Impact of Modern Low Dose Involved Site Radiation Therapy on Normal Tissue Toxicity in Cervicothoracic Non-Hodgkin Lymphomas: A Biophysical Study.

This biophysical study aimed to determine fitting parameters for the Lyman-Kutcher-Burman (LKB) dose-response model for normal tissue complication probability (NTCP) calculations of acute side effects and to investigate the impact of reduced radiation doses on the probability of their occurrence in supradiaphragmatic non-Hodgkin lymphoma (NHL) irradiation. A cohort of 114 patients with NHL in the cervicothoracic region, treated between 2015 and 2021 at the University Hospitals of Münster, Hamburg, and Essen, with involved site radiation therapy (ISRT), were included. Among them, 68 patients with aggressive NHL (a-NHL) received consolidative radiation therapy with 24-54 Gy following (R-)CHOP chemotherapy. Additionally, 46 patients with indolent NHL (i-NHL) underwent radiotherapy with 22.5-45.0 Gy. Two treatment plans were prospectively created for each patient (a-NHL: 30.0/40.0 Gy; i-NHL: 24.0/30.0 Gy). NTCP were then calculated using the optimized LKB model. The adapted dose-response models properly predicted the patient's probability of developing acute side effects when receiving doses ≤ 50 Gy. In addition, it was shown that reduced radiation doses can influence the NTCP of acute side effects depending on the aggressiveness of NHL significantly. This study provided a foundation to prospectively assess the probability of adverse side effects among today's reduced radiation doses in the treatment of NHL.

Ultrahypofractionated Low-Dose Total Skin Electron Beam in Advanced-Stage Mycosis Fungoides and Sézary Syndrome.

PURPOSE: The aim of this study was to assess the safety and efficacy of an ultrahypofractionated low-dose total skin electron beam therapy (TSEBT) regimen in patients with advanced mycosis fungoides (MF) or Sézary syndrome (SS). METHODS AND MATERIALS: In this multicenter observational study from 5 German centers, 18 total patients with MF or SS underwent TSEBT with a total dose of 8 Gy in 2 fractions. The primary endpoint was the overall response rate. RESULTS: Fifteen of 18 patients with stage IIB-IV MF or SS were heavily pretreated with a median of 4 prior systemic therapies. The overall response rate was 88.9% (95% confidence interval [CI], 65.3-98.6), with 3 complete responses (16.9%; 95% CI, 3.6-41.4). At a median follow-up period of 13 months, the median time to next treatment (TTNT) was 12 months (95% CI, 8.2-15.8), and the median progression-free survival was 8 months (95% CI, 2-14). A significant reduction in the modified severity-weighted assessment tool, total Skindex-29 score (Bonferroni-corrected P < .005), and all subdomains (Bonferroni-corrected P < .05) was observed after TSEBT. Half of the irradiated patients (n = 9) developed grade 2 acute and subacute toxicities. One patient had confirmed grade 3 acute toxicity. Chronic grade 1 toxicity has been observed in 33% of patients. Patients with erythroderma/SS or prior radiation therapy appear at higher risk of skin toxicities. CONCLUSIONS: TSEBT with 8 Gy in 2 fractions achieves good disease control and symptom palliation with acceptable toxicity, greater convenience, and fewer hospital visits.

Planning Benchmark Study for Stereotactic Body Radiation Therapy of Liver Metastases: Results of the DEGRO/DGMP Working Group on Stereotactic Radiation Therapy and Radiosurgery.

