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The role of postoperative radiation therapy (PORT) in stage III N2 nonsmall cell lung cancer patients remains controversial. PORT is still widely used among European thoracic radiation oncology experts with a clear decrease in its use for patients with completely resected pN+ NSCLC after the presentation of LungART trial results at ESMO 2020. The full publication of the LungART trial hopefully will shed additional light on the dilemma of the decision-making process for PORT in completely resected pN+ patients and identify the appropriate patients who might benefit from PORT.Background: The role of postoperative radiation therapy (PORT) in stage III N2 NSCLC is controversial. We analyzed decision-making for PORT among European radiation oncology experts in lung cancer. Methods: Twenty-two experts were asked before and after presentation of the results of the LungART trial to describe their decision criteria for PORT in the management of pN+ NSCLC patients. Treatment strategies were subsequently converted into decision trees and analyzed. Results: Following decision criteria were identified: extracapsular nodal extension, incomplete lymph node resection, multistation lymph nodes, high nodal tumor load, poor response to induction chemotherapy, ineligibility to receive adjuvant chemotherapy, performance status, resection margin, lung function and cardiopulmonary comorbidities. The LungART results had impact on decision-making and reduced the number of recommendations for PORT. The only clear indication for PORT was a R1/2 resection. Six experts out of ten who initially recommended PORT for all R0 resected pN2 patients no longer used PORT routinely for these patients, while four still recommended PORT for all patients with pN2. Fourteen experts used PORT only for patients with risk factors, compared to eleven before the presentation of the LungART trial. Four experts stated that PORT was never recommended in R0 resected pN2 patients regardless of risk factors. Conclusion: After presentation of the LungART trial results at ESMO 2020, 82% of our experts still used PORT for stage III pN2 NSCLC patients with risk factors. The recommendation for PORT decreased, especially for patients without risk factors. Cardiopulmonary comorbidities became more relevant in the decision-making for PORT. (C) 2021 Elsevier Inc. All rights reserved.

Objective. To compare a not adapted (NA) robust planning strategy with three fully automated online adaptive proton therapy (OAPT) workflows based on the same optimization method: dose mimicking (DM). The added clinical value and limitations of the OAPT methods are investigated for head and neck cancer (HNC) patients. Approach. The three OAPT strategies aimed at compensating for inter-fractional anatomical changes by mimiking different dose distributions on corrected cone beam CT images (corrCBCTs). Order by complexity, the OAPTs were: (1) online adaptive dose restoration (OADR) where the approved clinical dose on the planning-CT (pCT) was mimicked, (2) online adaptation using DM of the deformed clinical dose from the pCT to corrCBCTs (OADEF), and (3) online adaptation applying DM to a predicted dose on corrCBCTs (OAML). Adaptation was only applied in fractions where the target coverage criteria were not met (D98% < 95% of the prescribed dose). For 10 HNC patients, the accumulated dose distributions over the 35 fractions were calculated for NA, OADR, OADEF, and OAML. Main results. Higher target coverage was observed for all OAPT strategies compared to no adaptation. OADEF and OAML outperformed both NA and OADR and were comparable in terms of target coverage to initial clinical plans. However, only OAML provided comparable NTCP values to those from the clinical dose without statistically significant differences. When the NA initial plan was evaluated on corrCBCTs, 51% of fractions needed adaptation. The adaptation rate decreased significantly to 25% when the last adapted plan with OADR was selected for delivery, to 16% with OADEF, and to 21% with OAML. The reduction was even greater when the best plan among previously generated adapted plans (instead of the last one) was selected. Significance. The implemented OAPT strategies provided superior target coverage compared to no adaptation, higher OAR sparing, and fewer required adaptations.

