Normal Tissue Complication Probability Reduction Research Articles

The dirty and clean dose concept: Towards creating proton therapy treatment plans with a photon-like dose response.

Applying tolerance doses for organs at risk (OAR) from photon therapy introduces uncertainties in proton therapy when assuming a constant relative biological effectiveness (RBE) of 1.1. This work introduces the novel dirty and clean dose concept, which allows for creating treatment plans with a more photon-like dose response for OAR and, thus, less uncertainties when applying photon-based tolerance doses. The concept divides the 1.1-weighted dose distribution into two parts: the clean and the dirty dose. The clean and dirty dose are deposited by protons with a linear energy transfer (LET) below and above a set LET threshold, respectively. For the former, a photon-like dose response is assumed, while for the latter, the RBE might exceed 1.1. To reduce the dirty dose in OAR, a MaxDirtyDose objective was added in treatment plan optimization. It requires setting two parameters: LET threshold and max dirty dose level. A simple geometry consisting of one target volume and one OAR in water was used to study the reduction in dirty dose in the OAR depending on the choice of the two MaxDirtyDose objective parameters during plan optimization. The best performing parameter combinations were used to create multiple dirty dose optimized (DDopt) treatment plans for two cranial patient cases. For each DDopt plan, 1.1-weighted dose, variable RBE-weighted dose using the Wedenberg RBE model and dose-average LETd distributions as well as resulting normal tissue complication probability (NTCP) values were calculated and compared to the reference plan (RefPlan) without MaxDirtyDose objectives. In the water phantom studies, LET thresholds between 1.5 and 2.5keV/µm yielded the best plans and were subsequently used. For the patient cases, nearly all DDopt plans led to a reduced Wedenberg dose in critical OAR. This reduction resulted from an LET reduction and translated into an NTCP reduction of up to 19 percentage points compared to the RefPlan. The 1.1-weighted dose in the OARs was slightly increased (patient 1: 0.45Gy(RBE), patient 2: 0.08Gy(RBE)), but never exceeded clinical tolerance doses. Additionally, slightly increased 1.1-weighted dose in healthy brain tissue was observed (patient 1: 0.81Gy(RBE), patient 2: 0.53Gy(RBE)). The variation of NTCP values due to variation of α/β from 2 to 3Gy was much smaller for DDopt (2 percentage points (pp)) than for RefPlans (5 pp). The novel dirty and clean dose concept allows for creating biologically more robust proton treatment plans with a more photon-like dose response. The reduced uncertainties in RBE can, therefore, mitigate uncertainties introduced by using photon-based tolerance doses for OAR.

Proton therapy and oral mucositis in oral & oropharyngeal cancers: outcomes, dosimetric and NTCP benefit

IntroductionRadiation-induced oral mucositis (RIOM), is a common, debilitating, acute side effect of radiotherapy for oral cavity (OC) and oropharyngeal (OPx) cancers; technical innovations for reducing it are seldom discussed. Intensity-modulated-proton-therapy (IMPT) has been reported extensively for treating OPx cancers, and less frequently for OC cancers. We aim to quantify the reduction in the likelihood of RIOM in treating these 2 subsites with IMPT compared to Helical Tomotherapy.Material and methodsWe report acute toxicities and early outcomes of 22 consecutive patients with OC and OPx cancers treated with IMPT, and compare the dosimetry and normal tissue complication probability (NTCP) of ≥ grade 3 mucositis for IMPT and HT.ResultsTwenty two patients, 77% males, 41% elderly and 73% OC subsite, were reviewed. With comparable target coverage, IMPT significantly reduced the mean dose and D32, D39, D45, and D50, for both the oral mucosa (OM) and spared oral mucosa (sOM). With IMPT, there was a 7% absolute and 16.5% relative reduction in NTCP for grade 3 mucositis for OM, compared to HT. IMPT further reduced NTCP for sOM, and the benefit was maintained in OC, OPx subsites and elderly subgroup.Acute toxicities, grade III dermatitis and mucositis, were noted in 50% and 45.5% patients, respectively, while 22.7% patients had grade 3 dysphagia. Compared with published data, the hospital admission rate, median weight loss, feeding tube insertion, unplanned treatment gaps were lower with IMPT. At a median follow-up of 15 months, 81.8% were alive; 72.7%, alive without disease and 9%, alive with disease.ConclusionThe dosimetric benefit of IMPT translates into NTCP reduction for grade 3 mucositis compared to Helical Tomotherapy for OPx and OC cancers and encourages the use of IMPT in their management.

