Plan robustness evaluation strategies in whole-pelvic proton therapy for high-risk prostate cancer patients within a randomised clinical trial.

BACKGROUND: Inter-fractional anatomical changes challenge robust delivery of whole-pelvic proton therapy for high-risk prostate cancer. Pre-treatment robust evaluation (PRE) takes uncertainties in isocenter shifts and distal beam edge in treatment plans into account. Using weekly control computed tomography scans (cCTs), the aim of this study was to evaluate the PRE strategy by comparing to an off-line during-treatment robust evaluation (DRE) while also assessing plan robustness with respect to protocol planning constraints. MATERIAL AND METHODS: Treatment plans and cCTs from ten patients included in the pilot phase of the PROstate PROTON Trial 1 were analysed. Treatment planning followed protocol guidelines with 78 Gy to the primary clinical target volume (CTVp) and 56 Gy to the elective target (CTVe) in 39 fractions. Recalculations of the treatment plans were performed for a total of 64 cCTs and dose/volume measures corresponding to clinical constraints were evaluated for this DRE against the simulated scenario interval from the PRE. RESULTS: Of the 64 cCTs, 59 showed DRE CTVp measures within the robustness range from the PRE; this was also the case for 39 of the cCTs for the CTVe measures. However, DRE CTVe coverage was still within constraints for 57 of the 64 cCTs. DRE dose/volume measures for CTVp fulfilled target coverage constraints in 59 of 64 cCTs. All DRE measures for the rectum, bladder, and bowel were inside the PRE range in 63, 39, and 31 cCTs, respectively. CONCLUSION: The PRE strategy predicted the DRE scenarios for CTVp and rectum. CTVe, bladder, and bowel showed more complex anatomical variations than simulated by the PRE isocenter shift. Both original and recalculated nominal treatment plans showed robust treatment delivery in terms of target coverage.

Proton therapy planning and image-guidance strategies within a randomized controlled trial for high-risk prostate cancer.

The Danish Prostate Cancer Group is launching the randomized trial, PROstate PROTON Trial 1 (NCT05350475), that compares photons and protons to the prostate and pelvic lymph nodes in treatment of high-risk prostate cancer. The aim of the work described in this paper was, in preparation of this trial, to establish a strategy for conventionally fractionated proton therapy of prostate and elective pelvic lymph nodes that is feasible and robust. Proton treatments are image-guided based on gold fiducial markers and on-board imaging systems in line with current practice. Our established proton beam configuration consists of four coplanar fields; two posterior oblique fields and two lateral oblique fields, chosen to minimize range uncertainties associated with penetrating a varying amount of material from both treatment couch and patient body. Proton plans are robustly optimized to ensure target coverage while keeping normal tissue doses as low as is reasonably achievable throughout the course of treatment. Specific focus is on dose to the bowel as a reduction in gastrointestinal toxicity is the primary endpoint of the trial. Strategies have been established using previously treated patients and will be further investigated and evaluated through the ongoing pilot phase of the trial.

Tissue-specific range uncertainty estimation in proton therapy.

Background and Purpose: Proton therapy is sensitive to range uncertainties, which typically are accounted for by margins or robust optimization, based on tissue-independent uncertainties. However, range uncertainties have been shown to depend on the specific tissues traversed. The aim of this study was to investigate the differences between range margins based on stopping power ratio (SPR) uncertainties which were tissue-specific (applied voxel-wise) or fixed (tissue-independent or composite). Materials and Methods: Uncertainties originating from imaging, computed tomography (CT) number estimation, and SPR estimation were calculated for low-, medium-, and high-density tissues to quantify the tissue-specific SPR uncertainties. Four clinical treatment plans (four different tumor sites) were created and recomputed after applying either tissue-specific or fixed SPR uncertainties. Plans with tissue-specific and fixed uncertainties were compared, based on dose-volume-histogram parameters for both targets and organs-at-risk. Results: The total SPR uncertainties were 7.0% for low-, 1.0% for medium-, and 1.3% for high-density tissues. Differences between the proton plans with tissue-specific and fixed uncertainties were mainly found in the vicinity of the target. Composite uncertainties were found to capture the tissue-specific uncertainties more accurately than the tissue-independent uncertainties. Conclusion: Different SPR uncertainties were found for low-, medium-, and high-density tissues indicating that range margins based on tissue-specific uncertainties may be more exact than the standard approach of using tissue-independent uncertainties. Differences between applying tissue-specific and fixed uncertainties were found, however, a fixed uncertainty might still be sufficient, but with a magnitude that depends on the body region.

