Long-term follow-up of children with neuroblastoma receiving radiotherapy to metastatic lesions within the German Neuroblastoma Trials NB97 and NB 2004.

PURPOSE: Neuroblastoma (NB) is the most common extracranial solid malignancy during childhood. Despite a multimodal treatment approach, the prognosis of patients with metastatic NB is not satisfactory. Although radiotherapy (RT) has become an integral part of treatment of the primary tumor, the role of RT in osteomedullary lesions is not well defined. A retrospective analysis was conducted to evaluate the impact of RT for metastatic sites in children with high-risk NB. METHODS: All patients with stage 4 NB from the prospective, multicenter NB trials NB97 and NB2004 who received RT to metastatic sites during frontline treatment were included in this retrospective analysis. RESULTS: A total of 18 children were irradiated with a median dose of 36 Gray (Gy; range 20-45 Gy) to one or more (range 1-3) osteomedullary metastases with or without concomitant RT to the primary tumor site. The median follow-up time was 149 months (range 55-220) in survivors. At 5 years, local relapse-free survival (LRFS) at irradiated metastatic sites and metastases-free survival (MFS) at distant, non-irradiated site rates were 51.4 and 39.9%, respectively. The estimated overall survival (OS) rate at 5 years was 49.4%. No high-grade acute or late toxicity and no secondary malignancy was reported. CONCLUSION: RT to metastases is feasible for patients with stage 4 NB. However, an impact of RT to residual metastatic sites on outcome was not found. Studies with larger cohorts or prospective trials would be desirable in order to elucidate the role of RT for metastases.

Uncertainties in ocular proton planning and their impact on required margins.

PURPOSE: To review required margins in ocular proton therapy (OPT) based on an uncertainty estimation and to compare them with widely used values. Further, uncertainties when using registered funduscopy images in the 3D model is investigated. METHODS: An uncertainty budget in planning and delivery was defined to determine required aperture and range margins. Setup uncertainties were considered for a cohort of treated patients and tested in a worst-case estimation. Other uncertainties were based on a best-guess and knowledge of institutional specifics, e.g. range reproducibility. Margins for funduscopy registration were defined resulting from scaling, rotation and translation of the image. Image formation for a wide-field fundus camera was reviewed and compared to the projection employed in treatment planning systems. RESULTS: Values for aperture and range with margins of 2.5 mm as reported in literature could be determined. Aperture margins appear appropriate for setup uncertainties below 0.5 mm, but depend on lateral penumbra. Range margins depend on depth and associated density uncertainty in tissue. Registration of funduscopy images may require margins of >2 mm, increasing towards the equator. Difference in the projection may lead to discrepancies of several mm. CONCLUSIONS: The commonly used 2.5 mm aperture margin was validated as an appropriate choice, while range margins could be reduced for lower ranges. Margins may however not include uncertainties in contouring and possible microscopic spread. If a target base is contoured on registered funduscopy images care must be taken as they are subject to larger uncertainties. Multimodal imaging approach in OPT remains advisable.

Is an Endorectal Balloon Beneficial for Rectal Sparing after Spacer Implantation in Prostate Cancer Patients Treated with Hypofractionated Intensity-Modulated Proton Beam Therapy? A Dosimetric and Radiobiological Comparison Study.

