Efficacy and Safety of Local Liver Radioablation in HCC Lesions within and beyond Limits of Thermal Ablation.

INTRODUCTION: CT-guided interstitial Brachytherapy (iBT) Radiotherapy has been established in the treatment of liver tumors. With iBT, HCC lesions can be treated beyond the limits of thermal ablation (i.e., size and location). However, a comprehensive analysis of the efficacy of iBT in patients within and beyond thermal ablation limits is lacking. MATERIALS AND METHODS: 146 patients with 216 HCC lesions have been analyzed retrospectively. Clinical and imaging follow-up data has been collected. Lesions were evaluated in terms of suitability for thermal ablation or not. The correlation between local tumor control (LTC), time-to-progression (TTP), and overall survival (OS), and clinical and imaging parameters have been evaluated using univariable and multivariable Cox regression analyses. RESULTS: LTC rates at 12 months, 24 months, and 36 months were 87%,75%, and 73%, respectively. 65% of lesions (n=141) were not suitable for RFA. The median TTP was 13 months, and the median OS was not reached (3-year OS rate: 70%). No significant difference in LTC, TTP, or OS regarding RFA suitability existed. However, in the overall multivariable analysis, lesion diameter > 5 cm was significantly associated with lower LTC (HR: 3.65, CI (1.60-8.31), p=0.002) and shorter TTP (HR: 2.08, CI (1.17-3.70), p=0.013). Advanced BCLC stage, Child-Pugh Stage, and hepatitis B were associated with shorter OS. CONCLUSION: iBT offers excellent LTC rates and OS in local HCC treatment regardless of the limits of thermal ablation, suggesting further evidence of its alternative role to thermal ablation in patients with early-stage HCC.

Hematologic Toxicity and Bone Marrow-Sparing Strategies in Chemoradiation for Locally Advanced Cervical Cancer: A Systematic Review.

The standard treatment for locally advanced cervical cancer typically includes concomitant chemoradiation, a regimen known to induce severe hematologic toxicity (HT). Particularly, pelvic bone marrow dose exposure has been identified as a contributing factor to this hematologic toxicity. Chemotherapy further increases bone marrow suppression, often necessitating treatment interruptions or dose reductions. A systematic search for original articles published between 1 January 2006 and 7 January 2024 that reported on chemoradiotherapy for locally advanced cervical cancer and hematologic toxicities was conducted. Twenty-four articles comprising 1539 patients were included in the final analysis. HT of grade 2 and higher was observed across all studies and frequently exceeded 50%. When correlating active pelvic bone marrow and HT, significant correlations were found for volumes between 10 and 45 Gy and HT of grade 3 and higher. Several dose recommendations for pelvic bone and pelvic bone marrow sparing to reduce HT were established, including V10 < 90-95%, V20 < 65-86.6% and V40 < 22.8-40%. Applying dose constraints to the pelvic bone/bone marrow is a promising approach for reducing HT, and thus reliable implementation of therapy. However, prospective randomized controlled trials are needed to define precise dose constraints and optimize clinical strategies.

Clinical outcome of combined intracavitary / interstitial brachytherapy using a hybrid applicator in locally advanced cervical cancer.

OBJECTIVE: The aim of this study was to evaluate the clinical outcome in locally advanced cervical cancer (LACC) after image-guided adaptive brachytherapy (IGABT) with combined intracavitary and interstitial (IC/IS) techniques using the hybrid Venezia applicator (Elekta AB, Sweden). METHODS: LACC patients (UICC Stage IIB - IVB) treated with radiochemotherapy followed by IGABT with the hybrid IC/IS Venezia applicator at a single institution were retrospectively analyzed. Treatment comprised EBRT of the pelvis with 45 Gy and concomitant weekly cisplatin chemotherapy (40 mg/m2) followed by MRI-based IGABT. Dosimetry, oncological outcome and toxicity were investigated. RESULTS: Forty-six patients underwent a total of 184 fractions of IGABT between 2017 and 2020. Median follow-up was 24 months. Combined IC/IS techniques were used in 40 patients (87%). The median HRCTV volume was 31.2 cm3 and the median HRCTV D90% was 92.3 Gy (EQD210). The median D2cm3 was 74.8 Gy for bladder, 57.9 Gy for rectum, 60.0 Gy for sigmoid and 52.2 Gy for bowel (EQD23). The 3-yr actuarial rates were 97.6% for local control, 97.6% for pelvic control, 59.9% for distant metastasis-free survival and 81.6% for overall survival. The crude rate for G2 and G3 late toxicity was 21.7% and 4.3%. CONCLUSIONS: IGABT with the hybrid Venezia applicator and a pronounced use of a combined IC/IS technique achieved high target doses, while maintaining low doses to organs at risk, leading to excellent local control and overall survival rates with acceptable toxicity.