Technical note: Temporal and thermal stability of optical response for silicone-based 3D radiochromic dosimeters.

BACKGROUND: Radiochromic silicone-based dosimeters are flexible 3D dosimeters, which at appropriate concentration of leucomalachite green (LMG) and curing agent are dose-rate independent for clinical photon beams. However, their dose response is based on chemical processes that can be influenced by temporal and thermal conditions, impacting measurement stability. PURPOSE: The aim of this study was to investigate the temporal stability of the dose response of radiochromic dosimeters for different curing times and post-irradiation storage temperatures. METHODS: Six cylindrical dosimeters (5 cm diameter, 5 cm length) were produced in a single batch and separated into two groups that were irradiated 72 and 118 h after production. The same photon plan, consisting of two 10 × 1.6 cm2 opposing fields, was delivered to all dosimeters. After irradiation, the dosimeters were separated into three groups, stored at 5°C, 15°C, and 20°C, and read out for five consecutive days. RESULTS: Storage temperature influenced the measurement stability, and changes in the optical response with time differed between irradiated and non-irradiated parts of the dosimeters. The relative change between signal and background was greater than 10% for all measurements performed 24 h or more after irradiation, except for dosimeters stored at 5°C, which changed by 2%-5% after 24 h. The dosimeter temporal stability was not influenced by curing time. CONCLUSIONS: For room temperature storage (15°C and 20°C), readout should take place as soon as possible after irradiation since the background color increased rapidly for both curing times (72 and 118 h), whereas the dosimeters are stored at 5°C, readout can be performed up to 24 h after.

Empirical quenching correction in radiochromic silicone-based three-dimensional dosimetry of spot-scanning proton therapy.

BACKGROUND AND PURPOSE: Three-dimensional dosimetry of proton therapy (PT) with chemical dosimeters is challenged by signal quenching, which is a lower dose-response in regions with high ionization density due to high linear-energy-transfer (LET) and dose-rate. This study aimed to assess the viability of an empirical correction model for 3D radiochromic silicone-based dosimeters irradiated with spot-scanning PT, by parametrizing its LET and dose-rate dependency. MATERIALS AND METHODS: Ten cylindrical radiochromic dosimeters (Ø50 and Ø75 mm) were produced in-house, and irradiated with different spot-scanning proton beam configurations and machine-set dose rates ranging from 56 to 145 Gy/min. Beams with incident energies of 75, 95 and 120 MeV, a spread-out Bragg peak and a plan optimized to an irregular target volume were included. Five of the dosimeters, irradiated with 120 MeV beams, were used to estimate the quenching correction factors. Monte Carlo simulations were used to obtain dose and dose-averaged-LET (LETd) maps. Additionally, a local dose-rate map was estimated, using the simulated dose maps and the machine-set dose-rate information retrieved from the irradiation log-files. Finally, the correction factor was estimated as a function of LETd and local dose-rate and tested on the different fields. RESULTS: Gamma-pass-rates of the corrected measurements were >94% using a 3%-3 mm gamma analysis and >88% using 2%-2 mm, with a dose deviation of <5.6 ± 1.8%. Larger dosimeters showed a 20% systematic increase in dose-response, but the same quenching in signal when compared to the smaller dosimeters. CONCLUSION: The quenching correction model was valid for different dosimeter sizes to obtain relative dosimetric maps of complex dose distributions in PT.

Development of an Immobilization Device for Total Marrow Irradiation.

PURPOSE: A body frame dedicated to total marrow (lymph node) irradiation (TMI/TMLI) could minimize patient motion during the potentially extended beam-on time with this technique. We present the development of a dedicated immobilization system for TMI/TMLI using volumetric modulated arc therapy. METHODS AND MATERIALS: Since 2010, 59 adult patients were treated with TMI/TMLI using a multi-isocenter volumetric modulated arc therapy technique. Two computed tomographies (CTs) were required (1 head-first supine and 1 feet-first supine) to cover the whole volume. For the first 10 patients, 2 standard commercial frames with personalized masks (with/without personalized vacuum cushion for the lower extremities) were used without specific interfixation (frame A). For the next 49 patients a homemade 3-frame immobilization system was adopted (frame B), where each frame was interlocked with the next one and thermoplastic masks used to fix the patient. The effectiveness of the 2 immobilization systems was assessed by offline/online matching between daily cone beam CT of each isocenter and the simulation CTs. RESULTS: Mean offline shifts for frame A were 3 to 12 mm in anterior-posterior, 2 to 5 mm in cranilal-caudal, and 2 to 6 mm in left-right directions. Larger shifts were found for feet-first supine series (shifts up to 23 mm). In frame B, mean offline shifts were 1 to 4 mm in anterior-posterior, 1 to 4 mm in cranial-caudal, and 1 to 4 mm in left-right directions. Mean online adjustments were -1 ± 4 mm in anterior-posterior, 0 ± 2 mm in cranial-caudal, and 0 ± 4 mm in left-right directions. CONCLUSIONS: The patient positioning shifts for TMI/TMLI irradiation were mitigated by a homemade immobilization system and the use of individualized masks.

