Comprehensive geriatric assessment predicts radiation-induced acute toxicity in prostate cancer patients.

PURPOSE: The purpose of the present prospective study was to evaluate the significance of geriatric conditions measured by a comprehensive geriatric assessment (GA) for the prediction of the risk of high-grade acute radiation-induced toxicity. METHODS: A total of 314 prostate cancer patients (age ≥ 65 years) undergoing definitive radiotherapy at a tertiary academic center were included. Prior to treatment, patients underwent a GA. High-grade toxicity was defined as acute toxicity grade ≥ 2 according to standard RTOG/EORTC criteria. To analyze the predictive value of the GA, univariable and multivariable logistic regression models were applied. RESULTS: A total of 40 patients (12.7%) developed acute toxicity grade ≥ 2; high grade genitourinary was found in 37 patients (11.8%) and rectal toxicity in 8 patients (2.5%), respectively. Multivariable analysis revealed a significant association of comorbidities with overall toxicity grade ≥ 2 (odds ratio [OR] 2.633, 95% confidence interval [CI] 1.260-5.502; p = 0.010) as well as with high-grade genitourinary and rectal toxicity (OR 2.169, 95%CI1.017-4.625; p = 0.045 and OR 7.220, 95%CI 1.227-42.473; p = 0.029, respectively). Furthermore, the Activities of Daily Living score (OR 0.054, 95%CI 0.004-0.651; p = 0.022), social status (OR 0.159, 95%CI 0.028-0.891; p = 0.036), and polypharmacy (OR 4.618, 95%CI 1.045-20.405; p = 0.044) were identified as independent predictors of rectal toxicity grade ≥ 2. CONCLUSION: Geriatric conditions seem to be predictive of the development of high-grade radiation-induced toxicity in prostate cancer patients treated with definitive radiotherapy.

Stereotactic body radiotherapy of adrenal metastases-A dose-finding study.

Optimal doses for the treatment of adrenal metastases with stereotactic radiotherapy (SBRT) are unknown. We aimed to identify dose-volume cut-points associated with decreased local recurrence rates (LRR). A multicenter database of patients with adrenal metastases of any histology treated with SBRT (biologically effective dose, BED10 ≥50 Gy, ≤12 fractions) was analyzed. Details on dose-volume parameters were required (planning target volume: PTV-D98%, PTV-D50%, PTV-D2%; gross tumor volume: GTV-D50%, GTV-mean). Cut-points for LRR were optimized using the R maxstat package. One hundred and ninety-six patients with 218 lesions were included, the largest histopathological subgroup was adenocarcinoma (n = 101). Cut-point optimization resulted in significant cut-points for PTV-D50% (BED10: 73.2 Gy; P = .003), GTV-D50% (BED10: 74.2 Gy; P = .006), GTV-mean (BED10: 73.0 Gy; P = .007), and PTV-D2% (BED10: 78.0 Gy; P = .02) but not for the PTV-D98% (P = .06). Differences in LRR were clinically relevant (LRR ≥ doubled for cut-points that were not achieved). Further dose-escalation was not associated with further improved LRR. PTV-D50%, GTV-D50%, and GTV-mean cut-points were also associated with significantly improved LRR in the adenocarcinoma subgroup. Separate dose optimizations indicated a lower cut-point for the PTV-D50% (BED10: 69.1 Gy) in adenocarcinoma lesions, other values were similar (<2% difference). Associations of cut-points with overall survival (OS) and progression-free survival were not significant but durable freedom from local recurrence was associated with OS in a landmark model (P < .001). To achieve a significant improvement of LRR for adrenal SBRT, a moderate escalation of PTV-D50% BED10 >73.2 Gy (adenocarcinoma: 69.1 Gy) should be considered.

Repeated SBRT for in- and out-of-field recurrences in the liver.