Interstitial High-Dose-Rate Brachytherapy of Liver Metastases in Oligometastatic Patients.

Local ablative treatments have emerged as a promising treatment strategy for patients with oligometastatic disease. Among others, interstitial brachytherapy (iBT) is an upcoming treatment option for unresectable liver metastases. We report the feasibility and oncologic outcome of iBT of oligometastatic liver metastases performed in patients with limited tumor burdens in a high-volume center. Patients undergoing iBT between August 2017and March 2019 were included. A retrospective analysis of patient outcomes and treatment complications was performed. Patients treated for metastatic colorectal carcinoma (CRC) were compared to other histologies. A total of 141 iBT procedures were performed in 106 patients (male:52; female:54) and 244 liver metastases. Overall, 51% (54/106) of patients had a diagnosis of metastatic CRC. The median follow-up was 9 months, and overall survival (OS) was 92.3% at 6 months and 76.3% at 12 months. Local-relapse-free survival (LRFS) was 88.4% at 6 months and 71.5% at 12 months, with a significant difference between patients with CRC (84.1% and 50.6%) versus other histologies (92.4% and 92.4%, p < 0.001). A sub-group analysis showed a significant advantage in patients with CRC receiving a minimal dose (D100) of 20 Gy to the planning target volume. Treatments of smaller total liver-tumor volumes (<18 ccm) resulted in better LRFS rates. iBT is a safe and effective treatment approach for oligometastatic liver disease. A higher treatment dose is needed for patients with CRC. Moreover, lower metastatic burdens may be favorable for LRFS. Prospective studies are needed to assess the role of iBT in the oligometastatic setting as an alternative to other local ablative treatment approaches in patients with liver metastases.

Combining inter-observer variability, range and setup uncertainty in a variance-based sensitivity analysis for proton therapy.

Margin concepts in proton therapy aim to ensure full dose coverage of the clinical target volume (CTV) in presence of setup and range uncertainty. Due to inter-observer variability (IOV), the CTV itself is uncertain. We present a framework to evaluate the combined impact of IOV, setup and range uncertainty in a variance-based sensitivity analysis (SA). For ten patients with skull base meningioma, the mean calculation time to perform the SA including 1.6 × 104 dose recalculations was 59 min. For two patients in this dataset, IOV had a relevant impact on the estimated CTV D95% uncertainty.

HDR Brachytherapy and SBRT as Bridging Therapy to Liver Transplantation in HCC Patients: A Single-Center Experience.

BACKGROUND: In the treatment of patients with HCC awaiting liver transplantation (LT), local ablative treatments (LAT) are available either for downstaging or as bridging treatment. We present our clinical experience with both available radiation-based techniques, brachytherapy (BT), and stereotactic body radiotherapy (SBRT). METHODS: All patients diagnosed with HCC and who were treated with BT or SBRT at our institution between 2011 and 2018 were retrospectively reviewed. The current analysis included all patients who subsequently underwent LT. RESULTS: A total of 14 patients (male=9; female=5) were evaluated. Seven underwent BT for bridging before LT, and seven were treated with SBRT. BT was performed with a prescribed dose of 1 × 15 Gy, while SBRT was applied with 37 Gy (65%-iso) in three fractions in six patients, and one patient was treated with 54 Gy (100%-iso) in nine fractions. The treatment was generally well tolerated. One case of grade 3 bleeding was reported after BT, and one case of liver failure occurred following SBRT. All patients underwent LT after a median time interval of 152 days (range 47-311) after BT and 202 days (range 44-775) following SBRT. In eight cases, no viable tumor was found in the explanted liver, while four liver specimens showed vital tumor. The median follow-up after SBRT was 41 months and 17 months following BT. Overall, no hepatic HCC recurrence occurred following LT. CONCLUSION: Both SBRT and BT are feasible and well tolerated as bridging to LT when applied with caution in patients with impaired liver function. Radiation-based treatments can close the gap for patients not suitable for other locally ablative treatment options.

Comparison of liver exposure in CT-guided high-dose rate (HDR) interstitial brachytherapy versus SBRT in hepatocellular carcinoma.