Evaluating the effect of setup uncertainty reduction and adaptation to geometric changes on normal tissue complication probability using online adaptive head and neck intensity modulated proton therapy

Objective. To evaluate the impact of setup uncertainty reduction (SUR) and adaptation to geometrical changes (AGC) on normal tissue complication probability (NTCP) when using online adaptive head and neck intensity modulated proton therapy (IMPT). Approach. A cohort of ten retrospective head and neck cancer patients with daily scatter corrected cone-beam CT (CBCT) was studied. For each patient, two IMPT treatment plans were created: one with a 3 mm setup uncertainty robustness setting and one with no explicit setup robustness. Both plans were recalculated on the daily CBCT considering three scenarios: the robust plan without adaptation, the non-robust plan without adaptation and the non-robust plan with daily online adaptation. Online-adaptation was simulated using an in-house developed workflow based on GPU-accelerated Monte Carlo dose calculation and partial spot-intensity re-optimization. Dose distributions associated with each scenario were accumulated on the planning CT, where NTCP models for six toxicities were applied. NTCP values from each scenario were intercompared to quantify the reduction in toxicity risk induced by SUR alone, AGC alone and SUR and AGC combined. Finally, a decision tree was implemented to assess the clinical significance of the toxicity reduction associated with each mechanism. Main results. For most patients, clinically meaningful NTCP reductions were only achieved when SUR and AGC were performed together. In these conditions, total reductions in NTCP of up to 30.48 pp were obtained, with noticeable NTCP reductions for aspiration, dysphagia and xerostomia (mean reductions of 8.25, 5.42 and 5.12 pp respectively). While SUR had a generally larger impact than AGC on NTCP reductions, SUR alone did not induce clinically meaningful toxicity reductions in any patient, compared to only one for AGC alone. Significance Online adaptive head and neck proton therapy can only yield clinically significant reductions in the risk of long-term side effects when combining the benefits of SUR and AGC.

Contralateral esophageal sparing technique in definitive radiotherapy for non-small cell lung cancer: dosimetric parameters and normal tissue complication probability modeling.

The purpose of this study was to assess the benefit of the contralateral esophageal sparing technique (CEST) in definitive radiotherapy of non-small cell lung cancer (NSCLC). We retrospectively reviewed radiation plans for 13 patients who underwent definitive chemoradiation for locally advanced NSCLC. Alternative plans were prepared with the use of CEST, with an additional margin of 5 mm from planning treatment volume (PTV). Normal tissue complication probability (NTCP) analyses for the esophagus and tumor control probability (TCP) for the PTV were performed for original and CEST plans using the equivalent uniform dose (EUD)-based mathematical model. In all cases, the CEST plan allowed for the reduction of esophageal dose, with a mean of 3.8 Gy (range, 0.7 to 8.7 Gy). The mean reductions of V40 and V60 to the esophagus were 6.4 Gy (range, 2.1 to 17.2 Gy) and 1.9 Gy (range, 3.4 to 10.0 Gy), respectively. There was no substantial decrease in the maximal dose to the esophagus. Reduction of NTCP was achieved for all patients (range, 5-73%), and TCP was not affected (-1.8 to +6.7%). The application of CEST in definitive radiotherapy of locally advanced NSCLC allows for reducing selected dosimetric parameters to the esophagus without compromising TCP.

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

PurposeIn 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 MethodsFor 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. ResultsReplanning 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. ConclusionFollowing an adaptive clinical workflow, adequate target dose coverage and stable OAR doses with corresponding NTCPs was assured for both IMPT and VMAT.

The impact of organ motion and the appliance of mitigation strategies on the effectiveness of hypoxia-guided proton therapy for non-small cell lung cancer

Background and PurposeTo investigate the impact of organ motion on hypoxia-guided proton therapy treatments for non-small cell lung cancer (NSCLC) patients. Materials and MethodsHypoxia PET and 4D imaging data of six NSCLC patients were used to simulate hypoxia-guided proton therapy with different motion mitigation strategies including rescanning, breath-hold, respiratory gating and tumour tracking. Motion-induced dose degradation was estimated for treatment plans with dose painting of hypoxic tumour sub-volumes at escalated dose levels. Tumour control probability (TCP) and dosimetry indices were assessed to weigh the clinical benefit of dose escalation and motion mitigation. In addition, the difference in normal tissue complication probability (NTCP) between escalated proton and photon VMAT treatments has been assessed. ResultsMotion-induced dose degradation was found for target coverage (CTV V95% up to −4%) and quality of the dose-escalation-by-contour (QRMS up to 6%) as a function of motion amplitude and amount of dose escalation. The TCP benefit coming from dose escalation (+4–13%) outweighs the motion-induced losses (<2%). Significant average NTCP reductions of dose-escalated proton plans were found for lungs (−14%), oesophagus (−10%) and heart (−16%) compared to conventional VMAT plans. The best plan dosimetry was obtained with breath hold and respiratory gating with rescanning. ConclusionNSCLC affected by hypoxia appears to be a prime target for proton therapy which, by dose-escalation, allows to mitigate hypoxia-induced radio-resistance despite the sensitivity to organ motion. Furthermore, substantial reduction in normal tissue toxicity can be expected compared to conventional VMAT. Accessibility and standardization of hypoxia imaging and clinical trials are necessary to confirm these findings in a clinical setting.