PURPOSE: To evaluate the feasibility and toxicity profile of repeated stereotactic body radiotherapy (SBRT) for recurrent primary or secondary liver tumors. METHODS: Consecutive patients with primary (hepatocellular carcinoma [HCC] or cholangiocarcinoma [CCC]) or secondary liver cancer (LM), with intrahepatic recurrence or progression after SBRT, underwent re-SBRT in 3 to 12 fractions with a median time of 15 (range 2-66) months between treatments. RESULTS: In all, 24 patients which were previously treated with SBRT (30 lesions) were retreated with SBRT for "in- and out-of-field" recurrences (2nd SBRT: n = 28, 3rd SBRT: n = 2). The median follow-up after re-irradiation was 14 months. The median prescribed dose for the first SBRT was 46.5 (range 33-66 Gy, EQD210 = 70.5) Gy and 48 (range 27-66 Gy, EQD210 = 71) Gy for the re-SBRT. The median mean liver dose (Dmean, liver) was 6 Gy (range 1-25, EQD22 = 7 Gy) for the first SBRT and 10 Gy (range 1-63 Gy, EQD22 = 9 Gy) for the re-SBRT. Of the 30 re-irradiated lesions 6 were re-irradiated in-field resulting in a median EQD22, maximum of 359 (range 120-500) Gy for both treatments, with an α/ß = 2 to account for liver parenchyma. Treatment was well tolerated. Two patients with stent placement before SBRT developed cholangitis 4 and 14 months after re-SBRT. There were no elevations of the serum liver parameters after re-SBRT. One patient developed a grade 3 gastrointestinal bleeding. There was no radiation induced liver disease (RILD) observed. CONCLUSIONS: Repeated liver SBRT is feasible, without excessive liver toxicity, when there is no considerable overlapping with pre-irradiated portions of the stomach or bowel and enough time for the liver to regenerate.

The role of albumin-bilirubin grade and inflammation-based index in patients with hepatocellular carcinoma treated with stereotactic body radiotherapy.

PURPOSE: We evaluated the prognostic accuracy of the albumin-bilirubin (ALBI) grade and the inflammation-based index (IBI) in estimating overall survival (OS) and toxicity in patients with hepatocellular carcinoma (HCC) treated with stereotactic body radiotherapy (SBRT). MATERIALS AND METHODS: Forty patients with 47 HCC lesions with a Barcelona Clinic Liver Cancer (BCLC) classification stage B or C were treated with SBRT in 3-12 fractions. The ALBI grade and the IBI were calculated at different time points (baseline, during, at the end of treatment and at follow-up) and compared with the Child-Pugh (CP) score as well as other patient- and treatment-related parameters, concerning OS and toxicity. RESULTS: The median follow-up was 14.3 months for patients alive. The median OS from SBRT was 10 (95% confidence interval 8.3-11.6) months. The local control at 1 year was 79%. A lower IBI during treatment was associated with better OS (p = 0.034) but not CP and ALBI. Higher C­reactive protein levels as well as higher alpha-fetoprotein concentrations correlated with worse survival (p = 0.001). Both higher ALBI (p = 0.02) and CTP (p = 0.001) at baseline correlated with a higher incidence of acute and late toxicities (CTC ≥2). Neither the mean radiation dose to the liver nor the dose to 700 cc of the liver correlated with the occurrence of toxicities. CONCLUSIONS: In this analysis, a higher ALBI grade as well as a higher CP were predictors of higher incidence of toxicity, whereas a lower IBI during treatment correlated with a better OS. These results should be further evaluated in prospective studies.

Stereotactic body radiotherapy (SBRT) for locally advanced intrahepatic and extrahepatic cholangiocarcinoma.

BACKGROUND: To evaluate the role of ablative radiotherapy doses in the treatment of hilar or intrahepatic cholangiocarcinoma (CCC) using stereotactic body radiotherapy (SBRT). METHODS: Consecutive patients treated from 2007 to 2016 with CCC were evaluated. Local control and toxicities were assessed every 3 months according to the Response Evaluation Criteria In Solid Tumors (RECIST) and the Common Terminology Criteria for Adverse Events v4.0, respectively. Overall survival (OS), local control (LC) and progression free survival were calculated from SBRT. RESULTS: Thirty seven patients with 43 lesions were retrospectively evaluated. The median dose delivered was 45 Gy (range 25-66 Gy) in 3-12 fractions, corresponding to a median equivalent dose in 2 Gy fractions (EQD210) of 56 (range 25-85) Gy. The median follow up was 24 months. The OS at 1 year was 56% with a median OS of 14 (95% CI: 7.8-20.2) months from start of SBRT and 22 (95% CI: 17.5-26.5) months from diagnosis. Eight lesions progressed locally. The local control rate (LC) at 1 year was 78%. The median progression free survival was 9 months (95% CI 2.8-15.2) 21 patients progressed in the liver but out of field and 15 progressed distantly. SBRT was well tolerated. Three patients (9%) developed a Grade III bleeding. Seven patients developed a cholangitis, one due to progression and the other because of a stent dysfunction 2-21(median 8) months from SBRT. CONCLUSION: In patients with locally advanced cholangiocarcinoma, SBRT is a local treatment option with an acceptable toxicity profile which warrants further investigation in prospective trials.

