Why "Radiation Oncology"

Radiotherapy continues to be a major treatment for solid tumours and is a cornerstone of modern oncology. The term 'radiation oncology' describes the integration of radiation therapy into the complexity of multi-modal therapy. Over the last ten years the crucial role of radiation therapy as part of multi-modality protocols in cancer care has been documented in numerous Phase III trials. Advances in treatment technology as well as the underlying biology of tumour resistance mechanisms will further strengthen the role of radiation oncology. The scientific role of radiation oncology is reflected by the increase in the number of papers related to radiation oncology in resources like Medline. In order to reflect the growing scientific importance of radiation oncology, radiation physics and radiation biology, we have initiated Radiation Oncology as the first open access journal in the field. Open access allows for a rapid and transparent publication process together with an unequalled opportunity to reach the widest reader spectrum possible

Evaluation of daily patient positioning for radiotherapy with a commercial 3D surface-imaging system (Catalyst (TM))

Background: To report our initial clinical experience with the novel surface imaging system Catalyst (TM) (C-RAD AB, Sweden) in connection with an Elekta Synergy linear accelerator for daily patient positioning in patients undergoing radiation therapy. Methods: We retrospectively analyzed the patient positioning of 154 fractions in 25 patients applied to thoracic, abdominal, and pelvic body regions. Patients were routinely positioned based on skin marks, shifted to the calculated isocenter position and treated after correction via cone beam CT which served as gold standard. Prior to CBCT an additional surface scan by the Catalyst (TM) system was performed and compared to a reference surface image cropped from the planning CT to obtain shift vectors for an optimal surface match. These shift vectors were subtracted from the vectors obtained by CBCT correction to assess the theoretical setup error that would have occurred if the patients had been positioned using solely the Catalyst (TM) system. The mean theoretical set up-error and its standard deviation were calculated for all measured fractions and the results were compared to patient positioning based on skin marks only. Results: Integration of the surface scan into the clinical workflow did not result in a significant time delay. Regarding the entire group, the mean setup error by using skin marks only was 0.0 +/- 2.1 mm in lateral, -0.4 +/- 2. 4 mm in longitudinal, and 1.1 +/- 2.6 mm vertical direction. The mean theoretical setup error that would have occurred using solely the Catalyst (TM) was -0.1 +/- 2.1 mm laterally, -1.8 +/- 5.4 mm longitudinally, and 1.4 +/- 3.2 mm vertically. No significant difference was found in any direction. For thoracic targets the mean setup error based on the Catalyst (TM) was 0.6 +/- 2.6 mm laterally, -5.0 +/- 7.9 mm longitudinally, and 0.5 +/- 3.2 mm vertically. For abdominal targets, the mean setup error was 0.3 +/- 2.2 mm laterally, 2.6 +/- 1.8 mm longitudinally, and 2.1 +/- 5.5 mm vertically. For pelvic targets, the setup error was -0.9 +/- 1.5 mm laterally, -1.7 +/- 2.8 mm longitudinally, and 1.6 +/- 2.2 mm vertically. A significant difference between Catalyst (TM) and skin mark based positioning was only observed in longitudinal direction of pelvic targets. Conclusion: Optical surface scanning using Catalyst (TM) seems potentially useful for daily positioning at least to complement usual imaging modalities in most patients with acceptable accuracy, although a significant improvement compared to skin mark based positioning could not be derived from the evaluated data. However, this effect seemed to be rather caused by the unexpected high accuracy of skin mark based positioning than by inaccuracy using the Catalyst (TM). Further on, surface registration in longitudinal axis seemed less reliable especially in pelvic localization. Therefore further prospective evaluation based on strictly predefined protocols is needed to determine the optimal scanning approaches and parameters

Combination of celecoxib with percutaneous radiotherapy in patients with localised prostate cancer – a phase I study

