Retrospective assessment of a single fiducial marker tracking regimen with robotic stereotactic body radiation therapy for liver tumours.

AIM: To investigate tumour motion tracking uncertainties in the CyberKnife Synchrony system with single fiducial marker in liver tumours. BACKGROUND: In the fiducial-based CyberKnife real-time tumour motion tracking system, multiple fiducial markers are generally used to enable translation and rotation corrections during tracking. However, sometimes a single fiducial marker is employed when rotation corrections are not estimated during treatment. MATERIALS AND METHODS: Data were analysed for 32 patients with liver tumours where one fiducial marker was implanted. Four-dimensional computed tomography (CT) scans were performed to determine the internal target volume (ITV). Before the first treatment fraction, the CT scans were repeated and the marker migration was determined. Log files generated by the Synchrony system were obtained after each treatment and the correlation model errors were calculated. Intra-fractional spine rotations were examined on the spine alignment images before and after each treatment. RESULTS: The mean (standard deviation) ITV margin was 4.1 (2.3) mm, which correlated weakly with the distance between the fiducial marker and the tumour. The mean migration distance of the marker was 1.5 (0.7) mm. The overall mean correlation model error was 1.03 (0.37) mm in the radial direction. The overall mean spine rotations were 0.27° (0.31), 0.25° (0.22), and 0.23° (0.26) for roll, pitch, and yaw, respectively. The treatment time was moderately associated with the correlation model errors and weakly related to spine rotation in the roll and yaw planes. CONCLUSIONS: More caution and an additional safety margins are required when tracking a single fiducial marker.

Fractionated stereotactic radiotherapy plus bevacizumab after response to bevacizumab plus irinotecan as a rescue treatment for high-grade gliomas.

AIM: To evaluate the possibility of implementing a new scheme of rescue treatment after relapse or progression of high-grade glioma (HGG) treated at the first-line with bevacizumab and irinotecan (BVZ+CPT11), evaluating the response and toxicity of associating BVZ and fractionated stereotactic radiotherapy (BVZ+FSRT). MATERIALS AND METHODS: We retrospectively analysed data from 59 patients with relapse of HGG. Nine patients with HGG relapse after treatment using the Stupp protocol that were treated with BVZ+CPT11 for progression between July 2007 and August 2012, after which the response was assessed according to the Revised Assessment in Neuro-Oncology (RANO) criteria. BVZ was administered at a dose of 10 mg/kg and FSRT up to a prescribed dose of 30 Gy, 500 cGy per fraction, three days a week. The median follow-up was 38 months. RESULTS: The treatment was well-tolerated by all patients. The response after nuclear magnetic resonance imaging (MRI) at 3-6 months was progression in two patients, stable disease in four, and three patients had a partial response. The median overall survival (OS) from diagnosis until death or the last control was 36.8 months. The median progression-free survival (PFS) was 10.8 months. The results from tumour sub-group analysis indicated that the PFS was not statistically significant although it seemed that it was higher in grade-III. The OS was higher in grade-III gliomas. CONCLUSIONS: The combination of BVZ+FSRT as a second-line HGG relapse rescue treatment is well-tolerated and seems to offer promising results. We believe that multi-centre prospective studies are needed to determine the long-term efficacy and toxicity of this therapeutic approach.

Time- and dose-dependent volume decreases in subcortical grey matter structures of glioma patients after radio(chemo)therapy.

Background and purpose: Radiotherapy (RT) is an adjuvant treatment option for glioma patients. Side effects include tissue atrophy, which might be a contributing factor to neurocognitive decline after treatment. The goal of this study was to determine potential atrophy of the hippocampus, amygdala, thalamus, putamen, pallidum and caudate nucleus in glioma patients having undergone magnetic resonance imaging (MRI) before and after RT. Materials and methods: Subcortical volumes were measured using T1-weighted MRI from patients before RT (N = 91) and from longitudinal follow-ups acquired in three-monthly intervals (N = 349). The volumes were normalized to the baseline values, while excluding structures touching the clinical target volume (CTV) or abnormal tissue seen on FLAIR imaging. A multivariate linear effects model was used to determine if time after RT and mean RT dose delivered to the corresponding structures were significant predictors of tissue atrophy. Results: The hippocampus, amygdala, thalamus, putamen, and pallidum showed significant atrophy after RT as function of both time after RT and mean RT dose delivered to the corresponding structure. Only the caudate showed no dose or time dependant atrophy. Conversely, the hippocampus was the structure with the highest atrophy rate of 5.2 % after one year and assuming a mean dose of 30 Gy. Conclusion: The hippocampus showed the highest atrophy rates followed by the thalamus and the amygdala. The subcortical structures here found to decrease in volume indicative of radiosensitivity should be the focus of future studies investigating the relationship between neurocognitive decline and RT.