PURPOSE: Our purpose was to investigate whether liver stereotactic body radiation therapy treatment planning can be harmonized across different treatment planning systems, delivery techniques, and institutions by using a specific prescription method and to minimize the knowledge gap concerning intersystem and interuser differences. We provide best practice guidelines for all used techniques. METHODS AND MATERIALS: A multiparametric specification of target dose (gross target volume [GTV]D50%, GTVD0.1cc, GTVV90%, planning target volume [PTV]V70%) with a prescription dose of GTVD50% = 3 × 20 Gy and organ-at-risk (OAR) limits were distributed with computed tomography and structure sets from 3 patients with liver metastases. Thirty-five institutions provided 132 treatment plans using different irradiation techniques. These plans were first analyzed for target and OAR doses. Four different renormalization methods were performed (PTVDmin, PTVD98%, PTVD2%, PTVDmax). The resulting 660 treatments plans were evaluated regarding target doses to study the effect of dose renormalization to different prescription methods. A relative scoring system was used for comparisons. RESULTS: GTVD50% prescription can be performed in all systems. Treatment plan harmonization was overall successful, with standard deviations for Dmax, PTVD98%, GTVD98%, and PTVDmean of 1.6, 3.3, 1.9, and 1.5 Gy, respectively. Primary analysis showed 55 major deviations from clinical goals in 132 plans, whereas in only <20% of deviations GTV/PTV dose was traded for meeting OAR limits. GTVD50% prescription produced the smallest deviation from target planning objectives and between techniques, followed by the PTVDmax, PTVD98%, PTVD2%, and PTVDmin prescription. Deviations were significant for all combinations but for the PTVDmax prescription compared with GTVD50% and PTVD98%. Based on the various dose prescription methods, all systems significantly differed from each other, whereas GTVD50% and PTVD98% prescription showed the least difference between the systems. CONCLUSIONS: This study showed the feasibility of harmonizing liver stereotactic body radiation therapy treatment plans across different treatment planning systems and delivery techniques when a sufficient set of clinical goals is given.

Hybrid volumetric modulated arc therapy for hypofractionated radiotherapy of breast cancer: a treatment planning study.

PURPOSE: This study aims to evaluate the best possible practice using hybrid volumetric modulated arc therapy (H-VMAT) for hypofractionated radiation therapy of breast cancer. Different combinations of H­VMAT-a combination of three-dimensional radiotherapy (3D-CRT) and VMAT-were analyzed regarding planning target volume (PTV), dose coverage, and exposure to organs at risk (OAR). METHODS: Planning computed tomography scans were acquired in deep-inspiration breath-hold. A total of 520 treatment plans were calculated and evaluated for 40 patients, comprising six different H­VMAT plans and a 3D-CRT plan as reference. H­VMAT plans consisted of two treatment plans including 3D-CRT and VMAT. During H­VMAT planning, the use of hard wedge filters (HWF) and beam energies were varied. The reference plans were planned with mixed beam energies and the inclusion/omission of HWF. RESULTS: Compared to the reference treatment plans, all H­VMAT plans showed consistently better PTV dose coverage, conformity, and homogeneity. Additionally, OAR protection was significantly improved with several H­VMAT combinations (p < 0.05). The comparison of different H­VMAT combinations showed that inclusion of HWF in the base plan had a negative impact on PTV dose coverage, conformity, and OAR exposure. It also increased the planned monitor units and beam-on time. Advantages of using lower beam energies (6-MV photons) in both the base plan and in the VMAT supplementary dose were observed. CONCLUSION: The H­VMAT technique is an effective possibility for generating homogenous and conformal dose distributions. With the right choice of H­VMAT combination, superior OAR protection is achieved compared to 3D-CRT.

Triple combination of heat, drug and radiation using alginate hydrogel co-loaded with gold nanoparticles and cisplatin for locally synergistic cancer therapy.

Although multimodal cancer therapy has shown superior antitumor efficacy in comparison to individual therapy due to the potential generation of synergistic interactions among the treatments, its clinical usage is highly hampered by systemic dose-limiting toxicities. Herein, we developed a multi-responsive nanocomplex constructed from alginate hydrogel co-loaded with cisplatin and gold nanoparticles (AuNPs) (abbreviated as ACA) to combine chemotherapy, radiotherapy (RT) and photothermal therapy. The nanocomplex markedly improved the efficiency of drug delivery where ACA resulted in noticeably higher tumor growth inhibition than free cisplatin. The tumor treated with ACA showed an increased heating rate upon 532 nm laser irradiation, indicating the photothermal conversion ability of the nanocomplex. While RT alone resulted in slight tumor growth inhibition, thermo-chemo therapy, chemoradiation therapy and thermo-radio therapy using ACA dramatically slowed down the rate of tumor growth. Upon 532 nm laser and 6 MV X-ray, the nanocomplex could enable a trimodal thermo-chemo-radio therapy that yielded complete tumor regression with no evidence of relapse during the 90-days follow up period. The results of this study demonstrated that the incorporation of AuNPs and cisplatin into alginate hydrogel network can effectively combine chemotherapy, RT and photothermal therapy to achieve a locally synergistic cancer therapy.

