Editing Radiation therapy (section)

==Technique==

===Mechanism of action===
Radiation therapy works by damaging the [[DNA]] of [[cancer cell]]s and can cause them to undergo [[mitotic catastrophe]].<ref>{{cite journal | vauthors = Vitale I, Galluzzi L, Castedo M, Kroemer G | title = Mitotic catastrophe: a mechanism for avoiding genomic instability | journal = Nature Reviews. Molecular Cell Biology | volume = 12 | issue = 6 | pages = 385–392 | date = June 2011 | pmid = 21527953 | doi = 10.1038/nrm3115 | s2cid = 22483746 }}</ref> This DNA damage is caused by one of two types of energy, [[photon]] or [[charged particle]]. This damage is either direct or indirect [[ionization]] of the atoms which make up the DNA chain. Indirect ionization happens as a result of the ionization of water, forming [[Radical (chemistry)|free radicals]], notably [[hydroxyl]] radicals, which then damage the DNA.

In photon therapy, most of the radiation effect is through free radicals. Cells have mechanisms for repairing single-strand DNA damage and [[double-stranded DNA]] damage. However, double-stranded DNA breaks are much more difficult to repair, and can lead to dramatic chromosomal abnormalities and genetic deletions. Targeting double-stranded breaks increases the probability that cells will undergo [[Apoptosis|cell death]]. Cancer cells are generally less [[cellular differentiation|differentiated]] and more [[stem cell]]-like; they reproduce more than most healthy differentiated cells, and have a diminished ability to repair sub-lethal damage. Single-strand DNA damage is then passed on through cell division; damage to the cancer cells' DNA accumulates, causing them to die or reproduce more slowly.

One of the major limitations of photon radiation therapy is that the cells of solid tumors become deficient in [[oxygen]]. Solid tumors can outgrow their blood supply, causing a low-oxygen state known as [[Hypoxia (medical)|hypoxia]]. Oxygen is a potent [[radiosensitizer]], increasing the effectiveness of a given dose of radiation by forming DNA-damaging free radicals. Tumor cells in a hypoxic environment may be as much as 2 to 3 times more resistant to radiation damage than those in a normal oxygen environment.<ref>{{cite journal | vauthors = Harrison LB, Chadha M, Hill RJ, Hu K, Shasha D | title = Impact of tumor hypoxia and anemia on radiation therapy outcomes | journal = The Oncologist | volume = 7 | issue = 6 | pages = 492–508 | year = 2002 | pmid = 12490737 | doi = 10.1634/theoncologist.7-6-492 | s2cid = 46682896 | doi-access = free }}</ref> Much research has been devoted to overcoming hypoxia including the use of high pressure oxygen tanks, [[hyperthermia therapy]] (heat therapy which dilates blood vessels to the tumor site), blood substitutes that carry increased oxygen, hypoxic cell radiosensitizer drugs such as [[misonidazole]] and [[metronidazole]], and hypoxic [[cytotoxins]] (tissue poisons), such as [[tirapazamine]].  Newer research approaches are currently being studied, including preclinical and clinical investigations into the use of an [[oxygen diffusion-enhancing compound]] such as [[trans sodium crocetinate]] as a radiosensitizer.<ref>{{cite journal | vauthors = Sheehan JP, Shaffrey ME, Gupta B, Larner J, Rich JN, Park DM | title = Improving the radiosensitivity of radioresistant and hypoxic glioblastoma | journal = Future Oncology | volume = 6 | issue = 10 | pages = 1591–1601 | date = October 2010 | pmid = 21062158 | doi = 10.2217/fon.10.123 }}</ref>

Charged particles such as [[proton]]s and [[boron]], [[carbon]], and [[neon]] ions can cause direct damage to cancer cell DNA through high-LET ([[linear energy transfer]]) and have an antitumor effect independent of tumor oxygen supply because these particles act mostly via direct energy transfer usually causing double-stranded DNA breaks. Due to their relatively large mass, protons and other charged particles have little lateral side scatter in the tissue – the beam does not broaden much, stays focused on the tumor shape, and delivers small dose side-effects to surrounding tissue. They also more precisely target the tumor using the [[Bragg peak]] effect. See [[proton therapy]] for a good example of the different effects of intensity-modulated radiation therapy (IMRT) vs. [[charged particle therapy]]. This procedure reduces damage to healthy tissue between the charged particle radiation source and the tumor and sets a finite range for tissue damage after the tumor has been reached. In contrast, IMRT's use of uncharged particles causes its energy to damage healthy cells when it exits the body. This exiting damage is not therapeutic, can increase treatment side effects, and increases the probability of secondary cancer induction.<ref>Curtis RE, Freedman DM, Ron E, Ries LAG, Hacker DG, Edwards BK, Tucker MA, Fraumeni JF Jr. (eds). New Malignancies Among Cancer Survivors: SEER Cancer Registries, 1973–2000. National Cancer Institute. NIH Publ. No. 05-5302. Bethesda, MD, 2006.</ref> This difference is very important in cases where the close proximity of other organs makes any stray ionization very damaging (example: [[head and neck cancers]]). This X-ray exposure is especially bad for children, due to their growing bodies, and while depending on a multitude of factors, they are around 10 times more sensitive to developing secondary malignancies after radiotherapy as compared to adults.<ref>{{cite journal | vauthors = Dracham CB, Shankar A, Madan R | title = Radiation induced secondary malignancies: a review article | journal = Radiation Oncology Journal | volume = 36 | issue = 2 | pages = 85–94 | date = June 2018 | pmid = 29983028 | pmc = 6074073 | doi = 10.3857/roj.2018.00290 }}</ref>