Evaluation of an a priori scatter correction algorithm for cone-beam computed tomography based range and dose calculations in proton therapy.

BACKGROUND AND PURPOSE: Scatter correction of cone-beam computed tomography (CBCT) projections may enable accurate online dose-delivery estimations in photon and proton-based radiotherapy. This study aimed to evaluate the impact of scatter correction in CBCT-based proton range/dose calculations, in scans acquired in both proton and photon gantries. MATERIAL AND METHODS: CBCT projections of a Catphan and an Alderson phantom were acquired on both a proton and a photon gantry. The scatter corrected CBCTs (corrCBCTs) and the clinical reconstructions (stdCBCTs) were compared against CTs rigidly registered to the CBCTs (rigidCTs). The CBCTs of the Catphan phantom were segmented by materials for CT number analysis. Water equivalent path length (WEPL) maps were calculated through the Alderson phantom while proton plans optimized on the rigidCT and recalculated on all CBCTs were compared in a gamma analysis. RESULTS: In medium and high-density materials, the corrCBCT CT numbers were much closer to those of the rigidCT than the stdCBCTs. E.g. in the 50% bone segmentations the differences were reduced from above 300 HU (with stdCBCT) to around 60-70 HU (with corrCBCT). Differences in WEPL from the rigidCT were typically well below 5 mm for the corrCBCTs, compared to well above 10 mm for the stdCBCTs with the largest deviations in the head and thorax regions. Gamma pass rates (2%/2mm) when comparing CBCT-based dose re-calculations to rigidCT calculations were improved from around 80% (with stdCBCT) to mostly above 90% (with corrCBCT). CONCLUSION: Scatter correction leads to substantial artefact reductions, improving accuracy of CBCT-based proton range/dose calculations.

Total marrow irradiation for hematopoietic malignancies using volumetric modulated arc therapy: A review of treatment planning studies.

Total Marrow Irradiation (TMI) has been introduced in the management of hematopoietic malignancies with the aim of reducing toxicities induced by total body irradiation. TMI is one of the most challenging planning and delivery techniques of radiotherapy, as the whole skeleton should be irradiated, while sparing nearby organs at risk (OARs). Target volumes of 7-10 k cm3 and healthy tissue volumes of 50-90 k cm3 should be considered and inverse treatment planning is needed. This review focused on aspects of TMI delivery using volumetric modulated arc therapy (VMAT). In particular, multiple arcs from isocenters with different positions are required for VMAT-TMI as the cranial-caudal lengths of patients are much larger than the jaw aperture. Therefore, many field junctions between arcs with different isocenters should be managed. This review covered, in particular, feasibility studies for managing multiple isocenters, optimization of plan parameters, plan optimization of the lower extremities, robustness of field junctions and dosimetric plan verification of VMAT-TMI. This review demonstrated the possibility of VMAT in delivering TMI with multi-arcs and multi-isocenters. Care should be paid in the patient repositioning, with particular attention to the cranial-caudal direction.

Statistical motion modelling for robust evaluation of clinically delivered accumulated dose distributions after curative radiotherapy of locally advanced prostate cancer.