BACKGROUND: Current approaches for the improvement of bNED for prostate cancer patients treated with radiotherapy mainly focus on dose escalation. However molecularly targeted approaches may also turn out to be of value. In this regard cyclooxygenase (COX)-2 inhibitors have been shown to exert some anti-tumour activities in human prostate cancer in vivo and in vitro. Although in vitro data indicated that the combination of COX-2 inhibition and radiation was not associated with an increased toxicity, we performed a phase I trial using high dose celecoxib together with percutaneous radiation therapy. METHODS: In order to rule out any increases of more than 20% incidence for a given side effect level 22 patients were included in the trial. Celecoxib was given 400 mg twice daily with onset of the radiation treatment. Risk adapted radiation doses were between 70 and 74 Gy standard fractionation. RTOG based gastrointestinal (GI) and genitourinary (GU) acute toxicity scoring was performed weekly during radiation therapy, at six weeks after therapy and three month after completing radiation treatment. RESULTS: Generally no major increase in the level and incidence of side effects potentially caused by the combined treatment was observed. In two cases a generalised skin rash occurred which immediately resolved upon discontinuation of the drug. No grade 3 and 4 toxicity was seen. Maximal GI toxicity grade 1 and 2 was observed in 85% and 10%, respectively. In terms of GU toxicity 80 % of the patients experienced a grade 1 toxicity and 10 % had grade 2 symptoms. CONCLUSION: The combination of irradiation to the prostate with concurrent high dose celecoxib was not associated with an increased level of side effects

Feasibility of CycleGAN enhanced low dose CBCT imaging for prostate radiotherapy dose calculation

Daily cone beam computed tomography (CBCT) imaging during the course of fractionated radiotherapy treatment can enable online adaptive radiotherapy but also expose patients to a non-negligible amount of radiation dose. This work investigates the feasibility of low dose CBCT imaging capable of enabling accurate prostate radiotherapy dose calculation with only 25% projections by overcoming under-sampling artifacts and correcting CT numbers by employing cycle-consistent generative adversarial networks (cycleGAN). Uncorrected CBCTs of 41 prostate cancer patients, acquired with ∼350 projections (CBCTorg), were retrospectively under-sampled to 25% dose images (CBCTLD) with only ∼90 projections and reconstructed using Feldkamp–Davis–Kress. We adapted a cycleGAN including shape loss to translate CBCTLD into planning CT (pCT) equivalent images (CBCTLD_GAN). An alternative cycleGAN with a generator residual connection was implemented to improve anatomical fidelity (CBCTLD_ResGAN). Unpaired 4-fold cross-validation (33 patients) was performed to allow using the median of 4 models as output. Deformable image registration was used to generate virtual CTs (vCT) for Hounsfield units (HU) accuracy evaluation on 8 additional test patients. Volumetric modulated arc therapy plans were optimized on vCT, and recalculated on CBCTLD_GAN and CBCTLD_ResGAN to determine dose calculation accuracy. CBCTLD_GAN, CBCTLD_ResGAN and CBCTorg were registered to pCT and residual shifts were analyzed. Bladder and rectum were manually contoured on CBCTLD_GAN, CBCTLD_ResGAN and CBCTorg and compared in terms of Dice similarity coefficient (DSC), average and 95th percentile Hausdorff distance (HDavg, HD95). The mean absolute error decreased from 126 HU for CBCTLD to 55 HU for CBCTLD_GAN and 44 HU for CBCTLD_ResGAN. For PTV, the median differences of D98%, D50% and D2% comparing both CBCTLD_GAN to vCT were 0.3%, 0.3%, 0.3%, and comparing CBCTLD_ResGAN to vCT were 0.4%, 0.3% and 0.4%. Dose accuracy was high with both 2% dose difference pass rates of 99% (10% dose threshold). Compared to the CBCTorg-to-pCT registration, the majority of mean absolute differences of rigid transformation parameters were less than 0.20 mm/0.20°. For bladder and rectum, the DSC were 0.88 and 0.77 for CBCTLD_GAN and 0.92 and 0.87 for CBCTLD_ResGAN compared to CBCTorg, and HDavg were 1.34 mm and 1.93 mm for CBCTLD_GAN, and 0.90 mm and 1.05 mm for CBCTLD_ResGAN. The computational time was ∼2 s per patient. This study investigated the feasibility of adapting two cycleGAN models to simultaneously remove under-sampling artifacts and correct image intensities of 25% dose CBCT images. High accuracy on dose calculation, HU and patient alignment were achieved. CBCTLD_ResGAN achieved better anatomical fidelity

