66%) and 40% (95% CI, 29%-51%), respectively. The 3- and 5-year LC rates after SBRT were 84% (95% CI, 77%-90%) and 82% (95% CI, 74%-88%), respectively. Tumor size was the only prognostic factor for LC. Tumor size and region were significantly associated with OS. Five-year LC and OS rates of 79% (95% CI, 0.74-0.84) and 25% (95% CI, 0.20-0.30), respectively, were observed in the individual patient data analyses. Factors prognostic for improved OS were tumor size <3 cm, Eastern region, Child-Pugh score ≤B7, and the Barcelona Clinic Liver Cancer stage of 0 and A. The incidence of severe hepatic toxicity varied according to the criteria applied. SBRT is an effective treatment modality for patients with HCC with mature follow-up. Clinical practice guidelines were developed on behalf of the International Stereotactic Radiosurgery Society (ISRS)., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Stereotactic radiotherapy is a fundamental change from the conventional fractionated radiotherapy and represents a new therapeutic indication. Stereotactic radiotherapy is now a standard of care for inoperable patients or patients who refuse surgery. The results are encouraging with local control and survival rates very high in selected populations. The rate of late toxicity remains acceptable. Good tolerability makes it appropriate even for elderly and frail patients. In these fragile patients or in certain specific clinical situations, different surgical, radiotherapy or interventional radiology attitudes can be discussed on a case-by-case basis. These situations are considered in this article for the pulmonary, hepatic and prostatic localizations., (Copyright © 2020 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

Purpose: Liver transplantation is the standard definitive treatment for nonmetastatic hepatocellular carcinoma (HCC). However, less than 5% of patients are ultimately candidates as a result of frequent comorbidities and graft shortage. The aim of this study was to evaluate stereotactic body radiation therapy (SBRT) as an ablative treatment for inoperable HCC., Methods and Materials: A prospective phase 2 trial included newly diagnosed single HCC lesions that were without extrahepatic extension and that were deemed unsuitable for standard locoregional therapies, with a tumor size ranging from 1 to 6 cm. The SBRT dose was 45 Gy in 3 fractions. Primary endpoint was the local control of irradiated HCC at 18 months, defined by Response Evaluation Criteria in Solid Tumors., Results: Forty-three patients were treated and evaluable. Median follow-up was 4.0 years (range, 1.2-4.6 years). All 43 patients had cirrhosis; 37 (88%) were Child-Pugh grade A and 5 (12%) grade B (1 missing data). No patients had received prior local treatment. Thirteen patients (31%) presented grade ≥3 acute adverse events, including 8 patients with an abnormality of the liver function tests (19%). Three patients (10%) experienced a decline in Child-Pugh at 3 months post-SBRT. The 18-month local control rate was 98% (95% confidence interval, 85%-99%). The 18-month overall survival rate was 72% (range, 56%-83%). Median overall survival was 3.5 years., Conclusions: Local control and overall survival after SBRT for untreated solitary HCC were excellent despite candidates being unfit for transplantation, resection, ablation, or embolization treatments. SBRT should be considered as a bridge to transplant or as definitive therapy for those ineligible for transplant., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background and Purpose: The TRENDY trial is an international multi-center phase-II study, randomizing hepatocellular carcinoma (HCC) patients between transarterial chemoembolization (TACE) and stereotactic body radiation therapy (SBRT) with a target dose of 48-54 Gy in six fractions. The radiotherapy quality assurance (QA) program, including prospective plan feedback based on automated treatment planning, is described and results are reported., Materials and Methods: Scans of a single patient were used as a benchmark case. Contours submitted by nine participating centers were compared with reference contours. The subsequent planning round was based on a single set of contours. A total of 20 plans from participating centers, including 12 from the benchmark case, 5 from a clinical pilot and 3 from the first study patients, were compared to automatically generated VMAT plans., Results: For the submitted liver contours, Dice Similarity Coefficients (DSC) with the reference delineation ranged from 0.925 to 0.954. For the GTV, the DSC varied between 0.721 and 0.876. For the 12 plans on the benchmark case, healthy liver normal-tissue complication probabilities (NTCPs) ranged from 0.2% to 22.2% with little correlation between NCTP and PTV-D95% (R 2  < 0.3). Four protocol deviations were detected in the set of 20 treatment plans. Comparison with co-planar autoVMAT QA plans revealed these were due to too high target dose and suboptimal planning. Overall, autoVMAT resulted in an average liver NTCP reduction of 2.2 percent point (range: 16.2 percent point to -1.8 percent point, p = 0.03), and lower doses to the healthy liver (p < 0.01) and gastrointestinal organs at risk (p < 0.001)., Conclusions: Delineation variation resulted in feedback to participating centers. Automated treatment planning can play an important role in clinical trials for prospective plan QA as suboptimal plans were detected., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Purposes: Early biomarkers of tumour response are needed to discriminate between responders and non-responders to radiotherapy. We evaluated the ability of ceramide, a bioactive sphingolipid, to predict tumour sensitivity in patients treated by hypofractionated stereotactic body radiation therapy (SBRT) combined with irinotecan chemotherapy., Materials and Methods: Plasma levels of total ceramide and of its subspecies were measured before and during treatment in 35 patients with liver and lung oligometastases of colorectal cancer included in a phase II trial. Cer levels were quantified by LC-ESI-MS/MS and compared to tumour volume response evaluated one year later by CT-scan., Results: Pretreatment plasma ceramide levels were not indicative of tumour response. Nevertheless, the levels of total ceramide and of its 4 main subspecies were significantly higher at days 3 and 10 of treatment in objective responders than in non-responders. According to Kaplan-Meier curves, almost complete tumour control was achieved at 1year in patients with increased total ceramide levels whereas 50% of patients with decreased levels experienced an increase in tumour volume., Conclusions: Total plasma ceramide is a promising biomarker of tumour response to SBRT combined with irinotecan that should enable to segregate patients with high risk of tumour escape., (Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Objective: The Response Evaluation Criteria in Solid Tumors (RECIST) can have limitations when used to evaluate local treatments for cancer, especially for liver malignancies treated by stereotactic body radiation therapy (SBRT). The aim of this study was to validate the relationship between the occurrence of lobulated enhancement (LE) and local relapse and to evaluate the utility of this relationship for predicting local progression., Patients and Methods: Imaging data of 59 lesions in 46 patients, including 281 computed tomographic (CT) scans, were retrospectively and blindly reviewed by 3 radiologists. One radiologist measured the lesion size, for each CT and overall, to classify responses using RECIST threshold criteria. The second studied LE occurrence. A third radiologist was later included and studied LE occurrence to evaluate the interobserver consistency for LE evaluation., Results: The mean duration of follow-up was 13.6 months. LE was observed in 16 of 18 progressive lesions, occurring before size-based progression in 50% of cases, and the median delay of LE detection was 3.2 months. The sensitivity of LE to predict progression was 89%, and its specificity was 100%. The positive predictive value was 100%, the negative predictive value was 95.3%, and the overall accuracy was 97%. The probability of local progression-free survival at 12 months was significantly higher for lesions without LE compared with all lesions: 0.80 (CI 95%: 0.65-0.89) versus 0.69 (CI 95%: 0.54-0.80), respectively. The overall concordance rate between the 2 readers of LE was 97.9%., Conclusion: Response assessment of liver metastases treated by SBRT can be improved by including LE. This study demonstrates the diagnostic and predictive utility of LE for assessing local progression at a size still eligible for local salvage treatment., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To report experience with fiducial marker insertion and describe an advantageous, novel technique for fiducial placement in the liver for stereotactic body radiation therapy with respiratory tracking., Methods and Materials: We implanted 1444 fiducials (single: 834; linked: 610) in 328 patients with 424 hepatic lesions. Two methods of implantation were compared: the standard method (631 single fiducials) performed on 153 patients from May 2007 to May 2010, and the cube method (813 fiducials: 610 linked/203 single) applied to 175 patients from April 2010 to March 2013. The standard method involved implanting a single marker at a time. The novel technique entailed implanting 2 pairs of linked markers when possible in a way to occupy the perpendicular edges of a cube containing the tumor inside., Results: Mean duration of the cube method was shorter than the standard method (46 vs 61 minutes; P<.0001). Median numbers of skin and subcapsular entries were significantly smaller with the cube method (2 vs 4, P<.0001, and 2 vs 4, P<.0001, respectively). The rate of overall complications (total, major, and minor) was significantly lower in the cube method group compared with the standard method group (5.7% vs 13.7%; P=.013). Major complications occurred while using single markers only. The success rate was 98.9% for the cube method and 99.3% for the standard method., Conclusions: We propose a new technique of hepatic fiducial implantation that makes use of linked fiducials and involves fewer skin entries and shorter time of implantation. The technique is less complication-prone and is migration-resistant., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Introduction: The last years are marked by the emergence of new molecules for the treatment of metastatic cutaneous melanoma with a significant benefit on the survival. Besides, some techniques are in development for the loco-regional treatment of the metastatic sites, bringing new therapeutic perspectives. However, their respective use and place in the therapeutic strategy are debated by healthcare professionals., Objective: The French National Cancer Institute leads a national clinical practice guidelines project since 2008. It realized a review of these modalities of treatment and developed recommendations., Methods: The clinical practice guidelines development process is based on systematic literature review and critical appraisal by a multidisciplinary expert workgroup. The recommendations are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines are reviewed by independent practitioners in cancer care delivery., Results: This article presents recommendations for loco-regional treatments of the pulmonary, bone, cutaneous, hepatic and digestive metastatic sites for patients with pauci-metastatic cutaneous melanoma.