BACKGROUND: In unresectable hepatocellular carcinoma several local ablative treatments are available. Among others, radiation based treatments such as stereotactic body radiotherapy (SBRT) and high-dose rate interstitial brachytherapy (HDR BT) have shown good local control rates. METHODS: We conducted a dose comparison between actually performed HDR BT versus virtually planned SBRT to evaluate the respective clinically relevant radiation exposure to uninvolved liver tissue. Moreover, dose coverage and conformity indices were assessed. RESULTS: Overall, 46 treatment sessions (71 lesions, 38 patients) were evaluated. HDR BT was applied in a single fraction with a dose prescription of 1 × 15 Gy. D98 was 17.9 ± 1.3 Gy, D50 was 41.8 ± 8.1 Gy. The SBRT was planned with a prescribed dose of 3 × 12.5 Gy (65%-Isodose), D98 was 50.7 ± 3.1 Gy, D2 was 57.0 ± 2.3 Gy, and D50 was 55.2 ± 2.3 Gy. Regarding liver exposure Vliver10GyBT was compared to Vliver15.9GySBRT, Vliver16.2GySBRT (EQD2 equivalent doses), and Vliver20GySBRT (clinically relevant dose), all results showed significant differences (p < .001). In a case by case analysis Vliver10GyBT was smaller than Vliver20GySBRT in 38/46 cases (83%). Dmean of the liver was significantly smaller in BT compared to SBRT (p < .001). GTV volume was correlated to the liver exposure and showed an advantage of HDR BT over SBRT in comparison of clinically relevant doses, and for EQD2 equivalent doses. The advantage was more pronounced for greater liver lesions The Conformity Index (CI) was significantly better for BT, while Healthy Tissue Conformity Index (HTCI) and Conformation Number (CN) showed an advantage for SBRT (p < .001). CONCLUSION: HDR BT can be advantageous in respect of sparing of normal liver tissue as compared to SBRT, while providing excellent target conformity.

Heart sparing radiotherapy in breast cancer: the importance of baseline cardiac risks.

BACKGROUND: Patients with left-sided breast cancer have an increased risk of cardiovascular disease (CVD) after radiotherapy (RT). While the awareness of cardiac toxicity has increased enormously over the last decade, the role of individual baseline cardiac risks has not yet been systematically investigated. Aim of the present study was to evaluate the impact of baseline CVD risks on radiation-induced cardiac toxicity. METHODS: Two hundred ten patients with left-sided breast cancer treated in the prospective Save-Heart Study using a deep inspiration breath-hold (DIBH) technique were analysed regarding baseline risk factors for CVD. Three frequently used prediction tools (Procam, Framingham and Reynolds score) were applied to evaluate the individual CVD risk profiles. Moreover, 10-year CVD excess absolute risks (EAR) were estimated using the individual mean heart dose (MHD) of treatment plans in free breathing (FB) and DIBH. RESULTS: The individual baseline CVD risk factors had a strong impact on the 10-year cumulative CVD risk. The mean baseline risks of the non-diabetic cohort (n = 200) ranged from 3.11 to 3.58%, depending on the risk estimation tool. A large number of the non-diabetic patients had a very low 10-year CVD baseline risk of ≤1%; nevertheless, 8-9% of patients reached ≥10% baseline 10-year CVD risk. In contrast, diabetic patients (n = 10) had significantly higher baseline CVD risks (range: 11.76-24.23%). The mean 10-year cumulative risk (Framingham score) following RT was 3.73% using the DIBH-technique (MHD:1.42Gy) and 3.94% in FB (MHD:2.33Gy), after adding a 10-year-EAR of + 0.34%(DIBH) and + 0.55%(FB) to the baseline risks, respectively. Smoking status was one of the most important and modifiable baseline risk factors. After DIBH-RT, the 182 non-smoking patients had a mean 10-year cumulative risk of 3.55% (3.20% baseline risk, 0.35% EAR) as compared to 6.07% (5.60% baseline risk, 0.47% EAR) for the 28 smokers. CONCLUSION: In the present study, all CVD prediction tools showed comparable results and could easily be integrated into daily clinical practice. A systematic evaluation and screening helps to identify high-risk patients who may benefit from primary prevention. This could result in an even higher benefit than from heart-sparing irradiation techniques alone.

Report of first recurrent glioma patients examined with PET-MRI prior to re-irradiation.