===Dose===
The amount of radiation used in photon radiation therapy is measured in [[Gray (unit)|grays]] (Gy), and varies depending on the type and stage of cancer being treated. For curative cases, the typical dose for a solid epithelial tumor ranges from 60 to 80&nbsp;Gy, while lymphomas are treated with 20 to 40&nbsp;Gy.

Preventive (adjuvant) doses are typically around 45–60&nbsp;Gy in 1.8–2&nbsp;Gy fractions (for breast, head, and neck cancers.) Many other factors are considered by [[radiation oncologist]]s when selecting a dose, including whether the patient is receiving chemotherapy, patient comorbidities, whether radiation therapy is being administered before or after surgery, and the degree of success of surgery.

Delivery parameters of a prescribed dose are determined during [[treatment planning]] (part of [[dosimetry]]). Treatment planning is generally performed on dedicated computers using specialized treatment planning software. Depending on the radiation delivery method, several angles or sources may be used to sum to the total necessary dose. The planner will try to design a plan that delivers a uniform prescription dose to the tumor and minimizes dose to surrounding healthy tissues.

In radiation therapy, three-dimensional dose distributions may be evaluated using the [[dosimetry]] technique known as [[gel dosimetry]].<ref>{{cite journal | vauthors = Baldock C, De Deene Y, Doran S, Ibbott G, Jirasek A, Lepage M, McAuley KB, Oldham M, Schreiner LJ | display-authors = 6 | title = Polymer gel dosimetry | journal = Physics in Medicine and Biology | volume = 55 | issue = 5 | pages = R1-63 | date = March 2010 | pmid = 20150687 | pmc = 3031873 | doi = 10.1088/0031-9155/55/5/r01 | bibcode = 2010PMB....55R...1B }}</ref>

====Fractionation====
{{hatnote|This section only applies to photon radiotherapy although other types of radiation therapy may be fractionated}}
{{Main|Dose fractionation}}
The total dose is fractionated (spread out over time) for several important reasons. Fractionation allows normal cells time to recover, while tumor cells are generally less efficient in repair between fractions. Fractionation also allows tumor cells that were in a relatively radio-resistant phase of the cell cycle during one treatment to cycle into a sensitive phase of the cycle before the next fraction is given. Similarly, tumor cells that were chronically or acutely hypoxic (and therefore more radioresistant) may reoxygenate between fractions, improving the tumor cell kill.<ref>{{cite journal | vauthors = Ang KK | title = Altered fractionation trials in head and neck cancer | journal = Seminars in Radiation Oncology | volume = 8 | issue = 4 | pages = 230–236 | date = October 1998 | pmid = 9873100 | doi = 10.1016/S1053-4296(98)80020-9 }}</ref>

Fractionation regimens are individualised between different radiation therapy centers and even between individual doctors. In North America, Australia, and Europe, the typical fractionation schedule for adults is 1.8 to 2&nbsp;Gy per day, five days a week. In some cancer types, prolongation of the fraction schedule over too long can allow for the tumor to begin repopulating, and for these tumor types, including head-and-neck and cervical squamous cell cancers, radiation treatment is preferably completed within a certain amount of time. For children, a typical fraction size may be 1.5 to 1.8&nbsp;Gy per day, as smaller fraction sizes are associated with reduced incidence and severity of late-onset side effects in normal tissues.

In some cases, two fractions per day are used near the end of a course of treatment. This schedule, known as a concomitant boost regimen or hyperfractionation, is used on tumors that regenerate more quickly when they are smaller. In particular, tumors in the head-and-neck demonstrate this behavior.