Feasibility of biology-guided radiotherapy using PSMA-PET to boost to dominant intraprostatic tumour.

Background: Biology-guided radiotherapy (BgRT) delivers dose to tumours triggered from positron emission tomography (PET) detection. Prostate specific membrane antigen (PSMA) PET uptake is abundant in the dominant intraprostatic lesion (DIL). This study investigates the feasibility of BgRT to PSMA-avid subvolume in the prostate region. Methods: Patients enrolled in the prospective randomized trial ProPSMA at our institution were included (ID: ANZCTR12617000005358). Gross tumour volumes (GTVs) were delineated on the PET component of a PET/CT scan from a standardized uptake value (SUV) threshold technique. Suitability for BgRT requires a strong signal-to-background ratio with a surrounding tissue free of significant PSMA uptake. The signal-to-background ratio was quantified from the calculation of the normalized SUV (nSUV), defined as the ratio between SUVmax within the GTV and SUVmean inside a 3D margin expansion of the GTV. The PSMA distribution surrounding the tumour was quantified as a function of the distance from the GTV. Results: In this cohort of 84 patients, 83 primary tumours were included. Prostate volume ranged from 19 cm3 to 148 cm3 (median = 52 cm3; IQR = 39 cm3 - 63 cm3). SUVmax inside the prostate was between 2 and 125 (median = 19; IQR = 11 - 30). More than 50% of GTVs generated with threshold between 25%SUVmax (median volume = 10.0 cm3; IQR = 4.5 cm3 - 20.0 cm3) and 50%SUVmax (median volume = 1.9 cm3; IQR = 1.1 cm3 - 3.8 cm3) were suitable for BgRT by using nSUV ≥ 3 and a margin expansion of 5 mm. Conclusions: It is feasible to identify GTVs suitable for BgRT in the prostate. These GTVs are characterized by a strong signal-to-background ratio and a surrounding tissue free of PSMA uptake.

GEC ESTRO ACROP consensus recommendations for contact brachytherapy for rectal cancer.

PURPOSE: To issue consensus recommendations for contact X-Ray brachytherapy (CXB) for rectal cancer covering pre-treatment evaluation, treatment, dosimetric issues and follow-up. These recommendations cover CXB in the definitive and palliative setting. METHODS: Members of GEC ESTRO with expertise in rectal CXB issued consensus-based recommendations for CXB based on literature review and clinical experience. Levels of evidence according to the Oxford Centre for Evidence based medicine guidance are presented where possible. RESULTS: The GEC ESTRO ACROP consensus recommendations support the use of CXB to increase the chances of clinical complete remission and cure for patients who are elderly with high surgical risk, surgically unfit or refusing surgery. For palliative treatment, the use of CXB is recommended for symptomatic relief and disease control. The use of CXB in an organ-preservation setting in surgically fit patients is recommended within the setting of a clinical trial or registry. CONCLUSIONS: The GEC ESTRO ACROP recommendations for CXB are provided. Recommendations towards standardisation of reporting and prescription are given. Practitioners are encouraged to follow these recommendations and to develop further clinical trials to examine this treatment modality and increase the evidence base for its use. The routine collection of outcomes both clinical and patient-reported is also encouraged.

Repeatability of radiotherapy dose-painting prescriptions derived from a multiparametric magnetic resonance imaging model of glioblastoma infiltration.

Background and purpose: Glioblastoma (GBM) patients have a dismal prognosis. Tumours typically recur within months of surgical resection and post-operative chemoradiation. Multiparametric magnetic resonance imaging (mpMRI) biomarkers promise to improve GBM outcomes by identifying likely regions of infiltrative tumour in tumour probability (TP) maps. These regions could be treated with escalated dose via dose-painting radiotherapy to achieve higher rates of tumour control. Crucial to the technical validation of dose-painting using imaging biomarkers is the repeatability of the derived dose prescriptions. Here, we quantify repeatability of dose-painting prescriptions derived from mpMRI. Materials and methods: TP maps were calculated with a clinically validated model that linearly combined apparent diffusion coefficient (ADC) and relative cerebral blood volume (rBV) or ADC and relative cerebral blood flow (rBF) data. Maps were developed for 11 GBM patients who received two mpMRI scans separated by a short interval prior to chemoradiation treatment. A linear dose mapping function was applied to obtain dose-painting prescription (DP) maps for each session. Voxel-wise and group-wise repeatability metrics were calculated for parametric, TP and DP maps within radiotherapy margins. Results: DP maps derived from mpMRI were repeatable between imaging sessions (ICC > 0.85). ADC maps showed higher repeatability than rBV and rBF maps (Wilcoxon test, p = 0.001). TP maps obtained from the combination of ADC and rBF were the most stable (median ICC: 0.89). Conclusions: Dose-painting prescriptions derived from a mpMRI model of tumour infiltration have a good level of repeatability and can be used to generate reliable dose-painting plans for GBM patients.