Purpose: Stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC) has been evaluated in several recent studies. The CyberKnife(®) is an SBRT system that allows for real-time tracking of the tumor. The purpose of this study was to evaluate the prognostic factors for local control and overall survival following this treatment., Patients and Methods: 75 patients with 96 liver-confined HCC were treated with SBRT at the Oscar Lambret Comprehensive Cancer Center. Fiducials were implanted in the liver before treatment and were used as markers to track the lesion's movement. Treatment response was scored according to RECIST v1.1. Local control and overall survival were calculated using the Kaplan and Meier method. A stepwise multivariate analysis (Cox regression) of prognostic factors was performed for local control and overall survival., Results: There were 67 patients with Child-Turcotte-Pugh (CTP) Class A and eight patients with CTP Class B. Treatment was administered in three sessions. A total dose of 40-45 Gy to the 80% isodose line was delivered. The median follow-up was 10 months (range, 3-49 months). The local control rate was 89.8% at 1 and 2 years. Overall survival was 78.5% and 50.4% at 1 and 2 years, respectively. Toxicity mainly consisted of grade 1 and grade 2 events. Higher alpha-fetoprotein (aFP) levels were associated with less favorable local control (HR=1.001; 95% CI [1.000, 1.002]; p=0.0063). A higher dose was associated with better local control (HR=0.866; 95% CI [0.753, 0.996]; p=0.0441). A Child-Pugh score higher than 5 was associated with worse overall survival (HR= 3.413; 95% CI [1.235, 9.435]; p=0.018)., Conclusion: SBRT affords good local tumor control and higher overall survival rates than other historical controls (best supportive care or sorafenib). High aFP levels were associated with lesser local control, but a higher treatment dose improved local control.

Objective: To describe post-CyberKnife® imaging characteristics of liver metastases as an aid in assessing response to treatment, and a novel set of combined criteria (CC) as an alternative to response according to change in size (RECIST)., Subjects and Methods: Imaging data and medical records of 28 patients with 40 liver metastases treated with stereotactic body radiotherapy (SBRT) were reviewed. Tumor size, CT attenuation coefficient, and contrast enhancement of lesions were evaluated up to 2 years post SBRT. Rates of local control, progression-free survival, time to progression, and overall survival according to RECIST and CC were estimated., Results: Complete response (CR) was 3.6% (95% CI: 0.1-18%) and 18% (95% CI: 6-37%) according to RECIST and combined criteria, respectively. Two progressive diseases and two partial responses according to RECIST were classified as CR by the combined criteria and one stable response according to RECIST was classified as progressive by CC (Stuart-Maxwell test, p = 0.012). The disease control rate was 60.7% (95% CI: 41-78%) by RECIST and 64% (95% CI: 44%-81%) by CC., Conclusion: Use of response criteria based on change in size alone in the interpretation of liver response to SBRT may be inadequate. We propose a simple algorithm with a combination of criteria to better assess tumor response. Further studies are needed to confirm their validity.

