Comparison of 3D and 4D robustly optimized proton treatment plans for non-small cell lung cancer patients with tumour motion amplitudes larger than 5 mm.

Background and purpose: There is no consensus about an ideal robust optimization (RO) strategy for proton therapy of targets with large intrafractional motion. We investigated the plan robustness of 3D and different 4D RO strategies. Materials and methods: For eight non-small cell lung cancer patients with clinical target volume (CTV) motion >5 mm, different RO approaches were investigated: 3DRO considering the average CT (AvgCT) with a target density override, 4DRO considering three/all 4DCT phases, and 4DRO considering the AvgCT and three/all 4DCT phases. Robustness against setup/range errors, interplay effects based on breathing and machine log file data for deliveries with/without rescanning, and interfractional anatomical changes were analyzed for target coverage and OAR sparing. Results: All nominal plans fulfilled the clinical requirements with individual CTV coverage differences <2pp; 4DRO without AvgCT generated the most conformal dose distributions. Robustness against setup/range errors was best for 4DRO with AvgCT (18% more passed error scenarios than 3DRO). Interplay effects caused fraction-wise median CTV coverage loss of 3pp and missed maximum dose constraints for heart and esophagus in 18% of scenarios. CTV coverage and OAR sparing fulfilled requirements in all cases when accumulating four interplay scenarios. Interfractional changes caused less target misses for RO with AvgCT compared to 4DRO without AvgCT (≤42%/33% vs. ≥56%/44% failed single/accumulated scenarios). Conclusions: All RO strategies provided acceptable plans with equally low robustness against interplay effects demanding other mitigation than rescanning to ensure fraction-wise target coverage. 4DRO considering three phases and the AvgCT provided best compromise on planning effort and robustness.

Impact of Blood Parameters and Normal Tissue Dose on Treatment Outcome in Esophageal Cancer Patients Undergoing Neoadjuvant Radiochemotherapy.

Despite technological advances, normal tissue sparing in photon beam irradiation is still challenging. Since in esophageal cancer this may inflict damage on the lungs, heart and bone marrow, possibly impacting on outcome, the aim of this study was to investigate the association of normal tissue dose and blood parameters on the survival of patients having undergone neoadjuvant radiochemotherapy (RCTx) followed by surgery. This retrospective study included 125 patients irradiated to 40−41.4 Gy with photons or protons combined with concurrent chemotherapy. On initial and restaging 18F-FDG-PET/CT, the lungs and heart were contoured as organs at risk for which standardized uptake values (SUV) were evaluated. The mean radiation dose (Dmean) to the lungs and heart, the volume of the lungs receiving at least 20 Gy (V20Gy_lung) and various pre- and per-treatment blood parameters were included in the Cox regression analyses. Results: The median follow-up time was 19.8 months and median overall survival 37 months (95% confidence interval: 16−58.9 months). In multivariate analysis, higher radiation doses to the lungs and heart were statistically significantly associated with decreased overall survival (Dmean_lung: p < 0.001; V20Gy_lung: p < 0.002; Dmean_heart: p = 0.005). Neither the 18F-FDG-PET nor blood parameters were predictive for overall survival. In patients with locally advanced esophageal cancer treated with RCTx, the radiation dose to the heart and lungs was significantly associated with overall survival.

Treatment planning comparison in the PROTECT-trial randomising proton versus photon beam therapy in oesophageal cancer: Results from eight European centres.

PURPOSE: To compare dose distributions and robustness in treatment plans from eight European centres in preparation for the European randomized phase-III PROTECT-trial investigating the effect of proton therapy (PT) versus photon therapy (XT) for oesophageal cancer. MATERIALS AND METHODS: All centres optimized one PT and one XT nominal plan using delineated 4DCT scans for four patients receiving 50.4 Gy (RBE) in 28 fractions. Target volume receiving 95% of prescribed dose (V95%iCTVtotal) should be >99%. Robustness towards setup, range, and respiration was evaluated. The plans were recalculated on a surveillance 4DCT (sCT) acquired at fraction ten and robustness evaluation was performed to evaluate the effect of respiration and inter-fractional anatomical changes. RESULTS: All PT and XT plans complied with V95%iCTVtotal >99% for the nominal plan and V95%iCTVtotal >97% for all respiratory and robustness scenarios. Lung and heart dose varied considerably between centres for both modalities. The difference in mean lung dose and mean heart dose between each pair of XT and PT plans was in median [range] 4.8 Gy [1.1;7.6] and 8.4 Gy [1.9;24.5], respectively. Patients B and C showed large inter-fractional anatomical changes on sCT. For patient B, the minimum V95%iCTVtotal in the worst-case robustness scenario was 45% and 94% for XT and PT, respectively. For patient C, the minimum V95%iCTVtotal was 57% and 72% for XT and PT, respectively. Patient A and D showed minor inter-fractional changes and the minimum V95%iCTVtotal was >85%. CONCLUSION: Large variability in dose to the lungs and heart was observed for both modalities. Inter-fractional anatomical changes led to larger target dose deterioration for XT than PT plans.