Influence of Beam Angle on Normal Tissue Complication Probability of Knowledge-Based Head and Neck Cancer Proton Planning.

Simple SummaryKnowledge-based treatment planning (KBP) solutions can be used to assist in the planning process by automatically generating patient-specific optimization objectives. A KBP model is typically derived from treatment plans with a similar planning methodology, for example beam angles. An end-user might deviate from this methodology for a variety of reasons. The effect of such deviations on KBP plan quality has not been widely explored. We therefore studied this using a human-interaction free proton planning solution to create comparative plans with the default angles used when building the model, and altered beam angle arrangements. Because normal tissue complication probability (NTCP) can be used to select patients for proton therapy, this was used as the primary outcome metric for plan quality. The results show that the beam angle and number of beams only had a small effect on the plan NTCP. This suggests that the model is robust to the various beam arrangements within the range described in this analysis, although a method that automatically further adapts the KBP planning objectives further decreased the NTCP by 1–3%.Knowledge-based planning solutions have brought significant improvements in treatment planning. However, the performance of a proton-specific knowledge-based planning model in creating knowledge-based plans (KBPs) with beam angles differing from those used to train the model remains unexplored. We used a previously validated RapidPlanPT model and scripting to create nine KBPs, one with default and eight with altered beam angles, for 10 recent oropharynx cancer patients. The altered-angle plans were compared against the default-angle ones in terms of grade 2 dysphagia and xerostomia normal tissue complication probability (NTCP), mean doses of several organs at risk, and dose homogeneity index (HI). As KBP could be suboptimal, a proof of principle automatic iterative optimizer (AIO) was added with the aim of reducing the plan NTCP. There were no statistically significant differences in NTCP or HI between default- and altered-angle KBPs, and the altered-angle plans showed a <1% reduction in NTCP. AIO was able to reduce the sum of grade 2 NTCPs in 66/90 cases with mean a reduction of 3.5 ± 1.8%. While the altered-angle plans saw greater benefit from AIO, both default- and altered-angle plans could be improved, indicating that the KBP model alone was not completely optimal to achieve the lowest NTCP. Overall, the data showed that the model was robust to the various beam arrangements within the range described in this analysis.

Including Volume Effects in Biological Treatment Plan Optimization for Carbon Ion Therapy: Generalized Equivalent Uniform Dose-Based Objective in TRiP98.

We describe a way to include biologically based objectives in plan optimization specific for carbon ion therapy, beyond the standard voxel-dose-based criteria already implemented in TRiP98, research planning software for ion beams. The aim is to account for volume effects—tissue architecture-dependent response to damage—in the optimization procedure, using the concept of generalized equivalent uniform dose (gEUD), which is an expression to convert a heterogeneous dose distribution (e.g., in an organ at risk (OAR)) into a uniform dose associated with the same biological effect. Moreover, gEUD is closely related to normal tissue complication probability (NTCP). The multi-field optimization problem here takes also into account the relative biological effectiveness (RBE), which in the case of ion beams is not factorizable and introduces strong non-linearity. We implemented the gEUD-based optimization in TRiP98, allowing us to control the whole dose–volume histogram (DVH) shape of OAR with a single objective by adjusting the prescribed gEUD 0 and the volume effect parameter a, reducing the volume receiving dose levels close to mean dose when a = 1 (large volume effect) while close to maximum dose for a >> 1 (small volume effect), depending on the organ type considered. We studied the role of gEUD 0 and a in the optimization, and we compared voxel-dose-based and gEUD-based optimization in chordoma cases with different anatomies. In particular, for a plan containing multiple OARs, we obtained the same target coverage and similar DVHs for OARs with a small volume effect while decreasing the mean dose received by the proximal parotid, thus reducing its NTCP by a factor of 2.5. Further investigations are done for this plan, considering also the distal parotid gland, obtaining a NTCP reduction by a factor of 1.9 for the proximal and 2.9 for the distal one. In conclusion, this novel optimization method can be applied to different OARs, but it achieves the largest improvement for organs whose volume effect is larger. This allows TRiP98 to perform a double level of biologically driven optimization for ion beams, including at the same time RBE-weighted dose and volume effects in inverse planning. An outlook is presented on the possible extension of this method to the target.

Intensity-modulated proton radiation therapy as a radical treatment modality for nasopharyngeal carcinoma in China: Cost-effectiveness analysis.

