Robustness assessment of clinical adaptive proton and photon radiotherapy for oesophageal cancer in the model-based approach.

PURPOSE: In the Netherlands, oesophageal cancer (EC) patients are selected for intensity modulated proton therapy (IMPT) using the expected normal tissue complication probability reduction (ΔNTCP) when treating with IMPT compared to volumetric modulated arc therapy (VMAT). In this study, we evaluate the robustness of the first EC patients treated with IMPT in our clinic in terms of target and organs-at-risk (OAR) dose with corresponding NTCP, as compared to VMAT. MATERIALS AND METHODS: For 20 consecutive EC patients, clinical IMPT and VMAT plans were created on the average planning 4DCT. Both plans were robustly evaluated on weekly repeated 4DCTs and if target coverage degraded, replanning was performed. Target coverage was evaluated for complete treatment trajectories with and without replanning. The planned and accumulated mean lung dose (MLD) and mean heart dose (MHD) were additionally evaluated and translated into NTCP. RESULTS: Replanning in the clinic was performed more often for IMPT (15x) than would have been needed for VMAT (8x) (p = 0.11). Both adaptive treatments would have resulted in adequate accumulated target dose coverage. Replanning in the first week of treatment had most clinical impact, as anatomical changes resulting in insufficient accumulated target coverage were already observed at this stage. No differences were found in MLD between the planned dose and the accumulated dose. Accumulated MHD differed from the planned dose (p < 0.001), but since these differences were similar for VMAT and IMPT (1.0 and 1.5 Gy, respectively), the ΔNTCP remained unchanged. CONCLUSION: Following an adaptive clinical workflow, adequate target dose coverage and stable OAR doses with corresponding NTCPs was assured for both IMPT and VMAT.

Development of a consensus-based delineation guideline for locally recurrent rectal cancer.

BACKGROUND AND PURPOSE: Neoadjuvant chemoradiotherapy (nCRT) is used in locally recurrent rectal cancer (LRRC) to increase chances of a radical surgical resection. Delineation in LRRC is hampered by complex disease presentation and limited clinical exposure. Within the PelvEx II trial, evaluating the benefit of chemotherapy preceding nCRT for LRRC, a delineation guideline was developed by an expert LRRC team. MATERIALS AND METHODS: Eight radiation oncologists, from Dutch and Swedish expert centres, participated in two meetings, delineating GTV and CTV in six cases. Regions at-risk for re-recurrence or irradical resection were identified by eleven expert surgeons and one expert radiologist. Target volumes were evaluated multidisciplinary. Inter-observer variation was analysed. RESULTS: Inter-observer variation in delineation of LRRC appeared large. Multidisciplinary evaluation per case is beneficial in determining target volumes. The following consensus regarding target volumes was reached. GTV should encompass all tumour, including extension into OAR if applicable. If the tumour is in fibrosis, GTV should encompass the entire fibrotic area. Only if tumour can clearly be distinguished from fibrosis, GTV may be reduced, as long as the entire fibrotic area is covered by the CTV. CTV is GTV with a 1 cm margin and should encompass all at-risk regions for irradical resection or re-recurrence. CTV should not be adjusted towards other organs. Multifocal recurrences should be encompassed in one CTV. Elective nodal delineation is only advised in radiotherapy-naïve patients. CONCLUSION: This study provides a first consensus-based delineation guideline for LRRC. Analyses of re-recurrences is needed to understand disease behaviour and to optimize delineation guidelines accordingly.

Towards the clinical implementation of intensity-modulated proton therapy for thoracic indications with moderate motion: Robust optimised plan evaluation by means of patient and machine specific information.

PURPOSE: Compared to volumetric modulated arc therapy (VMAT), clinical benefits are anticipated when treating thoracic tumours with intensity-modulated proton therapy (IMPT). However, the current concern of plan robustness as a result of motion hampers its wide clinical implementation. To define an optimal protocol to treat lung and oesophageal cancers, we present a comprehensive evaluation of IMPT planning strategies, based on patient 4DCTs and machine log files. MATERIALS AND METHODS: For ten lung and ten oesophageal cancer patients, a planning 4DCT and weekly repeated 4DCTs were collected. For these twenty patients, the CTV volume and motion were assessed based on the 4DCTs. In addition to clinical VMAT plans, layered rescanned 3D and 4D robust optimised IMPT plans (IMPT_3D and IMPT_4D respectively) were generated, and approved clinically, for all patients. The IMPT plans were then delivered in dry runs at our proton facility to obtain log files, and subsequently evaluated through our 4D robustness evaluation method (4DREM). With this method, for each evaluated plan, fourteen 4D accumulated scenario doses were obtained, representing 14 possible fractionated treatment courses. RESULTS: From VMAT to IMPT_3D, nominal Dmean(lungs-GTV) decreased 2.75 ± 0.56 GyRBE and 3.76 ± 0.92 GyRBE over all lung and oesophageal cancer patients, respectively. A more pronounced reduction was verified for Dmean(heart): 5.38 ± 7.36 GyRBE (lung cases) and 9.51 ± 2.25 GyRBE (oesophagus cases). Target coverage robustness of IMPT_3D was sufficient for 18/20 patients. Averaged dose in critical structures over all 4DREM scenarios changed only slightly for both IMPT_3D and IMPT_4D. Relative to IMPT_3D, no gain in IMPT_4D was observed. CONCLUSION: The dosimetric superiority of IMPT over VMAT has been established. For most thoracic tumours, our IMPT_3D planning protocol showed to be robust and clinically suitable. Nevertheless, accurate patient positioning and adapting to anatomical variations over the course of treatment remain compulsory.