Longitudinal changes of blood parameters and weight in inoperable stage III NSCLC patients treated with concurrent chemoradiotherapy followed by maintenance treatment with durvalumab

Background Investigating dynamic changes in blood-parameters and weight in patients with locally advanced non-small cell lung cancer (NSCLC) receiving durvalumab maintenance therapy after chemoradiotherapy (cCRT). Laboratory outcomes were determined based on the number of durvalumab administrations received. Methods Twenty-two patients completed platinum-based cCRT followed by maintenance treatment with durvalumab. Different parameters such as hemoglobin (Hb), leukocytes, Lactate dehydrogenase (LDH), C-reactive protein (CRP), body weight and albumin were analyzed before cCRT, after cCRT, 3, 6, 9 and 12 months after starting durvalumab maintenance. Results Sixteen (72.7%) patients were male; twelve (54.5%) and fifteen (68.2%) patients had non-squamous histology and Union for International Cancer Control (UICC) stage IIIB-C disease, respectively. Median follow-up time was 24.4 months; 12- and 18-months- progression-free and overall-survival rates were 55.0% and 45.0 as well as 90.2 and 85.0%, respectively. During maintenance treatment Hb increased by 1.93 mg/dl (17.53%) after 9 months ( p < 0.001) and 2.02 mg/dl (18.46%) after 12 months compared to the start of durvalumab ( p < 0.001). LDH decreased by 29.86 U/l (− 11.74%) after 3 months ( p = 0.022). Receipt of at least 12 cycles of durvalumab was beneficial in terms of Hb-recovery (Hb 6 months: 12.64 vs. 10.86 [mg/dl]; Hb 9 months: 13.33 vs 11.74 [mg/dl]; ( p = 0.03)). Median weight change [kilogram (kg)] was + 6.06% (range: − 8.89 − + 18.75%) after 12 months. The number of durvalumab cycles significantly correlated with total weight gain [kg] (Spearman-Rho-correlation: r = 0.502*). Conclusion In the investigated cohort, no severe hematologic toxicity occurred by laboratory blood tests within 1 year of durvalumab maintenance therapy after cCRT for unresectable stage III NSCLC. Receiving at least 12 cycles of durvalumab appears to have a significant effect on recovery of hemoglobin levels and body weight

Irradiation specifically sensitises solid tumour cell lines to TRAIL mediated apoptosis

BACKGROUND: TRAIL (tumor necrosis factor related apoptosis inducing ligand) is an apoptosis inducing ligand with high specificity for malignant cell systems. Combined treatment modalities using TRAIL and cytotoxic drugs revealed highly additive effects in different tumour cell lines. Little is known about the efficacy and underlying mechanistic effects of a combined therapy using TRAIL and ionising radiation in solid tumour cell systems. Additionally, little is known about the effect of TRAIL combined with radiation on normal tissues. METHODS: Tumour cell systems derived from breast- (MDA MB231), lung--(NCI H460) colorectal--(Colo 205, HCT-15) and head and neck cancer (FaDu, SCC-4) were treated with a combination of TRAIL and irradiation using two different time schedules. Normal tissue cultures from breast, prostate, renal and bronchial epithelia, small muscle cells, endothelial cells, hepatocytes and fibroblasts were tested accordingly. Apoptosis was determined by fluorescence microscopy and western blot determination of PARP processing. Upregulation of death receptors was quantified by flow cytometry. RESULTS: The combined treatment of TRAIL with irradiation strongly increased apoptosis induction in all treated tumour cell lines compared to treatment with TRAIL or irradiation alone. The synergistic effect was most prominent after sequential application of TRAIL after irradiation. Upregulation of TRAIL receptor DR5 after irradiation was observed in four of six tumour cell lines but did not correlate to tumour cell sensitisation to TRAIL. TRAIL did not show toxicity in normal tissue cell systems. In addition, pre-irradiation did not sensitise all nine tested human normal tissue cell cultures to TRAIL. CONCLUSIONS: Based on the in vitro data, TRAIL represents a very promising candidate for combination with radiotherapy. Sequential application of ionising radiation followed by TRAIL is associated with an synergistic induction of cell death in a large panel of solid tumour cell lines. However, TRAIL receptor upregulation may not be the sole mechanism by which sensitation to TRAIL after irradiation is induced

