Radiation-induced cognitive decline

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https://en.wikipedia.org/wiki/Radiation-induced_cognitive_decline 

Radiation-induced cognitive decline describes the possible correlation between radiation therapy and cognitive impairment. Radiation therapy is used mainly in the treatment of cancer. Radiation therapy can be used to cure care or shrink tumors that are interfering with quality of life. Sometimes radiation therapy is used alone; other times it is used in conjunction with chemotherapy and surgery. For people with brain tumors, radiation can be an effective treatment because chemotherapy is often less effective due to the blood–brain barrier. Unfortunately for some patients, as time passes, people who received radiation therapy may begin experiencing deficits in their learning, memory, and spatial information processing abilities. The learning, memory, and spatial information processing abilities are dependent on proper hippocampus functionality. Therefore, any hippocampus dysfunction will result in deficits in learning, memory, and spatial information processing ability.

The hippocampus is one of two structures of the central nervous system where neurogenesis continues after birth. The other structure that undergoes neurogenesis is the olfactory bulb. Therefore, it has been proposed that neurogenesis plays some role in the proper functionality of the hippocampus and the olfactory bulb. To test this proposal, a group of rats with normal hippocampal neurogenesis (control) were subjected to a placement recognition exercise that required proper hippocampus function to complete. Afterwards a second group of rats (experimental) were subjected to the same exercise but in that trial their neurogenesis in the hippocampus was arrested. It was found that the experimental group was not able to distinguish between its familiar and unexplored territory. The experimental group spent more time exploring the familiar territory, while the control group spent more time exploring the new territory. The results indicate that neurogenesis in the hippocampus is important for memory and proper hippocampal functionality. Therefore, if radiation therapy inhibits neurogenesis in the hippocampus it would lead to the cognitive decline observed in patients who have received this radiation therapy.

In animal studies discussed by Monje and Palmer in "Radiation Injury and Neurogenesis", it has been proven that radiation does indeed decrease or arrest neurogenesis altogether in the hippocampus. This decrease in neurogenesis is due to apoptosis of the neurons which usually occurs after irradiation. However it has not been proven whether the apoptosis is a direct result of the radiation itself or if there are other factors that cause neuronal apoptosis, namely changes in the hippocampus micro-environment or damage to the precursor pool. Determining the exact cause of the cell apoptosis is important because then it may be possible to inhibit the apoptosis and reverse the effects of the arrested neurogenesis.

Radiation therapy

Ionizing radiation is classified as a neurotoxicant. A 2004 cohort study concluded that irradiation of the brain with dose levels overlapping those imparted by computed tomography can, in at least some instances, adversely affect intellectual development.

Radiation therapy at doses around "23.4 Gy" was found to cause cognitive decline that was especially apparent in young children who underwent the treatment for cranial tumors, between the ages of 5 to 11. Studies found, for example, that the IQ of 5-year-old children declined each year after treatment by additional several IQ points, thereby the child's IQ decreased and decreased while growing older though may plateau at adulthood.

Radiation of 100 mGy to the head at infancy resulted in the beginning appearance of statistically significant cognitive-deficits in one Swedish/radiation-therapy follow-up study. Radiation of 1300-1500mGy to the head at childhood was similarly found to be roughly the threshold dose for the beginning increase in statistically significant rates of schizophrenia.

From soliciting for participants in a study and then examination of the prenatally exposed at Hiroshima & Nagasaki, those who experienced the prompt burst of ionizing radiation at the 8-15 and 16–25 week periods after gestation were to, especially in the closest survivors, have a higher rate of severe mental retardation as well as variation in intelligence quotient (IQ) and school performance. It is uncertain, if there exists a threshold dose, under which one or more of these effects, of prenatal exposure to ionizing radiation, do not exist, though from analysis of the limited data, "0.1" Gy is suggested for both.

Warfare

Adult humans receiving an acute whole body incapacitating dose (30 Gy) have their performance degraded almost immediately and become ineffective within several hours. A dose of 5.3 Gy to 8.3 Gy is considered lethal within months to half of male adults but not immediately incapacitating. Personnel exposed to this amount of radiation have their cognitive performance degraded in two to three hours. Depending on how physically demanding the tasks they must perform are, and remain in this disabled state at least two days. However, at that point they experience a recovery period and can perform non-demanding tasks for about six days, after which they relapse for about four weeks. At this time they begin exhibiting symptoms of radiation poisoning of sufficient severity to render them totally ineffective. Death follows for about half of males at approximately six weeks after exposure.

Nausea and vomiting generally occur within 24–48 hours after exposure to mild (1–2 Gy) doses of radiation. Headache, fatigue, and weakness are also seen with mild exposure.

Exposure of adults to 150−500 mSv results in the beginning observance of cerebrovascular pathology, and exposure to 300 mSv results in the beginning of the observance of neuropsychiatric and neurophysiological dose-related effects. Cumulative equivalent doses above 500 mSv of ionizing radiation to the head, were proven with epidemiological evidences to cause cerebrovascular atherosclerotic damage, thus increasing the chances of stroke in later life. The equivalent dose of 0.5 Gy (500 mGy) x-rays is 500 mSv.

Acute ablation of precursor cells

Recent studies have shown that there is a decrease in neurogenesis in the hippocampus after irradiation therapy. The decrease in neurogenesis is the result of a reduction in the stem cell pool due to apoptosis. However, the question remains whether radiation therapy results in a complete ablation of the stem cell pool in the hippocampus or whether some stem cells survive. Animal studies have been performed by Monje and Palmer to determine if there is an acute ablation of the stem cell pool. In the study, rats were subjected to 10 Gy dosage of radiation. The 10 Gy radiation dosage is comparable to that used in irradiation therapy in humans. One month after the reception of the dosage, living precursor cells from these rats’ hippocampus were successfully isolated and cultured. Therefore, a complete ablation of the precursor cell pool by irradiation does not occur.