The use of tumour markers in oesophageal cancer to quantify setup errors and baseline shifts during treatment.

PURPOSE: To prospectively evaluate the feasibility of solid gold marker placement in oesophageal cancer patients and to quantify inter-fractional and intra-fractional (baseline shift) marker motion during radiation treatment. Radiotherapy target margins and matching strategies were investigated. MATERIALS/METHODS: Thirty-four markers were implanted by echo-endoscopy in 10 patients. Patients received a planning 4D CT, daily pre-treatment cone-beam CT (CBCT) and a post-treatment CBCT for at least five fractions. For fractions with both pre- and post-treatment CBCT, marker displacement between planning CT and pre-treatment CBCT (inter-fractional) and between pre-treatment and post-treatment CBCT (intra-fractional; only for fractions without rotational treatment couch correction) were calculated in left-right (LR), cranio-caudal (CC) and anterior-posterior (AP) direction after bony-anatomy and soft-tissue matching. Systematic/random setup errors were estimated; treatment margins were calculated. RESULTS: No serious adverse events occurred. Twenty-three (67.6%) markers were visible during radiotherapy (n = 3 middle oesophagus, n = 16 distal oesophagus, n = 4 proximal stomach). Margins for inter-fractional displacement after bony-anatomy match depended on the localisation of the primary tumour and were 11.2 mm (LR), 16.4 mm (CC) and 8.2 mm (AP) for distal markers. Soft-tissue matching reduced the CC margin for these markers (16.4 mm to 10.5 mm). The mean intra-fractional shift of 12 distal markers was 0.4 mm (LR), 2.3 mm (CC) and 0.7 mm (AP). Inclusion of this shift resulted in treatment margins for distal markers of 12.8 mm (LR), 17.3 mm (CC) and 10.4 mm (AP) after bony-anatomy matching and 12.4 mm (LR), 11.4 mm (CC) and 9.7 mm (AP) after soft-tissue matching. CONCLUSION: This study demonstrated that the implantation of gold markers was safe, albeit less stable compared to other marker types. Inter-fractional motion was largest cranio-caudally for markers in the distal oesophagus, which was reduced after soft-tissue compared to bony-anatomy matching. The impact of intra-fractional baseline shifts on margin calculation was rather small.

Efficacy and feasibility of re-irradiation using carbon ions for pancreatic cancer that recurs after carbon-ion radiotherapy.

BACKGROUND AND PURPOSE: Patients who receive carbon-ion radiotherapy (C-ion RT) for primary pancreatic cancer may experience locoregional recurrence; however, the treatment options for such patients are limited. We aimed to investigate the feasibility and efficacy of carbon-ion re-irradiation for patients with pancreatic cancer who experienced recurrence after initial C-ion RT. MATERIALS AND METHODS: Twenty-one patients with recurrent pancreatic cancer who underwent repeat C-ion RT between December 2010 and November 2016 at our institute were retrospectively evaluated. The sites of post-initial C-ion RT failure were in-field central in 16 patients (76.2%) and marginal in 5 (23.8%). The median doses of initial and repeat C-ion RT were both 52.8 Gy (relative biological effectiveness [RBE]). Thirteen patients (61.9%) received concurrent chemotherapy with re-irradiation, while 11 (52.4%) received adjuvant chemotherapy. RESULTS: The median follow-up period after re-irradiation was 11 months. The 1-year local control, progression-free survival, and overall survival rates were 53.5%, 24.5%, and 48.7%, respectively. Toxicity data was obtained from the patients' charts. Only 1 patient (4.8%) developed grade 3 acute toxicities and none developed grade ≥3 late toxicities. Univariate analysis indicated that patients who received adjuvant chemotherapy had significantly improved local control rates compared with those who did not; the 1-year local control rates were 80.0% and 0.0%, respectively (P = 0.0469). CONCLUSION: Repeating C-ion RT may be a reasonable option with tolerable toxicity for patients with recurrent pancreatic cancers. Adjuvant chemotherapy appears to improve the local control rate. This is the first study to examine re-irradiation using C-ion for recurrent pancreatic cancer after initial C-ion RT.

Analysis of dose using CBCT and synthetic CT during head and neck radiotherapy: A single centre feasibility study.