BACKGROUND AND PURPOSE: There are several alternatives to the widespread ITV strategy in order to account for breathing-induced motion in PTV margins. The most sophisticated one includes the generation of a motion-compensated CT scan with the CTV placed in its average position - the mid-position approach (MidP). In such configuration, PTV margins integrate breathing as another random error. Despite overall irradiated volume reduction, such approach is barely used in clinical practice because of its dependence to deformable registration and its unavailability in commercial treatment planning systems. As an alternative, the mid-ventilation approach (MidV) selects the phase in the 4D-CT scan that is the closest to the MidP, with a residual error accounted for in the PTV margin. We propose a treatment planning system-integrated strategy, aiming at better approximating the MidP approach without its drawbacks: Hybrid MidV-MidP approach, i.e., the delineation on the MidV-CT and translation at the mid-position coordinates using treatment planning system built-in capabilities. MATERIAL AND METHODS: Forty-five lung lesions treated with stereotactic radiotherapy were selected. PTV was defined using MidP, MidV, Hybrid MidV-MidP and ITV strategies. Margin definitions were adapted and resulting PTVs were compared. RESULTS: Hybrid MidV-MidP showed similar target volume and location than the MidP and confirmed that margin-incorporated tumor motion strategies lead to significantly smaller PTVs than the ITV with mean reduction of 26 ± 7%. CONCLUSION: We report on the successful implementation of a pseudo-MidP solution without its inherent drawbacks. It answers the need for TPS-embedded tumor motion range identification and related margin's component calculation. ispartof: MEDICAL DOSIMETRY vol:46 issue:3 pages:253-258 ispartof: location:United States status: published

Background: Whole brain radiotherapy (WBRT) is a common treatment option for brain metastases secondary to non-small cell lung cancer (NSCLC). Data from the QUARTZ trial suggest that WBRT can be omitted in selected patients and treated with optimal supportive care alone. Nevertheless, WBRT is still widely used to treat brain metastases secondary to NSCLC. We analysed decision criteria influencing the selection for WBRT among European radiation oncology experts. Methods: Twenty-two European radiation oncology experts in lung cancer as selected by the European Society for Therapeutic Radiation Oncology (ESTRO) for previous projects and by the Advisory Committee on Radiation Oncology Practice (ACROP) for lung cancer were asked to describe their strategies in the management of brain metastases of NSCLC. Treatment strategies were subsequently converted into decision trees and analysed for agreement and discrepancies. Results: Eight decision criteria (suitability for SRS, performance status, symptoms, eligibility for targeted therapy, extra-cranial tumour control, age, prognostic scores and "Zugzwang" (the compulsion to treat)) were identified. WBRT was recommended by a majority of the European experts for symptomatic patients not suitable for radiosurgery or fractionated stereotactic radiotherapy. There was also a tendency to use WBRT in the ALK/EGFR/ROS1 negative NSCLC setting. Conclusion: Despite the results of the QUARTZ trial WBRT is still widely used among European radiation oncology experts. Keywords: Decision tree; Decision-making; NSCLC; QUARTZ; WBRT.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The Funds Pierre Masure, Alphonse and Marie Walckiers & De Winter-Vermant, by King Baudouin Foundation Background Radiation therapy (RXT) is a keystone in breast cancer (BC) treatment which allows to reduce risk of local recurrence and cancer related mortality. Yet these benefits may be offset by increases in cardiovascular mortality due to late radiation induced cardiotoxicity. Indeed, prior works in patients exposed to high cardiac radiation dose demonstrated development of diffuse and focal myocardial fibrosis by cMR. However, whether such effects may also occur after contemporary BC-RXT with lower cardiac dose exposure, has not yet been evaluated. Purpose To evaluate the long-term cardiac safety of contemporary RXT for BC, we sought to estimate the prevalence of cardiac functional and structural focal and myocardial abnormalities in BC survivors treated by RXT 10 years earlier, in direct relation to measured local radiation dose exposure. Methods In a prospective cross-sectional study, we studied 27 women (mean age 62 ± 7 years) treated with adjuvant RXT but without chemotherapy for a first left (n= 12) or right sided (n= 15) BC between 2009 and 2011, which had no history of coronary artery or cardiac disease and compared them to 20 age matched (64 ± 10 years) healthy female controls (without history of BC or RXT). All subjects underwent 3T cMR to measure LV volumes, function, global longitudinal (GLS), circumferential (GRS) and radial strains (GRS) as well as extracellular volume (ECV) and late gadolinium enhancement (LGE). Functional and structural abnormalities in women with BC were compared to healthy controls. We also compared abnormalities among patients with left vs right BC and related them to mean heart radiation dose measured at the time of RXT (Figure). Results Mean cardiac radiation exposure in BC survivors was 1.87 ± 1.7 Gy (range 0-7.9 Gy). Exposure was significantly (p Conclusions In this preliminary work, patients with BC treated by adjuvant RXT 10 years ago, presented no significant structural or functional abnormalities in relation to cardiac dose exposure nor in comparison to healthy controls. This suggests that current RXT protocols for BC are safe without long-term functional or morphological cardiac side effects.

