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Hypofractionation guioded by dose painting

MAURO MI IORI, PhD

PATRIZIA PC CIAMMELLA, MD

Relapsed GBMs have a life expectancy of a few months and re-radiation has proven to be safe in terms of toxicity and effective in increasing OS. One of our studies \[Ciammella P, 2013, 8:222\] reported a median survival of 9.5 months in patients with recurrent GBM and treated with stereotactic radiotherapy with a total dose of 25 Gy in 5 consecutive sessions, in which the dose was prescribed to 70% isodose with a homogeneous gradient towards the center of the target volume. The identification with functional imaging of specific areas with higher tumor cell density, and the possibility of delivering precisely, thanks to the most advanced therapy units, different doses to the different sub-volumes, can lead to an increase in the maximum dose that can be delivered at the expense of the most aggressive areas (with a greater effect on the tumor), compared to smaller doses in areas with lower signal alteration. This selectivity of the doses should allow an increase in the efficacy of the therapy and therefore a hypothetical increase in local control, compared to a radio-induced toxicity on the surrounding healthy tissues almost comparable to that achieved with the previous hypofractionated treatments \[Ciammella P, 2013\]. In fact, delivering many high doses to the entire volume would result in an excess of radio-induced necrosis within the irradiated regions with high dose, as well as the impossibility of minimizing the doses on healthy areas and / or on non-neoplastic critical areas keeping them at internal dose ranges related to minimal and acceptable toxicity levels. Since there are no studies providing clear indications on the acute and late toxicity of irradiated healthy tissues that have already been the subject of a first course of radiotherapy (STUPP), the choice of safety is the primary objective of the study.

It is an exploratory, prospective, experimental, monocentric study. Having identified a main safety endpoint (toxicity of radiotherapy treatment) and in the absence of data currently available from previous studies and useful for sizing the sample, the sample is defined according to opportunity and feasibility criteria, (12 cases), with a drawing (3 cases + 3 cases + 6 cases) which provides for two intermediate safety assessment steps one month after the end of the third and sixth patient treatment. The study will be continued only in case of positive evaluation of both steps. For each individual patient the treatment is considered completed if: a) the experimental radiotherapy treatment has been completed; b) the first follow-up radiological assessment (NMR) was performed; c) the study treatment was prematurely interrupted due to lack of efficacy (documented disease progression) or unacceptable toxicity.

* Treatment: the treatment foreseen by the protocol foresees the planning and the execution of a hypofractionated radiotherapy (RT) treatment, administered in 5 daily sessions, with intensity modulated technique and inhomogeneous distribution of the dose guided by the diffusion images obtained with magnetic resonance (RM). The radiotherapy treatment must start within 7 days from the date of execution of the centering MRI which will include both the classic morphological sequences with administration of contrast medium and functional ones. In selected cases and according to clinical judgment it will be possible to request the revision of the anatomopathological and radiological findings.
* Radiation technique: for each patient, a radiotherapy treatment plan will be performed with conformed techniques such as intensity-modulated radiotherapy (IMRT) with dose redistribution: dose-painting.
* Positioning and immobilization of the patient: the patient must be treated in a supine position. The arms must be positioned along the body. The use of a knee support is recommended. The garment will be immobilized with a thermoplastic mask and corresponding neck rest supports.
* TC and planning RM: the planning CT should be acquired possibly with reduced layer thickness that contains the entire volume of the skull and the upper part of the shoulders. This is done to allow the possibility of planning non-coplanar type treatments. The last follow-up MRI, or the radiotherapy centering RM, composed of standard and functional sequences, is used for planning, in addition to those that the neuroradiologist will have considered useful to better characterize the clinical case under examination. More details on this are described in the Technical Annex.
* Target volume and organs at risk (OAR): the following target volumes must be identified: • Gross tumor volume (GTV): it is defined using and combining the conventional and advanced sequences of the NMR. • Planning target volume (PTV): it is represented by the GTV with three-dimensional expansion between 0 and 5 mm according to the problems highlighted during the tumor segmentation phase. See the Technical Annex in this regard.
* The following risky organs (OAR) must be identified: • Optical nerves: the definition of the related planning risk volume is also suggested (PRV: organ at risk with three-dimensional expansion; this margin must be chosen taking into account the acquisition thickness of the centering TC and the chosen GTV-PTV expansion margin). • chiasm. We also suggest the definition of the relative PRV (organ at risk with three-dimensional expansion; this margin must be chosen taking into account the acquisition thickness of the centering CT and the chosen GTV-PTV expansion margin). • retinas. We also suggest the definition of the relative PRV (organ at risk with three-dimensional expansion; this margin must be chosen taking into account the acquisition thickness of the centering CT and the chosen GTV-PTV expansion margin). Alternatively the eye globes can be surrounded. • Encefalic trunk.
* The following secondary OARs must be identified: • Lenses / Crystalline. We also suggest the definition of the relative PRV (organ at risk with three-dimensional expansion; this margin must be chosen taking into account the acquisition thickness of the centering CT and the chosen GTV-PTV expansion margin). • Healthy brain tissue. It is represented by the encephalon volume minus the PTV. • Screw. We also suggest the definition of the relative PRV (organ at risk with three-dimensional expansion; this margin must be chosen taking into account the acquisition thickness of the centering CT and the chosen GTV-PTV expansion margin).
* Dose prescription: i) Dose to the target: the prescription dose foresees a minimum dose of 30 Gy (6 Gy per session) for the areas with the highest ADC with a gradual increase in the dose of the lower ADC areas. The maximum hypothesized dose is 50 Gy, with a dose of 10 Gy per session to no more than 1cc of the irradiated brain tissue. The treatment plan, however, will be processed in the following order of priority: 1. Compliance with dose limits for primary OARs. 2. PTV coverage. 3. Compliance with dose limits for secondary OARs.
* Dose limits for primary risk organs: in the scientific literature there are various studies that indicate the dose limits of the organs at risk for brain radiation treatments.

