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Radiation oncology in the era of precision medicine

Key Points

  • Radiotherapy has proven potential to cure tumours by eradicating cancer stem cells.

  • Current state-of-the-art techniques of photon-based radiotherapy are approaching the physical limits of shaping high doses to the target volume.

  • Particle therapy reduces the volume of normal tissues irradiated with low or intermediate radiation doses and has the potential to reduce side effects in normal tissue as well as to escalate doses to radioresistant tumours.

  • Photon and especially particle radiotherapy will benefit from further improvements to image guidance with full adaptation of dose delivery to motion and anatomical changes of tumours and normal tissues during treatment.

  • Treatment planning algorithms that enable much faster planning and replanning, include uncertainties to improve robustness and enable optimization of multi-objective planning or plan comparison are on the verge of widespread clinical implementation.

  • The basic biological mechanisms of radiosensitivity and radioresistance are known and part of today's population-based treatment strategies.

  • Biomarkers and bio-imaging that enable mechanisms of radioresistance to be assessed in individual tumours and normal tissues are rapidly emerging.

  • Biomarkers have unexplored potential for predicting the extent of subclinical spread of tumour cells to help define the clinical target volume.

  • Biomarkers, when integrated into treatment planning, may potentiate the degree of personalization of radiotherapy that is already achieved today on a technological basis.

  • Radiation oncology has high potential to showcase the efficacy of precision medicine in oncology.

Abstract

Technological advances and clinical research over the past few decades have given radiation oncologists the capability to personalize treatments for accurate delivery of radiation dose based on clinical parameters and anatomical information. Eradication of gross and microscopic tumours with preservation of health-related quality of life can be achieved in many patients. Two major strategies, acting synergistically, will enable further widening of the therapeutic window of radiation oncology in the era of precision medicine: technology-driven improvement of treatment conformity, including advanced image guidance and particle therapy, and novel biological concepts for personalized treatment, including biomarker-guided prescription, combined treatment modalities and adaptation of treatment during its course.

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Figure 1: Techniques of IMRT.
Figure 2: Physics of photon and proton radiotherapy.
Figure 3: Consequences of set-up or motion uncertainties in photon or proton radiotherapy.
Figure 4: Risk of geographic miss owing to microscopic tumour extensions.
Figure 5: Exploitation of biological knowledge in radiation oncology.

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Correspondence to Michael Baumann.

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Competing interests

J.O. is listed as a co-inventor on a provisional patent application for a method of determining clinically relevant hypoxia in cancer that is owned by Aarhus University, Aarhus, Denmark, and the part concerning prediction of benefit from nimorazole is licensed to Azanta Denmark A/S, Hellerup, Denmark. All other authors declare no competing interests.

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Glossary

Cancer stem cells

(CSCs). Tumour cells that have unlimited potential to proliferate and to repopulate a whole tumour. For radiation oncology, CSCs are cells that have the potential to cause recurrences if they survive treatment.

Radiation dose conformity

3D-planned radiotherapy with application of the prescribed high dose to the target volume and low dose to surrounding areas. Can be measured by the conformity index, which is the ratio between the planning target volume (PTV) and the irradiated volume. This ratio is ideally as high as possible, but cannot exceed a value of 1.

Intensity-modulated radiation therapy

(IMRT). Characterized by inhomogeneous dose distribution within each individual radiation field. The resulting cumulative dose distribution usually achieves better target coverage with protection of normal tissues for irregular target volumes.

Image-guided radiation therapy

(IGRT). Positioning control of organs and/or target volumes using in-room imaging modalities (X-ray, computed tomography (CT), magnetic resonance imaging (MRI)) directly, before application of the radiation fraction and correction of patient position accordingly.

Multileaf collimators

(MLCs). Devices made from individually movable leaves that block the beam and can thereby form the treatment field.

Stereotactic radiotherapy

Photon multi-field or arc radiotherapy that uses external coordinates for localization of the target. Usually applied to relatively small target volumes, for example, brain metastases or metastases in the body.

Gantry

Part of the treatment machine that can be rotated around the patient and thereby apply the beam from different directions.

Tomotherapy

Type of radiation therapy in which radiation is delivered slice by slice by a rotating beam.