Background About 50% of non-small cell lung cancer (NSCLC) patients have metastatic disease at initial diagnosis, which limits their treatment options and, consequently, the 5-year survival rate (15%). Immune checkpoint inhibitors (ICI), either alone or in combination with chemotherapy, have become standard of care (SOC) for most good performance status patients. However, most patients will not obtain long-term benefit and new treatment strategies are therefore needed. We previously demonstrated clinical safety of the tumour-selective immunocytokine L19-IL2, consisting of the anti-ED-B scFv L19 antibody coupled to IL2, combined with stereotactic ablative radiotherapy (SABR). Methods This investigator-initiated, multicentric, randomised controlled open-label phase II clinical trial will test the hypothesis that the combination of SABR and L19-IL2 increases progression free survival (PFS) in patients with limited metastatic NSCLC. One hundred twenty-six patients will be stratified according to their metastatic load (oligo-metastatic: ≤5 or poly-metastatic: 6 to 10) and randomised to the experimental-arm (E-arm) or the control-arm (C-arm). The C-arm will receive SOC, according to the local protocol. E-arm oligo-metastatic patients will receive SABR to all lesions followed by L19-IL2 therapy; radiotherapy for poly-metastatic patients consists of irradiation of one (symptomatic) to a maximum of 5 lesions (including ICI in both arms if this is the SOC). The accrual period will be 2.5-years, starting after the first centre is initiated and active. Primary endpoint is PFS at 1.5-years based on blinded radiological review, and secondary endpoints are overall survival, toxicity, quality of life and abscopal response. Associative biomarker studies, immune monitoring, CT-based radiomics, stool collection, iRECIST and tumour growth rate will be performed. Discussion The combination of SABR with or without ICI and the immunocytokine L19-IL2 will be tested as 1st, 2nd or 3rd line treatment in stage IV NSCLC patients in 14 centres located in 6 countries. This bimodal and trimodal treatment approach is based on the direct cytotoxic effect of radiotherapy, the tumour selective immunocytokine L19-IL2, the abscopal effect observed distant from the irradiated metastatic site(s) and the memory effect. The first results are expected end 2023. Trial registration ImmunoSABR Protocol Code: NL67629.068.18; EudraCT: 2018–002583-11; Clinicaltrials.gov: NCT03705403; ISRCTN ID: ISRCTN49817477; Date of registration: 03-April-2019.

Background: Tumor hypoxia increases resistance to radiotherapy and systemic therapy. Our aim was to develop and validate a disease-agnostic and disease-specific CT (+FDG-PET) based radiomics hypoxia classification signature.Material and methods: A total of 808 patients with imaging data were included: N = 100 training/N = 183 external validation cases for a disease-agnostic CT hypoxia classification signature, N = 76 training/N = 39 validation cases for the H&N CT signature and N = 62 training/N = 36 validation cases for the Lung CT signature. The primary gross tumor volumes (GTV) were manually defined by experts on CT. In order to dichotomize between hypoxic/well-oxygenated tumors a threshold of 20% was used for the [F-18]-HX4-derived hypoxic fractions (HF). A random forest (RF)-based machine-learning classifier/regressor was trained to classify patients as hypoxia-positive/negative based on radiomic features.Results: A 11 feature "disease-agnostic CT model" reached AUC's of respectively 0.78 (95% confidence interval [CI], 0.62-0.94), 0.82 (95% CI, 0.67-0.96) and 0.78 (95% CI, 0.67-0.89) in three external validation datasets. A "disease-agnostic FDG-PET model" reached an AUC of 0.73 (0.95% CI, 0.49-0.97) in validation by combining 5 features. The highest "lung-specific CT model" reached an AUC of 0.80 (0.95% CI, 0.65-0.95) in validation with 4 CT features, while the "H&N-specific CT model" reached an AUC of 0.84 (0.95% CI, 0.64-1.00) in validation with 15 CT features. A tumor volume-alone model was unable to significantly classify patients as hypoxia-positive/negative. A significant survival split (P = 0.037) was found between CT-classified hypoxia strata in an external H&N cohort (n = 517), while 117 significant hypoxia gene-CT signature feature associations were found in an external lung cohort (n = 80).Conclusion: The disease-specific radiomics signatures perform better than the disease agnostic ones. By identifying hypoxic patients our signatures have the potential to enrich interventional hypoxia-targeting trials. (C) 2020 The Author(s). Published by Elsevier B.V.