Survival benefit of transarterial chemoembolization in patients with metastatic hepatocellular carcinoma: a single center experience.

BACKGROUND: As prognosis of patients with metastatic hepatocellular carcinoma (HCC) is mainly determined by intrahepatic HCC progression, local treatment with TACE may result in improved OS, although it is not recommended. The purpose of this study was to analyze retrospectively the efficacy of TACE and its impact on OS in patients with metastatic hepatocellular carcinoma (HCC). METHODS: Two hundred and fifteen patients with metastatic HCC who were treated at our Liver Center between 2003 and 2014 were included in this retrospective analysis. Medical records, laboratory parameters and imaging studies were analyzed. Treatment of metastatic HCC and OS were assessed RESULTS: One hundred and two patients (47.4%) did not receive any HCC specific treatment while 48 patients (22.3%) were treated with sorafenib, 42 patients (19.5%) with TACE and 23 patients (10.7%) received treatment with TACE and sorafenib in combination. Survival analyses and Cox regression models revealed that TACE and a combination therapy of TACE and sorafenib were significant prognostic factors in metastatic HCC. However, further analyses revealed that there was no additional prognostic effect of adding sorafenib to TACE treatment in this patient cohort. CONCLUSIONS: In metastatic HCC, treatment of intrahepatic tumor by TACE may be associated with improved survival. These results support the prognostic importance of treating intrahepatic HCC even in patients with metastatic disease. Therefore, we suggest evaluating the technical feasibility of TACE in all metastatic patients.

The Pre-Treatment Platelet-to-Lymphocyte Ratio as a Prognostic Factor for Loco-Regional Control in Locally Advanced Rectal Cancer.

Chronic inflammatory reactions have been proven to represent relevant mechanisms for the development and progression of cancer in numerous tumor entities. There is evidence that the platelet-to-lymphocyte ratio (PLR) is associated with the prognostic outcome. In rectal cancer, the prognostic role of this parameter has not yet been conclusively clarified. The aim of this study was to further clarify the prognostic significance of the pre-treatment PLR in patients with locally advanced rectal cancer (LARC). In the present study, 603 patients with LARC, who were treated with neoadjuvant chemoradiotherapy (nCRT) and subsequent surgical resection between 2004 and 2019, were retrospectively evaluated. The influence of clinico-pathological and laboratory factors on locoregional control (LC), metastasis-free survival (MFS) and overall survival (OS) was investigated. In univariate analyses, high PLR was significantly associated with worse LC (p = 0.017) and OS (p = 0.008). In multivariate analyses, the PLR remained an independent parameter for the LC (HR = 1.005, 95% CI: 1.000-1.009, p = 0.050). Pre-treatment lactate dehydrogenase (LDH) (HR: 1.005 95% CI:1.002-1.008; p = 0.001) and carcinoembryonic antigen (CEA) (HR: 1.006, 95% CI:1.003-1.009; p < 0.001) were independent predictors for MFS; additionally, age (HR: 1.052, 95% CI:1.023-1.081; p < 0.001), LDH (HR: 1.003, 95% CI:1.000-1.007; p = 0.029) and CEA (HR: 1.006, 95% CI:1.003-1.009; p < 0.001) independently predicted OS. Pre-treatment PLR before nCRT is an independent prognostic factor for LC in LARC, which could be used to further individualize tumor treatment.

Stereotactic Body Radiation Therapy as an Alternative Treatment for Patients with Hepatocellular Carcinoma Compared to Sorafenib: A Propensity Score Analysis.

BACKGROUND AND AIMS: Stereotactic body radiation therapy (SBRT) has emerged as a safe and effective treatment for patients with hepatocellular carcinoma (HCC), but its role in patients with advanced HCC is not yet defined. In this study, we aim to assess the efficacy and safety of SBRT in comparison to sorafenib treatment in patients with advanced HCC. METHODS: We included 901 patients treated with sorafenib at six tertiary centers in Europe and Asia and 122 patients treated with SBRT from 13 centers in Germany and Switzerland. Medical records were reviewed including laboratory parameters, treatment characteristics and development of adverse events. Propensity score matching was performed to adjust for differences in baseline characteristics. The primary endpoint was overall survival (OS) and progression-free survival. RESULTS: Median OS of SBRT patients was 18.1 (10.3-25.9) months compared to 8.8 (8.2-9.5) in sorafenib patients. After adjusting for different baseline characteristics, the survival benefit for patients treated with SBRT was still preserved with a median OS of 17.0 (10.8-23.2) months compared to 9.6 (8.6-10.7) months in sorafenib patients. SBRT treatment of intrahepatic lesions in patients with extrahepatic metastases was also associated with improved OS compared to patients treated with sorafenib in the same setting (17.0 vs. 10.0 months, p = 0.012), whereas in patients with portal vein thrombosis there was no survival benefit in patients with SBRT. CONCLUSIONS: In this retrospective comparative study, SBRT showed superior efficacy in HCC patients compared to patients treated with sorafenib.