BACKGROUND: The aim of this study is to examine the dosimetric influence of endorectal balloons (ERB) on rectal sparing in prostate cancer patients with implanted hydrogel rectum spacers treated with dose-escalated or hypofractionated intensity-modulated proton beam therapy (IMPT). METHODS: Ten patients with localized prostate cancer included in the ProRegPros study and treated at our center were investigated. All patients underwent placement of hydrogel rectum spacers before planning. Two planning CTs (with and without 120 cm3 fluid-filled ERB) were applied for each patient. Dose prescription was set according to the h strategy, with 72 Gray (Gy)/2.4 Gy/5× weekly to prostate + 1 cm of the seminal vesicle, and 60 Gy/2 Gy/5× weekly to prostate + 2 cm of the seminal vesicle. Planning with two laterally opposed IMPT beams was performed in both CTs. Rectal dosimetry values including dose-volume statistics and normal tissue complication probability (NTCP) were compared for both plans (non-ERB plans vs. ERB plans). RESULTS: For ERB plans compared with non-ERB, the reductions were 8.51 ± 5.25 Gy (RBE) (p = 0.000) and 15.76 ± 11.11 Gy (p = 0.001) for the mean and the median rectal doses, respectively. No significant reductions in rectal volumes were found after high dose levels. The use of ERB resulted in significant reduction in rectal volume after receiving 50 Gy (RBE), 40 Gy (RBE), 30 Gy (RBE), 20 Gy (RBE), and 10 Gy (RBE) with p values of 0.034, 0.008, 0.003, 0.001, and 0.001, respectively. No differences between ERB and non-ERB plans for the anterior rectum were observed. ERB reduced posterior rectal volumes in patients who received 30 Gy (RBE), 20 Gy (RBE), or 10 Gy (RBE), with p values of 0.019, 0.003, and 0.001, respectively. According to the NTCP models, no significant reductions were observed in mean or median rectal toxicity (late rectal bleeding ≥ 2, necrosis or stenosis, and late rectal toxicity ≥ 3) when using the ERB. CONCLUSION: ERB reduced rectal volumes exposed to intermediate or low dose levels. However, no significant reduction in rectal volume was observed in patients receiving high or intermediate doses. There was no benefit and also no disadvantage associated with the use of ERB for late rectal toxicity, according to available NTCP models.

Dosimetric feasibility of moderately hypofractionated/dose escalated radiation therapy for localised prostate cancer with intensity-modulated proton beam therapy using simultaneous integrated boost (SIB-IMPT) and impact of hydrogel prostate-rectum spacer.

PURPOSE: To examine the dosimetric feasibility of hypofractionated/dose escalated radiation therapy in patients with localized prostate carcinoma using simultaneous integrated boost intensity-modulated proton beam therapy (SIB-IMPT) in absence or presence of prostate-rectum spacer. METHODS: IMPT technique was implemented in 23 patients with intermediate- and high-risk prostate cancer treated at West German Proton Therapy Centre from March 2016 till June 2018, using SIB technique prescribing 60 GyRBE and 72 GyRBE in 30 fractions to PTV1 (prostate and seminal vesicle) and PTV2 boost (prostate and proximal seminal vesicle), respectively. In 15 patients, a transperineal injection of hydrogel was applied prior to radiotherapy to increase the distance between prostate and rectum. Planning and all treatments were performed with a 120 ml fluid-filled endorectal balloon customised daily for each patient. For each patient, 2 lateral IMPT beams were implemented taking a field-specific range uncertainty (RU) into account. Dose volume histograms (DVH) were analyzed for PTV2, PTV2 with range uncertainty margin (PTV2RU), rectum, bladder, right/left femoral heads, and penile bulb. For late rectal toxicities, the normal tissue complication probabilities (NTCP) were calculated using different biological models. A DVH- and NTCP-based dosimetric comparison was carried out between non-spacer and spacer groups. RESULTS: For the 23 patients, high-quality plans could be achieved for target volume and for other organs at risk (OARs). For PTV2, the V107% was 0% and the Dmax did not exceed 106.2% of the prescribed dose. The volume PTV2RU covered by 95% of the dose ranged from 96.16 to 99.95%. The conformality index for PTV2RU was 1.12 ± 0.057 and the homogeneity index (HI) was 1.04 ± 0.014. Rectum Dmax and rectal volume receiving 73-50 Gy could be further reduced for the spacer-group. Significant reductions in mean and median rectal NTCPs (stenosis/necrosis, late rectal bleeding ≥ 2, and late rectal toxicities ≥ 3) were predicted for the spacer group in comparison to the non-spacer group. CONCLUSION: Hypofractionated/dose escalated radiotherapy with SIB-IMPT is dosimetrically feasible. Further reduction of the rectal volumes receiving high and medium dose levels (73-50 Gy) and rectal NTCP could be achieved through injection of spacers between rectum and prostate.

