• altered fractionation
• concurrent chemoradiation
• head and neck cancer
• hyperthermia
• immunotherapy
• nanoparticle
• targeted therapy

• dose painting by numbers
• hypoxia
• lung cancer
• normal tissue complication probability
• tumor control probability

• Humans
• Lung Neoplasms/radiotherapy
• Lung Neoplasms/diagnostic imaging
• Lung Neoplasms/pathology
• Radiotherapy Planning, Computer-Assisted/methods
• Radiotherapy, Intensity-Modulated/methods
• Radiotherapy Dosage
• Retrospective Studies
• Organs at Risk/radiation effects
• Positron Emission Tomography Computed Tomography/methods
• Radiotherapy, Image-Guided/methods
• Tumor Hypoxia
• Male
• Female

• 2022YFC2401503 National Key Research and Development Program of China
• 2023-9 Top Leading Talents Project of Gansu Province
• 23YFFA0010 Key Research and Development Program of Gansu Province
• National Key Research and Development Program of China

• FMISO
• HNSCC
• Hypoxia
• PET
• Partial volume effect

• Misonidazole/analogs & derivatives
• Humans
• Positron Emission Tomography Computed Tomography/methods
• Image Processing, Computer-Assisted/methods
• Oxygen/metabolism
• Retrospective Studies
• Head and Neck Neoplasms/diagnostic imaging
• Head and Neck Neoplasms/metabolism
• Tumor Burden
• Tumor Hypoxia
• Male
• Aged
• Middle Aged
• Female
• Hypoxia/diagnostic imaging

• Radiotherapy
• intrinsic radiosensitivity
• mechanistic modelling
• personalised radiotherapy
• radiobiology

• FMISO
• PET/CT
• fluoromisonidazole
• interpretation criteria

• Aged
• Female
• Humans
• Male
• Middle Aged
• Image Interpretation, Computer-Assisted/methods
• Misonidazole/analogs & derivatives
• Observer Variation
• Oropharyngeal Neoplasms/diagnostic imaging
• Positron Emission Tomography Computed Tomography/methods
• Reproducibility of Results
• Tumor Hypoxia

• P30 CA008748 NCI NIH HHS

• 18F‐FMISO PET
• dose escalation
• hypoxia
• intensity‐modulated proton therapy
• nasopharyngeal cancer

• Humans
• Misonidazole/analogs & derivatives
• Misonidazole/administration & dosage
• Radiotherapy, Intensity-Modulated/methods
• Proton Therapy/methods
• Male
• Positron Emission Tomography Computed Tomography/methods
• Middle Aged
• Radiotherapy Planning, Computer-Assisted/methods
• Nasopharyngeal Neoplasms/radiotherapy
• Nasopharyngeal Neoplasms/diagnostic imaging
• Female
• Nasopharyngeal Carcinoma/radiotherapy
• Adult
• Radiotherapy Dosage
• Aged
• Radiopharmaceuticals/administration & dosage

• National Medical Research Council of Singapore
• Terry Fox Foundation

• DNA repair
• Monte Carlo
• cell death
• modelling
• radiobiology

• Neoplasms/genetics
• Neoplasms/radiotherapy
• Humans
• Radiobiology
• Radiotherapy/adverse effects
• Radiotherapy/standards
• Radiation Injuries/genetics
• Dose-Response Relationship, Radiation
• Radiation Tolerance
• Models, Biological
• DNA Damage

• Humans
• Radiotherapy Planning, Computer-Assisted/methods
• Prostatic Neoplasms/radiotherapy
• Prostatic Neoplasms/diagnostic imaging
• Hyperthermia, Induced/methods
• Male
• Organs at Risk/radiation effects
• Rectum/radiation effects
• Radiotherapy Dosage
• Combined Modality Therapy/methods
• Proof of Concept Study
• Dose Fractionation, Radiation

• EUD
• FMISO
• PET
• TCP
• hypoxia
• linear-quadratic model

• Humans
• Glioblastoma
• Hypoxia/pathology
• Lung Neoplasms/radiotherapy
• Misonidazole/analogs & derivatives
• Oxygen/metabolism
• Cell Hypoxia
• Positron-Emission Tomography/methods
• Radiopharmaceuticals