Correction: Is serum level of CC chemokine ligand 18 a biomarker for the prediction of radiation induced lung toxicity (RILT)?

[This corrects the article DOI: 10.1371/journal.pone.0185350.].

Excellent local control and tolerance profile after stereotactic body radiotherapy of advanced hepatocellular carcinoma.

BACKGROUND: To evaluate the efficacy and toxicity of stereotactic body radiotherapy (SBRT) in the treatment of advanced hepatocellular carcinoma (HCC). MATERIAL AND METHODS: Patients with large HCCs (median diameter 7 cm, IQR 5-10 cm) with a Child-Turcotte-Pugh (CTP) score A (60%) or B (40%) and Barcelona-Clinic Liver Cancer (BCLC) classification stage B or C were treated with 3 to 12 fractions to allow personalized treatment according to the size of the lesions and the proximity of the lesions to the organs at risk aiming to give high biologically equivalent doses assuming an α/ß ratio of 10 Gy for HCC. Primary end points were in-field local control and toxicity assessment. RESULTS: Forty seven patients with 64 lesions were treated with SBRT (median 45 Gy in 3-12 fractions) with a median follow up for patients alive of 19 months. The median biological effective dose was 76 Gy (IQR 62-86 Gy). Tumor vascular thrombosis was present in 28% and an underlying liver disease in 87% (hepatitis B or C in 21%, alcohol related in 51%, nonalcoholic steatohepatitis in 13% of the patients, primary biliary cirrhosis 2%). Eighty three percent received prior and in most cases multiple therapies. Local control at 1 year was 77%. The median overall survival from the start of SBRT was 9 months (95% CI 7.7-10.3). Gastrointestinal toxicities grade ≥ 2 were observed in 3 (6.4%) patients. An increase in CTP score without disease progression was observed in 5 patients, of whom one patient developed a radiation induced liver disease. One patient died due to liver failure 4 months after treatment. CONCLUSION: SBRT is an effective local ablative therapy which leads to high local control rates with moderate toxicity for selected patients with large tumors.

Is serum level of CC chemokine ligand 18 a biomarker for the prediction of radiation induced lung toxicity (RILT)?

The CC chemokine ligand 18 (CCL18) is produced by alveolar macrophages in patients with fibrosing lung disease and its concentration is increased in various fibrotic lung diseases. Furthermore CCL18 is elevated in several malignancies as it is produced by tumor associated macrophages. In this study we aimed to analyze the role of CCL18 as a prognostic biomarker for the development of early radiation induced lung toxicity (RILT), i.e. radiation pneumonitis after thoracic irradiation and its significance in the course of the disease. Sixty seven patients were enrolled prospectively in the study. Patients were treated with irradiation for several thoracic malignancies (lung cancer, esophageal cancer, thymoma), either with conventionally fractionated or hypo-fractionated radiotherapy. The CCL18 serum levels were quantified with ELISA (enzyme-linked immunosorbent assay) at predefined time points: before, during and at the end of treatment as well as in the first and second follow-up. Treatment parameters and functional tests were also correlated with the development of RILT.Fifty three patients were evaluable for this study. Twenty one patients (39%) developed radiologic signs of RILT Grade >1 but only three of them (5.6%) developed clinical symptoms (Grade 2). We could not find any association between the different CCL18 concentrations and a higher incidence of RILT. Statistical significant factors were the planning target volume (odds ratio OR: 1.003, p = 0.010), the volume of the lung receiving > 20 Gy (OR: 1.132 p = 0.004) and age (OR: 0.917, p = 0.008). There was no association between serial CCL18 concentrations with tumor response and overall survival.In our study the dosimetric parameters remained the most potent predictors of RILT. Further studies are needed in order to estimate the role of CCL18 in the development of early RILT.