Effectiveness and tolerability of radiotherapy for patients with indolent non-Hodgkin's lymphoma: a monocenter analysis

To analyze the effectiveness and toxicities of radiotherapy in indolent non-Hodgkin's lymphoma (iNHL) patients treated in our institution. Patients with iNHL treated with radiotherapy between 1999 and 2016 were included. The primary endpoint was progression-free survival (PFS). Secondary endpoints were local control (LC), overall survival (OS) and toxicities. PFS, LC, and OS were analyzed using Kaplan-Meier method. Log-rank test was used to investigate the differences between subgroups. Cox proportional hazard model was used for univariate continuous analysis. Seventy-five patients were identified in our institutional database between 1999 and 2016. Fifty-eight (77.3%) had stage I after Ann-Arbor and 17 patients (22.7%) had stage II. The median follow-up was 87~months (95% CI 72-102~months). Median single dose per fraction was 2.0~Gy (range 1.5-2~Gy) and median total dose was 30.6~Gy (range 16-45~Gy). Radiotherapy was performed in 2D (n = 10; 13.3%), 3D (n = 63; 84.0%) and VMAT (n = 2; 2.7%) techniques, respectively. The median PFS was 14.0~years (95% CI 8.3-19.7~years). The estimated PFS after 5 and 10~years were 73.0% and 65.5% in Kaplan-Meier analysis, respectively. The 5- and 10-year LC were 94.9% and 92.3%, respectively. The 5- and 10-year OS were 88.6% and 73.9%. In univariate analyses of PFS, younger patients (≤ 60~years old) had significantly superior PFS to those older than 60~years old (5-year PFS 81.9% vs. 65.1%, p = 0.021). Dose escalation > 36.0~Gy had no prognostic influence in term of PFS (p = 0.425). Extranodal involvement, stage and histology had no prognostic impact on PFS. Depending on the site of lymphomas, the most common acute side effects were: dermatitis CTCAE° I-II (8.0%), xerostomia CTC° I (8.0%), cataract CTC° I (12.0%) and dry eyes CTC° I-II (14.6%). No adverse event CTC° III was reported. Most acute side effects recovered at 3 to 6~months after radiotherapy except for CTC° I cataract and xerostomia. Local Radiotherapy was highly effective for treatment of early stage iNHL with no serious side effects in our cohort. The most acute CTCAE° I-II side effects recovered 3 to 6~months later. Technique advances seem to have further improved effectiveness and tolerability of radiotherapy.Trial registration: Local ethics committee of Ludwig-Maximilian-University (LMU) Munich approved this retrospective analysis on the May 7th, 2019 (Nr. 19-137)

Targeted therapy of the XIAP/proteasome pathway overcomes TRAIL-resistance in carcinoma by switching apoptosis signaling to a Bax/Bak-independent 'type I' mode

TRAIL is a promising anticancer agent, capable of inducing apoptosis in a wide range of treatment-resistant tumor cells. In 'type II' cells, the death signal triggered by TRAIL requires amplification via the mitochondrial apoptosis pathway. Consequently, deregulation of the intrinsic apoptosis-signaling pathway, for example, by loss of Bax and Bak, confers TRAIL-resistance and limits its application. Here, we show that despite resistance of Bax/Bak double-deficient cells, TRAIL-treatment resulted in caspase-8 activation and complete processing of the caspase-3 proenzymes. However, active caspase-3 was degraded by the proteasome and not detectable unless the XIAP/proteasome pathway was inhibited. Direct or indirect inhibition of XIAP by RNAi, Mithramycin A or by the SMAC mimetic LBW-242 as well as inhibition of the proteasome by Bortezomib overcomes TRAIL-resistance of Bax/Bak double-deficient tumor cells. Moreover, activation and stabilization of caspase-3 becomes independent of mitochondrial death signaling, demonstrating that inhibition of the XIAP/proteasome pathway overcomes resistance by converting 'type II' to 'type I' cells. Our results further demonstrate that the E3 ubiquitin ligase XIAP is a gatekeeper critical for the 'type II' phenotype. Pharmacological manipulation of XIAP therefore is a promising strategy to sensitize cells for TRAIL and to overcome TRAIL-resistance in case of central defects in the intrinsic apoptosis-signaling pathway