Risk of ischaemic cerebrovascular events in head and neck cancer patients is associated with carotid artery radiation dose.

BACKGROUND AND PURPOSE: Radiotherapy in the head and neck area may cause vascular damage to the carotid arteries, increasing the risk of anterior circulation ischaemic cerebrovascular events (ICVEs). However, limited data exists on the relationship between radiation dose to the carotid arteries and risk of ICVE. The purpose of this study was therefore to determine the relationship between radiation dose to the carotid arteries and anterior circulation ICVE risk. MATERIALS AND METHODS: A retrospective analysis of a prospective study cohort of 750 head and neck cancer patients treated with definitive (chemo)radiotherapy was performed. Carotid arteries were delineated, and dose-volume parameters of the treatment plans were calculated. ICVEs were scored prospectively and checked retrospectively by analysing all patient records. Cox proportional hazards analysis was performed to analyse the dose-effect relationships. RESULTS: The median follow-up period was 3.4 years, 27 patients experienced an ICVE and the 5-year cumulative risk was 4.6%. ICVE risk was significantly associated with dose to the carotid arteries. Multivariable analysis showed that the absolute volume (cm3) of the carotid arteries that received at least a radiation dose of 10 Gy was the most important prognostic factor for ICVE (HR = 1.11, AUC = 0.68, p < 0.001). CONCLUSION: This is the first large prospective cohort study that demonstrates an independent dose-effect relationship between radiation dose to the carotid arteries and the risk of ICVE. These findings may be used to identify patients at risk for ICVE after radiotherapy who may benefit from primary or secondary preventive measures.

A comprehensive motion analysis - consequences for high precision image-guided radiotherapy of esophageal cancer patients.

BACKGROUND AND PURPOSE: When treating patients for esophageal cancer (EC) with photon or proton radiotherapy (RT), breathing motion of the target and neighboring organs may result in deviations from the planned dose distribution. The aim of this study was to evaluate the magnitude and dosimetric impact of breathing motion. Results were based on comparing weekly 4D computed tomography (4D CT) scans with the planning CT, using the diaphragm as an anatomical landmark for EC. MATERIAL AND METHODS: A total of 20 EC patients were included in this study. Diaphragm breathing amplitudes and off-sets (changes in position with respect to the planning CT) were determined from delineated left diaphragm structures in weekly 4D CT-scans. The potential dosimetric impact of respiratory motion was shown in several example patients for photon and proton radiotherapy. RESULTS: Variation in diaphragm amplitudes were relatively small and ranged from 0 to 0.8 cm. However, the measured off-sets were larger, ranging from -2.1 to 1.9 cm. Of the 70 repeat CT-scans, the off-set exceeded the ITV-PTV margin of 0.8 cm during expiration in 4 CT-scans (5.7%) and during inspiration in 13 CT-scans (18.6%). The dosimetric validation revealed under- and overdosages in the VMAT and IMPT plans. CONCLUSIONS: Despite relatively constant breathing amplitudes, the variation in the diaphragm position (off-set), and consequently tumor position, was clinically relevant. These motion effects may result in either treatments that miss the target volume, or dose deviations in the form of highly localized over- or underdosed regions.

Weekly robustness evaluation of intensity-modulated proton therapy for oesophageal cancer.