Definition and quality requirements for stereotactic radiotherapy: consensus statement from the DEGRO/DGMP Working Group Stereotactic Radiotherapy and Radiosurgery.

Stereotactic radiotherapy with its forms of intracranial stereotactic radiosurgery (SRS), intracranial fractionated stereotactic radiotherapy (FSRT) and stereotactic body radiotherapy (SBRT) is today a guideline-recommended treatment for malignant or benign tumors as well as neurological or vascular functional disorders. The working groups for radiosurgery and stereotactic radiotherapy of the German Society for Radiation Oncology (DEGRO) and for physics and technology in stereotactic radiotherapy of the German Society for Medical Physics (DGMP) have established a consensus statement about the definition and minimal quality requirements for stereotactic radiotherapy to achieve best clinical outcome and treatment quality in the implementation into routine clinical practice.

Technological quality requirements for stereotactic radiotherapy : Expert review group consensus from the DGMP Working Group for Physics and Technology in Stereotactic Radiotherapy.

This review details and discusses the technological quality requirements to ensure the desired quality for stereotactic radiotherapy using photon external beam radiotherapy as defined by the DEGRO Working Group Radiosurgery and Stereotactic Radiotherapy and the DGMP Working Group for Physics and Technology in Stereotactic Radiotherapy. The covered aspects of this review are 1) imaging for target volume definition, 2) patient positioning and target volume localization, 3) motion management, 4) collimation of the irradiation and beam directions, 5) dose calculation, 6) treatment unit accuracy, and 7) dedicated quality assurance measures. For each part, an expert review for current state-of-the-art techniques and their particular technological quality requirement to reach the necessary accuracy for stereotactic radiotherapy divided into intracranial stereotactic radiosurgery in one single fraction (SRS), intracranial fractionated stereotactic radiotherapy (FSRT), and extracranial stereotactic body radiotherapy (SBRT) is presented. All recommendations and suggestions for all mentioned aspects of stereotactic radiotherapy are formulated and related uncertainties and potential sources of error discussed. Additionally, further research and development needs in terms of insufficient data and unsolved problems for stereotactic radiotherapy are identified, which will serve as a basis for the future assignments of the DGMP Working Group for Physics and Technology in Stereotactic Radiotherapy. The review was group peer-reviewed, and consensus was obtained through multiple working group meetings.

A novel approach to SBRT patient quality assurance using EPID-based real-time transit dosimetry : A step to QA with in vivo EPID dosimetry.

PURPOSE: Intra- and inter-fraction organ motion is a major concern in stereotactic body radiation therapy (SBRT). It may cause substantial differences between the planned and delivered dose distribution. Such delivery errors may lead to medical harm and reduce life expectancy for patients. The project presented here investigates and improves a rapid method to detect such errors by performing online dose verification through the analysis of electronic portal imaging device (EPID) images. METHODS: To validate the method, a respiratory phantom with inhomogeneous insert was examined under various scenarios: no-error and error-simulated measurements. Simulation of respiratory motions was practiced for target ranges up to 2 cm. Three types of treatment planning technique - 3DCRT (three-dimensional conformal radiation therapy), IMRT (intensity modulated radiation therapy), and VMAT (volumetric modulated arc therapy - were generated for lung SBRT. A total of 54 plans were generated to assess the influence of techniques on the performance of portal dose images. Subsequently, EPID images of 52 SBRT patients were verified. Both for phantom and patient cases, dose distributions were compared using the gamma index method according to analysis protocols in the target volume. RESULTS: The comparison of error-introduced EPID-measured images to reference images showed no significant differences with 3%/3 mm gamma evaluation, though target coverage was strongly underestimated. Gamma tolerance of 2%/2 mm reported noticeable detection in EPID sensitivity for simulated errors in 3DCRT and IMRT techniques. The passing rates for 3DCRT, IMRT, and VMAT with 1%/1 mm in open field were 84.86%, 92.91%, and 98.75%, and by considering MLC-CIAO + 1 cm (threshold 5%), were 68.25%, 83.19%, and 95.29%, respectively. CONCLUSION: This study demonstrates the feasibility of EPID for detecting the interplay effects. We recommend using thin computed tomography slices and adding sufficient tumor margin in order to limit the dosimetric organ motion in hypofractionated irradiation with preserved plan quality. In the presence of respiratory and gastrointestinal motion, tighter criteria and consequently using local gamma evaluation should be considered, especially for VMAT. This methodology offers a substantial step forward in in vivo dosimetry and the potential to distinguish errors depending on the gamma tolerances. Thus, the approach/prototype provides a fast and easy quality assurance procedure for treatment delivery verification.