Purpose: Robotic Stereotactic Body Radiation Therapy with real-time tumor tracking has shown encouraging results for hepatic tumors with good efficacy and low toxicity. We studied the factors associated with local control of primary or secondary hepatic lesions post-SBRT., Methods and Materials: Since 2007, 153 stereotactic liver treatments were administered to 120 patients using the CyberKnife® System. Ninety-nine liver metastases (72 patients), 48 hepatocellular carcinomas (42 patients), and six cholangiocarcinomas were treated. On average, three to four sessions were delivered over 12 days. Twenty-seven to 45 Gy was prescribed to the 80% isodose line. Margins consisted of 5 to 10 mm for clinical target volume (CTV) and 3 mm for planning target volume (PTV)., Results: Median size was 33 mm (range, 5-112 mm). Median gross tumor volume (GTV) was 32.38 cm3 (range, 0.2-499.5 cm3). Median total dose was 45 Gy in three fractions. Median minimum dose was 27 Gy in three fractions. With a median follow-up of 15.0 months, local control rates at one and two years were 84% and 74.6%, respectively. The factors associated with better local control were lesion size < 50 mm (p = 0.019), GTV volume (p < 0.05), PTV volume (p < 0.01) and two treatment factors: a total dose of 45 Gy and a dose-per-fraction of 15 Gy (p = 0.019)., Conclusions: Dose, tumor diameter and volume are prognostic factors for local control when a stereotactic radiation therapy for hepatic lesions is considered. These results should be considered in order to obtain a maximum therapeutic efficacy.

Purpose: The purpose of this study is to evaluate the feasibility, efficacy and toxicity of SBRT for treatment of unresectable hepatic or lung metastases regardless of their primary tumor site for patients who received prior systemic chemotherapy., Methods and Materials: Between July 2007 and June 2010, 90 patients were treated with the CyberKnife® SBRT system for hepatic or pulmonary metastatic lesions. Medical records were retrospectively reviewed. The endpoints of this study were local control, overall survival (OS), disease-free survival (DFS), local relapse free-survival (LRFS), and treatment toxicity., Results: A total of 113 liver and 26 lung metastatic lesions in 52 men (58%) and 38 women (42%) were treated. Median follow-up was 17 months. Median age at treatment was 65 years (range, 23-84 years). Primary cancers were 63 GI, three lung, eight breast, four melanoma, three neuro-endocrine tumors, and three sarcomas. Median diameter of the lesions was 28 mm (range, 7-110 mm) for liver and 12.5 mm (range, 5-63.5 mm) for lung. Local control rates at 1 and 2 years were 84.5% and 66.1%, respectively. Two-year overall survival rate was 70% (95% CI: 55-81%). The 1 and 2-year disease-free survival rates were 27% (95% CI: 18-37%) and 10% (95% CI: 4-20%), respectively. Median duration of disease-free survival was 6.7 months (95% CI: 5.1-9.5 months). Observed toxicities included grade 1-3 acute toxicities. One grade 3 and no grade 4 toxicity were reported., Conclusion: High-dose SBRT for metastatic lesions is both feasible and effective with high local control rates. Overall survival is comparable with other available techniques. Treatment is well tolerated with low toxicity rates. It could represent an interesting treatment option for oligometastatic patients not amenable to surgery, even when patients had been pre-treated with chemotherapy., Summary: Stereotactic body radiotherapy (SBRT) has previously been successfully used in the treatment of metastatic lesions. It could be considered as a curative option for oligometastatic patients. This retrospective study involved 90 patients, designed to test potential effectiveness of SBRT in the treatment of oligometastases irrespective of primary. Results suggest SBRT could be an effective treatment extending patients' life span. This treatment appears to be more effective when used prior to multiple systemic treatment regimens.