Compared to conventional intensity-modulated photon radiation therapy (IMRT), intensity-modulated proton radiation therapy (IMPT) has potential to reduce irradiation-induced late toxicities while maintaining excellent tumor control in patients with nasopharyngeal carcinoma (NPC). However, the relevant cost-effectiveness remains controversial. A Markov decision tree analysis was performed under the assumption that IMPT offered normal tissue complication probability reduction (NTCP reduction) in long-term dysphagia, xerostomia, and hearing loss, compared to IMRT. Base-case evaluation was performed on T2N2M0 NPC of median age (43 years old). A Chinese societal willingness-to-pay threshold (33558 US dollars [$])/quality-adjusted life-year [QALY]) was adopted. For patients at median age and having NTCP reduction of 10%, 20%, 30%, 40%, 50%, and 60%, their incremental cost-effectiveness ratios were $102684.0/QALY, $43161.2/QALY, $24134.7/QALY, $13991.6/QALY, $8259.8/QALY, and $4436.1/QALY, respectively; IMPT should provide an NTCP reduction of ≥24% to be considered cost-effective. IMPT has potential to be cost-effective for average Chinese NPC patients and should be validated clinically.

Effective Organs-at-Risk Dose Sparing in Volumetric Modulated Arc Therapy Using a Half-Beam Technique in Whole Pelvic Irradiation.

BackgroundAlthough there are some controversies regarding whole pelvic radiation therapy (WPRT) due to its gastrointestinal and hematologic toxicities, it is considered for patients with gynecological, rectal, and prostate cancer. To effectively spare organs-at-risk (OAR) doses using multi-leaf collimator (MLC)’s optimal segments, potential dosimetric benefits in volumetric modulated arc therapy (VMAT) using a half-beam technique (HF) were investigated for WPRT.MethodsWhile the size of a fully opened field (FF) was decided to entirely include a planning target volume in all beam’s eye view across arc angles, the HF was designed to use half the FF from the isocenter for dose optimization. The left or the right half of the FF was alternatively opened in VMAT-HF using a pair of arcs rotating clockwise and counterclockwise. Dosimetric benefits of VMAT-HF, presented with dose conformity, homogeneity, and dose–volume parameters in terms of modulation complex score, were compared to VMAT optimized using the FF (VMAT-FF). Consequent normal tissue complication probability (NTCP) by reducing the irradiated volumes was evaluated as well as dose–volume parameters with statistical analysis for OAR. Moreover, beam-on time and MLC position precision were analyzed with log files to assess plan deliverability and clinical applicability of VMAT-HF as compared to VMAT-FF.ResultsWhile VMAT-HF used 60%–70% less intensity modulation complexity than VMAT-FF, it showed superior dose conformity. The small intestine and colon in VMAT-HF showed a noticeable reduction in the irradiated volumes of up to 35% and 15%, respectively, at an intermediate dose of 20–45 Gy. The small intestine showed statistically significant dose sparing at the volumes that received a dose from 15 to 45 Gy. Such a dose reduction for the small intestine and colon in VMAT-HF presented a significant NTCP reduction from that in VMAT-FF. Without sacrificing the beam delivery efficiency, VMAT-HF achieved effective OAR dose reduction in dose–volume histograms.ConclusionsVMAT-HF led to deliver conformal doses with effective gastrointestinal-OAR dose sparing despite using less modulation complexity. The dose of VMAT-HF was delivered with the same beam-on time with VMAT-FF but precise MLC leaf motions. The VMAT-HF potentially can play a valuable role in reducing OAR toxicities associated with WPRT.

How can scanned proton beam treatment planning for low-grade glioma cope with increased distal RBE and locally increased radiosensitivity for late MR-detected brain lesions?

A novel risk model has recently been proposed for the occurrence of late contrast-enhancing brain lesions (CEBLs) after proton irradiation of low-grade glioma (LGG) patients. It predicts a strong dependence on dose-weighted linear-energy transfer (LETd effect) and an increased radiosensitivity of the ventricular proximity, a 4-mm fringe surrounding the ventricular system (VP4mm effect). On this basis, we investigated (A) how these two risk factors and patient-specific anatomical and treatment plan (TP) features contribute to normal tissue complication probability (NTCP) and (B) if conventional LETd -reduction techniques like multiple-field TP are able to reduce NTCP. (A) The LGG model cohort (N=110) was stratified with respect to prescribed dose, tumor grade, and treatment field configuration. NTCP predictions and CEBL occurrence rates per strata were analyzed. (B) The effect of multiple-field TP was investigated in two patient groups: (i) nine high-risk subjects with extended lateral target volumes who had developed CEBLs after single-beam treatments were retrospectively replanned with a clinical standard two-field setting using almost orthogonal fields and strictly opposing fields, (ii) single-field treatments were simulated for seven low-risk patients with small central target volumes clinically treated with two strictly opposing fields. (A) In the model cohort, we identified the exposure of the radiosensitive VP4mm fringe with proton field components of increased biological effectiveness as dominant NTCP driving factor. We observed that larger target volumes and location lateral to the main ventricles, both being characteristic for WHO°II tumors, presented with the highest complication risks. Among subjects of an equal dose prescription of 54Gy(RBE), the highest median NTCP was obtained for the WHO°II group treated with two fields using sharp angles. (B) Regarding the effect of multiple-field plans, we found that an NTCP reduction was only achievable in the low-risk group where the LETd effect dominates and the VP4mm effect is small. NTCP of the single-field plans was 23% higher compared to the clinical opposing field plan. In the high-risk group, where the VP4mm effect dominates the risk, both two-field scenarios yielded 44% higher NTCP predictions compared to the clinical single-field plans. The interplay of an increased radiosensitivity in the VP4mm fringe with proton field components of increased biological effectiveness creates a geometric complexity that can hardly be managed by current clinical TP. Our results underline that advanced biologically guided TP approaches become crucial for an effective risk minimization in proton therapy of LGG.