BACKGROUND AND PURPOSE: The advantage of combined PET-MRI over sequential PET and MRI is the high spatial conformity and the absence of time delay between the examinations. The benefit of this technique for planning of re-irradiation (re-RT) treatment is unkown yet. Imaging data from a phase 1 trial of re-RT for recurrent glioma was analysed to assess whether planning target volumes and treatment margins in glioma re-RT can be adjusted by PET-MRI with rater independent PET based biological tumour volumes (BTVs). PATIENTS AND METHODS: Combined PET-MRI with the tracer O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) prior to re-RT was performed in recurrent glioma patients in a phase I trial. GTVs including all regions suspicious of tumour on contrast enhanced MRI were delineated by three experienced radiation oncologists and included into MRI based consensus GTVs (MRGTVs). BTVs were semi-automatically delineated with a fixed threshold of 1.6 x background activity. Corresponding BTVs and MRGTVs were fused into union volume PET-MRGTVs. The Sørensen-Dice coefficient and the conformity index were used to assess the geometric overlap of the BTVs with the MRGTVs. A recurrence pattern analysis was performed based on the original planning target volumes (PTVs = GTV + 10 mm margin or 5 mm in one case) and the PET-MRGTVs with margins of 10, 8, 5 and 3 mm. RESULTS: Seven recurrent glioma patients, who received PET-MRI prior to re-RT, were included into the present planning study. At the time of re-RT, patients were in median 54 years old and had a median Karnofsky Performance Status (KPS) score of 80. Median post-recurrence survival after the beginning of re-RT was 13 months. Concomitant bevacizumab therapy was applied in six patients and one patient received chemoradiation with temozolomide. Median GTV volumes of the three radiation oncologists were 35.0, 37.5 and 40.5 cubic centimeters (cc) and median MRGTV volume 41.8 cc. Median BTV volume was 36.6 cc and median PET-MRGTV volume 59.3 cc. The median Sørensen-Dice coefficient for the comparison between MRGTV and BTV was 0.61 and the median conformity index 0.44. Recurrence pattern analysis revealed two central, two in-field and one distant recurrence within both, the original PTV, as well as the PET-MRGTV with a reduced margin of 3 mm. CONCLUSION: PET-MRI provides radiation treatment planning imaging with high spatial and timely conformity for high-grade glioma patients treated with re-RT with potential advancements for target volume delineation. Prospective randomised trials are warranted to further investigate the treatment benefits of PET-MRI based re-RT planning.

Impact of surface-guided positioning on the use of portal imaging and initial set-up duration in breast cancer patients.

OBJECTIVE: The impact of optical surface guidance on the use of portal imaging and the initial set-up duration in patients receiving postoperative radiotherapy of the breast or chest wall was investigated. MATERIAL AND METHODS: A retrospective analysis was performed including breast cancer patients who received postoperative radiotherapy between January 2016 and December 2016. One group of patients received treatment before the optical surface scanner was installed (no-OSS) and the other group was positioned using the additional information derived by the optical surface scanner (OSS). The duration of the initial set-up was recorded for each patient and a comparison of both groups was performed. Accordingly, the differences between planned and actually acquired portal images during the course of radiotherapy were compared between both groups. RESULTS: A total of 180 breast cancer patients were included (90 no-OSS, 90 OSS) in this analysis. Of these, 30 patients with left-sided breast cancer received radiotherapy in deep inspiration breath hold (DIBH). The mean set-up time was 10 min and 18 s and no significant difference between the two groups of patients was found (p = 0.931). The mean set-up time in patients treated without DIBH was 9 min and 45 s compared to 13 min with DIBH (p < 0.001), as portal imaging was performed in DIBH. No significant difference was found in the number of acquired to the planned number of portal images during the entire radiotherapy treatment for both groups (p = 0.287). CONCLUSION: Optical surface imaging is a valuable addition for primary patient set-up. The findings confirm that the addition of surface-based imaging did not prolong the clinical workflow and had no significant impact on the number of portal verification images carried out during the course of radiotherapy.

Stereoscopic X-ray imaging, cone beam CT, and couch positioning in stereotactic radiotherapy of intracranial tumors: preliminary results from a cross-modality pilot installation.

