Radiation Therapy Personal Dosage and Linear AccelerationIntroduction:Medicine is evolving to combat various disease and conditions.  The second highest cause of death is cancer.  Cancer is defined as a growth of an abnormal cells that forms a tumor.  Cancer can form almost anywhere in the body such as the digestive systems, the blood vessels, the livers, lungs and even bones (Sloan 2007).  The good news is that cancer does not always kill the patient but left uncheck or untreated will yield dire results.  To minimize the risk from cancer early detection is key.  Once the cancer cells have been identified, there are various methods to terminate it.  One method is chemotherapy in which chemotherapy drugs are injected or ingested.  Chemotherapy is body wide so it is best used when the cancer is malignant or can be used side-by-side with radiation therapy (Baskar 2012).  Another method is surgery to remove the tumor.  Lastly radiation therapy is a procedure that uses ionization beams to kill localize tumors while sparing neighboring tissues (Baskar 2012).  Radiation therapy is typically used when the tumor is localized, but can be used when the tumor has spread.  Radiation therapy can be branch into two types of procedure as well.  The most common is using the external beam, where a radiation source is directed to the site of the cancer to eliminate it.  The second source is known as a brachytherapy, where a radiation source is placed inside the body as close to the tumor as possible with catheters or directly into the tumor (Baskar 2012), which is uncommon but is often used for pelvis treatment.  The common method of radiation therapy is externally via the Linear Accelerator also known as the “Linac”. Causes of cancer There are numerous causes for cancers in terms of occupational activity, food and drug, exposure to radiation, and genetics.  Consumption of food contaminated with fungi known as aflatoxins, which accumulate on grains and peanuts is known to cause cancer in Asia, Africa, and South America.  In the U.S. food contaminated with pesticide and industrial chemicals are known to be carcinogenic or can contain chemicals that become carcinogenic when cooked (Sloan 2007).  Drugs with hormonal actions or immunosuppressive can increase one’s likeliness to contract cancer (Sloan 2007).  Exposure to ionizing radiation has a long history of causing cancer.  Radon decay byproduct emits an alpha that can enter the lungs and cause serious damage through charged interaction.  Extended exposure to ultraviolet rays can yield consequential effect in low melanin skinned people.  Eighty percent of UV related cancer occurs in North America, New Zealand, Europe, and Australia (Sloan 2007).  Occupational exposure in many industries has present cases of cancers from chemicals and materials.  It was estimated that among 2.7 billion workers, 2 million workers died a year worldwide.  Genetic has shown to raises a person’s susceptibility to cancer due to the mutation in the genes.  For women with mutation in BRCA 1 gene, have a 70 percent chance of developing breast cancer within their lifetime (Sloan 2007). Cancer cell lifecycle The first stage of a cancer cell is the mutation of a cell where the cell is undergoing changes in its genetic coding.  The changes can be minor or major, but nonetheless it will cause the cell to function irregularly.  Heavy combination of mutations in important genes can lead to development of cancer.  When the mutated cells divide, it’s daughter cells will inherit its mutation or acquire different mutations and behaviors overtime.  The daughters can become resistant to death and division which will pass down to future daughter cells.  These cells will appear like normal cells but will localize in the region of the tissue known as hyperplasia (CancerQuest).  More genetic changes will occur inside the hyperplastic cells and it will grow abnormally and will become disorganize with the tissue, no longer resembling what it looks like before.  The abnormal growth will continue; however, it is still isolated inside the region of the specific tissues.  Some cells have devolved to no longer serve their original function.  These cells are known as “carcinoma in situ” and since they are located in one area, they are able to be removed with surgery before invading other tissues (CancerQuest).  The last stage is the Malignant tumors, in which the tumor will intrude into neighboring tissues, where death is highly likely to happen.  Not all tumor in this stage will be intrusive, those are benign and can obstruct or apply pressure to the organ, causing significant issues (CancerQuest). Radiation Therapy Radiation therapy is the process of using high-energy particles or waves to destroy or damage cancer cells.  How radiation therapy achieves this is by attacking the DNA of the cancer cells and damaging the DNA preventing the cells from dividing any further and causing them to die.  Unlike chemotherapy, where the entire body is expose to the chemical, radiation therapy targets localize area of the cancer cells.  Proper usage of radiation therapy will result in killing the cancer while posing little to no harm to neighboring cells.  Other forms of radiation therapy include injection or ingestion of radioisotopes.  These radioactive materials will flow in the stream and be ingested by the cancer cell, thus having similar effect as using radiation therapy.  