BACKGROUND AND PURPOSE: Intensity-modulated proton therapy (IMPT) is expected to result in clinical benefits by lowering radiation dose to organs-at-risk (OARs). However, there are concerns about plan robustness due to motion. To address this uncertainty we evaluated the robustness of IMPT compared to the widely clinically used volumetric modulated arc therapy (VMAT) on weekly repeated computed tomographies (CT). MATERIALS AND METHODS: 19 patients with oesophageal cancer were evaluated. IMPT and VMAT plans were created on a planning 4-Dimensional CT (p4DCT) and evaluated on weekly repeated 4DCTs (r4DCT). In case of inadequate target coverage or unacceptable high dose to normal tissue, re-planning was performed. Dose distributions of the r4DCTs were warped to p4DCT, resulting in an estimated actual given dose (EAGD). RESULTS: Compared to VMAT, IMPT resulted in significantly lowered dose to heart, lungs, spleen, liver and kidneys. For IMPT, target coverage was adequate (after max 1 replanning) in 17/19 cases. In two cases target coverage remained insufficient. However, in one of these patients the summed dose was insufficient (due to tumor shrinkage) while weekly coverage was adequate. For the other patient the target coverage was also insufficient by VMAT, due to large anatomical changes during treatment. For VMAT, adequate target coverage was achieved in 18/19 cases without re-planning. However, for reasons of high OAR dose re-planning was required in two cases. CONCLUSION: IMPT reduces the dose to OARs significantly, while achieving adequate target coverage in the majority of patients. Re-planning was necessary for both IMPT and VMAT due to anatomical changes.

Investigation of inter-fraction target motion variations in the context of pencil beam scanned proton therapy in non-small cell lung cancer patients.

PURPOSE: For locally advanced-stage non-small cell lung cancer (NSCLC), inter-fraction target motion variations during the whole time span of a fractionated treatment course are assessed in a large and representative patient cohort. The primary objective is to develop a suitable motion monitoring strategy for pencil beam scanning proton therapy (PBS-PT) treatments of NSCLC patients during free breathing. METHODS: Weekly 4D computed tomography (4DCT; 41 patients) and daily 4D cone beam computed tomography (4DCBCT; 10 of 41 patients) scans were analyzed for a fully fractionated treatment course. Gross tumor volumes (GTVs) were contoured and the 3D displacement vectors of the centroid positions were compared for all scans. Furthermore, motion amplitude variations in different lung segments were statistically analyzed. The dosimetric impact of target motion variations and target motion assessment was investigated in exemplary patient cases. RESULTS: The median observed centroid motion was 3.4 mm (range: 0.2-12.4 mm) with an average variation of 2.2 mm (range: 0.1-8.8 mm). Ten of 32 patients (31.3%) with an initial motion <5 mm increased beyond a 5-mm motion amplitude during the treatment course. Motion observed in the 4DCBCT scans deviated on average 1.5 mm (range: 0.0-6.0 mm) from the motion observed in the 4DCTs. Larger motion variations for one example patient compromised treatment plan robustness while no dosimetric influence was seen due to motion assessment biases in another example case. CONCLUSIONS: Target motion variations were investigated during the course of radiotherapy for NSCLC patients. Patients with initial GTV motion amplitudes of < 2 mm can be assumed to be stable in motion during the treatment course. For treatments of NSCLC patients who exhibit motion amplitudes of > 2 mm, 4DCBCT should be considered for motion monitoring due to substantial motion variations observed.

Organ sparing potential and inter-fraction robustness of adaptive intensity modulated proton therapy for lung cancer.

Background: The aim of this study was to compare adaptive intensity modulated proton therapy (IMPT) robustness and organ sparing capabilities with that of adaptive volumetric arc photon therapy (VMAT).Material and methods: Eighteen lung cancer patients underwent a planning 4DCT (p4DCT) and 5 weekly repeated 4DCT (r4DCT) scans. Target volumes and organs at risk were manually delineated on the three-dimensional (3D) average scans of the p4DCT (av_p4DCT) and of the r4DCT scans (av_r4DCT). Planning target volume (PTV)-based VMAT plans and internal clinical target volume (ICTV)-based robust IMPT plans were optimized in 3D on the av_p4DCT and re-calculated on the av_r4DCTs. Re-planning on av_r4DCTs was performed when indicated and accumulated doses were evaluated on the av_p4DCT.Results: Adaptive VMAT and IMPT resulted in adequate ICTV coverage on av_r4DCT in all patients and adequate accumulated-dose ICTV coverage on av_p4DCT in 17/18 patients (due to a shrinking target in one patient). More frequent re-planning was needed for IMPT than for VMAT. The average mean heart dose reduction with IMPT compared with VMAT was 4.6 Gy (p = .001) and it was >5 Gy for five patients (6, 7, 8, 15, and 22 Gy). The average mean lung dose reduction was 3.2 Gy (p < .001). Significant reductions in heart and lung V5 Gy were observed with IMPT.Conclusion: Robust-planned IMPT required re-planning more often than VMAT but resulted in similar accumulated ICTV coverage. With IMPT, heart and lung mean dose values and low dose regions were significantly reduced. Substantial cardiac sparing was obtained in a subgroup of five patients (28%).