Gold nanoparticles promote a multimodal synergistic cancer therapy strategy by co-delivery of thermo-chemo-radio therapy.

Multimodal cancer therapy has become a new trend in clinical oncology due to potential generation of synergistic therapeutic effects. Herein, we propose a multifunctional nanoplatform comprising alginate hydrogel co-loaded with cisplatin and gold nanoparticles (abbreviated as ACA) for triple combination of photothermal therapy, chemotherapy and radiotherapy (thermo-chemo-radio therapy). The therapeutic potential of ACA was assessed in combination with 532 nm laser and 6 MV X-ray against KB human mouth epidermal carcinoma cells. The results demonstrated that tri-modal thermo-chemo-radio therapy using ACA induced a superior anticancer efficacy than mono- or bi-modality treatments. The intracellular reactive oxygen species (ROS) level in KB cells treated with tri-modal therapy was increased by 4.4-fold compared to untreated cells. The gene expression analysis demonstrated the up-regulation of Bax pro-apoptotic factor (by 4.5-fold) and the down-regulation of Bcl-2 anti-apoptotic factor (by 0.3-fold). The massive cell injury and the appearance of morphological characteristics of apoptosis were also evident in the micrograph of KB cells caused by thermo-chemo-radio therapy. Therefore, ACA nanocomplex can be offered as a promising platform to combine photothermal therapy, chemotherapy and radiotherapy, thereby affording an opportunity for combating chemo- and radio-resistant tumors.

Low-dose total skin electron beam therapy: Quality of life improvement and clinical impact of maintenance and adjuvant treatment in patients with mycosis fungoides or Sezary syndrome.

PURPOSE: Total skin electron beam therapy (TSEBT) has proved to be a safe and effective treatment for cutaneous T­cell lymphomas. Here, we examined the impact of this treatment on patient quality of life and outcome. PATIENTS AND METHODS: Forty-four patients with mycosis fungoides (MF) or Sezary syndrome (SS) received 48 TSEBT courses with a median dose of 12 Gy within the past 8 years at our institute. Patient and treatment characteristics for these cases as well as the impact of TSEBT on quality of life and duration of response were retrospectively analyzed and compared. RESULTS: The median modified Severity-Weighted Assessment Tool score before the start of TSEBT was 44. The overall response rate was 88%, with a complete response (CR) rate of 33%. The median follow-up period was 13 months. The median duration of response (DOR) and progression-free survival (PFS) for the entire cohort were 10 months and 9 months, respectively. Patient-reported symptom burden was measured with the Dermatological Life Quality Index and Skindex-29 questionnaires. The mean symptom reductions were 6 ± 8 (P = 0.005) and 21 ± 24 (P = 0.002), respectively. In the Functional Assessment of Cancer Therapy-General Assessment, significant improvements in the emotional (P = 0.03) domains were observed after TSEBT. Patients who received maintenance or adjuvant treatments had a longer PFS (P = 0.01). CONCLUSION: TSEBT improved disease symptoms and significantly improved emotional domains of patients' quality of life in patients with MF or SS. In addition, our results indicate that maintenance or adjuvant therapy after TSEBT may improve the PFS.

Using Image-guided Intensity-modulated Radiotherapy on Patients With Head and Neck Soft-tissue Sarcoma.