Dose-Volume and Radiobiological Model-Based Comparative Evaluation of the Gastrointestinal Toxicity Risk of Photon and Proton Irradiation Plans in Localized Pancreatic Cancer Without Distant Metastasis.

Background: Radiobiological model-based studies of photon-modulated radiotherapy for pancreatic cancer have reported reduced gastrointestinal (GI) toxicity, although the risk is still high. The purpose of this study was to investigate the potential of 3D-passive scattering proton beam therapy (3D-PSPBT) in limiting GI organ at risk (OAR) toxicity in localized pancreatic cancer based on dosimetric data and the normal tissue complication probability (NTCP) model.Methods: The data of 24 pancreatic cancer patients were retrospectively analyzed, and these patients were planned with intensity-modulated radiotherapy (IMRT), volume-modulated arc therapy (VMAT), and 3D-PSPBT. The tumor was targeted without elective nodal coverage. All generated plans consisted of a 50.4-GyE (Gray equivalent) dose in 28 fractions with equivalent OAR constraints, and they were normalized to cover 50% of the planning treatment volume (PTV) with 100% of the prescription dose. Physical dose distributions were evaluated. GI-OAR toxicity risk for different endpoints was estimated by using published NTCP Lyman–Kutcher–Burman (LKB) models. Analysis of variance (ANOVA) was performed to compare the dosimetric data, and ΔNTCPIMRT−PSPBT and ΔNTCPVMAT−PSPBT were also computed.Results: Similar homogeneity and conformity for the clinical target volume (CTV) and PTV were exhibited by all three planning techniques (P > 0.05). 3D-PSPBT resulted in a significant dose reduction for GI-OARs in both the low-intermediate dose range (below 30 GyE) and the highest dose region (Dmax and V50 GyE) in comparison with IMRT and VMAT (P < 0.05). Based on the NTCP evaluation, the NTCP reduction for GI-OARs by 3D-PSPBT was minimal in comparison with IMRT and VMAT.Conclusion: 3D-PSPBT results in minimal NTCP reduction and has less potential to substantially reduce the toxicity risk of upper GI bleeding, ulceration, obstruction, and perforation endpoints compared to IMRT and VMAT. 3D-PSPBT may have the potential to reduce acute dose-limiting toxicity in the form of nausea, vomiting, and diarrhea by reducing the GI-OAR treated volume in the low-to-intermediate dose range. However, this result needs to be further evaluated in future clinical studies.

Individualized Prophylactic Neck Irradiation in Patients with cN0 Head and Neck Cancer Based on Sentinel Lymph Node(s) Identification: Definitive Results of a Prospective Phase 1-2 Study

This prospective, nonrandomized, interventional phase 1-2 study investigated the individualization of elective node irradiation in clinically N0 head and neck squamous cell carcinoma by sentinel lymph node (SLN) mapping with single-photon emission computed tomography/computed tomography (SPECT/CT) and its impact on tumor control and radiation-related toxicity. Forty-four patients with clinically N0 head and neck squamous cell carcinoma treated with definitive (chemo-)radiation therapy were imaged with SPECT/CT after 99mTc nanocolloid injection around the tumor. The neck levels containing up to the 4 hottest SLNs were selected for prophylactic irradiation. A comparative virtual planning was performed with the selection of neck levels based on the current international guidelines. Regional control was monitored as a function of the selected volume. Dosimetric data for the organs at risk were compared between the plans. Normal tissue complication probability (NTCP) rates were derived for xerostomia, dysphagia, and hypothyroidism to predict the clinical benefit and correlated to quality-of-life (QoL) assessments at 6 months. Sixteen percent of patients presented unpredicted lymphatic drainage, and 48% drained unilaterally. The nodal clinical target volume based on lymphoscintigraphy was smaller than the nodal clinical target volume based on international guidelines by a factor of 2 (P < .0001). After a median follow-up of 46 months, only 1 patient experienced a regional relapse in a nonirradiated area. Significant median dose reductions to organs at risk were observed, particularly to contralateral salivary glands in patients with unilateral drainage (14.6-28.1 Gy) and to the thyroid gland in all patients (22.4-48.9 Gy). Median NTCP reductions were observed for xerostomia (0.3% to 13.7%), dysphagia (1.7% to 10.8%), and hypothyroidism (14.0% to 36.1%). QoL at 6 months was improved, particularly in patients irradiated unilaterally. Neck SLN mapping with SPECT/CT individualizes and reduces the elective nodal target volumes without compromising the regional control. The NTCP rates were reduced and favorable QoL were observed in all patients, particularly in the case of unilateral irradiation.