Purpose: The CyberKnife(®) system is a recent radiation therapy technique that allows treatment of liver lesions with real-time tracking. Because of its high precision, the dose administered to the tumor can be increased. We report Oscar-Lambret Cancer Centre experience in the treatment of primary and secondary liver lesions., Patients and Methods: It is a retrospective study analyzing all the patients who have been treated for their liver lesions since July 2007. A hundred and twenty patients have been treated: 42 for hepatocellular carcinoma, 72 for liver metastases and six for cholangiocarcinoma. Gold seeds need to be implanted before the treatment and are used as markers to follow the movement of the lesion due to respiration. On average, the treatment is administered in three to four sessions over 12 days. A total dose of 40 to 45 Gy at the 80% isodose is delivered. Local control and overall survival analysis with Log-rank is performed for each type of lesion., Results: Treatment tolerance is good. The most common toxicities are of digestive type, pain and asthenia. Six gastro-duodenal ulcers and two radiation-induced liver disease (RILD) were observed. At a median follow-up of 15 months, the local control rate is respectively of 80.4% and 72.5% at 1 and 2 years. Overall survival is 84.6 and 58.3% at 1 and 2 years. The local control is significantly better for the hepatocellular carcinoma and overall survival is significantly better for liver metastases (P<0.05). The local control rate and overall survival at 1 year for cholangiocarcinoma is 100%., Conclusion: CyberKnife(®) is a promising technique, well tolerated, with tumoral local control rates comparable to other techniques. Its advantage is that it is very minimally invasive delivered as an outpatient procedure in a frail population of patient (disease, age)., (Copyright © 2011 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

Purpose: To evaluate the outcome, tolerance, and toxicity of stereotactic body radiotherapy, using image-guided robotic radiation delivery, for the treatment of patients with unresectable liver metastases., Methods and Material: Patients were treated with real-time respiratory tracking between July 2007 and April 2009. Their records were retrospectively reviewed. Metastases from colorectal carcinoma and other primaries were not necessarily confined to liver. Toxicity was evaluated using National Cancer Institute Common Criteria for Adverse Events version 3.0., Results: Forty-two patients with 62 metastases were treated with two dose levels of 40 Gy in four Dose per Fraction (23) and 45 Gy in three Dose per Fraction (13). Median follow-up was 14.3 months (range, 3-23 months). Actuarial local control for 1 and 2 years was 90% and 86%, respectively. At last follow-up, 41 (66%) complete responses and eight (13%) partial responses were observed. Five lesions were stable. Nine lesions (13%) were locally progressed. Overall survival was 94% at 1 year and 48% at 2 years. The most common toxicity was Grade 1 or 2 nausea. One patient experienced Grade 3 epidermitis. The dose level did not significantly contribute to the outcome, toxicity, or survival., Conclusion: Image-guided robotic stereotactic body radiation therapy is feasible, safe, and effective, with encouraging local control. It provides a strong alternative for patients who cannot undergo surgery., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Stereotactic radiotherapy (SRT) offers a treatment option for hepatocellular carcinoma (HCC) patients that are not eligible for surgery, embolization, chemotherapy, or radiofrequency ablation. We have evaluated the feasibility, tolerance and toxicity of SRT for 25 HCC patients who were not eligible for these other modalities. The patients (6 women and 19 men) were treated with CyberKnife stereotactic radiotherapy using respiratory motion tracking. All patients had liver cirrhosis with an Eastern Cooperative Oncology Group (ECOG) performance score of less than 2 and pre-treatment Child scores ranging from A5 to B9. A total dose of 45 Gy in three fractions of 15 Gy each was prescribed to the 80% isodose line (95% of the PTV received 45 Gy) and delivered to the target volume over 10 to 12 days. Overall the treatment was well tolerated with two Grade 3 acute toxicities and no acute Grade 4 toxicities. Late toxicity was minimal with all observed late toxicities occurring within the first six months of follow-up. Three hepatic recurrences at a distance from the target and one metastasis were observed. The actuarial 1- and 2-year local control rate was 95% (95% CI: 69-95%). At a median overall follow-up of 12,7 months (range, 1-24 months), six of the twenty-five (24%) patients have died. Overall actuarial survival at 1- and 2-years was 79% (95% CI: 52-92%) and 52% (95% CI: 19-78%), respectively. Our results suggest promising therapeutic efficacy and good clinical tolerance to CyberKnife SRT treatment for HCC patients not eligible for other treatment modalities.

In June 2007, the CyberKnife has been implemented at Centre Oscar-Lambret in Lille. The program has been developed around specific clinical indications: head and neck reirradiation, liver. Early results are presented. The system includes several way of repositioning fixed targets and tracking moving targets with breathing. With each way, there is a dedicated tool for the quality control.