BACKGROUND: Image-guided intensity-modulated radiotherapy (IG-IMRT) is increasingly being used to treat patients with soft-tissue sarcoma (STS) of the head and neck. Although there is no comparison between IMRT and conventional radiation therapy (CRT) concerning their efficacy. In this analysis, we compared CRT and IMRT outcomes for head and neck STS. PATIENTS AND METHODS: Sixty-seven patients who underwent radiotherapy between 1994 and 2017 were identified. RESULTS: The median follow-up was 31 months. Of the 67 patients, 34% were treated with CRT technique and 66% with IG-IMRT. The locoregional relapse rate following IMRT was 21% versus 70% with CRT (p<0.001) and the 5-year locoregional control was 69% versus 28%, respectively (p=0.01). IG-IMRT was associated with non-significant, less acute, and chronic adverse events. In the multivariate analysis, a significant influence of radiation technique on locoregional control was confirmed (p=0.04). CONCLUSION: IG-IMRT seems to be associated both with higher locoregional control as well as lower acute and chronic toxicities.

ICRU report 91 on prescribing, recording, and reporting of stereotactic treatments with small photon beams : Statement from the DEGRO/DGMP working group stereotactic radiotherapy and radiosurgery.

The International Commission on Radiation Units and Measurements (ICRU) report 91 with the title "prescribing, recording, and reporting of stereotactic treatments with small photon beams" was published in 2017. This extensive publication covers different relevant aspects of stereotactic radiotherapy such as small field dosimetry, accuracy requirements for volume definition and planning algorithms, and the precise application of treatment by means of image guidance. Finally, recommendations for prescribing, recording and reporting are given.

Five-year effectiveness of low-dose-rate brachytherapy: comparisons with nomogram predictions in patients with non-metastatic prostate cancer presenting significant control of intra- and periprostatic disease.

PURPOSE: To assess the effectiveness of low-dose-rate (LDR) brachytherapy in patients with localized prostate cancer and to compare the outcome with predictions from Kattan and Partin nomograms at 60 months after seed implantation. MATERIAL AND METHODS: One thousand, one hundred and eighty-seven patients with localized prostate cancer at low-, intermediate-, or high-risk of progression received LDR brachytherapy using iodine-125 seeds with curative intent, applied as monotherapy or in combination with external beam radiation therapy (EBRT), and/or androgen deprivation therapy (ADT). At 60 months after seed implantation, data of 1,064 patients (1,058 alive + 6 who died of prostate cancer) were analyzed for biochemical progression-free survival (bPFS) based on prostate-specific antigen (PSA) levels using the Phoenix definition. Five-year bPFS probabilities were determined for various risk group classifications (d'Amico, Mt. Sinai, MSKCC/Seattle, NCCN). Outcomes were also compared to patient-individualized nomogram predictions of 5-year bPFS (Kattan 2002) and probability of organ-confined disease (Kattan 2002, Partin 2007). RESULTS: Overall, 93.3% (993/1,064) of the patients were free of biochemical progression within 5 years, while the average 5-year bPFS probability according to the Kattan nomogram was significantly lower (85%, p < 0.001). Outcomes were significantly better than Kattan nomogram predictions in the subgroup of patients with monotherapy as well as in patients additionally treated with EBRT. Comparison of the overall outcome with nomogram predictions for organ-confined disease (Kattan nomogram: 50%; Partin nomogram: 65%) revealed a significant probability of LDR brachytherapy to destroy periprostatic tumor spread (p < 0.001) in all risk group constellations, even in high-risk patients. CONCLUSIONS: The results indicate high effectiveness of LDR brachytherapy in all risk groups, significantly better than predicted with the Kattan nomogram in most subgroups. The significant superiority of LDR brachytherapy compared to nomogram predictions of organ-confined disease suggests that LDR brachytherapy effectively controls both intra- and periprostatic disease.

Treatment planning for spinal radiosurgery : A competitive multiplatform benchmark challenge.