Radiotherapy (RT) plays a major role in the treatment of small cell lung cancer (SCLC). Therefore, the ACROP committee was asked by ESTRO to provide recommendations on target volume delineation for standard clinical scenarios in definitive (chemo)-radiotherapy (CRT), adjuvant RT for stages I-III SCLC and consolidation thoracic RT for stage IV disease. The aim of these guidelines is to standardise and optimise the process of RT treatment planning for clinical practice and prospective studies. The process for the development of the guidelines included the evaluation of a structured questionnaire followed by a consensus discussion, voting and writing process within the committee. Firstly, we provide recommendations for both the imaging to be performed as part of the diagnostic work-up and for the RT planning process. Secondly, recommendations are made for target volume delineation including delineation of the primary gross tumour volume (GTV) and lymph node GTV and clinical tumour volume (CTV) expansion in the context of definitive and adjuvant RT. With regard to internal target volume (ITV) and planning target volume (PTV) definitions, we make recommendations about the management of geometric uncertainties and target motion. Finally, we provide our opinions on organ at risk (OAR) delineation and organisational issues to be considered. (C) 2020 Published by Elsevier B.V.

Background: PET-guided dose painting (DP) aims to target radioresistant tumour regions in order to improve radiotherapy (RT) outcome. Besides the well-known [18F]fluorodeoxyglucose (FDG), the hypoxia positron emission tomography (PET) tracer [18F]fluoroazomycin arabinoside (FAZA) could provide further useful information to guide the radiation dose prescription. In this study, we compare the spatial distributions of FDG and FAZA PET uptakes in lung tumours.Material and methods: Fourteen patients with unresectable lung cancer underwent FDG and FAZA 4D-PET/CT on consecutive days at three time-points: prior to RT (pre), and during the second (w2), and the third (w3) weeks of RT. All PET/CT were reconstructed in their time-averaged midposition (MidP). The metabolic tumour volume (MTV: FDG standardised uptake value (SUV) > 50% SUVmax), and the hypoxic volume (HV: FAZA SUV > 1.4) were delineated within the gross tumour volume (GTVCT). FDG and FAZA intratumoral PET uptake distributions were subsequently p...

Introduction: Thoracic or abdominal tumours present a breathing-related motion that can reduce accuracy of radiation treatments. Therefore, motion mitigation strategies have been developed to ensure adequate target dose coverage during successive radiotherapy fractions. In this trial, we investigated a technique that intends to prolong breath-hold while coupling it with Intrapulmonary Percussive Ventilation (IPV), performed with a non-invasive IPV device (Pegaso A-Cough Perc). Our aim was to determine a standardized training protocol allowing a prolonged breath-hold combined to IPV (BHPV), with a maximal reduction of thoracic movement. Methods: Ten volunteers underwent a training protocol divided in three training sessions in order to get used to IPV and to attempt to achieve a BHPV of 10 min. Afterwards, the volunteers performed a final BHPV for a least 10 min (max. 20 min) in the radiotherapy simulation room. During this final BHPV, residual thoracic motion was measured from a tracked point, using an optical tracking system. Stabilization time and stable phase duration were also recorded. Results: All the 10 subjects achieved BHPV of 10 min. During the final BHPV, all the subjects even reached the maximal duration allowed of 20 min. Seven out of ten subjects presented a motion deviation of only 1mm around the mean position for more than 95% of the duration of the stable phase. The mean stabilization time was 2.1 ± 3.3 min and the mean stable phase duration was 16.6 ± 5.5 min. Conclusion: This training protocol allowed a 20min-BHPV. It is based on the combination of breath-hold with IPV while using a commercially available device.