BACKGROUND AND PURPOSE: Planned doses are used as surrogate for the actually delivered dose in radiotherapy. We have estimated the delivered dose in a dose-escalation trial of locally advanced prostate cancer by statistical dose-accumulation and by DVH-summation, and compared to planned dose. MATERIALS AND METHOD: Prescribed dose-escalation to the prostate was 67.5 Gy/25fr., corresponding to 81GyEQD2 assuming α/ß = 1.5. The 21 patients had three targets (i.e. CTV67.5 + 2 mm, CTV60 + 5 mm, CTV50 + 10 mm) irradiated by a simultaneous-integrated-boost technique. Analysis was based on 213 CT scans and 5-years of follow-up. For statistical dose-accumulation, we modelled 10000 possible treatment courses based on planned dose and deformation-vector-fields from contour-based registration. For DVH-summation we recalculated dose on repeat-CTs and estimated median D98%/EUD. Groups with/without disease recurrence were compared. RESULTS: Discrepancies between planned and accumulated dose were mostly seen for CTV67.5, where under-dosage was found at different locations in the prostate in 12/21 patients. Delivered dose-escalation (D98%) was on average 73.9GyEQD2 (range: 68.3-78.7GyEQD2). No significant difference in accumulated-D98% was found in patients with (n = 8) and without (n = 13) recurrence (p > 0.05). Average D98%/EUD with statistical dose-accumulation vs DVH-summation was significantly different in CTV60, CTV50, rectum and bladder but not in CTV67.5. CONCLUSION: The planned dose escalation was not received by more than half-of-the patients. Robustness of the prostate target (CTV67.5) should therefore be better prioritized in these patients given the low toxicity profile. Estimates of delivered dose were less conservative for dose-accumulation due to interaction of random organ motion with the dose matrix.

Comparison of single and dual energy CT for stopping power determination in proton therapy of head and neck cancer.

BACKGROUND AND PURPOSE: Patients with head and neck (HN) cancer may benefit from proton therapy due to the potential for sparing of normal tissue. For planning of proton therapy, dual-energy CT (DECT) has been shown to provide superior stopping power ratio (SPR) determination in phantom materials and organic tissue samples, compared to single-energy CT (SECT). However, the benefit of DECT in HN cancer patients has not yet been investigated. This study therefore compared DECT- and SECT-based SPR estimation for HN cancer patients. MATERIALS AND METHODS: Fourteen HN cancer patients were DECT scanned. Eight patients were scanned using a dual source DECT scanner and six were scanned with a conventional SECT scanner by acquiring two consecutive scans. SECT image sets were computed as a weighted summation of the low and high energy DECT image sets. DECT- and SECT-based SPR maps were derived. Water-equivalent path lengths (WEPLs) through the SPR maps were compared in the eight cases with dual source DECT scans. Mean SPR estimates over region-of-interests (ROIs) in the cranium, brain and eyes were analyzed for all patients. RESULTS: A median WEPL difference of 1.9 mm (1.5%) was found across the eight patients. Statistically significant SPR differences were seen for the ROIs in the brain and eyes, with the SPR estimates based on DECT overall lower than for SECT. CONCLUSIONS: Clinically relevant WEPL and SPR differences were found between DECT and SECT, which could imply that the accuracy of treatment planning for proton therapy would benefit from DECT-based SPR estimation.

The influence of inter-fractional anatomy variation on secondary cancer risk estimates following radiotherapy.

PURPOSE: In silico studies comparing estimated risks of radiation-induced secondary cancer (SC) are frequently performed in assessment of radiotherapy techniques. Since inter-patient anatomy variations can result in considerable differences in estimated risk we aimed to explore the influence of inter-fractional organ motion patterns on SC risk. METHODS: Volumetric modulated arc therapy (VMAT) and intensity-modulated proton therapy (IMPT) plans were generated on the planning CT (pCT) scans of eight prostate cancer patients. In addition, the treatment plans were re-calculated on 8-9 repeat CTs (rCTs) of each patient acquired throughout the treatment course. Relative risk (RR) of SC (VMAT/IMPT) was calculated for the planned and the re-calculated dose distributions using the organ equivalent dose concept adapted to a linear and a bell-shaped competition dose-response model. RESULTS: Day-to-day variations in anatomy lead to fluctuations in SC risk estimates of the same order of magnitude as those caused by inter-patient variations. Using the competition model, the RR range for bladder cancer based on the pCTs was 0.4-3.4, while a considerably wider range was found when including all rCTs (0.2-6.7). There was nevertheless a correlation in RR based on repeat CTs for individual patients, indicating that patient-specific SC risks could be estimated. CONCLUSIONS: The estimated relative risks varied considerably across rCTs and could change the risk in favour of VMAT/IMPT depending on the anatomy of the day. The results demonstrate the importance of performing in silico studies of SC risk on a cohort of patients or multiple CTs when structures subject to organ motion are involved.

Spatial rectal dose/volume metrics predict patient-reported gastro-intestinal symptoms after radiotherapy for prostate cancer.