In many cases with certain cancer patient, radiation therapy is only solution. Linac Machine Components The linear accelerator (Linac) is a device used to create a customizable high energy x-rays or electrons to adapt to the shape of the tumor and kill it, while minimizing damages to surrounding tissues.  It is designed to ensure proper dosage of to the patient.   KlystronStarting at the RF power generator are comprised of two components that can be used, either the magnetron or klystron. No microwave is generated in the Klystron, instead existing microwave is amplified.  The klystron operates like a radio frequency amplifier.  High voltage DC beam is produced and low power radio frequency is used to excite the input cavity of the klystron.  Electrons are accelerated or decelerated in the input cavity by the electric field generated by the microwave.  This will result in clumps of electrons traveling to the cavity, that induce a charge that.  The electrons will then decelerate, thus the kinetic energy is converted to high power microwave.  The beams gather and excite the output cavity.  Then the spent beam is stopped once the process is completed (Ashikin 2017). MagnetronThe magnetron contains an electron tube that provides microwave power for the acceleration of the electrons.  This is normally used for low level application (4MeV-6MeV).  The central cathode serves as a filament, a magnetic field is applied and cause the electrons to spiral outward.  As the electrons pass the cavity it will induce a resonant RF field in the cavity through the oscillation of charges.  The RF field can then be extracted with an antenna attach to one of the spokes.  The magnetron starts with electrons from the filament travelling radially to the outside ring.  The magnetic field applied would then reflect the electrons to cause a sweeping motion around in a circle.  This will pump the natural resonant frequency of the cavities.  The current around the cavity cause the electrons to radiate electromagnetic energy at that natural resonant frequency (Ashikin 2017). Electron GunThe gantry is a component that helps direct the X-ray or electron beam to the patient tumor.  The gantry consists of three main components: electron gun, buncher (accelerator), and treatment head.  The electron gun contains a cathode that is negatively charged, that comes from heating the cathode.  The cathode is made with Barium Aluminum and when heated the electrons will break free from their atoms.  The gate contains a copper screen grid and serves as an anode.  The anode is surfaced with a positive charge, where every 500 millionth of a second, the gate is more positively charged to accelerate the electrons from the cathode towards it.  As the electrons reach the gate, it will further be attracted to the anode, assisting it in passing through the gate.  Due to the 500 millionth of a second pulse, the electrons will flow through the anodes in short burst vice a steady stream.  As shown the anode is a donut shape to created a magnetic field to guide the electrons through it into the buncher (Linac).  BuncherThe purpose of the buncher is to use microwave amplified by the klystron to accelerate the electron in packets.  The way the electrons are accelerated is based on the motion of the sinusoidal wave of the microwave.  As the voltage of the microwave is moving towards it crest, the electron will accelerate great and as it moves down the wavelength the acceleration is less but not negative (does not slow down).  Once the electrons pass through the buncher it will make it way towards the rest of the system (Linac). Treatment Head The treatment head is used to shape and monitor the treatment beam.  The treatment head is comprised of various components:  The bending magnet, x-ray target, primary collimator, beam flattening filter, and scattering foil.  The bending magnet is used to change the direction of the electron beam to point it toward the patient.  It bends the electron in a curved path to allow for proper steering of the electrons.  It can either bend it towards the target if using x-ray or towards the scattering foil for electron treatments (Ashikin 2017). The x-ray target is used to concentrate the collisions of electrons to target the tumor.  Most of the energy from beam is loss to heat (approximately 94%).  The primary collimator uses its upper and lower jaw to collimate the beam (Ashikin 2017).  These jaws are comprised of heavy metal such as tungsten or lead and can direct a rectangular shape beam up to 40×40 cm of x-ray beam.  Collimators also come in form of independent moving mechanism to allow flexibility to minimize or prevent damages to normal tissue while delivering the dosage directly to the tumor (multi-leaf collimator). The beam flattening filter is a cone shape piece comprised of metal typically steel, lead, or copper, that filters the non-uniformed beam through primary collimator into a safer beam.  Positioning of these beams must be precise to minimize hot or cold spots or areas with too much or too little exposure.  The flattening filter also ensure that the beam’s intensity is uniform from one edge to another (+/- 6%) and that it is symmetrical from one side to the other (+/- 4%).  The scattering foil is a thin dual lead sheet that scatters the electrons thus widening the beam.  Between both the scattering foil and the flattening filters is two ionization chamber that is used for dose monitor for the safety of the patient (Ashikin 2017). Beam ModificationOnce the beam has passed through the collimators, there are many different modifications that can be utilize to ensure proper dosage and treatment for the patient.  