• R50 CA211270 NCI NIH HHS

• Fractional calculus
• Kinetic modeling
• Mittag-Leffler function
• Perfusion
• Upper incomplete gamma function

• Mathematical Concepts
• Models, Biological
• Epidemiological Models
• Kinetics

• Dose painting
• Monte Carlo
• PET
• Proton therapy
• RBE

• Humans
• Protons
• Radiotherapy Dosage
• Head and Neck Neoplasms/diagnostic imaging
• Head and Neck Neoplasms/radiotherapy
• Proton Therapy/methods
• Positron-Emission Tomography
• Radiotherapy Planning, Computer-Assisted/methods

• Radiotherapy Planning, Computer-Assisted
• Hypoxia-Inducible Factor 1, alpha Subunit
• Humans
• Precision Medicine
• Tumor Hypoxia/radiation effects
• Neoplasms/radiotherapy

• HNSCC
• Warburg effect
• head and neck cancers
• radio-resistance
• radio-sensitivity

Glioblastoma multiforme (GBM) is the most frequent primary malignant brain tumor, and despite advances in imaging techniques and treatment options, the outcome remains poor and recurrence is inevitable. Salvage therapy presents a challenge, and re-irradiation can be a therapeutic option in recurrent GBM. The decision-making process for re-irradiation is a challenge for radiation oncologists due to the expected toxicity of a second course of radiotherapy and the limited radiation tolerance of normal tissue; nevertheless, it is being increasingly used, as several studies have demonstrated its feasibility. The current study aimed to investigate the safety of moderate–high-voxel-based dose escalation radiotherapy in recurrent GBM patients after conventional concurrent chemoradiation. Twelve patients were enrolled in this prospective single-center study. Retreatment consisted of re-irradiation with a total dose range of 30–50 Gy over 5 days using the IMRT (arc VMAT) technique using dose painting planning. The treatment was well tolerated. No toxicities greater than 3 were recorded; only one patient had severe G3 acute toxicity, characterized by muscle weakness and fatigue. Median overall survival (OS2) and progression-free survival (PFS2) from the time of re-irradiation were 10.4 months and 5.7 months, respectively. Our phase I study demonstrated an acceptable tolerance profile of this approach, and the future prospective phase II study will analyze the efficacy in terms of PFS and OS.

Glioblastoma multiforme (GBM) is the most aggressive astrocytic primary brain tumor, and concurrent temozolomide (TMZ) and radiotherapy (RT) followed by maintenance of adjuvant TMZ is the current standard of care. Despite advances in imaging techniques and multi-modal treatment options, the median overall survival (OS) remains poor. As an alternative to surgery, re-irradiation (re-RT) can be a therapeutic option in recurrent GBM. Re-irradiation for brain tumors is increasingly used today, and several studies have demonstrated its feasibility. Besides differing techniques, the published data include a wide range of doses, emphasizing that no standard approach exists. The current study aimed to investigate the safety of moderate–high-voxel-based dose escalation in recurrent GBM. From 2016 to 2019, 12 patients met the inclusion criteria and were enrolled in this prospective single-center study. Retreatment consisted of re-irradiation with a total dose of 30 Gy (up to 50 Gy) over 5 days using the IMRT (arc VMAT) technique. A dose painting by numbers (DPBN)/dose escalation plan were performed, and a continuous relation between the voxel intensity of the functional image set and the risk of recurrence in that voxel were used to define target and dose distribution. Re-irradiation was well tolerated in all treated patients. No toxicities greater than G3 were recorded; only one patient had severe G3 acute toxicity, characterized by muscle weakness and fatigue. Median overall survival (OS2) and progression-free survival (PFS2) from the time of re-irradiation were 10.4 months and 5.7 months, respectively; 3-, 6-, and 12-month OS2 were 92%, 75%, and 42%, respectively; and 3-, 6-, and 12-month PFS2 were 83%, 42%, and 8%, respectively. Our work demonstrated a tolerable tolerance profile of this approach, and the future prospective phase II study will analyze the efficacy in terms of PFS and OS.

