Questions from the Clinic:
Hey doc, I know radiation is dangerous and may damage normal cells in certain doses. How do I reduce or avoid the potential of damage from therapeutic and diagnostic X-ray tests that are recommended for my cancer treatment, workup and follow-up?
Over the last few decades, increased use of medical imaging modalities such as the computed tomography (CT) scan has resulted in substantially greater patient exposure to ionizing radiation.(1) According to a report published by the National Council on Radiation Protection and Measurements, Americans received seven times as much ionizing radiation from medical procedures in 2006 than they did during the early 1980s. At the time the survey was conducted, investigators additionally noted that medical imaging accounted for nearly half of the total radiation exposure in the United States population.(2) Even though doses associated with individual scans have decreased, low levels of radiation exposure pose significant risks to human health and elevate the risk for various forms of cancer.(3,4) More concentrated forms of radiation, used to treat many forms of cancer, can also cause serious side effects such as secondary cancers to occur.(5) These well-characterized drawbacks of ionizing radiation necessitate the examination of prophylactic radioprotective agents – substances that can be taken before radiation exposure to minimize cellular damage.
II. Mechanism of Action
When ionizing radiation passes through cells, it interacts with water and other, small oxygen-containing molecules to produce a subclass of free radicals known as reactive oxygen species (ROS). Members of the ROS family, such as hydroxide (OH-) and superoxide (O2-), have an unpaired electron (e-) that makes the molecule relatively unstable. To achieve stability, free radicals will react readily with various organic substrates such as lipids, proteins, and DNA and damage them in the process. In an attempt to restore homeostasis, cells respond to the increased concentrations of free radicals by generating antioxidants. For example, the enzyme superoxide dismutase converts superoxide to hydrogen peroxide (H2O2), which itself undergoes conversion to water (H2O) through the action of another enzyme known as catalase. Another antioxidant enzyme, glutathione peroxidase, catalyzes the conversion of hydroxide back to water. Functionally, antioxidants can be conceived as donors that supply free radicals with a stabilizing electron; this change makes free radicals less dangerous to our cells (Figure 2). When the quantity of ROS outnumbers the number of antioxidants available, damage occurs in a dose-dependent manner. Cells unable to repair double-stranded breaks in DNA will accumulate mutations and have a higher chance of becoming cancerous.(3)
Although exposure tiers vary, the following cutoffs were utilized in a study measuring radiation received from medical imaging procedures:
“Moderate” dose: 3-20 (millisieverts) mSv/yr.
“High” dose: 20-50 mSv/yr.
“Very high” dose: >50 mSv/yr.
In this investigation, researchers noted that 18.6 per 1,000 individuals enrolled from the general population had high annual exposure to ionizing radiation, with another 193.8 per 1,000 falling into the moderate exposure category. Exposure to radiation generally correlated with age, as older individuals underwent a greater number of imaging procedures during the study period. Average effective doses varied dramatically; the amount of radiation from mammography (0.4 mSv) and chest x-rays (0.02 mSv) paled in comparison to that received from CT scans of the abdomen (8 mSv) and myocardial perfusion imaging (15.6 mSv).(6) Combined CT and positron emission tomography (PET) scans, useful for revealing the metabolic function of tissues and organs, expose individuals to 25 mSv!(7) This higher exposure, in part, results from the administration of a radioactive sugar such as fluorodeoxyglucose ([18F]FDG), which functions as a tracer. Active cancer cells will take up [18F]FDG as a part of metabolism and show up brighter on a scan.(8) For reference, individuals at-risk for repeated radiation exposure such as healthcare workers, are typically restricted to doses of 100 mSv every 5 years.6 Radiation doses exceeding 100 mSv in a year are estimated to increase one’s lifetime risk of cancer by 5%; and doses associated with the most common imaging examinations are listed at the end of this post in Table 1.(9) As one can calculate, aggressive scanning in a cancer patient’s course can quickly accumulate mSv lifetime doses and add additional risk for second malignancies especially if the therapeutic radiation is used as well.
Applying these exposure standards to patients is logistically challenging at best and often infeasible, as many require diagnostic procedures out of medical necessity. Broadly, the risks from medical imaging appear underappreciated among radiologists, with less than half reporting awareness that CT scans increase cancer risk.(10) Taken together, these findings underscore the urgent need for monitoring individuals’ accumulated doses of exposure and adopting radioprotective agents in oncology care paradigms. A patient should always weigh the potential benefits of an imaging procedure against the time, money, and biological risk impact they may incur. Getting a scan simply to “check-in” that will not change the therapy may be a poor choice when considering long-term, biological costs.