We developed a training protocol based on Intrapulmonary Percussive Ventilation in order to prolong breath-hold while nearly suppressing the thorax motion. This protocol allowed ten subjects to achieve a 20-minutes-breath-hold, while reducing the residual surface motion to 1 mm around its mean position for more than 95% of the breath-hold duration.

Irradiation log-files store useful information about the plan delivery, and together with independent Monte Carlo dose engine calculations can be used to reduce the time needed for patient-specific quality assurance (PSQA). Nonetheless, machine log-files carry an uncertainty associated to the measurement of the spot position and intensity that can influence the correct evaluation of the quality of the treatment delivery. This work addresses the problem of the inclusion of these uncertainties for the final verification of the treatment delivery. Dedicated measurements performed in an IBA Proteus Plus gantry with a pencil beam scanning (PBS) dedicated nozzle have been carried out to build a 'room-dependent' model of the spot position uncertainties. The model has been obtained through interpolation of the look-up tables describing the systematic and random uncertainties, and it has been tested for a clinical case of a brain cancer patient irradiated in a dry-run. The delivered dose has been compared with the planned dose with the inclusion of the errors obtained applying the model. Our results suggest that the accuracy of the treatment delivery is higher than the spot position uncertainties obtained from the log-file records. The comparison in terms of DVHs shows that the log-reconstructed dose is compatible with the planned dose within the 95% confidence interval obtained applying our model. The initial mean dose difference between the calculated dose to the patient based on the plan and recorded data is around 1%. The difference is essentially due to the log-file uncertainties and it can be removed with a correct treatment of these errors. In conclusion our new PSQA protocol allows for a fast verification of the dose delivered after every treatment fraction through the use of machine log-files and an independent Monte Carlo dose engine. Moreover, the inclusion of log-file uncertainties in the dose calculation allows for a correct evaluation of the quality of the treatment plan delivery., SCOPUS: ar.j, info:eu-repo/semantics/published

Introduction et but de l’etude La gestion de la variabilite pendant et entre les fractions respiro-induite des tumeurs thoraciques ou abdominales reste sub-optimale malgre les strategies de mitigation du mouvement respiratoire. Par cette etude, nous voulions demontrer l’avantage de la ventilation mecanique et non-invasive en radiotherapie, et son innocuite pour les patients. Materiel et methodes Une premiere cohorte A incluait des patients avec des tumeurs pulmonaires ou hepatiques. Ces patients, non-anesthesies, etaient ventiles avec le mode volume-controle (qui impose un volume courant et une frequence respiratoire), et le mode shallow-controle (qui vise a reduire l’amplitude du mouvement en accelerant la frequence respiratoire et diminuant proportionnellement le volume courant). La cohorte B incluait des patientes adressees pour une irradiation du sein gauche. Elles etaient ventilees en mode slow-controle, qui produit des inspirations bloquees par un jeu de pression. Deux seances de 6 minutes en IRM evaluaient le mouvement interne de la tumeur/du sein pendant et entre les fractions. Resultats et analyse statistique Vingt-deux patients ont ete inclus dans cette etude (âges de 49 a 83 ans). Aucune complication n’a ete observee. Dans la cohorte A, comparativement a la respiration libre, la variation de la frequence respiratoire etait diminuee de 35 % en mode volume-controle et 45 % en mode shallow-controle (p Conclusion La ventilation mecanique et non-invasive pourrait etre proposee a un large eventail de patients en radiotherapie et faciliter les differentes strategies de mitigation du mouvement respiratoire en reduisant les marges, et regularisant le mouvement tant pendant qu’entre les fractions.