Precursor cell integrity

Precursor cells may be damaged by radiation. This damage of the cells may prevent the precursor cells from differentiating into neurons and result in decreased neurogenesis. To determine whether the precursor cells are impaired in their ability to differentiate, two cultures were prepared by Fike et al. One of these cultures contained precursor cells from an irradiated rat's hippocampus and the second culture contained non-irradiated precursor cells from a rat hippocampus. The precursor cells were then observed while they continued to develop. The results indicated that the irradiated culture contained a higher number of differentiated neuron and glial cells in comparison to the control. It was also found that the ratios of glial cells to neurons in both cultures were similar. These results suggest that the radiation did not impair the precursor cells ability to differentiate into neurons and therefore neurogenesis is still possible.

Alterations in hippocampus microenvironment

The microenvironment is an important component to consider for precursor survival and differentiation. It is the microenvironment that provides the signals to the precursor cells that help it survive, proliferate, and differentiate. To determine if the microenvironment is altered as a result of radiation, an animal study was performed by Fike et al. where highly enriched, BrdU labeled, non-irradiated stem cells from a rat hippocampus were implanted into a hippocampus that was irradiated one month prior. The stem cells were allowed to remain in the live rat for 3–4 weeks. Afterwards, the rat was killed and the stem cells were observed using immunohistochemistry and confocal microscopy. The results show that stem cell survival was similar to that found in a control subject (normal rat hippocampus); however, the number of neurons generated was decreased by 81%. Therefore, alterations of the microenvironment post radiation can lead to a decrease in neurogenesis.

In addition, studies mentioned by Fike et al. found that there are two main differences between the hippocampus of an irradiated rat and a non-irradiated rat that are part of the microenvironment. There was a significantly larger number of activated microglia cells in the hippocampus of irradiated rats in comparison to non-irradiated rats. The presence of microglia cells is characteristic of the inflammatory response which is most likely due to radiation exposure. Also the expected clustering of stem cells around the vasculature of the hippocampus was disrupted. Therefore, focusing on the microglial activation, inflammatory response, and microvasculature may produce a direct link to the decrease in neurogenesis post irradiation.

Inflammatory response affects neurogenesis

Radiation therapy usually results in chronic inflammation, and in the brain this inflammatory response comes in the form of activated microglia cells. Once activated, these microglia cells start to release stress hormones and various pro-inflammatory cytokines. Some of what is released by the activated microglia cells, like the glucocorticoid stress hormone, may result in a decrease in neurogenesis. To investigate this concept, an animal study was performed by Monje et al. in order to determine the specific cytokines or stress hormones that were released by activated microglial cells that decrease neurogenesis in an irradiated hippocampus. In this study, microglia cells were exposed to bacterial lipopolysaccharide to elicit an inflammatory response, thus activating the microglia cells. These activated microglia were then co-cultured with normal hippocampal neural stem cells. Also, as a control, non-activated microglia cells were co-cultured with normal hippocampal neural stem cells. In comparing the two co-cultures, it was determined that neurogenesis in the activated microglia cell culture was 50% less than in the control. A second study was also performed to ensure that the decrease in neurogenesis was the result of released cytokines and not cell-to-cell contact of microglia and stem cells. In this study, neural stem cells were cultured on preconditioned media from activated microglia cells and a comparison was made with a neural stem cells cultured on plain media. The results of this study indicated that neurogenesis also showed a similar decrease in the preconditioned media culture versus the control.

When microglia cells are activated, they release the pro-inflammatory cytokine IL-1β, TNF-α, INF-γ, and IL-6. In order to identify the cytokines that decreased neurogenesis, Monje et al. allowed progenitor cells to differentiate while exposed to each cytokine. The results of the study showed that only the recombinant IL-6 and TNF-α exposure significantly reduced neurogenesis. Then the IL-6 was inhibited and neurogenesis was restored. This implicates IL-6 as the main cytokine responsible for the decrease of neurogenesis in the hippocampus.

Microvasculature and neurogenesis

The microvasculature of the subgranular zone, located in dentate gyrus of hippocampus, plays an important role in neurogenesis. As precursor cells develop in the subgranular zone, they form clusters. These clusters usually contain dozens of cells. The clusters are made up of endothelial cells and neuronal precursor cells that have the ability to differentiate into either neurons or glia cells. With time, these clusters eventually migrate towards microvessels in the subgranular zone. As the clusters get closer to the vessels, some of the precursor cells differentiate in glia cells and eventually the remaining precursor cells will differentiate into neurons. Upon investigation of the close association between the vessels and clusters, it is apparent that the actual migration of the precursor cells to these vessels is not random. Since endothelial cells forming the vessel wall do secrete brain-derived neurotrophic factor, it is plausible that the neuronal precursor cells migrate to those regions in order to grow, survive, and differentiate. Also, since the clusters do contain endothelial cells, they might be attracted to the vascular endothelial growth factor that is released in the area of vessels to promote endothelial survival and angiogenesis. However, as noted previously, clustering along the capillaries in the subgranular zone does decrease when the brain is subject to radiation. The exact reasoning for this disruption of the close association between cluster and vessels remains unknown. It is possible that any signaling that would normally attract the clusters to the region, for example the bone-derived growth factor and the vascular endothelial growth factor, may be suppressed.

Reversal

Blocking inflammatory cascade

Neurogenesis in the hippocampus usually decreases after exposure to radiation and usually leads to a cognitive decline in patients undergoing radiation therapy. As discussed above, the decrease in neurogenesis is heavily influenced by changes in the microenvironment of the hippocampus upon exposure to radiation. Specifically, disruption of the cluster/vessel association in the subgranular zone of the dentate gyrus and cytokines released by activated microglia as part of the inflammatory response do impair neurogenesis in the irradiated hippocampus. Thus several studies have used this knowledge to reverse the reduction in neurogenesis in the irradiated hippocampus. In one study, indomethacin treatment was given to the irradiated rat during and after irradiation treatment. It was found that the indomethacin treatment caused a 35% decrease in the number of activated microglia per dentate gyrus in comparison to microglia activation in irradiated rats without indomethacin treatment. This decrease in microglia activation reduces the amount of cytokines and stress-hormone release, thus reducing the effect of the inflammatory response. When the number of precursor cells adopting a neuronal fate was quantified, it was determined that the ratio of neurons to glia cells increased. This increase in neurogenesis was only 20-25% of that observed in control animals. However, in this study the inflammatory response was not eliminated entirely, and some cytokines or stress hormones continued to be secreted by the remaining activated microglia cells causing the reduction in neurogenesis. In a second study, the inflammatory cascade was also blocked at another stage. This study focused mainly on the c-Jun NH2 – terminal kinase pathway which when activated results in the apoptosis of neurons. This pathway was chosen because, upon irradiation, it is the only mitogen-activated protein kinase that is activated. The mitogen-activated protein kinases are important for regulation of migration, proliferation, differentiation, and apoptosis. The JNK pathway is activated by cytokines released by activated microglia cells, and blocking this pathway significantly reduces neuronal apoptosis. In the study, the JNK was inhibited using 5 μM SP600125 dosage, and this resulted in a decrease of neural stem cells apoptosis. This decrease in apoptosis results in increased neuronal recovery.