III. Approved and Investigational Agents
To date, the U.S. Food and Drug Administration (FDA) has only approved a radiation therapy level protective drug named amifostine. There are no approved drugs for diagnostic level testing at this point. In a clinical trial (focusing on radiation for treatment, not as a diagnostic test), investigators observed that amifostine conferred protection against adverse events associated with combination therapy consisting of carboplatin, Taxol, and radiotherapy. Encouragingly, amifostine also exhibited selectivity for normal cells, which means that this adjunctive approach does not provide unintentional protection to cancerous cells.(12) That said, in the years since amifostine’s approval, uptake of the drug has proven limited. Despite its proven efficacy, amifostine use remains restricted to patients experiencing moderate-to-severe xerostomia (dry mouth) after radiation treatment for head and neck cancers and those taking chemotherapy (cisplatin) for ovarian cancer.(13) Undesirable side effects, namely nausea, vomiting, fatigue, and fever, constrain the wider adoption of amifostine in other patients with cancer; non-clinical, diagnostic use cases have not received regulatory approval.
Promising findings from preclinical and pilot studies potentially support the use of Vitamin C as a natural, radioprotective supplement. In one experiment conducted in 1994, researchers extracted white blood cell samples from human volunteers 1 hour before and after eating breakfast with oral vitamin C supplementation (35 mg/kg). After extracting the samples, investigators subjected the isolated blood to irradiation and measured DNA damage through the use of the ‘comet’ assay. This test allows scientists to visualize and quantify damage to genetic material, as DNA with single strand breaks will streak out from the cell nucleus and form a ‘comet tail’ (Figure 3). Analysts comparing the samples noted less damage in those taken from study participants who had ingested vitamin C (35 mg/kg) with their breakfast.(14) The protective effect appeared to peak at 4 hours and notably was still significant when subjects only took vitamin C without breakfast. These findings corroborate those from an animal study in which mice received intra-testicular injections of iodine-131 – a procedure that models internal radiation injury. Mice that received vitamin C orally or parenterally sustained less sperm loss from iodine-131 than their counterparts with no pretreatment.(15)
More recently, in the wake of the 2011 Fukushima nuclear disaster, Japanese scientists conducted a pilot study designed to clarify the effect of vitamin C and anti-oxidative nutrition on radiation-induced gene expression. Participants enrolled in the investigation were male contract workers aged 32 to 59 years of age who worked between 5 and 6 weeks within the radiation-contaminated zone in Fukushima. Of these 16 men, 5 workers received intravenous vitamin C twice monthly and oral, anti-oxidative nutritional supplements containing alpha-lipoic acid, selenium, and vitamin E. After 2 months had passed, researchers noted a decline in circulating free DNA from strand breaks, – a biomarker for cancer – and significantly lower cancer risk scores. Another 4 workers who took a single, intravenous dose of vitamin C before working along with periodic anti-oxidative supplements during the working period did not achieve significant reductions in circulating free DNA and cancer risk scores. Collectively, the data suggest that vitamin C and the cocktail may offer significant, albeit transient, protective benefits to humans exposed to elevated levels of radiation. Because of the study’s small sample size and methodological limitations, further examination of this effect is warranted in well-designed clinical trials with control groups.
IV. Cost, Accessibility, and Other Considerations
Although supplements with purported radioprotective properties are relatively inexpensive to purchase, figuring out their precise value has been difficult since the measurement of long-term cancer risk is difficult. Data from in vitro studies suggest that other nutrients, namely alpha-lipoic acid, glutathione, selenium, vitamin C and vitamin E, may warrant additional investigation in studies with more participants and better controls.(17,18) That said, enrolling individuals into such hypothetical clinical trials would be logistically challenging, as it would be unethical to expose human subjects to high levels of ionizing radiation to figure out what is protective. Moreover, in the United States, there is a history of sordid, human radiation experiments dating back through the 20th century; unsuspecting participants who were enrolled in these tests suffered physically from their involvement.(19) Even if study authors obtained informed consent from prospective patients and gained regulatory approval, other methodological hurdles would hinder research. If patients with previous medical imaging radiation exposure are enrolled, how do study designers determine how much a person had received? If the diet does indeed influence response to radiation, how is this factor controlled? Can radioprotective interventions selectively shield healthy cells and allow other therapies to kill cancer cells? Addressing these questions and other unknowns is essential for scientific knowledge to advance in this area of medicine.
Although advances in medical imaging improve the quality of care delivered to many patients with cancer, many procedures expose people to additional levels of radiation. Because CT scans and other imaging modalities have become essential parts of modern medicine, eliminating, or greatly reducing their use fully is impractical. Magnetic Resonance Imaging or MRI does not use ionizing radiation and sometimes can be substituted for CT scans with similar and at certain sites better efficacy. To address this rising concern, radiology services are striving to monitor lifetime doses and reduce scan exposures as technology allows. Researchers are also investigating the radioprotective properties of natural antioxidants that can mitigate the side effects of therapeutic radiation and diagnostic procedures. Certain supplements, particularly vitamin C, and others mentioned above, appear to offer some protective benefit when given before radiation exposure, but available data has not yet been corroborated in larger, clinical trials.