This is the method of beam modification in which the beam is alter.  There are four methods of modification that can used before the beam come in contact with the patient:  Shielding, compensation, wedge filtration, and flattening (Ashikin 2017).  The shielding method is used to protect a specific part of the body where the radiation is interacting.  This method uses the multi-leaf collimator which are composed of a blocks and leaves that are independent from one another to form any shape (Ashikin 2017).  The compensation method utilizes a compensator, which is a device that even outs the contour by adjusting the intensity throughout the wave to ensure no hot or cold spots.  This method allows for depth dose data for irregular skin surfaces.  Another method of compensation is the use of a spoiler.  This follows the principle that the closer to the tray the higher the dosage, thus altering the angles to ensure even distribution or to direct more towards an area and less to another (Ashikin 2017).  The wedge filtration uses angled wedges to alter the wave form of the photon as it leaves.  It is to compensate the differences in thicknesses of the parts being exposed by adjusting the wave shape (Ashikin 2017). Lastly flattening is the wave modification that lowers the peak of the wave in comparison to its edge (flattening the wave) to ensure that the waves are uniform when it interact with the patient (Ashikin 2017). Risk of secondary cancer: One of the known risks with radiation therapy is the chance of another onset of cancer.  As mentioned before ionizing radiation has yield a chance of causing cancer due to the damage it does to the DNA of the cell.  For radiation therapy, the ionizing radiation from the linear accelerator is no different and precaution is to be taken.  Many different variable attributes to secondary cancer risk:  Age of patient at time of the treatment, genetic risk factor, organs that received the treatment, and dosage and volume of tissue irradiated (Ng 2015). There are evidences to show that younger patient has a higher risk of developing a second cancer following radiation therapy.  Studies used where from the lifespan of Atomic Survivor and Childhood cancer survivor.  The Atomic survivor group shows that the risk decreases by 17% every decade, while the childhood cancer survivor group shows that 7.9% of children developed them after 30 years (Ng 2015).  Studies were performed on individuals with Hodgkin’s lymphoma that were treated with radiation therapy.  The study shows a lapse of neoplasm of 7% within 15 years after diagnosis of the Hodgkin’s with breast cancer being the most common.  From major studies it was conclude that patients during their teenage or young adult years have a higher chance of a secondary cancer, but once they reach 30, the risk is very small and not rising (Ng 2015).Genetic is a significant factor in secondary cancer risk (Ng 2015).  But there are ways to identify genetic marks that are associated with high secondary cancer risk.  One of the main genetic marks are single-nucleotide polymorphism or genes that associate with radiation response pathway.  Following the genetic markers will help identify possible issues in the future (Ng 2015).  Studies were done on female breast cancer survivor with either radiation exposure and genetic disposition.  They paid particular attention to women with the ATM, BRCA1/BRCA2 mutation in their genome with respect to radiation exposure, genetic roles in radiation response pathways and genome instabilities and their risk to secondary cancer.  The study concluded that there is no risk of a second cancer for women who carries BRCA1/BRCA2 mutation, but women who carries the ATM mutation are at risk for a second cancer following therapy (Ng 2015)              . The next factor that determine the risk of a second cancer is the tissues that has been radiated.  Using data from the survivor of the Hodgkin’s lymphoma who received the radiation therapy, it was determine that risk of cancer in other areas are lower.  The Institute Curie group studied over 13,000 patients who receive breast radiotherapy and found a small increase risk of sarcomas and lung cancers, but no other form of cancers (Ng 2015).  Another study was done on patient who receive treatment for prostate cancer and it yield an increase in risk of tumors in the bladder and rectum.  This present evidence that there are other tissues that are not accounted for during treatment that is receiving unnecessary radiation.  This also shows that the beam is going through certain tissues and interacting with tissues behind the intended area.   These provided guidance on what risk are associated with radiotherapy in terms of what other form of cancer can occur based on the location of the treatment (Ng 2015). With the growth of radiation therapy technology, intensity modulated radiation therapy (IMRT) has become more utilized.  This method is concentrating the dose to a specific area, while minimizing dosage to surrounding tissue.  While the IMRT method delivers a great deal, it still provides a small amount of dose to surrounding tissues (Ng 2015).  There are also issues with background leakages from IMRT compared to other forms that expose various parts to minor doses.  Though the radiotherapy has evolved beyond IMRT, the debate of other methods contributing to secondary cancer risk is still unknown (Ng 2015).  