PURPOSE: To investigate the quality of treatment plans of spinal radiosurgery derived from different planning and delivery systems. The comparisons include robotic delivery and intensity modulated arc therapy (IMAT) approaches. Multiple centers with equal systems were used to reduce a bias based on individual's planning abilities. The study used a series of three complex spine lesions to maximize the difference in plan quality among the various approaches. METHODS: Internationally recognized experts in the field of treatment planning and spinal radiosurgery from 12 centers with various treatment planning systems participated. For a complex spinal lesion, the results were compared against a previously published benchmark plan derived for CyberKnife radiosurgery (CKRS) using circular cones only. For two additional cases, one with multiple small lesions infiltrating three vertebrae and a single vertebra lesion treated with integrated boost, the results were compared against a benchmark plan generated using a best practice guideline for CKRS. All plans were rated based on a previously established ranking system. RESULTS: All 12 centers could reach equality (n = 4) or outperform (n = 8) the benchmark plan. For the multiple lesions and the single vertebra lesion plan only 5 and 3 of the 12 centers, respectively, reached equality or outperformed the best practice benchmark plan. However, the absolute differences in target and critical structure dosimetry were small and strongly planner-dependent rather than system-dependent. Overall, gantry-based IMAT with simple planning techniques (two coplanar arcs) produced faster treatments and significantly outperformed static gantry intensity modulated radiation therapy (IMRT) and multileaf collimator (MLC) or non-MLC CKRS treatment plan quality regardless of the system (mean rank out of 4 was 1.2 vs. 3.1, p = 0.002). CONCLUSIONS: High plan quality for complex spinal radiosurgery was achieved among all systems and all participating centers in this planning challenge. This study concludes that simple IMAT techniques can generate significantly better plan quality compared to previous established CKRS benchmarks.

In-vivo dosimetric analysis in total skin electron beam therapy.

BACKGROUND AND PURPOSE: Thermoluminescent dosimetry (TLD) is an important element of total skin electron beam therapy (TSEBT). In this study, we compare radiation dose distributions to provide data for dose variation across anatomic sites. MATERIALS AND METHODS: Retrospectively collected data on 85 patients with cutaneous lymphoma or leukemia underwent TSEBT were reviewed. Patients were irradiated on two linear accelerators, in one of two positions (standing, n = 77; reclined, n = 8) and 1830 in vivo TLD measurements were obtained for various locations on 76 patients. RESULTS: The TLD results showed that the two TSEBT techniques were dosimetrically heterogeneous. At several sites, the dose administered correlated with height, weight, and gender. After the first TLD measurement, fourteen patients (18%) required MU modification, with a mean 10% reduction (range, -25 to +35). Individual TLD results allowed us to customize the boost treatment for each patient. For patients who were evaluated in the standing position, the most common underdosed sites were the axilla, perineum/perianal folds, and soles (each receiving 69%, 20%, and 34% of the prescribed dose, respectively). For patients evaluated in a reclining position, surface dose distribution was more heterogeneous. The sites underdosed most commonly were the axilla and perineum/perianal folds (receiving less than one third of prescribed dose). Significant variables were detected with model building. CONCLUSION: TLD measurements were integral to quality assurance for TSEBT. Dose distribution at several anatomical sites correlated significantly with gender, height, and weight of the treated individual and might be predicted.

Low-dose total skin electron beam therapy for cutaneous lymphoma : Minimal risk of acute toxicities.

BACKGROUND: Low-dose total skin electron beam therapy (TSEBT) is attracting increased interest for the effective palliative treatment of primary cutaneous T­cell lymphoma (pCTCL). In this study, we compared toxicity profiles following various radiation doses. PATIENTS AND METHODS: We reviewed the records of 60 patients who underwent TSEBT for pCTCL between 2000 and 2016 at the University Hospital of Munster. The treatment characteristics of the radiotherapy (RT) regimens and adverse events (AEs) were then analyzed and compared. RESULTS: In total, 67 courses of TSEBT were administered to 60 patients. Of these patients, 34 (51%) received a standard dose with a median surface dose of 30 Gy and 33 patients (49%) received a low dose with the median surface dose of 12 Gy (7 salvage low-dose TSEBT courses were administered to 5 patients). After a median follow-up of 15 months, the overall AE rate was 100%, including 38 patients (57%) with grade 2 and 7 (10%) with grade 3 AEs. Patients treated with low-dose TSEBT had significantly fewer grade 2 AEs than those with conventional dose regimens (33 vs. 79%, P < 0.001). A lower grade 3 AE rate was also observed in patients who had received the low-dose regimen compared to those with the conventional dose regimens (6 vs. 15%, P = 0.78). Multiple/salvage low-dose TSEBT courses were not associated with an increased risk of acute AEs. CONCLUSION: Low-dose TSEBT regimens are associated with significantly fewer grade 2 acute toxicities compared with conventional doses of TSEBT. Repeated/Salvage low-dose TSEBT, however, appears to be tolerable and can even be applied safely in patients with cutaneous relapses.