Until more insights emerge from well-designed trials, patients with cancer should not independently take antioxidant level doses of vitamin C, vitamin E, or other supplements with the belief that it will prevent side effects from therapeutic radiotherapy. This combination in the setting of cancer treatment may even partially neutralize the lethal effect of the radiation on cancer and weaken the treatment. When Vitamin C is used in high doses via IV or large oral doses in the range of 10 grams to 150 grams, it becomes an oxidant and has cytotoxic effects on cancer cells that have inadequate detoxification pathways, and this is a different situation. (See the blog on vitamin C as a therapy). That said, these mitigation therapies for ionizing radiation from the diagnostic test are affordable, accessible, and safe; patients interested in advancing scientific understanding of radioprotective agents should work closely with their physician and oncology care team to determine whether they can add these agents.
Stay strong and curious and be your own best doctor,
Charles J. Meakin MD, MHA, MS
Disclaimer: This information is not meant as direct medical advice. Readers should always review options with their local medical team. This is the sole opinion of Dr. Meakin based on a literature review at the time of the blog and may change as new evidence evolves.
1 Gorenberg M, Agbarya A, Groshar D, et al. Novel nanotech antioxidant cocktail prevents medical diagnostic procedures ionizing radiation effects. Sci Rep. 2021;11(1):5315.
2 NCRP Report No. 160: Ionizing Radiation Exposure of the Population of the United States. National Council on Radiation Protection and Measurements. https://ncrponline.org/publications/reports/ncrp-report-160-2/. Accessed August 22, 2022.
3 Smith TA, Kirkpatrick DR, Smith S, et al. Radioprotective agents to prevent cellular damage due to ionizing radiation. J Transl Med. 2017;15:232.
4 Gilbert ES. Ionizing radiation and cancer risks: what have we learned from epidemiology? Int J Radiat Biol. 2009;85(6):467-482.
5 Dilalla V, Chaput G, Williams T, et al. Radiotherapy side effects: integrating a survivorship clinical lens to better serve patients. Curr Oncol. 2020;27(2):107-112.
6 Fazel R, Krumholz HM, Wang Y, et al. Exposure to low-dose ionizing radiation from medical imaging procedures in the United States. N Engl J Med. 2009;361(9):849-857.
7 Understanding radiation risk from imaging tests. American Cancer Society. https://www.cancer.org/treatment/understanding-your-diagnosis/tests/understanding-radiation-risk-from-imaging-tests.html/. Updated August 3, 2018. Accessed August 26, 2022.
8 PET scan. Cancer Research UK. https://www.cancerresearchuk.org/about-cancer/cancer-in-general/tests/pet-scan/. Updated May 2, 2019. Accessed August 26, 2022.
9 Patient safety: radiation dose chart for physicians. RadiologyInfo.org. https://www.acr.org/-/media/ACR/Files/Radiology-Safety/Radiation-Safety/Dose-Reference-Card.pdf?la=en&hash=2FFAD1C34DB0FDA39E4D4AC94F4EA34185819277/. Published May 2022. Accessed August 26, 2022.
10 Lee CI, Haims AH, Monico EP, et al. Diagnostic CT scans: assessment of patient, physician, and radiologist awareness of radiation dose and possible risks. Radiology. 2004;231:393-398.
11 Obrador E, Salvador R, Villaescusa JI, et al. Radioprotection and radiomitigation: from the bench to clinical practice. Biomedicines. 2020;8(11):461.
12 Kouvaris JR, Kouloulias VE, Vlahos LJ. Amifostine: the first selective-target and broad-spectrum radioprotector. The Oncologist. 2007;12(6):738-747.
13 Amifostine injection. Medline Plus. https://medlineplus.gov/druginfo/meds/a696014.html/. Updated December 15, 2012. Accessed August 22, 2022.
14 Green MHL, Lowe JE, Waugh APW, et al. Effect of diet and vitamin C on DNA strand breakage in freshly-isolated human white blood cells. Mut Res. 1994;316:91-102.
15 Narra VR, Howell RW, Sastry KS, et al. Vitamin C as a radioprotector against iodine-131 in vivo. J Nucl Med. 1993;34(4):637-640.
16 Yanagisawa A, Iwata M, Akiyama S. Effect of vitamin C and anti-oxidative nutrition on radiation-induced gene expression in Fukushima nuclear plant workers – a pilot study. Japanese College of Intravenous Therapy.
17 Kuefner MA, Brand M, Ehrlich J, et al. Effect of antioxidants on X-ray-induced γ-H2AX foci in human blood lymphocytes: preliminary observations. Radiology. 2012;264(1):59-67.
18 Alcaraz M, Armero D, Martinez-Beneyto Y, et al. Chemical genoprotection: reducing biological damage to as low as reasonably achievable levels. Dentomaxillofac Radiol. 2011;40(5):310-314.
19 Human radiation experiments. Atomic Heritage Foundation. https://www.atomicheritage.org/history/human-radiation-experiments/. Published July 11, 2017. Accessed August 24, 2022.