Environmental enrichment

In previous work, environmental enrichment has been used to determine its effect on brain activity. In these studies, the environmental enrichment has positively impacted the brain functionality in both normal, healthy animals and animals that had suffered severe brain injury. It has already been shown by Elodie Bruel-Jungerman et al. that subjecting animals to learning exercises that are heavily dependent on the hippocampus results in increased neurogenesis. Therefore, the question of whether environmental enrichment can enhance neurogenesis in an irradiated hippocampus is raised. In a study performed by Fan et al., the effects of environmental enrichment on gerbils were tested. There were four groups of gerbils used for this experiment, where group one consisted on non-irradiated animals that lived in a standard environment, group two were non-irradiated animals that lived in an enriched environment, group three were irradiated animals that lived in a standard environment, and group four were irradiated animals that lived in an enriched environment. After two months of maintaining the gerbils in the required environments, they were killed and hippocampal tissue was removed for analysis. It was found that the number of precursor neurons that were differentiated into neurons from group four (irradiated and enriched environment) was significantly more than group three (irradiated and standard environment). Similarly, the number of neuron precursor cells was more in group two (non-irradiated and enriched environment), in comparison to group one (non-irradiated and standard environment). The results indicate that neurogenesis was increased in the animals that were exposed to the enriched environment, in comparison to animals in the standard environment. This outcome indicates that environmental enrichment can indeed increase neurogenesis and reverse the cognitive decline.

 

Experimental cancer treatment

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Experimental_cancer_treatment 

Experimental cancer treatments are non-medical therapies intended to treat cancer by improving on, supplementing or replacing conventional methods (surgery, chemotherapy, radiation, and immunotherapy). Experimental cancer treatments cannot make medical claims. The term experimental cancer treatment could thus be substituted for "non FDA approved cancer treatment."

The entries listed below vary between theoretical therapies to unproven controversial therapies. Many of these treatments are alleged to help against only specific forms of cancer. It is not a list of treatments widely available at hospitals.

Studying treatments for cancer

The twin goals of research are to determine whether the treatment actually works (called efficacy) and whether it is sufficiently safe. Regulatory processes attempt to balance the potential benefits with the potential harms, so that people given the treatment are more likely to benefit from it than to be harmed by it.

Medical research for cancer begins much like research for any disease. In organized studies of new treatments for cancer, the pre-clinical development of drugs, devices, and techniques begins in laboratories, either with isolated cells or in small animals, most commonly rats or mice. In other cases, the proposed treatment for cancer is already in use for some other medical condition, in which case more is known about its safety and potential efficacy.

Clinical Trials are the study of treatments in humans. The first-in-human tests of a potential treatment are called Phase I studies. Early clinical trials typically enroll a very small number of patients, and the purpose is to identify major safety issues and the maximum tolerated dose, which is the highest dose that does not produce serious or fatal adverse effects. The dose given in these trials may be far too small to produce any useful effect. In most research, these early trials may involve healthy people, but cancer studies normally enroll only people with relatively severe forms of the disease in this stage of testing. On average, 95% of the participants in these early trials receive no benefit, but all are exposed to the risk of adverse effects. Most participants show signs of optimism bias (the irrational belief that they will beat the odds).

Later studies, called Phase II and Phase III studies, enroll more people, and the goal is to determine whether the treatment actually works. Phase III studies are frequently randomized controlled trials, with the experimental treatment being compared to the current best available treatment rather than to a placebo. In some cases, the Phase III trial provides the best available treatment to all participants, in addition to some of the patients receiving the experimental treatment.

Bacterial treatments

Chemotherapeutic drugs have a hard time penetrating tumors to kill them at their core because these cells may lack a good blood supply. Researchers have been using anaerobic bacteria, such as Clostridium novyi, to consume the interior of oxygen-poor tumours. These should then die when they come in contact with the tumor's oxygenated sides, meaning they would be harmless to the rest of the body. A major problem has been that bacteria do not consume all parts of the malignant tissue. However, combining the therapy with chemotherapeutic treatments can help to solve this problem.

Another strategy is to use anaerobic bacteria that have been transformed with an enzyme that can convert a non-toxic prodrug into a toxic drug. With the proliferation of the bacteria in the necrotic and hypoxic areas of the tumor, the enzyme is expressed solely in the tumor. Thus, a systemically applied prodrug is metabolised to the toxic drug only in the tumor. This has been demonstrated to be effective with the nonpathogenic anaerobe Clostridium sporogenes.

Drug therapies

HAMLET (human alpha-lactalbumin made lethal to tumor cells)

HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a molecular complex derived from human breast milk that kills tumor cells by a process resembling programmed cell death (apoptosis). It has been tested in humans with skin papillomas and bladder cancer.

Dichloroacetate treatment

Dichloroacetate (DCA) has been found to shrink tumors in vivo in rats, and has a plausible scientific mechanism: DCA appears to reactivate suppressed mitochondria in some types of oxygen-starved tumor cells, and thus promotes apoptosis. Because it was tested for other conditions, DCA is known to be relatively safe, available, and inexpensive, and it can be taken by mouth as a pill, which is convenient. Five patients with brain cancer have been treated with DCA in a clinical trial, and the authors say that the lives of four were 'probably' extended. However, without a large controlled trial it is impossible to say whether the drug is truly effective against cancer.