Intensity modulated proton therapy compared to volumetric modulated arc therapy in the irradiation of young female patients with hodgkin\u2019s lymphoma. Assessment of risk of toxicity and secondary cancer induction

BackgroundTo investigate the role of intensity modulated proton therapy (IMPT) compared to volumetric modulated arc therapy (VMAT) for advanced supradiaphragmatic Hodgkin’s lymphoma (HL) in young female patients by assessing dosimetric features and modelling the risk of treatment related complications and radiation-induced secondary malignancies.MethodsA group of 20 cases (planned according to the involved-site approach) were retrospectively investigated in a comparative planning study. Intensity modulated proton plans (IMPT) were compared to VMAT RapidArc plans (RA). Estimates of toxicity were derived from normal tissue complication probability (NTCP) calculations with either the Lyman or the Poisson models for a number of endpoints. Estimates of the risk of secondary cancer induction were determined for lungs, breasts, esophagus and thyroid. A simple model-based selection strategy was considered as a feasibility proof for the individualized selection of patients suitable for proton therapy.ResultsIMPT and VMAT plans resulted equivalent in terms of target dose distributions, both were capable to ensure high coverage and homogeneity. In terms of conformality, IMPT resulted ~ 10% better than RA plans. Concerning organs at risk, IMPT data presented a systematic improvement (highly significant) over RA for all organs, particularly in the dose range up to 20Gy. This lead to a composite average reduction of NTCP of 2.90 ± 2.24 and a reduction of 0.26 ± 0.22 in the relative risk of cardiac failures. The excess absolute risk per 10,000 patients-years of secondary cancer induction was reduced, with IMPT, of 9.1 ± 3.2, 7.2 ± 3.7 for breast and lung compared to RA. The gain in EAR for thyroid and esophagus was lower than 1. Depending on the arbitrary thresholds applied, the selection rate for proton treatment would have ranged from 5 to 75%.ConclusionIn relation to young female patients with advanced supradiaphragmatic HL, IMPT can in general offer improved dose-volume sparing of organs at risk leading to an anticipated lower risk of early or late treatment related toxicities. This would reflect also in significantly lower risk of secondary malignancies induction compared to advanced photon based techniques. Depending on the selection thresholds and with all the limits of a non-validated and very basic model, it can be anticipated that a significant fraction of patients might be suitable for proton treatments if all the risk factors would be accounted for.

Trade-off between the conflicting planning goals in correlation with patient’s anatomical parameters for intensity-modulated radiotherapy of prostate cancer patients

AbstractAimTo quantify the relationship between the planning target volume (PTV) dose homogeneity and organs at risk (OARs) sparing in correlation with anatomical parameters in prostate intensity-modulated radiotherapy (IMRT).Materials and methodsNine IMRT plans with various target dose constraints’ priorities were created for 15 prostate cancer patients. Selected PTV and OARs parameters were calculated for the patients. A trade-off was assessed between homogeneity index (HI) and OAR sparing. Several anatomical parameters were evaluated to investigate their effects on the OAR sparing and HI.ResultsInverse exponential relationships were found between the OAR sparing and HI (average R 2 of 0·983 and 0·994 for bladder and rectum, respectively). Decreasing the priority led to more OARs sparing (normal tissue complication probability reduction: 97·6 and 74·5%; mean dose reduction: 16·3 and 11·3% for bladder and rectum, respectively) and worsening of the HI (0·095–0·322) but with no significant effect on tumour control probability. Furthermore, OARs volumes, distances between OARs and PTV and their joint volumes had stronger correlations with OARs’ mean doses.ConclusionEnforcement of target dose constraints was more effective on the improvement of HIs for the patients with initial high HI values at low dose constraints’ priorities. Reducing the priority had more effects on the OARs sparing compared to HI, especially for the patients with high OAR doses in high priority plans. This can be attributed to smaller distances or greater joint volumes between the OARs and PTV.

The normal tissue complication probability model-based approach considering uncertainties for the selective use of radiation modality in primary liver cancer patients