Safety of IMRT Treatment With Inhomogeneous Dose in Patients With Relapsed High-grade Gliomas.

Safety of Intensity-modulated Radiotherapy Treatment With Inhomogeneous Dose Distribution in Patients With Relapsed High-grade Gliomas.

Evaluation of side effects in order to assess the risk / benefit ratio. Values greater than G3 according to the CTCAE v.4.0 scale will be considered adverse events.

Evaluation of the response rate according to the RANO criteria

Incidence of treatment-related radionecrosis measured with advanced magnetic resonance sequences.

Evaluation of survival in retreated patients

Health related QOL (HRQOL) evaluations using the EORTC QLQ-C30 (version 3) questionnaire. Raw scores will be transformed to a linear scale ranging from 0 to 100 (according to the standard EORTC) with a higher score representing a higher level for functioning or higher livel of symptomatology or problems.

\[N.W.Scott et al, Qual Life, 2009, 18:381-388\]

Brain cancer specific QOL evaluated by using the EORTC QLQ - BN20 questionnaire. Raw scores will be transformed to a linear scale ranging from 0 to 100 (according to the standard EORTC) with a higher score representing a higher level for functioning or higher livel of symptomatology or problems.

\[MJB Taphoorn et al, EJC, 2010, 46:1033-1040\]

Evaluation of disease progression in retreated patients

Arcispedale Santa Maria Nuova-IRCCS

Head and Neck Neoplasms

All Drugs and Chemicals

Fluorodeoxyglucose F18

The radiation dose inside the gross tumor volume is increased according to the voxel intensity (SUV - standardized uptake value) of pre-treatment FDG PET.

FDG-PET guided dose painting

Stein Kaasa, MD PhD

Dose-painting may increase the chance of cure at minimised radiation-induced toxicity in volumetric-arc radiotherapy (VMAT) for head and neck cancer. This trial (RADPAINT) investigates the safety of FDG-PET guided radiotherapy using VMAT dose-painting by contours for patients with head and neck cancer of poor prognosis.

In this study, radiotherapy is planned using 18F-FDG PET/CT (18F-2-fluoro-2-deoxy-D-glucose fluorodeoxyglucose positron emission tomography) making one experimental "dose-painting by contours" SIB (simultaneous integrated boost) plan with a maximum point dose of 83 Gy. The participants will be given 73 Gy and 78 Gy minimum doses to two GTVs (gross tumor volumes inside the conventional GTV (68 Gy). GTV_73Gy and GTV_78Gy are determined from the SUV (standardized uptake values) from the 18F-FDG PET/CT according to the formula proposed by the Ghent group (Van der Straeten et al, R\&O -06). It is expected to keep the level of normal tissue side-effects within or slightly above the level of conventional radiotherapy (i.e. maximum dose of 68 Gy).

In addition to the routine follow-up, the participants will be examined with 18F-FDG PET/CT (3 months after treatment and toxicity scoring at 6 weeks, 6 months, 1 year, 1.5 years and 3 years after radiotherapy (in addition to the routine follow-up).

