Key Points
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The availability of high-energy beams of photons, protons and carbon ions has contributed to increases in tumour control and the sparing of normal tissues from acute radiation toxicity.
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Advances in cancer therapies for children have produced impressive prospects for long-term survival. Approximately 80% of children and adolescents treated for cancer survive more than 5 years, but roughly 73% of them develop treatment-related complications. The complication of perhaps greatest concern is the risk for developing a radiogenic second malignant neoplasm (SMN), which can develop years or decades after treatment.
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Although the patient receives a high dose of therapeutic radiation, which is focused at the diseased tissue, the entire body is exposed to comparatively low doses of unwanted radiation that are caused by radiation leaking from the treatment apparatus and by scattering of the therapeutic radiation within the body.
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Mechanisms of therapy-related cancers are similar to those of sporadic tumorigenesis, but the carcinogenic potential of low doses of photons is not completely understood, and the uncertainty is much higher for cancer that is induced by charged particles.
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Epidemiological studies have conclusively shown that some SMNs can develop in tissues that are located in-field (that is, in the path of the therapeutic beam) and out-of-field (outside the path of the therapeutic beam).
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Recent models predict that particle therapy lowers the risk of SMNs compared with contemporary photon therapies.
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Regardless of the type of radiation beams used, nascent approaches to personalized, risk-adapted radiotherapy seem to be likely to yield further reductions in risk from out-of-field exposures, and research in genetic susceptibility and radiobiology should help to identify biomarkers of long-term risk in cancer survivors.
Abstract
Recent advances in radiotherapy have enabled the use of different types of particles, such as protons and heavy ions, as well as refinements to the treatment of tumours with standard sources (photons). However, the risk of second cancers arising in long-term survivors continues to be a problem. The long-term risks from treatments such as particle therapy have not yet been determined and are unlikely to become apparent for many years. Therefore, there is a need to develop risk assessments based on our current knowledge of radiation-induced carcinogenesis.
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Acknowledgements
This work was supported in part by the US National Cancer Institute (awards 1R01CA131463-01A1) and by Northern Illinois University, USA, through a subcontract of the US Department of Defense (award W81XWH-08-1-0205). Research on particle therapy at GSI is partially supported by EU FP7 (ALLEGRO project), ESA (IBER-project) and Beilstein Stiftung (NanoBiC program). The authors would like to thank K. B. Carnes for her assistance in preparing this manuscript.
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Related links
Glossary
- Medulloblastoma
-
Malignant primary brain tumour that originates in the cerebellum or posterior fossa.
- Atomic bomb survivors database
-
Survivors of the atomic bombs dropped in 1945 in Japan have been followed for cancers for more than 60 years, and represent the main source of epidemiological data on radiogenic cancers.
- Stray radiation
-
Therapeutic beam radiation that is emitted through the accelerator housing and reaches the patient outside of the treatment volume.
- Radiation quality
-
Ionizing radiation includes many different qualities: high-energy electromagnetic radiation (such as X-rays), neutrons, electrons, protons and heavy ions. Their different biological effectiveness is scaled using weighting factors (Box 1).
- Relative biological effectiveness
-
The ratio of the dose, DR, of a reference radiation (typically γ-ray or X-rays) and Dt of a test radiation (for example, neutrons, protons and heavy ions) that produce the same biological effect. It depends on several factors including the dose, dose rate, biological end point, radiation test LET and tissue.
- α-particles
-
Helium nuclei emitted by some heavy elements by a natural radioactive process known as α-decay. They represent the high-LET component of the natural radiation background for the general population, mostly caused by inhalation of Radon gas.
- Intensity-modulated radiation therapy
-
Currently the most advanced type of photon radiotherapy. Accurate conformation to the target tumour is achieved by increasing the intensity of the rays to the target, and reducing the intensity of the beams that cross sensitive structures. The resulting inhomogenous dose distribution in the single field is compensated by cold and hot spots in the beams coming from other directions.
- Monitor units
-
A monitor unit (MU) is a measure of the linear accelerator (Linac) output. The dose to the target is calibrated with a detector (monitor), and therefore MUs correspond to a given dose to the tumour.
- Bragg peak
-
Region where charged particles release most of their energy in matter, before stopping.
- Passive proton beam shaping
-
A technique that spreads the Bragg peak, using attenuators and collimators.
- Magnetically scanned beams
-
Also known as spot scanning, a technique to deliver particle therapy. A small pencil beam is deflected by a magnet in two dimensions to cover a slice of the tumour, and the next slice is exposed by changing the energy in the accelerator. Unlike passive beam shaping, it does not require attenuators to modulate the Bragg peak, and therefore the production of neutrons outside the patient's body is negligible.
- Linear-no-threshold
-
The model commonly adopted by the International Regulatory Agencies to extrapolate the radiation risk at low doses. It is assumed that the cancer risk is always directly proportional to the absorbed dose.
- Sterilization effects
-
At high radiation doses, the cell killing (sterilization) overcomes the radiation transforming potential, and hence the neoplastic transformation per exposed cell decreases.
- Fractionation
-
The therapeutic radiation dose is very high (up to 60–70 Gy), but is normally delivered in daily fractions of approximately 2 Gy for effective sparing of the normal tissue.
- Ataxia telangectasia
-
A rare and severe neurodegenerative disease (also known as Boder–Sedgwick or Louis–Bar syndrome). It is caused by a defect in ATM, which encodes a serine/threonine protein kinase involved in DNA repair and cell cycle regulation.
- Non-targeted effects
-
Radiation effect observed in cells, tissue or organs not directly exposed to radiation. It can be caused by cell-to-cell communication via gap junctions, release of cytokines in the body, or mediated by the immune or nervous system.
- Bystander effect
-
A non-targeted effect generally observed in cellular experiments. The 'bystander' cell can receive radiation damage, although only the neighbouring target cell is exposed.
- Abscopal effect
-
A radiation response in an organ not directly exposed to the radiation field.
- Harderian gland
-
A subcutaneous accessory lacrimal gland found within the eye's orbit in many vertebrates (not in humans).
- Sparing effect
-
When the same radiation dose is delivered in multiple fractions, at intervals of several hours (typically 1 day), the biological damage is generally reduced.
- Fission-spectrum neutrons
-
Neutrons produced during the nuclear fission process, typically in nuclear reactors for energy production. The energy spectrum peaks at about 1 MeV.
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Newhauser, W., Durante, M. Assessing the risk of second malignancies after modern radiotherapy. Nat Rev Cancer 11, 438–448 (2011). https://doi.org/10.1038/nrc3069
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DOI: https://doi.org/10.1038/nrc3069
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