Proton Beam Therapy for Children With Neuroblastoma: Experiences From the Prospective KiProReg Registry.

OBJECTIVE: Radiotherapy (RT) is an integral part of the interdisciplinary treatment of patients with high-risk neuroblastoma (NB). With the continuous improvements of outcome, the interest in local treatment strategies that reduce treatment-related side effects while achieving optimal oncological results is growing. Proton beam therapy (PBT) represents a promising alternative to conventional photon irradiation with regard to the reduction of treatment burden. METHOD: Retrospective analysis of children with high or intermediate risk NB receiving PBT of the primary tumor site during first-line therapy between 2015 and 2020 was performed. Data from the prospective in-house registry Standard Protonentherapie WPE - Kinder- (KiProReg) with respect to tumor control and treatment toxicity were analyzed. Adverse events were classified according to CTCAE Version 4 (V4.0) before, during, and after PBT. RESULTS: In total, 44 patients (24 male, 20 female) with high (n = 39) or intermediate risk NB (n = 5) were included in the analysis. Median age was 3.4 years (range, 1.4-9.9 years). PBT doses ranged from 21.0 to 39.6 Gray (Gy) (median 36.0 Gy). Five patients received PBT to the MIBG-avid residual at the primary tumor site at time of PBT according to the NB-2004 protocol. In 39 patients radiation was given to the pre-operative tumor bed with or without an additional boost in case of residual tumor. After a median follow-up (FU) of 27.6 months, eight patients developed progression, either local recurrence (n = 1) or distant metastases (n = 7). Four patients died due to tumor progression. At three years, the estimated local control, distant metastatic free survival, progression free survival, and overall survival was 97.7, 84.1, 81.8, and 90.9%, respectively. During radiation, seven patients experienced higher-grade (CTCAE ≥ °3) hematologic toxicity. No other higher grade acute toxicity occurred. After PBT, one patient developed transient myelitis while receiving immunotherapy. No higher grade long-term toxicity was observed up to date. CONCLUSION: PBT was a well tolerated and effective local treatment in children with high and intermediate risk NB. The role of RT in an intensive multidisciplinary treatment regimen remains to be studied in the future in order to better define timing, doses, target volumes, and general need for RT in a particularly sensitive cohort of patients.

Motion effects in proton treatments of hepatocellular carcinoma-4D robustly optimised pencil beam scanning plans versus double scattering plans.

Pencil beam scanning (PBS) proton therapy enables better dose conformality for complex anatomical geometries than passive proton scattering techniques, but is more susceptible to organ motion. This becomes an issue when treating moving tumours in the thorax or abdomen. Novel four-dimensional treatment planning approaches have been developed to increase the robustness of PBS plans against motion. However, their efficacy still needs to be examined by means of 4D dynamically accumulated dose (4DDD) analyses. This study investigates the potential use of 4D robust optimisation to maintain sufficient target coverage in the presence of organ motion, while sparing surrounding healthy tissue, for hepatocellular carcinoma (HCC). The liver is particularly suited to study motion interplay effects since the treatment region exhibits smaller density gradients and more homogeneous tissue than targets in the thorax, making it less prone to range errors. A facility-specific beam time model, developed and experimentally validated previously, was used for the clinical evaluation. 4DDD analyses of eleven target volumes did not show a significant improvement of the target coverage using 4D robust optimisation, but a reduction of the dose to close-by organs at risk. Interplay effects were averaged out for the applied fractionation scheme of 15 fractions. Contrary to PBS, passive double scattering (DS) plans yielded homogeneous 4DDD dose distributions in a single fraction. But, in some cases, they exceeded organ at risk dose limits, which were only satisfied in PBS. The average normal liver dose could be decreased by almost 6% compared to non-robustly optimised PBS plans and by 16% compared to DS plans when implementing 4D robust optimisation. Except for some very small tumours with large motion amplitudes, 4D robustly optimised PBS plans were found to be clinically acceptable even without supplementary motion mitigation techniques.