info:eu-repo/semantics/published, 30e Congrès national de la Société française de radiothérapie oncologique

Background: Dose painting (DP) aims to improve radiation therapy (RT) outcome by targeting radioresistant tumour regions identified through functional imaging, e.g., positron emission tomography (PET). Importantly, the expected benefit of DP relies on the ability of PET imaging to identify tumour areas which could be consistently targeted throughout the treatment. In this study, we analysed the spatial stability of two potential DP targets in lung cancer patients undergoing RT: the tumour burden surrogate [18F]fluorodeoxyglucose (FDG) and the hypoxia surrogate [18F]fluoroazomycin arabinoside (FAZA). Materials and methods: Thirteen patients with unresectable lung tumours underwent FDG and FAZA 4D-PET/CT before (pre), and during the second (w2) and third (w3) weeks of RT. All PET/CT were reconstructed in their time-averaged midposition (MidP) for further analysis. The metabolic tumour volume (MTV: FDG standardised uptake value (SUV) > 50% SUVmax) and the hypoxic volume (HV: FAZA SUV >1.4) were delineated within the gross tumour volume (GTVCT). The stability of FDG and FAZA PET uptake distributions during RT was subsequently assessed through volume-overlap analysis and voxel-based correlation analysis. Results: The volume-overlap analysis yielded median overlapping fraction (OF) of 0.86 between MTVpre and MTVw2 and 0.82 between MTVpre and MTVw3. In patients with a detectable HV, median OF was 0.82 between HVpre and HVw2 and 0.90 between HVpre and HVw3. The voxel-based correlation analysis yielded median Spearman’s correlation coefficient (rS) of 0.87 between FDGpre and FDGw2 and 0.83 between FDGpre and FDGw3. Median rS was 0.78 between FAZApre and FAZAw2 and 0.79 between FAZApre and FAZAw3. Conclusions: FDG and FAZA PET uptake distributions were spatially stable during the 3 first weeks of RT in patients with unresectable lung cancer, both based on volume- and voxel-based indicators. This might allow for a consistent targeting of high FDG or FAZA PET uptake regions as part of a DP strategy.

The recent progresses performed in imaging, computational and technological fields bring new opportunities to achieve high precision radiation dose delivery. However, IMRT requires a particular attention at the target delineation step to avoid inadequate dosage to TVs/OARs. In this context, the biological information provided by PET might advantageously complete CT-Scan to refine the target delineation in HNSCC and lung cancer. Integrating PET into the treatment planning however requires the use and validation of accurate and reproducible segmentation methods, which adequately integrate the PET image properties such as the blur effect and the high level of noise. In this context, we developed specific tools, i.e. edge-preserving filters for denoising and deconvolution algorithms for deblurring that allowed the detection of gradient intensity peaks. Our gradient-based method has been validated on phantom and patient materials, and proved to be more accurate than threshold-based approaches. With this tool in hand, we demonstrated that the use of FDG-PET resulted in smaller TVs than the CT-based TVs, on both pre- and per-treatment images, and significantly improved the dose distributions to the TVs/OARs. This opens avenues for dose escalation strategies that might potentially improve the tumor local control.

Metabolic imaging by positrons emission tomography (PET) offers new perspectives in the field of non-small-cell lung cancer radiation therapy. First, it can be used to refine the way nodal and primary tumour target volumes are selected and delineated, in better agreement with the underlying tumour reality. In addition, the non-invasive spatiotemporal mapping of the tumour biology and the organs at risk function might be further used to steer radiation dose distribution. Delivering higher dose to low responsive tumour area, in a way that better preserves the normal tissue function, should thus reconcile the tumour radiobiological imperatives (maximising tumour local control) with dose related to the treatment safety (minimising late toxicity). By predicting response early in the course of radiation therapy, PET may also participate to better select patients who are believed to benefit most from treatment intensification. Altogether, these technological advances open avenues to in-depth modify the way the treatment plan is designed and the dose is delivered, in better accordance with the radiobiology of individual solid cancers and normal tissues.