• biomarker
• cancer
• imaging
• oxygen
• predictive marker
• theranostics
• therapy
• tumor hypoxia

• Dose escalation
• Dose painting
• FMISO PET/CT
• IMRT
• Local control
• Radiotherapy
• Tumor hypoxia

Intensity-modulated radiation therapy (IMRT) has been used for high-accurate physical dose distribution sculpture and employed to modulate different dose levels into Gross Tumor Volume (GTV), Clinical Target Volume (CTV) and Planning Target Volume (PTV). GTV, CTV and PTV can be prescribed at different dose levels, however, there is an emphasis that their dose distributions need to be uniform, despite the fact that most types of tumour are heterogeneous. With traditional radiomics and artificial intelligence (AI) techniques, we can identify biological target volume from functional images against conventional GTV derived from anatomical imaging. Functional imaging, such as multi parameter MRI and PET can be used to implement dose painting, which allows us to achieve dose escalation by increasing doses in certain areas that are therapy-resistant in the GTV and reducing doses in less aggressive areas. In this review, we firstly discuss several quantitative functional imaging techniques including PET-CT and multi-parameter MRI. Furthermore, theoretical and experimental comparisons for dose painting by contours (DPBC) and dose painting by numbers (DPBN), along with outcome analysis after dose painting are provided. The state-of-the-art AI-based biomarker diagnosis techniques is reviewed. Finally, we conclude major challenges and future directions in AI-based biomarkers to improve cancer diagnosis and radiotherapy treatment.

• dose painting by contours
• dose painting by numbers
• functional imaging
• personalized radiation dose
• radiotherapy

•

Higher osteopontin plasma levels correlate with more hypoxic tumors at baseline.

• EPR
• MRI
• PET
• imaging
• tumor microenvironment

• Electron Spin Resonance Spectroscopy/methods
• Humans
• Hypoxia
• Magnetic Resonance Imaging/methods
• Oxygen
• Positron-Emission Tomography

•

DPBN was delivered to a phantom based on the anatomy of a lung cancer patient examined by FDG PET/CT prior to radiotherapy.

Dose painting by numbers (DPBN) require a high degree of dose modulation to fulfill the image-based voxel wise dose prescription. The aim of this study was to assess the dosimetric accuracy of ¹⁸F-fluoro-2-deoxy-glucose positron emission tomography(¹⁸F-FDG-PET)-based DPBN in an anthropomorphic lung phantom using alanine dosimetry.

A linear dose prescription based on ¹⁸F-FDG-PET image intensities within the gross tumor volume (GTV) of a lung cancer patient was employed. One DPBN scheme with low dose modulation (Scheme A; minimum/maximum fraction dose to the GTV 2.92/4.26 Gy) and one with a high modulation (Scheme B; 2.81/4.52 Gy) were generated. The plans were transferred to a computed tomograpy (CT) scan of a thorax phantom based on CT images of the patient. Using volumetric modulated arc therapy (VMAT), DPBN was delivered to the phantom with embedded alanine dosimeters. A plan was also delivered to an intentionally misaligned phantom. Absorbed doses at various points in the phantom were measured by alanine dosimetry.

A pointwise comparison between GTV doses from prescription, treatment plan calculation and VMAT delivery showed high correspondence, with a mean and maximum dose difference of <0.1 Gy and 0.3 Gy, respectively. No difference was found in dosimetric accuracy between scheme A and B. The misalignment caused deviations up to 1 Gy between prescription and delivery.

DPBN can be delivered with high accuracy, showing that the treatment may be applied correctly from a dosimetric perspective. Still, misalignment may cause considerable dosimetric erros, indicating the need for patient immobilization and monitoring.

Intratumoral hypoxia increases resistance of head-and-neck squamous cell carcinoma (HNSCC) to radiotherapy. [¹⁸F]FMISO PET imaging enables noninvasive hypoxia monitoring, though requiring complex logistical efforts. We investigated the role of plasma interleukin-6 (IL-6) as potential surrogate parameter for intratumoral hypoxia in HNSCC using [¹⁸F]FMISO PET/CT as reference.