BACKGROUND: Gastro-intestinal (GI) toxicity after radiotherapy (RT) for prostate cancer reduces patient's quality of life. In this study, we explored associations between spatial rectal dose/volume metrics and patient-reported GI symptoms after RT for localized prostate cancer, and compared these with those of dose-surface/volume histogram (DSH/DVH) metrics. MATERIAL AND METHODS: Dose distributions and six GI symptoms (defecation urgency/emptying difficulties/fecal leakage, ≥Grade 2, median follow-up: 3.6 y) were extracted for 200 patients treated with image-guided RT in 2005-2007. Three hundred and nine metrics assessed from 2D rectal dose maps or DSHs/DVHs were subject to 50-times iterated five-fold cross-validated univariate and multivariate logistic regression analysis (UVA, MVA). Performance of the most frequently selected MVA models was evaluated by the area under the receiving-operating characteristics curve (AUC). RESULTS: The AUC increased for dose-map compared to DSH/DVH-based models (mean SD: 0.64 ± 0.03 vs. 0.61 ± 0.01), and significant relations were found for six versus four symptoms. Defecation urgency and faecal leakage were explained by high doses at the central/upper and central areas, respectively; while emptying difficulties were explained by longitudinal extensions of intermediate doses. CONCLUSIONS: Predictability of patient-reported GI toxicity increased using spatial metrics compared to DSH/DVH metrics. Novel associations were particularly identified for emptying difficulties using both approaches in which intermediate doses were emphasized.

Beam angle evaluation to improve inter-fraction motion robustness in pelvic lymph node irradiation with proton therapy.

BACKGROUND: Proton therapy dose distributions are sensitive to range variations, e.g. arising from inter-fraction organ motion. The aim of this study was to evaluate the inter-fraction motion robustness of proton beams from different beam angles in irradiation of pelvic lymph nodes (LNs). MATERIAL AND METHODS: Planning CT (pCT) and multiple repeat CT (rCT) scans of 18 prostate cancer patients were used. Considering left and right LNs separately, the average water equivalent path length (WEPL) over all ray paths in the beams eye view of the LNs were calculated for all gantry/couch angle combinations across all rCTs versus the corresponding pCT. Single beam proton plans were optimized on the pCT for all gantry angles (0° couch) and were re-calculated on all rCTs for each respective patient. WEPL and dose parameters were extracted and a statistical clustering analysis performed to identify patient sub-populations in terms of patterns in which angles were robust. RESULTS: The WEPL analysis showed a general pattern of least variation for 0° couch beam angles where three minima were found across gantry angles for the left LNs and two for the right LNs. The clustering analysis identified three patient sub-groups for the left LNs and two groups for the right LNs. The dose calculations showed similar results as the WEPL variation, e.g. for the left LNs angles around 25°-35°, 100°-110°, and 160°-170° were consistently preferable for both target and organs at risk. CONCLUSIONS: Sub-populations of patients with similar patterns of WEPL variations across beam angles were identified. The most robust angles found for WEPL variations were also confirmed by the dose/volume analysis.

Functional image-guided dose escalation in gliomas using of state-of-the-art photon vs. proton therapy.

BACKGROUND: Recurrences of glioma are usually local, suggesting the need for higher tumor dose. We investigated the boundaries for dose escalation of an 18F-fluoro-ethyl-tyrosine positron emission tomography defined target by intensity-modulated photon therapy (IMRT), volumetric modulated arc therapy (VMAT) and intensity-modulated proton therapy (IMPT). MATERIALS AND METHODS: Standard dose (60 Gy) and dose-escalated plans were calculated for seven patients using IMRT, VMAT and IMPT. The achieved boost dose, the dose to the organs at risk (OAR), the dose homogeneity (defined as overdose volume, ODV) and the ratio of the 30 Gy isodose curve and the boost volume (R30) were compared. The risk of radionecrosis was estimated using the ratio of the dose volume histograms of the brain (range 30-60 Gy). RESULTS: The mean boost dose was 77.1 Gy for IMRT, 79.2 Gy for VMAT and 85.1 GyE for IMPT. Compared with the standard plan, the ODV was unchanged and the R30 increased (17%) for IMRT. For VMAT, the ODV decreased (7%) and the R30 was unchanged whereas IMPT substantially decreased ODV (61%), R30 (22%), OAR doses as well as the risk of radionecrosis. CONCLUSIONS: Dose escalation can be achieved with IMRT, VMAT and IMPT while respecting normal tissue constraints, yet with IMPT being most favorable.