PurposeTo predict the probability of radiation-induced liver toxicity (RILT) and implement the normal tissue complication probability (NTCP) model-based approach considering confidence intervals (CIs) to select patients for new treatment techniques, such as proton beam therapy, based on a certain NTCP reduction (ΔNTCP) threshold for primary liver cancer patients. Methods and materialsCommon Toxicity Criteria for Adverse Events (CTCAE) grade ≥2 RILT was scored. The Lyman NTCP models predicting the probability of CTCAE grade ≥2 RILT as a function of the fraction-size adjusted mean liver dose (MLD), using reference fraction size = 2 Gy/fraction and α/β ratio = 2 Gy, were fitted using the maximum likelihood method. At certain combinations of MLDs, ΔNTCP with a CI was evaluated by the delta method. ResultsOf the 239 patients, the incidence of CTCAE grade ≥2 RILT was 55% (46% in the Child–Pugh (CP)-A vs. 81% in the CP-B/C, p < 0.001). Among 180 CP-A patients, 40% who had viral hepatitis infections experienced toxicity vs. 32% in the nonhepatitis subgroup. The MLD was 18 Gy in the toxicity group vs. 16.1 Gy in the nontoxicity group (p = 0.002). The estimated NTCP model parameters specific to the patient subgroups and the ΔNTCP with CI assuming a particular CP classification and viral hepatitis infection status were considerably different which possible changed treatment decision. ConclusionsPatients with CP-A and viral hepatitis infection or CP-B/C cirrhosis had greater susceptibility to CTCAE grade ≥2 RILT. The estimated NTCP and ΔNTCP for individual patients along with a consideration of uncertainties improve the reliability of the NTCP model-based approach.

Estimation of the risk for radiation-induced liver disease following photon- or proton-beam radiosurgery of liver metastases

BackgroundRadiotherapy of liver metastases is commonly being performed with photon-beam based stereotactic body radiation therapy (SBRT). The high risk for radiation-induced liver disease (RILD) is a limiting factor in these treatments. The use of proton-beam based SBRT could potentially improve the sparing of the healthy part of the liver. The aim of this study was to use estimations of normal tissue complication probability (NTCP) to identify liver-metastases patients that could benefit from being treated with intensity-modulated proton therapy (IMPT), based on the reduction of the risk for RILD.MethodsTen liver metastases patients, previously treated with photon-beam based SBRT, were retrospectively planned with IMPT. A CTV-based robust optimisation (accounting for setup and range uncertainties), combined with a PTV-based conventional optimisation, was performed. A robustness criterion was defined for the CTV (V95% > 98% for at least 10 of the 12 simulated scenarios). The NTCP was estimated for different endpoints using the Lyman-Kutcher-Burman model. The ΔNTCP (NTCPIMPT − NTCPSBRT) for RILD was registered for each patient. The patients for which the NTCP (RILD) < 5% were also identified. A generic relative biological effectiveness of 1.1 was assumed for the proton beams.ResultsFor all patients, the objectives set for the PTV and the robustness criterion set for the CTV were fulfilled with the IMPT plans. An improved sparing of the healthy part of the liver, right kidney, lungs, spinal cord and the skin was achieved with the IMPT plans, compared to the SBRT plans. Mean liver doses larger than the threshold value of 32 Gy led to NTCP values for RILD exceeding 5% (7 patients with SBRT and 3 patients with the IMPT plans). ΔNTCP values (RILD) ranging between − 98% and − 17% (7 patients) and between 0 and 2% (3 patients), were calculated.ConclusionsIn this study, liver metastases patients that could benefit from being treated with IMPT, based on the NTCP reductions, were identified. The clinical implementation of such a model-based approach to select liver metastases patients to proton therapy needs to be made with caution while considering the uncertainties involved in the NTCP estimations.

SPECT/CT-guided elective nodal irradiation for head and neck cancer: Estimation of clinical benefits using NTCP models

Background and purposeThe great majority of patients with lateralized head and neck squamous cell carcinoma (HNSCC) treated with radiotherapy routinely undergo bilateral elective nodal irradiation (ENI), even though the incidence of contralateral regional failure after unilateral ENI is low. Excluding the contralateral neck from elective irradiation could reduce radiation-related toxicity and improve quality-of-life. The current study investigated the dosimetric benefits of a novel approach using lymph drainage mapping by SPECT/CT to select patients for unilateral ENI. Patients and methodsForty patients with lateralized cT1-3N0-2bM0 HNSCC underwent lymph drainage mapping. Two radiation plans were made; the real plan with which patients were actually treated (selective SPECT/CT-guided plan irradiating the ipsilateral neck ± any contralateral draining level); and the virtual plan (standard plan according to institutional guidelines, as if the same patient would have been treated bilaterally). Radiation doses to clinically important organs-at-risk were compared between the two plans. We used five normal tissue complication probability (NTCP) models to predict the clinical benefits of this approach. ResultsMedian dose reductions to the contralateral parotid gland, contralateral submandibular gland, glottic larynx, supraglottic larynx, constrictor muscle and thyroid gland were 19.2, 27.3, 11.4, 9.7, 12.1 and 18.4 Gy, respectively. Median NTCP reductions for xerostomia, contralateral parotid function, dysphagia, hypothyroidism and laryngeal edema were 20%, 14%, 10%, 20% and 5% respectively. ConclusionsSelective SPECT/CT-guided ENI results in significant dose reductions to various organs-at-risk and corresponding NTCP values, and will subsequently reduce the incidence and severity of different troublesome radiation-related toxicities and improve quality-of-life.