Dose Painting of Head and Neck Cancer

Dose Painting of Head and Neck Cancer - The RADPAINT Pilot Study

The study will be stopped if ≥ 2 patients experience mucosal ulcers grade ≥ 3 (CTCAE v 3.0/v4.0) without healing within the first year after radiotherapy. This endpoint will be assessed by clinical examination.

Any life-threatening toxicity (CTCAE v4.0) related to radiotherapy. This endpoint will be assessed by clinical examination.

FDG PET/CT at 3 months. Imaging thereafter if clinical progression.

Oslo University Hospital

Senior Consultant

In this study, radiotherapy is planned using 18F-FDG PET/CT (18F-2-fluoro-2-deoxy-D-glucose fluorodeoxyglucose positron emission tomography) making one experimental "dose-painting by contours" SIB (simultaneous integrated boost) plan with a maximum point dose of 83 Gy. The participants will be given 73 Gy and 78 Gy minimum doses to two GTVs (gross tumor volumes inside the conventional GTV (68 Gy). GTV_73Gy and GTV_78Gy are determined from the SUV (standardized uptake values) from the 18F-FDG PET/CT according to the formula proposed by the Ghent group (Van der Straeten et al, R\&O -06). It is expected to keep the level of normal tissue side-effects within or slightly above the level of conventional radiotherapy (i.e. maximum dose of 68 Gy).

In addition to the routine follow-up, the participants will be examined with 18F-FDG PET/CT (3 months after treatment and toxicity scoring at 6 weeks, 3 months, 6 months, 1 year, 1.5 years and 3 years after radiotherapy (in addition to the routine follow-up).

RAdiotherapy With FDG-PET Guided Dose-PAINTing for Primary Head and Neck

The study will be stopped if ≥ 3 patients experience late toxicity as assessed by CTCAE v5.0; mucosal ulcers grade ≥ 3 without healing within the first year after radiotherapy. This endpoint will be assessed by clinical examination.

Any life-threatening toxicity (CTCAE v5.0) related to radiotherapy. This endpoint will be assessed by clinical examination.

Einar Dale, MD PhD

Dose-painting may increase the chance of cure at minimised radiation-induced toxicity in intensity-modulated radiotherapy (IMRT) for primary head and neck cancer. This could also apply for recurrent and second primary head and neck cancers in previously irradiated volumes. This trial (RIDPAINT) investigates the feasibility of FDG-PET guided radiotherapy using IMRT dose-painting by contours for patients with recurrent and second primary head and neck cancer.

The standard re-irradiation regimen for head and neck cancer patients treated at the Oslo University Hospital is 1.5 Gy twice daily during 4 weeks with a total dose of 60 Gy.

In this study the radiotherapy is planned using 18F-FDG PET/CT making one experimental "dose-painting by contours" SIB (simultaneous integrated boost) plan with a maximum point dose of 75 Gy. The participants will be given 65 Gy and 70 Gy minimum doses to two GTVs inside the conventional GTV (60 Gy). GTV_65Gy and GTV_70Gy are determined from the SUV values from the 18F-FDG PET/CT according to the formula proposed by the Ghent group (Van der Straeten et al, R\&O -06). It is expected to keep the level of normal tissue side-effects within or slightly above the level of conventional radiotherapy (i.e. maximum dose of 60 Gy). In addition to the routine follow-up, the participants will be examined with 18F-FDG PET/CT 6 months after inclusion (4 1/2 months after end of radiotherapy) and HRQL measurements.

ReIrradiation With FDG-PET Guided Dose Painting

ReIrradiation With FDG-PET Guided Dose Painting for Recurrent and Second Primary Head and Neck Cancer

Number of participants with toxicity using CTCAE v3.0.

Norwegian Cancer Society

Radiation dose will be escalated to the hypermetabolic part of the tumor (maximum point dose 83.3 Gy), shown in pre-treatment FDG-PET images. Dose escalation will be applied to these regions during the first half of the fractionated treatment (17 of 34 fractions).