Proton Therapy (PT) has gained interest recently. Indeed, protons have the advantage of depositing minimal dose until the end of its path, where a peak of energy deposition occurs (Bragg Peak). As a consequence of the reduced entrance dose and no exit dose, PT is expected to better spare normal tissues from radiation exposure, and should therefore facilitate the delivery of high radiation dose to the targets that are close to critical dose-limiting organs, or when severe late effects are foreseen. From the clinical perspective, children would benefit most from the ballistic advantage of protons. First, they have a high susceptibility to the deleterious effects of radiation on organ growth and function which can cause significant morbidity and devastating cosmetic outcomes. In addition, since the incidence of radiation-induced cancers rises over the lifetime period, with a long latent period, secondary tumours are mainly a concern when radiation is given at young ages, especially during the paediatric period. For such specific population, the benefit of reducing integral dose to normal tissues is intuitively clear. On the other hand, adults are less prone to secondary malignancies and developmental issues. Because of the higher cost of PT, superior dosimetry alone cannot justify its choice. A measurable clinical advantage must be demonstrated, either in terms of tumor local control (radioresistant tumours, dose escalation strategies) and/or in terms of late toxicities or quality of life. Chondrosarcomas and chordomas are typical examples of tumours for which PT may help at resolving the dilemma of achieving high tumour dose while preserving organs at risk in complex anatomical sites. In the coming years, the PT indications will certainly expand to more frequent cancers, like locally-advanced head and neck, lung, liver or pancreatic tumours, for which conventional radiotherapy (RT) still faces severe limitations in terms of efficacy and safety. To achieve this goal, the scientific community together with industrial partners will have first to address some technological issues (interplay effect for moving tumours, range uncertainty related to anatomical changes), and to prove the superiority of PT over conventional RT with proper randomized trials and prospective collection of clinical data.

Hypoxia has historically been relevant to radiation oncology as it relates to radioresistance, poor response to therapy and unfavorable patient's outcome in many solid tumors. In that regard, the recent advances in imaging, computation and radiation delivery techniques have been offering new perspectives to prescribe and deliver radiation dose in accordance with the spatial distribution of hypoxia mapped with molecular or functional imaging modalities, i.e., the so-called dose painting (DP). At first glance, the concept of dose painting appears promising and let foresee likely improvement in tumor local control at an acceptable clinical cost. However, adapting radiotherapy planning and delivery according to hypoxia imaging implicitly assumes: 1) that the imaging variable actually correlates with a local biological property associated with individual therapy outcome; 2) that the spatial distribution of the imaging parameter can be adequately converted into dose; and 3) that an irradiation device can actually deliver such a heterogeneous dose in fractionated RT treatments. In that regard, many uncertainties and difficulties remain at each step of the DP process, mainly related to the limitations of the current imaging techniques and the treatment fractionation. This paper will thus review the state of the art of DP with a specific focus on hypoxia, going from cancer biology to adaptive dose delivery. It will address the technological challenges and the clinical validation, which are both essential to translate an intuitively appealing concept into a clinically meaningful practice.

Il fine ultimo della radioterapia (RT) e l’eradicazione della totalita delle cellule tumorali clonogeniche (cellule staminali), con contenimento del danno ai tessuti irradiati entro livelli accettabili. A tale scopo le recenti innovazioni nell’ambito delle tecniche di radioterapia si sono tradotte in un miglioramento nella selezione e nel contornamento dei volumi di interesse e nella messa a punto di piani di trattamento per l’ottimizzazione del calcolo delle dosi. Inoltre, si e aggiunta la disponibilita di nuovi macchinari dotati di congegni per l’acquisizione di immagini e controllati da computer molto veloci, che consentono una maggiore precisione nell’erogazione delle dosi. I trattamenti convenzionali sono stati sostituiti da tecniche di radioterapia altamente conformazionale, quali la radioterapia a intensita modulata (IMRT) e la terapia ad arco con modulazione d’intensita (IMAT), che consentono di individualizzare la distribuzione della dose rispetto all’esatta morfologia del tumore, con un migliore risparmio dei tessuti sani e degli organi a rischio circostanti.