OBJECTIVES: The study aimed to assess the suitability of deformable image registration (DIR) software to generate synthetic CT (sCT) scans for dose verification during radiotherapy to the head and neck. Planning and synthetic CT dose volume histograms were compared to evaluate dosimetric changes during the treatment course. METHODS: Eligible patients had locally advanced (stage III, IVa and IVb) oropharyngeal cancer treated with primary radiotherapy. Weekly CBCT images were acquired post treatment at fractions 1, 6, 11, 16, 21 and 26 over a 30 fraction treatment course. Each CBCT was deformed with the planning CT to generate a sCT which was used to calculate the dose at that point in the treatment. A repeat planning CT2 was acquired at fraction 16 and deformed with the fraction 16 CBCT to compare differences between the calculations mid-treatment. RESULTS: 20 patients were evaluated generating 138 synthetic CT sets. The single fraction mean dose to PTV_HR between the synthetic and planning CT did not vary, although dose to 95% of PTV_HR was smaller at week 6 compared to planning (difference 2.0%, 95% CI (0.8 to 3.1), p = 0.0). There was no statistically significant difference in PRV_brainstem or PRV_spinal cord maximum dose, although greater variation using the sCT calculations was reported. The mean dose to structures based on the fraction 16 sCT and CT2 scans were similar. CONCLUSIONS: Synthetic CT provides comparable dose calculations to those of a repeat planning CT; however the limitations of DIR must be understood before it is applied within the clinical setting.

Nitroglycerin as a radiosensitizer in non-small cell lung cancer: Results of a prospective imaging-based phase II trial.

BACKGROUND: Nitroglycerin is proposed as an agent to reduce tumour hypoxia by improving tumour perfusion. We investigated the potential of nitroglycerin as a radio-sensitizer in non-small cell lung cancer (NSCLC) and the potential of functional imaging for patient selection. MATERIAL AND METHODS: Trial NCT01210378 is a single arm phase II trial, designed to detect 15% improvement in 2-year overall survival (primary endpoint) in stage IB-IV NSCLC patients treated with radical (chemo-) radiotherapy and a Transiderm-Nitro 5 patch during radiotherapy. Patients underwent dynamic contrast-enhanced CTs (DCE-CT) and HX4 (hypoxia) PET/CTs before and after nitroglycerin. Secondary endpoints were progression-free survival, toxicity and the prognostic value of tumour perfusion/hypoxia at baseline and after nitroglycerin. RESULTS: The trial stopped after a futility analysis after 42 patients. At median follow-up of 41 months, two-year and median OS were 58% (95% CI: 44-78%) and 38 months (95% CI: 22-54 months), respectively. Nitroglycerin could not reduce tumour hypoxia. DCE-CT parameters did not correlate with OS, whereas hypoxic tumours had a worse OS (p = 0.029). Changes in high-uptake fraction of HX4 and tumour blood flow were negatively correlated (r = -0.650, p = 0.022). The heterogeneity in treatment modalities and patient characteristics combined with a small sample size made further subgroup analysis of survival results impossible. Toxicity related to nitroglyerin was limited to headache (17%) and hypotension (2.4%). CONCLUSION: Nitroglycerin did not improve OS of NSCLC patients treated with (chemo-)radiotherapy. A general ability of nitroglycerin to reduce hypoxia was not shown.

Gross tumour delineation on computed tomography and positron emission tomography-computed tomography in oesophageal cancer: A nationwide study.

BACKGROUND AND PURPOSE: Accurate delineation of the primary tumour is vital to the success of radiotherapy and even more important for successful boost strategies, aiming for improved local control in oesophageal cancer patients. Therefore, the aim was to assess delineation variability of the gross tumour volume (GTV) between CT and combined PET-CT in oesophageal cancer patients in a multi-institutional study. MATERIALS AND METHODS: Twenty observers from 14 institutes delineated the primary tumour of 6 cases on CT and PET-CT fusion. The delineated volumes, generalized conformity index (CIgen) and standard deviation (SD) in position of the most cranial/caudal slice over the observers were evaluated. For the central delineated region, perpendicular distance between median surface GTV and each individual GTV was evaluated as in-slice SD. RESULTS: After addition of PET, mean GTVs were significantly smaller in 3 cases and larger in 1 case. No difference in CIgen was observed (average 0.67 on CT, 0.69 on PET-CT). On CT cranial-caudal delineation variation ranged between 0.2 and 1.5 cm SD versus 0.2 and 1.3 cm SD on PET-CT. After addition of PET, the cranial and caudal variation was significantly reduced in 1 and 2 cases, respectively. The in-slice SD was on average 0.16 cm in both phases. CONCLUSION: In some cases considerable GTV delineation variability was observed at the cranial-caudal border. PET significantly influenced the delineated volume in four out of six cases, however its impact on observer variation was limited.