Quercetin treatment

Quercetin is a principal flavonoid compound and an excellent free-radical-scavenging antioxidant that promotes apoptosis. In vitro it shows some antitumor activity in oral cancer and leukemia. Cultured skin and prostate cancer cells showed significant mortality (compared to nonmalignant cells) when treated with a combination of quercetin and ultrasound. Note that ultrasound also promotes topical absorption by up to 1,000 times, making the use of topical quercetin and ultrasound wands an interesting proposition.

High dietary intake of fruits and vegetables is associated with reduction in cancer, and some scientists, such as Gian Luigi Russo at the Institute of Food Sciences in Italy, suspect quercetin may be partly responsible. Research shows that quercetin influences cellular mechanisms in vitro and in animal studies. According to the American Cancer society, "there is no reliable clinical evidence that quercetin can prevent or treat cancer in humans".

Insulin potentiation therapy

Insulin potentiation therapy is practice of injecting insulin, usually alongside conventional cancer drugs, in the belief that this improves the overall effect of the treatment. Quackwatch state: "Insulin Potentiation Therapy (IPT) is one of several unproven, dangerous treatments that is promoted by a small group of practitioners without trustworthy evidence that it works."

p53 activation therapy

Several drug therapies are being developed based on p53, the tumour suppressor gene that protects the cell in response to damage and stress. It is analogous to deciding what to do with a damaged car: p53 brings everything to a halt, and then decides whether to fix the cell or, if the cell is beyond repair, to destroy the cell. This protective function of p53 is disabled in most cancer cells, allowing them to multiply without check. Restoration of p53 activity in tumours (where possible) has been shown to inhibit tumour growth and can even shrink the tumour.

As p53 protein levels are usually kept low, one could block its degradation and allow large amounts of p53 to accumulate, thus stimulating p53 activity and its antitumour effects. Drugs that utilize this mechanism include nutlin and MI-219, which are both in phase I clinical trials. There are also other drugs that are still in the preclinical stage of testing, such as RITA and MITA.

BI811283

BI811283 is a small molecule inhibitor of the aurora B kinase protein being developed by Boehringer Ingelheim for use as an anti-cancer agent. BI 811283 is currently in the early stages of clinical development and is undergoing first-in-human trials in patients with solid tumors and Acute Myeloid Leukaemia.

Gene therapy

Introduction of tumor suppressor genes into rapidly dividing cells has been thought to slow down or arrest tumor growth. Adenoviruses are a commonly utilized vector for this purpose. Much research has focused on the use of adenoviruses that cannot reproduce, or reproduce only to a limited extent, within the patient to ensure safety via the avoidance of cytolytic destruction of noncancerous cells infected with the vector. However, new studies focus on adenoviruses that can be permitted to reproduce, and destroy cancerous cells in the process, since the adenoviruses' ability to infect normal cells is substantially impaired, potentially resulting in a far more effective treatment. Another use of gene therapy is the introduction of enzymes into these cells that make them susceptible to particular chemotherapy agents; studies with introducing thymidine kinase in gliomas, making them susceptible to aciclovir, are in their experimental stage.

Epigenetic options

Epigenetics is the study of heritable changes in gene activity that are not caused by changes in the DNA sequence, often a result of environmental or dietary damage to the histone receptors within the cell. Current research has shown that epigenetic pharmaceuticals could be a putative replacement or adjuvant therapy for currently accepted treatment methods such as radiation and chemotherapy, or could enhance the effects of these current treatments. It has been shown that the epigenetic control of the proto-onco regions and the tumor suppressor sequences by conformational changes in histones directly affects the formation and progression of cancer. Epigenetics also has the factor of reversibility, a characteristic that other cancer treatments do not offer.

Some investigators, like Randy Jirtle, PhD, of Duke University Medical Center, think epigenetics may ultimately turn out to have a greater role in disease than genetics.

Telomerase deactivation therapy

Because most malignant cells rely on the activity of the protein telomerase for their immortality, it has been proposed that a drug that inactivates telomerase might be effective against a broad spectrum of malignancies. At the same time, most healthy tissues in the body express little if any telomerase, and would function normally in its absence. Currently, inositol hexaphosphate, which is available over-the-counter, is undergoing testing in cancer research due to its telomerase-inhibiting abilities.

A number of research groups have experimented with the use of telomerase inhibitors in animal models, and as of 2005 and 2006 phase I and II human clinical trials are underway. Geron Corporation is currently conducting two clinical trials involving telomerase inhibitors. One uses a vaccine (GRNVAC1) and the other uses a lipidated oligonucleotide (GRN163L).

Radiation therapies

Photodynamic therapy

Photodynamic therapy (PDT) is generally a non-invasive treatment using a combination of light and a photosensitive drug, such as 5-ALA, Foscan, Metvix, padeliporfin (Tookad, WST09, WST11), Photofrin, or Visudyne. The drug is triggered by light of a specific wavelength.

Hyperthermiatic therapy

Localized and whole-body application of heat has been proposed as a technique for the treatment of malignant tumours. Intense heating will cause denaturation and coagulation of cellular proteins, rapidly killing cells within a tumour.

More prolonged moderate heating to temperatures just a few degrees above normal (39.5 °C) can cause more subtle changes. A mild heat treatment combined with other stresses can cause cell death by apoptosis. There are many biochemical consequences to the heat shock response within the cell, including slowed cell division and increased sensitivity to ionizing radiation therapy. The purpose of overheating the tumor cells is to create a lack of oxygen so that the heated cells become overacidified, which leads to a lack of nutrients in the tumor. This in turn disrupts the metabolism of the cells so that cell death (apoptosis) can set in. In certain cases chemotherapy or radiation that has previously not had any effect can be made effective. Hyperthermia alters the cell walls by means of so-called heat shock proteins. The cancer cells then react very much more effectively to the cytostatics and radiation. If hyperthermia is used conscientiously it has no serious side effects.