Within a prospective trial, serial blood samples of 27 HNSCC patients undergoing definitive chemoradiation were collected to analyze plasma IL-6 levels. Intratumoral hypoxia was assessed in treatment weeks 0, 2, and 5 using [¹⁸F]FMISO PET/CT imaging. The association between PET-based hypoxia and IL-6 was examined using Pearson’s correlation and multiple regression analyses, and the diagnostic power of IL-6 for tumor hypoxia response prediction was determined with receiver-operating characteristic analyses.

Mean IL-6 concentrations were 15.1, 19.6, and 31.0 pg/mL at baseline, week 2 and week 5, respectively. Smoking (p=0.050) and reduced performance status (p=0.011) resulted in higher IL-6 levels, whereas tumor (p=0.427) and nodal stages (p=0.334), tumor localization (p=0.439), and HPV status (p=0.294) had no influence. IL-6 levels strongly correlated with the intratumoral hypoxic subvolume during treatment (baseline: r=0.775, p<0.001; week 2: r=0.553, p=0.007; week 5: r=0.734, p<0.001). IL-6 levels in week 2 were higher in patients with absent early tumor hypoxia response (p=0.016) and predicted early hypoxia response (AUC=0.822, p=0.031). Increased IL-6 levels at week 5 resulted in a trend towards reduced progression-free survival (p=0.078) and overall survival (p=0.013).

Plasma IL-6 is a promising surrogate marker for tumor hypoxia dynamics in HNSCC patients and may facilitate hypoxia-directed personalized radiotherapy concepts.

The prospective trial was registered in the German Clinical Trial Register (DRKS00003830). Registered 20 August 2015

The online version contains supplementary material available at 10.1007/s00259-021-05602-x.

• Biomarker
• FMISO-PET
• Head-and-neck cancer
• Hypoxia
• Interleukin-6
• Radiotherapy

• 18F-EF5
• dose painting
• hypoxia
• positron emission tomography
• radiotherapy
• repeatability
• treatment planning system

• NSCLC
• PET
• Proton therapy
• Tumor hypoxia

• SBRT
• dose painting
• hypoxia
• pancreatic canacer

• artificial intelligence
• local relapse
• magnetic resonance imaging
• prostate cancer
• quantitative imaging biomarkers
• radiation therapy

• SW-TCRC Partner Program 2019 Cancer Institute NSW
• 1126955 National Health and Medical Research Council

Theoretical studies have shown that dose‐painting‐by‐numbers (DPBN) could lead to large gains in tumor control probability (TCP) compared to conventional dose distributions. However, these gains may vary considerably among patients due to (a) variations in the overall radiosensitivity of the tumor, (b) variations in the 3D distribution of intra‐tumor radiosensitivity within the tumor in combination with patient anatomy, (c) uncertainties of the 3D radiosensitivity maps, (d) geometrical uncertainties, and (e) temporal changes in radiosensitivity. The goal of this study was to investigate how much of the theoretical gains of DPBN remain when accounting for these factors. DPBN was compared to both a homogeneous reference dose distribution and to nonselective dose escalation (NSDE), that uses the same dose constraints as DPBN, but does not require 3D radiosensitivity maps.

A fully automated DPBN treatment planning strategy was developed and implemented in our in‐house developed treatment planning system (TPS) that is robust to uncertainties in radiosensitivity and patient positioning. The method optimized the expected TCP based on 3D maps of intra‐tumor radiosensitivity, while accounting for normal tissue constraints, uncertainties in radiosensitivity, and setup uncertainties. Based on FDG‐PETCT scans of 12 non‐small cell lung cancer (NSCLC) patients, data of 324 virtual patients were created synthetically with large variations in the aforementioned parameters. DPBN was compared to both a uniform dose distribution of 60 Gy, and NSDE. In total, 360 DPBN and 24 NSDE treatment plans were optimized.

The average gain in TCP over all patients and radiosensitivity maps of DPBN was 0.54 ± 0.20 (range 0–0.97) compared to the 60 Gy uniform reference dose distribution, but only 0.03 ± 0.03 (range 0–0.22) compared to NSDE. The gains varied per patient depending on the radiosensitivity of the entire tumor and the 3D radiosensitivity maps. Uncertainty in radiosensitivity led to a considerable loss in TCP gain, which could be recovered almost completely by accounting for the uncertainty directly in the optimization.

