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Therapeutic proton and heavier ion beams generate prompt gamma photons that may escape from the patient. In principle, this allows for real-time, in situ monitoring of the treatment delivery, in particular, the hadron range within the patient, by imaging the emitted prompt gamma rays. Unfortunately, the neutrons simultaneously created with the prompt photons create a background that may obscure the prompt gamma signal. To enhance the accuracy of proton dose verification by prompt gamma imaging, we therefore propose a time-of-flight (TOF) technique to reject this neutron background, involving a shifting time window to account for the propagation of the protons through the patient. Time-resolved Monte Carlo simulations of the generation and transport of prompt gamma photons and neutrons upon irradiation of a PMMA phantom with 100, 150 and 200 MeV protons were performed using Geant4 (version 9.2.p02) and MCNPX (version 2.7.D). The influence of angular collimation and TOF selection on the prompt gamma and neutron longitudinal profiles is studied. Furthermore, the implications of the proton beam microstructure (characterized by the proton bunch width and repetition period) are investigated. The application of a shifting TOF window having a width of ΔTOF(z) = 1.0 ns appears to reduce the neutron background by more than 99%. Subsequent application of an energy threshold does not appear to sharpen the distal falloff of the prompt gamma profile but reduces the tail that is observed beyond the proton range. Investigations of the influence of the beam time structure show that TOF rejection of the neutron background is expected to be effective for typical therapeutic proton cyclotrons.

Purpose: Conventional techniques (3D-CRT) for craniospinal irradiation (CSI) are still widely used. Modern techniques (IMRT, VMAT, TomoTherapy V R , proton pencil beam scanning [PBS]) are applied in a limited number of centers. For a 14-year-old patient, we aimed to compare dose distributions of five CSI techniques applied across Europe and generated according to the participating institute protocols, therefore representing daily practice. Material and methods: A multicenter (n ¼ 15) dosimetric analysis of five different techniques for CSI (3D-CRT, IMRT, VMAT, TomoTherapy V R , PBS; 3 centers per technique) was performed using the same patient data, set of delineations and dose prescription (36.0/1.8 Gy). Different treatment plans were optimized based on the same planning target volume margin. All participating institutes returned their best treatment plan applicable in clinic. Results: The modern radiotherapy techniques investigated resulted in superior conformity/homogeneity-indices (CI/HI), particularly in the spinal part of the target (CI: 3D-CRT:0.3 vs. modern:0.6; HI: 3D-CRT:0.2 vs. modern:0.1), and demonstrated a decreased dose to the thyroid, heart, esophagus and pancreas. Dose reductions of >10.0 Gy were observed with PBS compared to modern photon techniques for parotid glands, thyroid and pancreas. Following this technique, a wide range in dosimetry among centers using the same technique was observed (e.g., thyroid mean dose: VMAT: 5.6-24.6 Gy; PBS: 0.3-10.1 Gy). Conclusions: The investigated modern radiotherapy techniques demonstrate superior dosimetric results compared to 3D-CRT. The lowest mean dose for organs at risk is obtained with proton therapy. However, for a large number of organs ranges in mean doses were wide and overlapping between techniques making it difficult to recommend one radiotherapy technique over another. ARTICLE HISTORY

BackgroundTreatment for locally advanced rectal cancer (LARC) consists of chemoradiation therapy (CRT) and surgery. Approximately 15% of patients show a pathological complete response (pCR). Increased pCR-rates can be achieved through dose escalation, thereby increasing the number patients eligible for organ-preservation to improve quality of life (QoL). A randomized comparison of 65 versus 50Gy with external-beam radiation alone has not yet been performed. This trial investigates pCR rate, clinical response, toxicity, QoL and (disease-free) survival in LARC patients treated with 65Gy (boost + chemoradiation) compared with 50Gy standard chemoradiation (sCRT).Methods/designThis study follows the ‘cohort multiple randomized controlled trial’ (cmRCT) design: rectal cancer patients are included in a prospective cohort that registers clinical baseline, follow-up, survival and QoL data. At enrollment, patients are asked consent to offer them experimental interventions in the future. Eligible patients—histologically confirmed LARC (T3NxM0 <1 mm from mesorectal fascia, T4NxM0 or TxN2M0) located ≤10 cm from the anorectal transition who provided consent for experimental intervention offers—form a subcohort (n = 120). From this subcohort, a random sample is offered the boost prior to sCRT (n = 60), which they may accept or refuse. Informed consent is signed only after acceptance of the boost. Non-selected patients in the subcohort (n = 60) undergo sCRT alone and are not notified that they participate in the control arm until the trial is completed.sCRT consists of 50Gy (25 × 2Gy) with concomitant capecitabine. The boost (without chemotherapy) is given prior to sCRT and consists of 15 Gy (5 × 3Gy) delivered to the gross tumor volume (GTV). The primary endpoint is pCR (TRG 1). Secondary endpoints include acute grade 3–4 toxicity, good pathologic response (TRG 1-2), clinical response, surgical complications, QoL and (disease-free) survival. Data is analyzed by intention to treat.DiscussionThe boost is delivered prior to sCRT so that GTV adjustment for tumor shrinkage during sCRT is not necessary. Small margins also aim to limit irradiation of healthy tissue. The cmRCT design provides opportunity to overcome common shortcomings of classic RCTs, such as slow recruitment, disappointment-bias in control arm patients and poor generalizability.Trial registrationThe Netherlands Trials Register NL46051.041.13. Registered 22 August 2013. ClinicalTrials.gov NCT01951521. Registered 18 September 2013.

Average motion and patient set-up uncertainties during radiotherapy treatment were found to be limited. However, uncertainties were larger for the cranio-caudal direction and outliers were found in all orthogonal directions. When having available 4D-CT and CBCT information, the use of patient-specific and anisotropic safety margin expansions is advised for both target volume and OAR.

Positron emission tomography (PET) is a promising tool for monitoring the three-dimensional dose distribution in charged particle radiotherapy. PET imaging during or shortly after proton treatment is based on the detection of annihilation photons following the ß(+)-decay of radionuclides resulting from nuclear reactions in the irradiated tissue. Therapy monitoring is achieved by comparing the measured spatial distribution of irradiation-induced ß(+)-activity with the predicted distribution based on the treatment plan. The accuracy of the calculated distribution depends on the correctness of the computational models, implemented in the employed Monte Carlo (MC) codes that describe the interactions of the charged particle beam with matter and the production of radionuclides and secondary particles. However, no well-established theoretical models exist for predicting the nuclear interactions and so phenomenological models are typically used based on parameters derived from experimental data. Unfortunately, the experimental data presently available are insufficient to validate such phenomenological hadronic interaction models. Hence, a comparison among the models used by the different MC packages is desirable. In this work, starting from a common geometry, we compare the performances of MCNPX, GATE and PHITS MC codes in predicting the amount and spatial distribution of proton-induced activity, at therapeutic energies, to the already experimentally validated PET modelling based on the FLUKA MC code. In particular, we show how the amount of ß(+)-emitters produced in tissue-like media depends on the physics model and cross-sectional data used to describe the proton nuclear interactions, thus calling for future experimental campaigns aiming at supporting improvements of MC modelling for clinical application of PET monitoring.

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