Many issues with regards to the technology is determining if it is technology and not the other three issues mention.  Many different models were used to determine the short term and long-term conditions, but does not eliminate issues such as age and genetics (Ng 2015). Personal dose monitoring:The biggest challenge faced in radiation therapy is the emergence of secondary cancer.  As described before, there are many risks involved that can bring about secondary cancers.  One of the major ways to minimize this issue is through personalize dosage.  Personalize dosage is the tracking the dosage of the individual patients to ensure that the proper amount of dosage is applied.  Though the process seems simple there any factors that plays into personal dosage monitoring. With regards to personal dosage one important factor is determining what is a safe dosage.  Numerous studies and models are used to determine the toxicity versus efficacy of radiation therapy based on the location and stages of the initial cancer cells.  This is important as not all patient are equally sensitives to radiation.  There are two ways of comparing toxicity and efficacy.  One is based on the model of toxicity as a function of scalar vector of marker values (M) with dosage to normal tissues (d) based on the equation: ?Ti = p* = f?1(di, Mi, ?) with p* being the probably of toxicity (Schipper 2014).    This method treats every patient as the same estimated probably and ignore efficacy as if there are no markers for toxicity on the patient.  The second method utilizes toxicity and efficacy outcome with the utility function of the selected dosage using the equation: U(di, ri, Mi, Gi) = P(Ei = 1|Di = ri*di, Gi)??*P(Ti = 1|di, Mi) where U is the utility factor, P* is the probability of toxicity and ? is used to tune the parameters for additional covariable such as smoking status and baseline lung function (Schipper 2014).  Biomarkers are used in determining dosage for patient.  Biomarkers are characteristics such as biological, genetics, or clinical that are used to determine a patient’s health.  These approaches typically are based on genetic mutation, translocation, or amplification (Ree 2015).  With advancement in technology, there are development of high-throughput omics technologies that uses genomics, proteomics, metabolomics, and kinomics, that are able to produce molecular signature of tumor tissues, serums, plasma, and other bodily fluid (Ree 2015).  With this method, detection of tumor is on a patient by patient basis vice just a broad detection.  Another method used is to determine the DNA damage repair mechanism in normal tissues.  Observation of a single nuclide polymorphism have been used as a biomarker of susceptibility for unwanted radiation effect.  Studies were performed on patient with prostate cancer that identified TANC1 as the susceptibility locus for late radiation-induced damage (Ree 2015).  A simulation was running with two separate group:  One group received higher dosage with regard to biomarkers, while another group receive lower dosage without biomarkers.  The result yielded that the lowest 1/3 had significantly worse local progression free survival and no dose effect compared to those with higher dosage.  Local progression free survival (LPFS) is the measurement of efficacy, that is the minimum time to either local progression of the treated tumor or death (Schipper 2014).  Further simulation provided evidence that patient with high LPFS would improve the most, but would yield a higher toxicity, while those with low efficacy but high toxicity is given lower doses (Schipper 2014).   With the utilization of modeling toxicity and efficacy and using biomarkers, a tool is that can be consider is the person organ dose archive (PODA).  Which is a system used to track patient exposure in great details (Research feature 2018).  The concept is to generate an organ-specific and time-realized map of the doses receive from the radiation therapy.  The information is compiled and merged that can be distributed to other institution and medical record database.  The information is well kept and archive in across all the other institution while preventing the loss of the vital record over the patient’s lifetime.  The system accurately accumulated all the personal organ dosage data for a period of time.  This process uses the Monte Carlo dose calculation, accelerated by GPU and parallel computing.  This method is designed to follow the electron particles from generation to the patient to accurately calculate the doses received (Research feature 2018).  This type of data pooling draws proper conclusion based on statistical inevitabilities.  This pooling of data will be electronically store and accessible to clinicians to make informed decision in the future.  This will benefit patient undergoing other procedures such as PET scan, CT scan, and fluoroscopy, which has a small risk of tissue damage and carcinogenesis.  This is important especially for children who can develop leukemia or other forms of cancer from image scans.  By retaining these data which logs all the exposure of each patient, it will ensure that future procedures are done with regards to accurate dosage data (Research feature 2018).    Design concept: The biggest concern with using the linear accelerator is the unaccounted dosages the patient is expose to along with the possibility of a secondary cancer from any amount of dosages.  