There are many techniques by which heat may be delivered. Some of the most common involve the use of focused ultrasound (FUS or HIFU), microwave heating, induction heating, magnetic hyperthermia, and direct application of heat through the use of heated saline pumped through catheters. Experiments with carbon nanotubes that selectively bind to cancer cells have been performed. Lasers are then used that pass harmlessly through the body, but heat the nanotubes, causing the death of the cancer cells. Similar results have also been achieved with other types of nanoparticles, including gold-coated nanoshells and nanorods that exhibit certain degrees of 'tunability' of the absorption properties of the nanoparticles to the wavelength of light for irradiation. The success of this approach to cancer treatment rests on the existence of an 'optical window' in which biological tissue (i.e., healthy cells) are completely transparent at the wavelength of the laser light, while nanoparticles are highly absorbing at the same wavelength. Such a 'window' exists in the so-called near-infrared region of the electromagnetic spectrum. In this way, the laser light can pass through the system without harming healthy tissue, and only diseased cells, where the nanoparticles reside, get hot and are killed.

Magnetic Hyperthermia makes use of magnetic nanoparticles, which can be injected into tumours and then generate heat when subjected to an alternating magnetic field.

One of the challenges in thermal therapy is delivering the appropriate amount of heat to the correct part of the patient's body. A great deal of current research focuses on precisely positioning heat delivery devices (catheters, microwave, and ultrasound applicators, etc.) using ultrasound or magnetic resonance imaging, as well as of developing new types of nanoparticles that make them particularly efficient absorbers while offering little or no concerns about toxicity to the circulation system. Clinicians also hope to use advanced imaging techniques to monitor heat treatments in real time—heat-induced changes in tissue are sometimes perceptible using these imaging instruments. In magnetic hyperthermia or magnetic fluid hyperthermia method, it will be easier to control temperature distribution by controlling the velocity of ferrofluid injection and size of magnetic nanoparticles.

Noninvasive cancer heat treatment

Heat treatment involves using radio waves to heat up tiny metals that are implanted in cancerous tissue. Gold nanoparticles or carbon nanotubes are the most likely candidate. Promising preclinical trials have been conducted, although clinical trials may not be held for another few years.

Another method that is entirely non-invasive referred to as Tumor Treating Fields has already reached clinical trial stage in many countries. The concept applies an electric field through a tumour region using electrodes external to the body. Successful trials have shown the process effectiveness to be greater than chemotherapy and there are no side-effects and only negligible time spent away from normal daily activities. This treatment is still in very early development stages for many types of cancer.

High-intensity focused ultrasound (HIFU) is still in investigatory phases in many places around the world. In China it has CFDA approval and over 180 treatment centres have been established in China, Hong Kong, and Korea. HIFU has been successfully used to treat cancer to destroy tumours of the bone, brain, breast, liver, pancreas, rectum, kidney, testes, and prostate. Several thousand patients have been treated with various types of tumours. HIFU has CE approval for palliative care for bone metastasis. Experimentally, palliative care has been provided for cases of advanced pancreatic cancer. High-energy therapeutic ultrasound could increase higher-density anti-cancer drug load and nanomedicines to target tumor sites by 20x fold higher than traditional target cancer therapy.

Cold atmospheric plasma treatment

Cold atmospheric plasma or CAP for short is an emerging modality for the treatment of solid tumors. Recently, cold atmospheric plasma (CAP) indicated promising anti-neoplastic effects on several tumors, e.g. melanoma, glioma, and pancreatic cancer cells [5, 6, 7], and therefore could be an efficient method for anti-cancer treatment in clinical urology in the future. One example of an experimental technology utilizing Cold Atmospheric plasma is Theraphi

Electromagnetic treatments

Tumor Treating Fields is a novel FDA-approved cancer treatment therapy that uses alternating electric field to disturb the rapid cell division exhibited by cancer cells.

Complementary and alternative treatments

Complementary and alternative medicine (CAM) treatments are the diverse group of medical and healthcare systems, practices, and products that are not part of conventional medicine and have not been proven to be effective. Complementary medicine usually refers to methods and substances used along with conventional medicine, while alternative medicine refers to compounds used instead of conventional medicine. CAM use is common among people with cancer.

Most complementary and alternative medicines for cancer have not been rigorously studied or tested. Some alternative treatments that have been proven ineffective continue to be marketed and promoted.

 

Spaceflight radiation carcinogenesis

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Spaceflight_radiation_carcinogenesis 

The Phantom Torso, as seen here in the Destiny laboratory on the International Space Station (ISS), is designed to measure the effects of radiation on organs inside the body by using a torso that is similar to those used to train radiologists on Earth. The torso is equivalent in height and weight to an average adult male. It contains radiation detectors that will measure, in real-time, how much radiation the brain, thyroid, stomach, colon, and heart and lung area receive on a daily basis. The data will be used to determine how the body reacts to and shields its internal organs from radiation, which will be important for longer duration space flights.

Astronauts are exposed to approximately 50-2,000 millisieverts (mSv) while on six-month-duration missions to the International Space Station (ISS), the Moon and beyond. The risk of cancer caused by ionizing radiation is well documented at radiation doses beginning at 100mSv and above.

Related radiological effect studies have shown that survivors of the atomic bomb explosions in Hiroshima and Nagasaki, nuclear reactor workers and patients who have undergone therapeutic radiation treatments have received low-linear energy transfer (LET) radiation (x-rays and gamma rays) doses in the same 50-2,000 mSv range.

Composition of space radiation

While in space, astronauts are exposed to radiation which is mostly composed of high-energy protons, helium nuclei (alpha particles), and high-atomic-number ions (HZE ions), as well as secondary radiation from nuclear reactions from spacecraft parts or tissue.

The ionization patterns in molecules, cells, tissues and the resulting biological effects are distinct from typical terrestrial radiation (x-rays and gamma rays, which are low-LET radiation). Galactic cosmic rays (GCRs) from outside the Milky Way galaxy consist mostly of highly energetic protons with a small component of HZE ions.

Prominent HZE ions:

• Carbon (C)
• Oxygen (O)
• Magnesium (Mg)
• Silicon (Si)
• Iron (Fe)

GCR energy spectra peaks (with median energy peaks up to 1,000 MeV/amu) and nuclei (energies up to 10,000 MeV/amu) are important contributors to the dose equivalent.

