Transarterial Chemoembolization With Drug-Eluting Beads Versus Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma: Outcomes From a Multicenter, Randomized, Phase 2 Trial (the TRENDY Trial).

PURPOSE: To compare transarterial chemoembolization delivered with drug eluting beads (TACE-DEB) with stereotactioc body radiation therapy (SBRT) in patients with hepatocellular carcinoma (HCC) in a multicenter randomized trial. METHODS AND MATERIALS: Patients were included if they were eligible for TACE. They could also be recruited if they required treatment prior to liver transplantation. A maximum of four TACE-DEB procedures and ablation after incomplete TACE-DEB were both allowed. SBRT was delivered in six fractions of 8-9Gy. Primary end point was time to progression (TTP). Secondary endpoints were local control (LC), overall survival (OS), response rate (RR), toxicity, and quality of life (QoL). The calculated sample size was 100 patients. RESULTS: Between May 2015 and April 2020, 30 patients were randomized to the study. Due to slow accrual the trial was closed prematurely. Two patients in the SBRT arm were considered ineligible leaving 16 patients in the TACE-DEB arm and 12 in the SBRT arm. Median follow-up was 28.1 months. Median TTP was 12 months for TACEDEB and 19 months for SBRT (p=0.15). Median LC was 12 months for TACE-DEB and >40 months (not reached) for SBRT (p=0.075). Median OS was 36.8 months for TACEDEB and 44.1 months for SBRT (p=0.36). A post-hoc analysis showed 100% for SBRT 1- and 2-year LC, and 54.4% and 43.6% for TACE-DEB (p=0.019). Both treatments resulted in RR>80%. Three episodes of possibly related toxicity grade ≥3 were observed after TACE-DEB. No episodes were observed after SBRT. QoL remained stable after both treatment arms. CONCLUSIONS: In this trial, TTP after TACE-DEB was not significantly improved by SBRT, while SBRT showed higher local antitumoral activity than TACE-DEB, without detrimental effects on OS, toxicity and QoL. To overcome poor accrual in randomized trials that include SBRT, and to generate evidence for including SBRT in treatment guidelines, international cooperation is needed.

Assessing the impact of adaptations to the clinical workflow in radiotherapy using transit in vivo dosimetry.

Background and Purpose: Currently in-vivo dosimetry (IVD) is primarily used to identify individual patient errors in radiotherapy. This study investigated possible correlations of observed trends in transit IVD results, with adaptations to the clinical workflow, aiming to demonstrate the possibility of using the bulk data for continuous quality improvement. Materials and methods: In total 84,100 transit IVD measurements were analyzed of all patients treated between 2018 and 2022, divided into four yearly periods. Failed measurements (FM) were divided per pathology and into four categories of causes of failure: technical, planning and positioning problems, and anatomic changes. Results: The number of FM due to patient related problems gradually decreased from 9.5% to 6.6%, 6.1% and 5.6% over the study period. FM attributed to positioning problems decreased from 10.0% to 4.9% in boost breast cancer patients after introduction of extra imaging, from 9.1% to 3.9% in Head&Neck patients following education of radiation therapists on positioning of patients' shoulders, from 6.1% to 2.8% in breast cancer patients after introduction of ultrahypofractionated breast radiotherapy with daily online pre-treatment imaging and from 11.2% to 4.3% in extremities following introduction of immobilization with calculated couch parameters and a Surface Guided Radiation Therapy solution. FM related to anatomic changes decreased from 10.2% to 4.0% in rectum patients and from 6.7% to 3.3% in prostate patients following more patient education from dieticians. Conclusions: Our study suggests that IVD can be a powerful tool to assess the impact of adaptations to the clinical workflow and its use for continuous quality improvement.

Oncological outcome, postoperative complications, and mammographic changes after intraoperative radiotherapy with electrons (IOERT) as a boost in a large single-institution cohort of breast cancer patients.

Advantages of using intraoperative radiotherapy with electrons (IOERT) as a boosting modality in breast-conserving therapy include the direct visualization of the tumor bed, a reduced skin dose, and patient convenience. We report oncological outcome, postoperative complication rate, and mammographic changes on follow-up imaging in women treated at our institution with IOERT as a boost modality in breast-conserving therapy for early-stage breast carcinoma. Between January 2007 and June 2018, 763 consecutive patients were enrolled. During breast-conserving surgery, an IOERT boost of 9 Gy was applied, followed by whole breast irradiation (WBI). At a median follow-up of 62.2 months (range: 0.5-135), 13 in-breast recurrences were observed, yielding a local tumor control rate of 98.4% at 5 years. In multivariable analysis, high tumor grading was predictive for local recurrence (HR = 5.6; 95%CI: 1.19-26.2). A total of 27 (3.5%) patients developed any kind of postoperative complication. None of the tumor characteristics nor any of the IOERT technical parameters were predictive for development of a postoperative complication. On follow-up imaging, 145 patients with mammographic changes BIRADS score ≥3 were found of which 50.3% required a biopsy. Only 17 patients had positive biopsies; none of the IOERT parameters were predictive for false-positive imaging. A 9 Gy IOERT boost combined with postoperative WBI provided outstanding local control rates, was well-tolerated, with limited postoperative complications. However, radiologists must be aware of a presumable higher prevalence of mammographic changes after IORT as a boost.

Evaluation of automated pre-treatment and transit in-vivo dosimetry in radiotherapy using empirically determined parameters.