As mention before there are many procedures that takes in consideration of the toxicity based on specific organs along with calculation using biomarkers to make a more informed decision.  Using the procedure in tandem with the PODA, will ensure that the patient will never exceed the decided threshold put into place based on the modeling of toxicity for a particular organ.  One of the design concepts that can be used to further improve this process is integrating the PODA into the linear accelerator itself.  The PODA on its own will provide the information of dosage history to the oncologist reviewing the data, but that can leave room for error with the operator at the linear accelerator.   One issue was in Poland wen the linear accelerator loss power, thus when power is returned the machine was check and shortly restored.  Moments later the patients complain of itching and the operation was stopped.  Investigation revealed that the machine output was higher than expected and the safety feature was damage.  This resulted in five patient developing local radiation injuries of various degrees (IAEA 2004).  Since then there has been many system put into place such as  an auto shutdown and regular maintenance on the electronic feature of the linac (IAEA 2004). By integrating in the PODA into the linear accelerator, the machine will only operate once the correct patient is selected and verified in the linac itself.  When the patient is selected the machine will only allow a maximum number of doses based on the updated information in the database that is distributed like how the PODA was mention.  With this the procedure can be changed to incorporate the patients’ awareness of the operation to ensure that the patient knows that their information is correct and that they are receiving proper treatment.  The linear accelerator will also have an alarm that will signal to the operator before the required dose is reach to provide a back-up for the safety of the patient. Conclusion The linear accelerator is a complex machine that is used to treat localize tumors.  The linear accelerator uses ionizing radiation to effectively kill the tumor and minimize damages to surrounding tissue based on its design.  Though the linear accelerator is a safe system, it does contain risk that can be impactful.  With the risk of a secondary cancer emerging from the exposure to ionizing radiation, many precautions are needed to be taken.  Modeling and simulation have been used to compare the toxicity versus the efficacy to ensure that patient who receives treatment have many factors considered vice just providing a standardize dose to every patient.  One consideration is using biomarker to ensure that certain sign of cancer can be recognized for early detection of secondary cancer along with proper procedure can be determined.  With regards to personal dosage, tracking and recording of doses of individual patient is keyed to ensuring that current and future procedure are perform safely.  The use of PODA create a structure that can eradicate cancer while minimizing the chances of secondary cancer.ReferencesAshikin, N. (2017). LINEAR ACCELERATOR. [online] Slide share. Available at: https://www.slideshare.net/InochiAshFull/linear-accelerator-73458214/61 [Accessed 20 Nov. 2018].Baskar, R., Lee, K., Yeo, R. and Yeoh, K. (2012). Cancer and Radiation Therapy: Current Advances and Future Directions. [online] National Center for Biotechnology Information. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3298009/ [Accessed 20 Nov. 2018].CancerQuest. (n.d.). Cancer Development. [online] Available at: https://www.cancerquest.org/cancer-biology/cancer-development [Accessed 20 Nov. 2018].IAEA. (2004). Accidental Overexposure of Radiotherapy Patients in Bia?ystok. [online] Available at: https://www-pub.iaea.org/MTCD/publications/PDF/Pub1180_web.pdf [Accessed 20 Nov. 2018].Anon, (n.d.). Linac. [online] Available at: http://www2.lbl.gov/MicroWorlds/ALSTool/ALS_Components/Linac/ [Accessed 20 Nov. 2018].Ng, J. and Shuryak, I. (2015). Minimizing second cancer risk following radiotherapy: current perspectives. [online] National Center for Biotechnology Information. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4274043/ [Accessed 20 Nov. 2018].Radiationtherapy.tk. (n.d.). Block Diagram of the Linear Accelerator. [online] Available at: http://radiationtherapy.0fees.net/radiationsemester3/ahs134lecture8.htm?i=1 [Accessed 20 Nov. 2018].Ree, A. and Redalen, K. (2015). Personalized radiotherapy: concepts, biomarkers and trial design. [online] National Center for Biotechnology Information. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4628523/ [Accessed 20 Nov. 2018].Research Features. (2018). Personalised tracking of radiation doses is becoming a reality. [online] Available at: https://researchfeatures.com/2018/04/05/personalised-tracking-radiation-doses/ [Accessed 20 Nov. 2018].Schipper, M., Taylor, J., TenHaken, R., Matuzak, M., Kong, F. and Lawrence, T. (2014). Personalized dose selection in radiation therapy using statistical models for toxicity and efficacy with dose and biomarkers as covariates. [online] National Center for Biotechnology Information. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367186/ [Accessed 20 Nov. 2018].Sloan, F. and Gelband, H. (2007). Cancer Causes and Risk Factors and the Elements of Cancer Control. [online] National Center for Biotechnology Information. Available at: https://www.ncbi.nlm.nih.gov/books/NBK54025/ [Accessed 20 Nov. 2018].