Uncertainties in cancer projections

One of the main roadblocks to interplanetary travel is the risk of cancer caused by radiation exposure. The largest contributors to this roadblock are: (1) The large uncertainties associated with cancer risk estimates, (2) The unavailability of simple and effective countermeasures and (3) The inability to determine the effectiveness of countermeasures. Operational parameters that need to be optimized to help mitigate these risks include:

• length of space missions
• crew age
• crew sex
• shielding
• biological countermeasures

Major uncertainties

• effects on biological damage related to differences between space radiation and x-rays
• dependence of risk on dose-rates in space related to the biology of DNA repair, cell regulation and tissue responses
• predicting solar particle events (SPEs)
• extrapolation from experimental data to humans and between human populations
• individual radiation sensitivity factors (genetic, epigenetic, dietary or "healthy worker" effects)

Minor uncertainties

• data on galactic cosmic ray environments
• physics of shielding assessments related to transmission properties of radiation through materials and tissue
• microgravity effects on biological responses to radiation
• errors in human data (statistical, dosimetry or recording inaccuracies)

Quantitative methods have been developed to propagate uncertainties that contribute to cancer risk estimates. The contribution of microgravity effects on space radiation has not yet been estimated, but it is expected to be small. The effects of changes in oxygen levels or in immune dysfunction on cancer risks are largely unknown and are of great concern during space flight.

Types of cancer caused by radiation exposure

Studies are being conducted on populations accidentally exposed to radiation (such as Chernobyl, production sites, and Hiroshima and Nagasaki). These studies show strong evidence for cancer morbidity as well as mortality risks at more than 12 tissue sites. The largest risks for adults who have been studied include several types of leukemia, including myeloid leukemia and acute lymphatic lymphoma as well as tumors of the lung, breast, stomach, colon, bladder and liver. Inter-sex variations are very likely due to the differences in the natural incidence of cancer in males and females. Another variable is the additional risk for cancer of the breast, ovaries and lungs in females. There is also evidence of a declining risk of cancer caused by radiation with increasing age, but the magnitude of this reduction above the age of 30 is uncertain.

It is unknown whether high-LET radiation could cause the same types of tumors as low-LET radiation, but differences should be expected.

The ratio of a dose of high-LET radiation to a dose of x-rays or gamma rays that produce the same biological effect are called relative biological effectiveness (RBE) factors. The types of tumors in humans who are exposed to space radiation will be different from those who are exposed to low-LET radiation. This is evidenced by a study that observed mice with neutrons and have RBEs that vary with the tissue type and strain.

Measured rate of cancer among astronauts

The measured change rate of cancer is restricted by limited statistics. A study published in Scientific Reports looked over 301 U.S. astronauts and 117 Soviet and Russian cosmonauts, and found no measurable increase in cancer mortality compared to the general population, as reported by LiveScience.

An earlier 1998 study came to similar conclusions, with no statistically significant increase in cancer among astronauts compared to the reference group.

Approaches for setting acceptable risk levels

The various approaches to setting acceptable levels of radiation risk are summarized below:

Comparison of radiation doses - includes the amount detected on the trip from Earth to Mars by the RAD on the MSL (2011 - 2013).

• Unlimited Radiation Risk - NASA management, the families of loved ones of astronauts, and taxpayers would find this approach unacceptable.
• Comparison to Occupational Fatalities in Less-safe Industries - The life-loss from attributable radiation cancer death is less than that from most other occupational deaths. At this time, this comparison would also be very restrictive on ISS operations because of continued improvements in ground-based occupational safety over the last 20 years.
• Comparison to Cancer Rates in General Population - The number of years of life-loss from radiation-induced cancer deaths can be significantly larger than from cancer deaths in the general population, which often occur late in life (> age 70 years) and with significantly less numbers of years of life-loss.
• Doubling Dose for 20 Years Following Exposure - Provides a roughly equivalent comparison based on life-loss from other occupational risks or background cancer fatalities during a worker's career, however, this approach negates the role of mortality effects later in life.
• Use of Ground-based Worker Limits - Provides a reference point equivalent to the standard that is set on Earth, and recognizes that astronauts face other risks. However, ground workers remain well below dose limits, and are largely exposed to low-LET radiation where the uncertainties of biological effects are much smaller than for space radiation.

NCRP Report No. 153 provides a more recent review of cancer and other radiation risks. This report also identifies and describes the information needed to make radiation protection recommendations beyond LEO, contains a comprehensive summary of the current body of evidence for radiation-induced health risks and also makes recommendations on areas requiring future experimentation.

Current permissible exposure limits

Career cancer risk limits

Astronauts' radiation exposure limit is not to exceed 3% of the risk of exposure-induced death (REID) from fatal cancer over their career. It is NASA's policy to ensure a 95% confidence level (CL) that this limit is not exceeded. These limits are applicable to all missions in low Earth orbit (LEO) as well as lunar missions that are less than 180 days in duration. In the United States, the legal occupational exposure limits for adult workers is set at an effective dose of 50 mSv annually.

Cancer risk to dose relationship

The relationship between radiation exposure and risk is both age- and sex-specific due to latency effects and differences in tissue types, sensitivities, and life spans between sexes. These relationships are estimated using the methods that are recommended by the NCRP  and more recent radiation epidemiology information 

The principle of As Low As Reasonably Achievable

The as low as reasonably achievable (ALARA) principle is a legal requirement intended to ensure astronaut safety. An important function of ALARA is to ensure that astronauts do not approach radiation limits and that such limits are not considered as "tolerance values." ALARA is especially important for space missions in view of the large uncertainties in cancer and other risk projection models. Mission programs and terrestrial occupational procedures resulting in radiation exposures to astronauts are required to find cost-effective approaches to implement ALARA.

Evaluating career limits

Organ (T)	Tissue weighting factor (wT)
Gonads	0.20
Bone Marrow (red)	0.12
Colon	0.12
Lung	0.12
Stomach	0.12
Bladder	0.05
Breast	0.05
Liver	0.05
Esophagus	0.05
Thyroid	0.05
Skin	0.01
Bone Surface	0.01
Remainder*	0.05
*Adrenals, brain, upper intestine, small intestine, kidney, muscle, pancreas, spleen, thymus and uterus.

The risk of cancer is calculated by using radiation dosimetry and physics methods.