BACKGROUND AND PURPOSE: First reports on clinical use of commercially automated systems for Electronic Portal Imaging Device (EPID)-based dosimetry in radiotherapy showed the capability to detect important changes in patient setup, anatomy and external device position. For this study, results for more than 3000 patients, for both pre-treatment verification and in-vivo transit dosimetry were analyzed. MATERIALS AND METHODS: For all Volumetric Modulated Arc Therapy (VMAT) plans, pre-treatment quality assurance (QA) with EPID images was performed. In-vivo dosimetry using transit EPID images was analyzed, including causes and actions for failed fractions for all patients receiving photon treatment (2018-2019). In total 3136 and 32,632 fractions were analyzed with pre-treatment and transit images respectively. Parameters for gamma analysis were empirically determined, balancing the rate between detection of clinically relevant problems and the number of false positive results. RESULTS: Pre-treatment and in-vivo results depended on machine type. Causes for failed in-vivo analysis included deviations in patient positioning (32%) and anatomy change (28%). In addition, errors in planning, imaging, treatment delivery, simulation, breath hold and with immobilization devices were detected. Actions for failed fractions were mostly to repeat the measurement while taking extra care in positioning (54%) and to intensify imaging procedures (14%). Four percent initiated plan adjustments, showing the potential of the system as a basis for adaptive planning. CONCLUSIONS: EPID-based pre-treatment and in-vivo transit dosimetry using a commercially available automated system efficiently revealed a wide variety of deviations and showed potential to serve as a basis for adaptive planning.

The TRENDY multi-center randomized trial on hepatocellular carcinoma - Trial QA including automated treatment planning and benchmark-case results.

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% (R2 < 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.

Do refined consensus guidelines improve the uniformity of clinical target volume delineation for rectal cancer? Results of a national review project.

In a previous national central review project, 74% of the rectal cancer clinical target volumes (CTVs) needed a modification. In a follow-up initiative, we evaluated whether the use of refined international consensus guidelines improves the uniformity of CTV delineation in clinical practice.

Apparent diffusion coefficient measurements as very early predictive markers of response to chemotherapy in hepatic metastasis: a preliminary investigation of reproducibility and diagnostic value.

PURPOSE: To evaluate the reproducibility and diagnostic value of apparent diffusion coefficient (ADC) as an early predictor of response to chemotherapy of liver metastasis in routine clinical practice. MATERIALS AND METHODS: A prospective study of 20 patients with histologically proven primary tumors with liver metastases was undertaken. Diffusion weighted MRI was performed twice before and 12-14 days after the start of treatment. Absolute and liver normalized ADC values were calculated. Bland Altman statistics were used to assess the reproducibility of ADC change for predicting lesion response as measured by RECIST. RESULTS: Nineteen of 31 metastases responded. Significant increases in absolute and normalized ADC values were found in responding (mean +208.7 × 10(-6) m(2)/s and +18% respectively, both P < 0.001) compared with nonresponding lesions (mean +98.6 × 10(-6) m(2)/s and 2%, respectively, P = 0.09 and 0.519). Reproducibility was better using normalized ADC compared with absolute ADC values (within patient coefficient of variability 8.0% and 10.1%, respectively). Using the repeatability threshold of ±22.3% for normalized ADC, only 8 of 19 responding and all but one nonresponding lesions could be prospectively detected. CONCLUSION: Increases in ADC values in responding liver metastases occurred within days after the start of chemotherapy but were of smaller magnitude than the variability of ADC measurement. These preliminary data suggest that the presently used technique is not reliable enough to predict final response at such an early time point in individual lesions.

Serum interleukin 6, plasma VEGF, serum VEGF, and VEGF platelet load in breast cancer patients.

Serum and plasma concentrations of vascular endothelial growth factor (sVEGF and pVEGF), serum concentrations of interleukin 6 (IL-6), and VEGF platelet load (VEGF/pl) in the blood of healthy controls (n = 26), breast cancer patients with locoregional disease (n = 31), and patients with progressive advanced disease (n = 73) have been compared. The 95th percentile values for the control population were 250 pg/mL for sVEGF, 30 pg/mL for pVEGF, and 1.6 pg/mL for IL-6. The 95th percentile value of the calculated VEGF/pl was 1.0 pg/10(6) platelets in the control population. Serum VEGF concentrations correlated with platelet number in all the groups. Patients with thrombocytosis had a median sVEGF concentration of 833 pg/mL, compared to 249 pg/mL in other patients (P = 0.018). Serum IL-6 levels correlated with sVEGF levels and with the calculated VEGF/pl. Serum IL-6 concentration was significantly higher in patients with breast cancer compared to healthy controls (P < 0.0001). Median IL-6 serum levels were nearly 10 times higher in patients with metastatic breast cancer as compared to the those with locoregional disease (6.0 pg/mL versus 0.7 pg/mL, respectively). Plasma VEGF and the VEGF/pl were also significantly different in the 3 groups. The ratio between sVEGF and pVEGF tended to be smaller in the metastatic breast cancer group compared to the patients with locoregional disease (median, 7.5 versus 10.1, respectively; P = 0.066), suggestive of more intravasal platelet degranulation in the former group. Serum IL-6 level is the most discriminative factor separating healthy controls and the locoregional and metastatic breast cancer patient groups. These results suggest a role for tumor-derived IL-6 in regulating VEGF expression in platelets and their precursors and also confirm the role of circulating platelets in the storage of VEGF.