Volumetric modulated arc therapy

(VMAT). Image-guided radiation therapy technique with application of radiation during rotation of the gantry around the patient and continuous adaptation of the field formation (leaf positions) to the beam direction.

Cone beam computed tomography

(CBCT). CT made from a rotating imaging source and detector, part of many modern radiotherapy machines.

Fiducial markers

Small markers placed in the field of view of an imaging system, used in radiotherapy as reference for the matching of images, for example, for positioning control.

MR-LINAC

Integrated linear accelerator with magnetic resonance imaging for image-guided radiotherapy.

MR-cobalt machine

Integrated cobalt-60-based irradiation device with magnetic resonance imaging for image-guided radiotherapy.

Particle therapy with protons

Radiotherapy with light ions (H+). Characterized by steep dose fall-off behind the target volume and relative biological effectiveness (RBE) values of 1.1–1.2 or, according to newer data, potentially up to 2 in specific areas of the beam.

Reverse depth dose profile

Describes the depth dose profile of particles (protons or heavy ions) inside the body and is an increase in the radiation dose with penetration depth. This is inverse to photon radiotherapy, in which the dose decreases with depth.

Bragg peak

A peak in the depth dose curve of particles (protons or heavy ions). The dose behind the Bragg peak is very small or zero. The depth of the Bragg peak depends on the energy of the beam. To cover a complete target volume in depth, the Bragg peak is spread out by combining several beam energies.

Passive scattering

Spreading of the proton beam within the target volume is achieved by scattering material placed into the path of the beam; field borders are defined by absorber material.

Active spot scanning

The beam scans the treatment volume voxel by voxel.

Heavy ion beams

Heavier particles used for radiotherapy, most frequently carbon (12C). Characterized by steep dose fall-off behind the target volume and higher relative biological effectiveness (RBE) (2.3).

Gross tumour volume

(GTV). The visible macroscopic tumour in the imaging modalities used for radiotherapy treatment planning.

Clinical target volume

(CTV). Consists of the visible tumour (gross tumour volume, GTV) plus a volume of suspected microscopic spread.

Planning target volume

(PTV). Consists of the clinical target volume (CTV) plus a margin for technical or positioning uncertainties, including movement of target volumes.

Phantom studies

Studies of, for example, dose distribution using a phantom that relates to the essential human structures, densities or processes. For example, for dose distribution experiments, water-filled phantoms are used and for experiments on breathing-related motion, moving phantoms are used.

Pareto optimality

A state in which it is not possible to improve one feature without worsening another.

Intrinsic radiosensitivity

Radiosensitivity of an individual tumour independent of the impact of microenvironment or of fractionation parameters.

Repopulation

Increase in the number of cancer stem cells between irradiation fractions by accelerated proliferation of surviving cells or reduced spontaneous cell loss between irradiation fractions.

Prognostic assay

Gives information on the likely course of a disease.

Predictive assay

In addition to the prognostic assay, gives information on the outcome of a specific treatment and thereby guides the optimal treatment for an individual patient.

Phosphorylated histone H2AX

(γH2AX). Contributes to nucleosome formation and structure of DNA, and is phosphorylated as a consequence of DNA double-strand breaks.

Single-arm model-based prospective trials

Non-randomized trials that select patients for specific treatments based on outcome models gained from previous treatments and, in the case of radiotherapy, based on radiation dose distributions for the actual patient.

Interventional matrix trials

Clinical trials that build on patients with the same disease and treatment situation and use several biomarkers as a basis for treatment intervention. Positivity for one biomarker or biomarker combination may provide an intervention.

Cohort multiple randomized controlled trials

A large cohort of patients with the disease of interest is recruited. For each trial, all eligible patients in the cohort are identified, and the group to receive the trial intervention is randomly selected. Outcomes of these patients are compared with those of eligible patients who were not randomly selected for the intervention.

Rapid learning health care approaches

Computer-based data collection of treatment and outcomes of patients, development of prediction models based on the collected data, application of this knowledge to patients in clinical practice and comparison of predicted and actual outcomes to refine the models.

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Baumann, M., Krause, M., Overgaard, J. et al. Radiation oncology in the era of precision medicine. Nat Rev Cancer 16, 234–249 (2016). https://doi.org/10.1038/nrc.2016.18

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