Our results suggest that the gains of DPBN can be considerable compared to a 60 Gy uniform reference dose distribution, but small compared to NSDE for most patients. Using the robust DPBN treatment planning system developed in this work, the optimal DPBN treatment plan could be derived for any patient for whom 3D intra‐tumor radiosensitivity maps are known, and can be used to select patients that might benefit from DPBN. NSDE could be an effective strategy to increase TCP without requiring biological information of the tumor.

• nonselective dose escalation (NSDE)
• radiotherapy
• robust dose-painting-by-numbers (DPBN)
• treatment planning
• tumor control probability (TCP)
• uncertainty-based planning

• Clinical application
• Ion beam radiotherapy
• Preclinical in vitro and in vivo studies
• RBE validation
• Relative biological effectiveness (RBE)

• Dose Fractionation, Radiation
• Humans
• Neoplasms/radiotherapy
• Neoplasms, Second Primary/radiotherapy
• Radiotherapy Dosage
• Radiotherapy Planning, Computer-Assisted/methods

• R43 CA153466 NCI NIH HHS
• R44 CA153466 NCI NIH HHS
• R44 CA228753 NCI NIH HHS

The ESCALOX trial was designed as a multicenter, randomized prospective dose escalation study for head and neck cancer. Therefore, feasibility of treatment planning via different treatment planning systems (TPS) and radiotherapy (RT) techniques is essential. We hypothesized the comparability of dose distributions for simultaneous integrated boost (SIB) volumes respecting the constraints by different TPS and RT techniques.

CT data sets of the first six patients (all male, mean age: 61.3 years) of the pre-study (up to 77 Gy) were used for comparison of IMRT, VMAT, and helical tomotherapy (HT). Oropharynx was the primary tumor location. Normalization of the three step SIB (77 Gy, 70 Gy, 56 Gy) was D95% = 77 Gy. Coverage (CVF), healthy tissue conformity index (HTCI), conformation number (CN), and dose homogeneity (HI) were compared for PTVs and conformation index (COIN) for parotids.

All RT techniques achieved good coverage. For SIB77Gy, CVF was best for IMRT and VMAT, HT achieved highest CN followed by VMAT and IMRT. HT reached good HTCI value, and HI compared to both other techniques. For SIB70Gy, CVF was best by IMRT. HTCI favored HT, consequently CN as well. HI was slightly better for HT. For SIB56Gy, CVF resulted comparably. Conformity favors VMAT as seen by HTCI and CN. Dmean of ipsilateral and contralateral parotids favor HT.

Different TPS for dose escalation reliably achieved high plan quality. Despite the very good results of HT planning for coverage, conformity, and homogeneity, the TPS also achieved acceptable results for IMRT and VMAT.

Trial registration ClinicalTrials.gov Identifier: NCT 01212354, EudraCT-No.: 2010-021139-15. ARO: ARO 14-01

• Combined chemoradiation therapy
• Dose escalation
• Head and neck cancer
• Helical tomotherapy
• IMRT
• RT planning comparison
• SIB
• VMAT

• ART
• IMR
• MRI
• PET
• Radiothérapie adaptive
• TEP

Tumor-associated hypoxia influences the radiation response of head-and-neck cancer (HNSCC) patients, and a lack of early hypoxia resolution during treatment considerably deteriorates outcomes. As the detrimental effects of hypoxia are partly related to the induction of an immunosuppressive microenvironment, we investigated the interaction between tumor hypoxia dynamics and the PD-1/PD-L1 axis in HNSCC patients undergoing chemoradiation and its relevance for patient outcomes in a prospective trial.