The impact of anatomical changes during photon or proton based radiation treatment on tumor dose in glioblastoma dose escalation trials.

PURPOSE/OBJECTIVE: Most dose-escalation trials in glioblastoma patients integrate the escalated dose throughout the standard course by targeting a specific subvolume. We hypothesize that anatomical changes during irradiation may affect the dose coverage of this subvolume for both proton- and photon-based radiotherapy. MATERIAL AND METHODS: For 24 glioblastoma patients a photon- and proton-based dose escalation treatment plan (of 75 Gy/30 fr) was simulated on the dedicated radiotherapy planning MRI obtained before treatment. The escalated dose was planned to cover the resection cavity and/or contrast enhancing lesion on the T1w post-gadolinium MRI sequence. To analyze the effect of anatomical changes during treatment, we evaluated on an additional MRI that was obtained during treatment the changes of the dose distribution on this specific high dose region. RESULTS: The median time between the planning MRI and additional MRI was 26 days (range 16-37 days). The median time between the planning MRI and start of radiotherapy was relatively short (7 days, range 3-11 days). In 3 patients (12.5%) changes were observed which resulted in a substantial deterioration of both the photon and proton treatment plans. All these patients underwent a subtotal resection, and a decrease in dose coverage of more than 5% and 10% was observed for the photon- and proton-based treatment plans, respectively. CONCLUSION: Our study showed that only for a limited number of patients anatomical changes during photon or proton based radiotherapy resulted in a potentially clinically relevant underdosage in the subvolume. Therefore, volume changes during treatment are unlikely to be responsible for the negative outcome of dose-escalation studies.

Photons or protons for reirradiation in (non-)small cell lung cancer: Results of the multicentric ROCOCO in silico study.

OBJECTIVE: Locally recurrent disease is of increasing concern in (non-)small cell lung cancer [(N)SCLC] patients. Local reirradiation with photons or particles may be of benefit to these patients. In this multicentre in silico trial performed within the Radiation Oncology Collaborative Comparison (ROCOCO) consortium, the doses to the target volumes and organs at risk (OARs) were compared when using several photon and proton techniques in patients with recurrent localised lung cancer scheduled to undergo reirradiation. METHODS: 24 consecutive patients with a second primary (N)SCLC or recurrent disease after curative-intent, standard fractionated radio(chemo)therapy were included in this study. The target volumes and OARs were centrally contoured and distributed to the participating ROCOCO sites. Remaining doses to the OARs were calculated on an individual patient's basis. Treatment planning was performed by the participating site using the clinical treatment planning system and associated beam characteristics. RESULTS: Treatment plans for all modalities (five photon and two proton plans per patient) were available for 22 patients (N = 154 plans). 3D-conformal photon therapy and double-scattered proton therapy delivered significantly lower doses to the target volumes. The highly conformal techniques, i.e., intensity modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), CyberKnife, TomoTherapy and intensity-modulated proton therapy (IMPT), reached the highest doses in the target volumes. Of these, IMPT was able to statistically significantly decrease the radiation doses to the OARs. CONCLUSION: Highly conformal photon and proton beam techniques enable high-dose reirradiation of the target volume. They, however, significantly differ in the dose deposited in the OARs. The therapeutic options, i.e., reirradiation or systemic therapy, need to be carefully weighed and discussed with the patients. ADVANCES IN KNOWLEDGE: Highly conformal photon and proton beam techniques enable high-dose reirradiation of the target volume. In light of the abilities of the various highly conformal techniques to spare specific OARs, the therapeutic options need to be carefully weighed and patients included in the decision-making process.

PRONTOX - proton therapy to reduce acute normal tissue toxicity in locally advanced non-small-cell lung carcinomas (NSCLC): study protocol for a randomised controlled trial.

BACKGROUND: Primary radiochemotherapy with photons is the standard treatment for locally advanced-stage non-small cell lung cancer (NSCLC) patients. Acute radiation-induced side effects such as oesophagitis and radiation pneumonitis limit patients' quality of life, and the latter can be potentially life-threatening. Due to its distinct physical characteristics, proton therapy enables better sparing of normal tissues, which is supposed to translate into a reduction of radiation-induced side effects. METHODS/DESIGN: This is a single-centre, prospective, randomised controlled, phase II clinical trial to compare photon to proton radiotherapy up to 66 Gy (RBE) with concomitant standard chemotherapy in patients with locally advanced-stage NSCLC. Patients will be allocated in a 1:1 ratio to photon or proton therapy, and treatment will be delivered slightly accelerated with six fractions of 2 Gy (RBE) per week. DISCUSSION: The overall aim of the study is to show a decrease of early and intermediate radiation-induced toxicity using proton therapy. For the primary endpoint of the study we postulate a decrease of radiation-induced side effects (oesophagitis and pneumonitis grade II or higher) from 39 to 12%. Secondary endpoints are locoregional and distant failure, overall survival and late side effects. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with Identifier NCT02731001 on 1 April 2016.