Impact of the NTCP modeling on medical decision to select eligible patient for proton therapy: the usefulness of EUD as an indicator to rank modern photon vs proton treatment plans

Purpose: The aim of this study is to evaluate the impact of normal tissue complication probability (NTCP)-based radiobiological models on the estimated risk for late radiation lung damages. The second goal is to propose a medical decision-making approach to select the eligible patient for particle therapy.Materials and methods: Fourteen pediatric patients undergoing cranio-spinal irradiation were evaluated. For each patient, two treatment plans were generated using photon and proton therapy with the same dose prescriptions. Late radiation damage to lung was estimated using three NTCP concepts: the Lyman-Kutcher-Burman, the equivalent uniform dose (EUD) and the mean lung dose according to the quantitative analysis of normal tissue effects in the clinic QUANTEC review. Wilcoxon paired test was used to calculate p-value.Results: Proton therapy achieved lower lung EUD (Gy). The average NTCP values were significantly lower with proton plans, p < .05, using the three NTCP concepts. However, applying the same TD50/5 using radiobiological models to compare NTCP from proton and photon therapy, the ΔNTCP was not a convincing method to measure the potential benefit of proton therapy. Late radiation pneumonitis estimated from the mean lung dose model correlated with QUANTEC data better.Conclusions: Treatment effectiveness assessed on NTCP reduction depends on radiobiological predictions and parameters used as inputs for in silico evaluation. Because estimates of absolute NTCP values from LKB and GN models are imprecise due to EUD ≪ TD50/5, a reduction of the EUD value with proton plans would better predict a reduction of dose/toxicity. The EUD concept appears as a robust radiobiological surrogate of the dose distribution to select the optimal patient’s plan.

Dosimetric Evaluation of Incorporating Patient Geometric Variations Into Adaptive Plan Optimization Through Probabilistic Treatment Planning in Head and Neck Cancers

Four-dimensional (4D) adaptive radiation therapy (ART) treatment planning is an alternative to the conventional margin-based treatment planning approach. In 4D ART, interfraction patient geometric variations, gathered from computed tomography (CT) or cone beam CT (CBCT) images acquired during the patient treatment course, are directly incorporated into the adaptive plan optimization using a probabilistic treatment planning method. The goal of the present planning study was to evaluate the dosimetric differences between 4D ART and conventional margin-based adaptive planning strategies for head and neck cancers. In addition, we examined whether the dose differences achieved with 4D ART would translate into clinically relevant toxicity reductions using the existing normal tissue complication probability (NTCP) models. For 18 head and neck cancer patients, the treatment plans were retrospectively generated for 4 different treatment strategies, including a solely image guided radiation therapy (IGRT) strategy (IGRT-only), 2 conventional adaptive treatment planning strategies using 3- and 0-mm planning target volume (PTV) margins, and the 4D ART strategy. In the IGRT-only strategy, a conventional 3-mm PTV margin treatment plan was applied for the entire treatment course. In the 2 conventional adaptive strategies, 2 new treatment plans were generated during the treatment course using diagnostic planning CT scans acquired after the 10th and 22nd fractions. The 4D ART followed the same adaptive schedule, except that the 4D adaptive plan was generated using 5 CBCT images acquired during the 5 most recent treatment fractions. For each strategy, the actual delivered dose for the entire treatment course was constructed by calculating the daily doses on 35 CBCT scans, deforming back to the pretreatment planning CT scan, and accumulating over all 35 fractions. The target coverage was evaluated using the percentage of target volume receiving ≥100% of the prescription dose (V100%) and the minimum dose to 99% of the target volume (D99). It was considered adequate if the V100% was ≥95% and the dose deficit in D99 was ≤2Gy (with respect to the prescription dose). For each strategy, the dose received by the organs at risk (OARs) was also evaluated, and the corresponding NTCP values were subsequently calculated using 3 NTCP models. Adequate target coverage was achieved for the primary clinical target volume (CTV1) and elective nodal CTV (CTV2) with a 3-mm PTV margin, regardless of adaptation. The 3-mm ART plan reduced the OAR mean dose by 1 to 2Gy compared with the IGRT-only plan. The 0-mm ART plan further reduced the OAR dose by another 2 to 3Gy at the expense of target coverage: 3 and 1 patient had V100% <95%, and 6 and 5 patients had a >2 Gy dose deficit in D99 for the CTV1 and CTV2, respectively. Use of 4D ART improved target coverage and attained OAR sparing similar to that with 0-mm ART. The number of patients with V100% <95% and >2 Gy D99 deficit decreased to 0 and 0 for CTV1 and 0 and 2 for CTV2, respectively. The NTCP calculations suggested that 4D ART could benefit a substantial portion of patients compared with IGRT-only because 17 and 12 patients had ≥5% and ≥10% NTCP reductions for parotid toxicity and 18 and 3 patients had ≥5% and ≥10% NTCP reductions for swallowing toxicity, respectively. Compared with margin-based adaptive planning strategies, 4D ART provides a better balance between target coverage and OAR sparing. NTCP estimation predicted for theoretical clinical benefits that warrant further clinical validation.