Methods: 49 patients treated with definitive chemoradiation for locally advanced HNSCC were enrolled in this trial and received longitudinal hypoxia PET imaging using fluorine-18 misonidazole ([¹⁸F]FMISO) at weeks 0, 2 and 5 during treatment. Pre-therapeutic tumor biopsies were immunohistochemically analyzed regarding the PD-1/PD-L1 expression both on immune cells and on tumor cells, and potential correlations between the PD-1/PD-L1 axis and tumor hypoxia dynamics during chemoradiation were assessed using Spearman's rank correlations. Hypoxia dynamics during treatment were quantified by subtracting the standardized uptake value (SUV) index at baseline from the SUV values at weeks 2 or 5, whereby SUV index was defined as ratio of maximum tumor [¹⁸F]FMISO SUV to mean SUV in the contralateral sternocleidomastoid muscle (i.e. tumor-to-muscle ratio). The impact of the PD-1/PD-L1 expression alone and in combination with persistent tumor hypoxia on locoregional control (LRC), progression-free survival (PFS) and overall survival (OS) was examined using log-rank tests and Cox proportional hazards models.

Results: Neither PD-L1 nor PD-1 expression levels on tumor-infiltrating immune cells influenced LRC (HR = 0.734; p = 0.480 for PD-L1, HR = 0.991; p = 0.989 for PD-1), PFS (HR = 0.813; p = 0.597 for PD-L1, HR = 0.796; p = 0.713 for PD-1) or OS (HR = 0.698; p = 0.405 for PD-L1, HR = 0.315; p = 0.265 for PD-1). However, patients with no hypoxia resolution between weeks 0 and 2 and PD-L1 expression on tumor cells, quantified by a tumor proportional score (TPS) of at least 1%, showed significantly worse LRC (HR = 3.374, p = 0.022) and a trend towards reduced PFS (HR = 2.752, p = 0.052). In the multivariate Cox regression analysis, the combination of absent tumor hypoxia resolution and high tumoral PD-L1 expression remained a significant prognosticator for impaired LRC (HR = 3.374, p = 0.022). On the other side, tumoral PD-L1 expression did not compromise the outcomes of patients whose tumor-associated hypoxia declined between week 0 and 2 during chemoradiation (LRC: HR = 1.186, p = 0.772, PFS: HR = 0.846, p = 0.766).

Conclusion: In this exploratory analysis, we showed for the first time that patients with both persistent tumor-associated hypoxia during treatment and PD-L1 expression on tumor cells exhibited a worse outcome, while the tumor cells' PD-L1 expression did not influence the outcomes of patients with early tumor hypoxia resolution. While the results have to be validated in an independent cohort, these findings form a foundation to investigate the combination of hypoxic modification and immune checkpoint inhibitors for the unfavorable subgroup, moving forward towards personalized radiation oncology treatment.

• FMISO PET
• PD-L1
• head-and-neck cancer
• hypoxia
• radiotherapy

• Dose-painting
• IMRT
• Multiparametric MRI
• Probabilistic treatment planning
• Tumour control probability

• Advanced imaging
• Functional imaging
• Head and neck cancer
• Individualized
• Personalized
• Radiation planning
• Tumor hypoxia

• Diagnostic Imaging/methods
• Head and Neck Neoplasms/diagnostic imaging
• Head and Neck Neoplasms/radiotherapy
• Humans
• Radiotherapy Planning, Computer-Assisted/methods
• Radiotherapy, Conformal

• Chemoradiation
• FMISO
• Head-and-neck cancer
• Hypoxia
• Multiparametric MRI

• Head and neck
• Hypoxia
• Positron emission tomography
• Prognosis
• Radiaton therapy
• [18F]-HX4

• biological optimisation
• precision medicine
• prostate cancer

• Computer simulation
• Hypoxia tracer uptake
• Positron-emission-tomography (PET)
• Radiotherapy

• Hadron therapy
• Hypoxic tumour
• Monte Carlo
• OER

• consensus
• head and neck cancer
• patterns of care
• practice patterns
• survey

• Imaging
• PET/CT
• Radiotherapy
• Target volume

• Brain Neoplasms/diagnostic imaging
• Brain Neoplasms/pathology
• Brain Neoplasms/radiotherapy
• Brain Neoplasms/secondary
• Head and Neck Neoplasms/diagnostic imaging
• Head and Neck Neoplasms/radiotherapy
• Humans
• Lung Neoplasms/diagnostic imaging
• Lung Neoplasms/radiotherapy
• Positron Emission Tomography Computed Tomography/methods
• Practice Guidelines as Topic
• Radiotherapy Planning, Computer-Assisted/methods