For the purpose of determining radiation exposure limits at NASA, the probability of fatal cancer is calculated as shown below:

1. The body is divided into a set of sensitive tissues, and each tissue, T, is assigned a weight, w_T, according to its estimated contribution to cancer risk.
2. The absorbed dose, D_γ, that is delivered to each tissue is determined from measured dosimetry. For the purpose of estimating radiation risk to an organ, the quantity characterizing the ionization density is the LET (keV/μm).
3. For a given interval of LET, between L and ΔL, the dose-equivalent risk (in units of sievert) to a tissue, T, H_γ(L) is calculated as
   ${\displaystyle H_{\gamma }(L)=Q(L)D_{\gamma }(L)}$
   where the quality factor, Q(L), is obtained according to the International Commission on Radiological Protection (ICRP).
4. The average risk to a tissue, T, due to all types of radiation contributing to the dose is given by
   ${\displaystyle H_{\gamma }=\int D_{\gamma }(L)Q(L)dL}$
   or, since ${\displaystyle D_{\gamma }(L)=LF_{\gamma }(L)}$, where F_γ(L) is the fluence of particles with LET=L, traversing the organ,
   ${\displaystyle H_{\gamma }=\int dLQ(L)F_{\gamma }(L)L}$
5. The effective dose is used as a summation over radiation type and tissue using the tissue weighting factors, w_γ
   ${\displaystyle E=\sum _{\gamma }w_{\gamma }H_{\gamma }}$
6. For a mission of duration t, the effective dose will be a function of time, E(t), and the effective dose for mission i will be
   ${\displaystyle E_{i}=\int E(t)dt}$
7. The effective dose is used to scale the mortality rate for radiation-induced death from the Japanese survivor data, applying the average of the multiplicative and additive transfer models for solid cancers and the additive transfer model for leukemia by applying life-table methodologies that are based on U.S. population data for background cancer and all causes of death mortality rates. A dose-dose rate effectiveness factor (DDREF) of 2 is assumed.

Evaluating cumulative radiation risks

The cumulative cancer fatality risk (%REID) to an astronaut for occupational radiation exposures, N, is found by applying life-table methodologies that can be approximated at small values of %REID by summing over the tissue-weighted effective dose, E_i, as

${\displaystyle Risk=\sum _{i=1}^{N}E_{i}R_{0}(age_{i},sex)}$

where R₀ are the age- and sex- specific radiation mortality rates per unit dose.

For organ dose calculations, NASA uses the model of Billings et al. to represent the self-shielding of the human body in a water-equivalent mass approximation. Consideration of the orientation of the human body relative to vehicle shielding should be made if it is known, especially for SPEs 

Confidence levels for career cancer risks are evaluated using methods that are specified by the NPRC in Report No. 126. These levels were modified to account for the uncertainty in quality factors and space dosimetry.

The uncertainties that were considered in evaluating the 95% confidence levels are the uncertainties in:

• Human epidemiology data, including uncertainties in
  • statistics limitations of epidemiology data
  • dosimetry of exposed cohorts
  • bias, including misclassification of cancer deaths, and
  • the transfer of risk across populations.
• The DDREF factor that is used to scale acute radiation exposure data to low-dose and dose-rate radiation exposures.
• The radiation quality factor (Q) as a function of LET.
• Space dosimetry

The so-called "unknown uncertainties" from the NCRP report No. 126 are ignored by NASA.

Models of cancer risks and uncertainties

Life-table methodology

The double-detriment life-table approach is what is recommended by the NPRC to measure radiation cancer mortality risks. The age-specific mortality of a population is followed over its entire life span with competing risks from radiation and all other causes of death described.

For a homogenous population receiving an effective dose E at age a_E, the probability of dying in the age-interval from a to a+1 is described by the background mortality-rate for all causes of death, M(a), and the radiation cancer mortality rate, m(E,a_E,a), as:

${\displaystyle q(E,a_{E},a)={\frac {M(a)+m(E,a_{E},a)}{1+{\frac {1}{2}}\left[M(a)+m(E,a_{E},a)\right]}}}$

The survival probability to age, a, following an exposure, E at age a_E, is:

${\displaystyle S(E,a_{E},a)=\prod _{u=a_{E}}^{a-1}\left[1-q(E,a_{E},u)\right]}$

The excessive lifetime risk (ELR - the increased probability that an exposed individual will die from cancer) is defined by the difference in the conditional survival probabilities for the exposed and the unexposed groups as:

${\displaystyle ELR=\sum _{a=a_{E}}^{\infty }\left[M(a)+m(E,a_{E},a)\right]S(E,a_{E},a)-\sum _{a=a_{E}}^{\infty }M(a)S(0,a_{E},a)}$

A minimum latency-time of 10 years is often used for low-LET radiation. Alternative assumptions should be considered for high-LET radiation. The REID (the lifetime risk that an individual in the population will die from cancer caused by radiation exposure) is defined by:

${\displaystyle REID=\sum _{a=a_{E}}^{\infty }m(E,a_{E},a)S(E,a_{E},a)}$

Generally, the value of the REID exceeds the value of the ELR by 10-20%.

The average loss of life-expectancy, LLE, in the population is defined by:

${\displaystyle LLE=\sum _{a=a_{E}}^{\infty }S(0,a_{E},a)-\sum _{a=a_{E}}^{\infty }S(E,a_{E},a)}$

The loss of life-expectancy among exposure-induced-deaths (LLE-REID) is defined by:

${\displaystyle LLE-REID={\frac {LLE}{REID}}}$

Uncertainties in low-LET epidemiology data

The low-LET mortality rate per sievert, m_i is written

${\displaystyle m(E,a_{x},a)={\frac {m_{0}(E,a_{x},a)}{DDREF}}{\frac {x_{D}x_{s}x_{T}x_{B}}{x_{Dr}}}}$

where m₀ is the baseline mortality rate per sievert and x_α are quantiles (random variables) whose values are sampled from associated probability distribution functions (PDFs), P(X_a).