BACKGROUND: To assess the accuracy and precision of a fully integrated pilot installation of stereoscopic X-ray imaging and kV-CBCT for automatic couch positioning in stereotactic radiotherapy of intracranial tumors. Positioning errors as detected by stereoscopic X-ray imaging are compared to those by kV-CBCT (i.e. the accuracy of the new method is verified by the established method), and repeated X-ray images are compared (i.e. the precision of new method is determined intra-modally). METHODS: Preliminary results are reported from a study with 32 patients with intracranial tumors. Patients were treated with stereotactic radiotherapy guided by stereoscopic X-ray imaging and kV-CBCT. Patient positioning was automatically corrected by a robotic couch. Cross-modal discrepancies in position detection were measured (N = 42). Intra-modal improvements after correction and re-verification by stereoscopic X-ray imaging were measured (N = 70). The accuracy and precision of stereoscopic X-ray imaging and the accuracy and precision of CBCT were confirmed in phantom measurements (N = 12 shifts of a ball bearing phantom, N = 24 shifts of a head phantom). RESULTS: After correction based on stereoscopic X-ray imaging 95% of residual mean errors were below 0.4, 0.4, 0.5, and 0.7 mm (lateral, longitudinal, vertical, radial, respectively). Stereoscopic X-ray imaging and CBCT were in close agreement with an average discrepancy of 0.1, 0.5, 0.3 and 0.8 mm, respectively. 95% of discrepancies were below 0.8, 1.2, 1.0, and 1.4 mm, respectively. After correction and re-verification by stereoscopic X-ray imaging, the remaining intra-modal residual error was consistent with zero (p = 0.31, p = 0.48, p = 0.81 in lateral, longitudinal, and vertical direction; p-values from two-tailed t-test). The inherent technical accuracy and precision of stereoscopic X-ray imaging and the accuracy and precision of CBCT were found to be of the order of 0.1 mm in controlled phantom settings. CONCLUSIONS: In a routine clinical setting, both stereoscopic X-ray imaging and CBCT were able to reduce positioning errors by an order of magnitude. The end-to-end precision of the system, measured from the discrepancy (mean) between ExacTrac and CBCT, in a clinical setting seems to be about 0.8 mm radially, including couch positioning. The precision (measured from repeatability of ExacTrac, intra-modal) was found to be about 0.7 mm radially in a clinical setting.

Bevacizumab and radiotherapy for the treatment of glioblastoma: brothers in arms or unholy alliance?

Glioblastoma (GBM) represents the most frequent primary brain tumor in adults and carries a dismal prognosis despite aggressive, multimodal treatment regimens involving maximal resection, radiochemotherapy, and maintenance chemotherapy. Histologically, GBMs are characterized by a high degree of VEGF-mediated vascular proliferation. In consequence, new targeted anti-angiogenic therapies, such as the monoclonal anti-VEGF-A antibody bevacizumab, have proven effective in attenuating tumor (neo)angiogenesis and were shown to possess therapeutic activity in several phase II trials. However, the role of bevacizumab in the context of multimodal therapy approaches appears to be rather complex. This review will give insights into current concepts, limitations, and controversies regarding the molecular mechanisms and the clinical benefits of bevacizumab treatment in combination with radio(chemo)therapy--particularly in face of the results of recent phase III trials, which failed to demonstrate convincing improvements in overall survival (OS).

Recurrence pattern analysis after re-irradiation with bevacizumab in recurrent malignant glioma patients.

BACKGROUND: The aim of the present analysis was to evaluate the recurrence pattern in patients with recurrent malignant glioma after re-irradiation in combination with bevacizumab as there is limited data on how to optimally choose dose, fractionation and delineation margins. METHODS: Thirty-one patients with recurrent malignant glioma treated with re-irradiation and bevacizumab after previous chemoradiotherapy (concurrent temozolomide 75 mg/m(2)/d according to the EORTC/NCIC trial) and [(18) F]FET-PET and/or MRI confirmed recurrence were retrospectively analyzed. Bevacizumab was applied twice during fractionated re-irradiation (10 mg/kg, d1+d15, median 36 Gy, conventionally fractionated). Recurrence patterns were assessed by means of [(18) F]FET-PET and/or MRI. RESULTS: Median follow-up was 34.0 months for all patients [95%-CI, 27.7-40.3] and median post-recurrence survival 10.8 months [95%-CI, 9.2-12.4]. Concerning the recurrence patterns, 61.3% of these were located in-field (19 patients), 22.6% were marginal (7 patients) and 16.1% ex-field (5 patients). No influence on the recurrence pattern was observed according to sex, WHO grade, maintenance chemotherapy or MGMT methylation status whereas planning target volume (PTV) size had a significant influence on the recurrence pattern (p=0.032). PTV sizes>75 ml were associated with a higher in-field recurrence rate and lower median post-recurrence progression-free survival (8.5 vs. 4.9 months, p=0.016). CONCLUSIONS: After the administration of re-irradiation with bevacizumab the recurrence pattern seems to be mainly centrally located. The PTV size was the main predictor for a marginal/ex-field recurrence.