Dose painting

Einar Dale, PhD

Einar Dale

The objective of the RADPAINT-3 trial is to investigate whether dose painting is safe compared to standard radiotherapy. RADPAINT-3 is a randomized, non-inferiority, multi-center phase II study, initiated at the Section for Head and Neck Cancer, Department of Oncology, Oslo University Hospital, accruing from first half of 2024. The primary endpoint is frequency of grade ≥ 3 (CTCAE v5.0) mucosal ulcers one year after treatment. The expected inclusion period is three years, total study duration is six years and planned inclusion number is 100 patients. The collaborating sites are St Olav´s Hospital and Haukeland University Hospital. The patients will be randomized 1:1 to either standard radiotherapy (2 Gy x 34; total dose 68 Gy) or experimental radiotherapy (dose painting). All patients will have 18F-2-fluoro-2-deoxy-D-glucose fluorodeoxyglucose positron emission computed tomography (FDG-PET/CT) prior to radiotherapy. In the experimental arm, we will escalate the dose to the hypermetabolic part of the tumor (maximum point dose 83.3 Gy), shown in pre-treatment FDG-PET images. Dose escalation will be applied to these regions during the first half of the fractionated treatment (17 of 34 fractions). The patients in both arms will receive concomitant nimorazole (hypoxic radiosensitizer) and concomitant cisplatin if indicated according to standard treatment. The main inclusion criterion is patients with human-papillomavirus (HPV)-unrelated head and neck cancer with poor prognosis.

The RADPAINT-3 trial includes a translational sub-study where we aim to elucidate underlying mechanisms related to the radiotherapy effect, by investigating blood samples. Analysis of cytokines in repetitive blood samples may predict both tumor response and toxicity. The data derived from this sub-study, will be further explored using artificial intelligence.

If RADPAINT-3 shows that there is no excess toxicity, we will continue the study after a new protocol has been approved. The new primary endpoint will be local control at 1 year after radiotherapy. Power analysis show that we will need in total 182 evaluable patients including the 100 patients from RADPAINT-3. The translational sub-study will then be extended to investigate genetic expression data from pre-therapy routine tumor biopsies and correlate this with the analysis of blood samples and tumor control.

RAdiotherapy With FDG-PET Guided Dose-PAINTing Compared With Standard Radiotherapy for Primary Head and Neck Cancer-3

RAdiotherapy With FDG-PET Guided Dose-PAINTing Compared With Standard Radiotherapy for Primary Head and Neck Cancer-3 Randomized, Multicentre, Phase II Trial

Identify panels of cytokines measured in blood at the start of RT to predict the risk of toxicity. Blood samples will be collected before the start of treatment, after 10 Gy of radiation, at the end of therapy (7 weeks after inclusion), after 3 months of follow up (coinciding with response evaluation with FDG-PET/CT), after 1 year and fresh frozen at -80°C. Cytokine profiling will be performed by the 48-plex Luminex assay,

Presence of grade ≥ 3 mucosal ulcers (as defined by CTCAE v5.0)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Safety of IMRT Treatment With Inhomogeneous Dose in Patients With Relapsed High-grade Gliomas.	NCT04610229	Glioblastoma Mu... Glioblastoma Glioblastoma, A...	Hypofractionati...	18 Years -	Arcispedale Santa Maria Nuova-IRCCS
Dose Painting of Head and Neck Cancer	NCT03847480	Head and Neck C...	FDG-PET guided ...	18 Years -	Oslo University Hospital
RAdiotherapy With FDG-PET Guided Dose-PAINTing for Primary Head and Neck	NCT04910308	Head and Neck C...	FDG-PET guided ...	18 Years -	Oslo University Hospital
Dose Painting of Head and Neck Cancer	NCT03847480	Head and Neck C...	FDG-PET guided ...	18 Years -	Oslo University Hospital
ReIrradiation With FDG-PET Guided Dose Painting	NCT02921581	Head and Neck C...	FDG-PET guided ...	18 Years -	Oslo University Hospital
ReIrradiation With FDG-PET Guided Dose Painting	NCT02921581	Head and Neck C...	FDG-PET guided ...	18 Years -	Oslo University Hospital
ReIrradiation With FDG-PET Guided Dose Painting	NCT02921581	Head and Neck C...	FDG-PET guided ...	18 Years -	Oslo University Hospital
RAdiotherapy With FDG-PET Guided Dose-PAINTing Compared With Standard Radiotherapy for Primary Head and Neck Cancer-3	NCT06297902	Head and Neck C... Radiotherapy Si...	Dose painting	18 Years -	Oslo University Hospital
ReIrradiation With FDG-PET Guided Dose Painting	NCT02921581	Head and Neck C...	FDG-PET guided ...	18 Years -	Oslo University Hospital
Safety of IMRT Treatment With Inhomogeneous Dose in Patients With Relapsed High-grade Gliomas.	NCT04610229	Glioblastoma Mu... Glioblastoma Glioblastoma, A...	Hypofractionati...	18 Years -	Arcispedale Santa Maria Nuova-IRCCS

Spots Global Cancer Trial Database for dose painting