NCRP, in Report No. 126, defines the following subjective PDFs, P(X_a), for each factor that contributes to the acute low-LET risk projection:

1. P_dosimetry is the random and systematic errors in the estimation of the doses received by atomic-bomb blast survivors.
2. P_statistical is the distribution in uncertainty in the point estimate of the risk coefficient, r₀.
3. P_bias is any bias resulting for over- or under-reporting cancer deaths.
4. P_transfer is the uncertainty in the transfer of cancer risk following radiation exposure from the Japanese population to the U.S. population.
5. P_Dr is the uncertainty in the knowledge of the extrapolation of risks to low dose and dose-rates, which are embodied in the DDREF.

Risk in context of exploration mission operational scenarios

The accuracy of galactic cosmic ray environmental models, transport codes and nuclear interaction cross sections allow NASA to predict space environments and organ exposure that may be encountered on long-duration space missions. The lack of knowledge of the biological effects of radiation exposure raise major questions about risk prediction.

The cancer risk projection for space missions is found by

${\displaystyle m_{J}(E,a_{E},a)_{lJ}(E,a_{E},a)\int dL{\frac {dF}{dL}}LQ_{trial-J}(L)X_{L-J}}$

where ${\displaystyle {\frac {dF}{dL}}}$ represents the folding of predictions of tissue-weighted LET spectra behind spacecraft shielding with the radiation mortality rate to form a rate for trial J.

Alternatively, particle-specific energy spectra, F_j(E), for each ion, j, can be used

${\displaystyle m_{J}(E,a_{E},a)=m_{lJ}(E,a_{E},a)\sum _{j}(E)L(E)Q_{trial-J}(L(E))x_{L-J}}$.

The result of either of these equations is inserted into the expression for the REID.

Related probability distribution functions (PDFs) are grouped together into a combined probability distribution function, P_cmb(x). These PDFs are related to the risk coefficient of the normal form (dosimetry, bias and statistical uncertainties). After a sufficient number of trials have been completed (approximately 10⁵), the results for the REID estimated are binned and the median values and confidence intervals are found.

The chi-squared (χ²) test is used for determining whether two separate PDFs are significantly different (denoted p₁(R_i) and p₂(R_i), respectively). Each p(R_i) follows a Poisson distribution with variance ${\displaystyle {\sqrt {p(R_{i})}}}$.

The χ² test for n-degrees of freedom characterizing the dispersion between the two distributions is

${\displaystyle \chi ^{2}=\sum _{n}{\frac {\left[p_{1}(R_{n})-p_{2}(R_{n})\right]^{2}}{\sqrt {p_{1}^{2}(R_{n})+p_{2}^{2}(R_{n})}}}}$.

The probability, P(ņχ²), that the two distributions are the same is calculated once χ² is determined.

Radiation carcinogenesis mortality rates

Age-and sex-dependent mortality rare per unit dose, multiplied by the radiation quality factor and reduced by the DDREF is used for projecting lifetime cancer fatality risks. Acute gamma ray exposures are estimated. The additivity of effects of each component in a radiation field is also assumed.

Rates are approximated using data gathered from Japanese atomic bomb survivors. There are two different models that are considered when transferring risk from Japanese to U.S. populations.

• Multiplicative transfer model - assumes that radiation risks are proportional to spontaneous or background cancer risks.
• Additive transfer model - assumes that radiation risk acts independently of other cancer risks.

The NCRP recommends a mixture model to be used that contains fractional contributions from both methods.

The radiation mortality rate is defined as:

${\displaystyle m(E,a_{E},a)=\left[ERR(a_{E},a)M_{c}(a)+(1-v)EAR(a_{E},a)\right]{\frac {\sum _{L}Q(L)F(L)L}{DDREF}}}$

Where:

• ERR = excess relative risk per sievert
• EAR = excess additive risk per sievert
• M_c(a) = the sex- and age-specific cancer mortality rate in the U.S. population
• F = the tissue-weighted fluence
• L = the LET
• v = the fractional division between the assumption of the multiplicative and additive risk transfer models. For solid cancer, it is assumed that v=1/2 and for leukemia, it is assumed that v=0.

Biological and physical countermeasures

Identifying effective countermeasures that reduce the risk of biological damage is still a long-term goal for space researchers. These countermeasures are probably not needed for extended duration lunar missions, but will be needed for other long-duration missions to Mars and beyond. On 31 May 2013, NASA scientists reported that a possible human mission to Mars may involve a great radiation risk based on the amount of energetic particle radiation detected by the RAD on the Mars Science Laboratory while traveling from the Earth to Mars in 2011-2012.

There are three fundamental ways to reduce exposure to ionizing radiation:

• increasing the distance from the radiation source
• reducing the exposure time
• shielding (i.e.: a physical barrier)

Shielding is a plausible option, but due to current launch mass restrictions, it is prohibitively costly. Also, the current uncertainties in risk projection prevent the actual benefit of shielding from being determined. Strategies such as drugs and dietary supplements to reduce the effects of radiation, as well as the selection of crew members are being evaluated as viable options for reducing exposure to radiation and effects of irradiation. Shielding is an effective protective measure for solar particle events. As far as shielding from GCR, high-energy radiation is very penetrating and the effectiveness of radiation shielding depends on the atomic make-up of the material used.

Antioxidants are effectively used to prevent the damage caused by radiation injury and oxygen poisoning (the formation of reactive oxygen species), but since antioxidants work by rescuing cells from a particular form of cell death (apoptosis), they may not protect against damaged cells that can initiate tumor growth.

Evidence sub-pages

The evidence and updates to projection models for cancer risk from low-LET radiation are reviewed periodically by several bodies, which include the following organizations:

• The NAS Committee on the Biological Effects of Ionizing Radiation
• The United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR)
• The ICRP
• The NCRP

These committees release new reports about every 10 years on cancer risks that are applicable to low-LET radiation exposures. Overall, the estimates of cancer risks among the different reports of these panels will agree within a factor of two or less. There is continued controversy for doses that are below 5 mSv, however, and for low dose-rate radiation because of debate over the linear no-threshold hypothesis that is often used in statistical analysis of these data. The BEIR VII report, which is the most recent of the major reports is used in the following sub-pages. Evidence for low-LET cancer effects must be augmented by information on protons, neutrons, and HZE nuclei that is only available in experimental models. Such data have been reviewed by NASA several times in the past and by the NCRP.

• Epidemiology data for low linear energy transfer radiation
• Radiobiology evidence for protons and HZE nuclei