Patients receiving [[palliative radiation]] to treat uncomplicated painful bone metastasis should not receive more than a single fraction of radiation.<ref name="AAHPMfive">{{Citation |author1 = American Academy of Hospice and Palliative Medicine |author1-link =  American Academy of Hospice and Palliative Medicine |title = Five Things Physicians and Patients Should Question |publisher = [[American Academy of Hospice and Palliative Medicine]] |work = [[Choosing Wisely]]: an initiative of the [[ABIM Foundation]] |url = http://www.choosingwisely.org/doctor-patient-lists/american-academy-of-hospice-palliative-medicine/ |access-date = August 1, 2013}}, which cites
* {{cite journal | vauthors = Lutz S, Berk L, Chang E, Chow E, Hahn C, Hoskin P, Howell D, Konski A, Kachnic L, Lo S, Sahgal A, Silverman L, von Gunten C, Mendel E, Vassil A, Bruner DW, Hartsell W | display-authors = 6 | title = Palliative radiotherapy for bone metastases: an ASTRO evidence-based guideline | journal = International Journal of Radiation Oncology, Biology, Physics | volume = 79 | issue = 4 | pages = 965–976 | date = March 2011 | pmid = 21277118 | doi = 10.1016/j.ijrobp.2010.11.026 | author18 = American Society for Radiation Oncology (ASTRO) | doi-access = free }}</ref> A single treatment gives comparable pain relief and morbidity outcomes to multiple-fraction treatments, and for patients with limited life expectancy, a single treatment is best to improve patient comfort.<ref name="AAHPMfive"/>

====Schedules for fractionation====
One fractionation schedule that is increasingly being used and continues to be studied is hypofractionation. This is a radiation treatment in which the total dose of radiation is divided into large doses. Typical doses vary significantly by cancer type, from 2.2&nbsp;Gy/fraction to 20&nbsp;Gy/fraction, the latter being typical of stereotactic treatments (stereotactic ablative body radiotherapy, or SABR – also known as SBRT, or stereotactic body radiotherapy) for subcranial lesions, or SRS (stereotactic radiosurgery) for intracranial lesions. The rationale of hypofractionation is to reduce the probability of local recurrence by denying clonogenic cells the time they require to reproduce and also to exploit the radiosensitivity of some tumors.<ref>[Pollack, Alan, and Mansoor Ahmed . Hypofractionation: Scientific Concepts and Clinical Experiences. 1st. Ellicot City: LimiText Publishing, 2011]</ref> In particular, stereotactic treatments are intended to destroy clonogenic cells by a process of ablation, i.e., the delivery of a dose intended to destroy clonogenic cells directly, rather than to interrupt the process of clonogenic cell division repeatedly (apoptosis), as in routine radiotherapy.

==== Estimation of dose based on target sensitivity ====
Different cancer types have different radiation sensitivity. While predicting the sensitivity based on genomic or proteomic analyses of biopsy samples has proven challenging,<ref>{{cite journal | vauthors = Scott JG, Berglund A, Schell MJ, Mihaylov I, Fulp WJ, Yue B, Welsh E, Caudell JJ, Ahmed K, Strom TS, Mellon E, Venkat P, Johnstone P, Foekens J, Lee J, Moros E, Dalton WS, Eschrich SA, McLeod H, Harrison LB, Torres-Roca JF | display-authors = 6 | title = A genome-based model for adjusting radiotherapy dose (GARD): a retrospective, cohort-based study | journal = The Lancet. Oncology | volume = 18 | issue = 2 | pages = 202–211 | date = February 2017 | pmid = 27993569 | pmc = 7771305 | doi = 10.1016/S1470-2045(16)30648-9 }}</ref><ref>{{cite journal | vauthors = Lacombe J, Azria D, Mange A, Solassol J | title = Proteomic approaches to identify biomarkers predictive of radiotherapy outcomes | journal = Expert Review of Proteomics | volume = 10 | issue = 1 | pages = 33–42 | date = February 2013 | pmid = 23414358 | doi = 10.1586/epr.12.68 | s2cid = 39888421 }}</ref> the predictions of radiation effect on individual patients from genomic signatures of intrinsic cellular radiosensitivity have been shown to associate with clinical outcome.<ref>{{cite journal | vauthors = Scott JG, Sedor G, Ellsworth P, Scarborough JA, Ahmed KA, Oliver DE, Eschrich SA, Kattan MW, Torres-Roca JF | display-authors = 6 | title = Pan-cancer prediction of radiotherapy benefit using genomic-adjusted radiation dose (GARD): a cohort-based pooled analysis | journal = The Lancet. Oncology | volume = 22 | issue = 9 | pages = 1221–1229 | date = September 2021 | pmid = 34363761 | doi = 10.1016/S1470-2045(21)00347-8 }}</ref> An alternative approach to genomics and proteomics was offered by the discovery that [[History of Radiation Protection|radiation protection]] in microbes is offered by non-enzymatic complexes of [[manganese]] and small organic metabolites.<ref>{{cite journal | vauthors = Daly MJ | title = A new perspective on radiation resistance based on Deinococcus radiodurans | journal = Nature Reviews. Microbiology | volume = 7 | issue = 3 | pages = 237–245 | date = March 2009 | pmid = 19172147 | doi = 10.1038/nrmicro2073 | s2cid = 17787568 }}</ref> The content and variation of manganese (measurable by electron paramagnetic resonance) were found to be good predictors of [[radiosensitivity]], and this finding extends also to human cells.<ref>{{cite journal | vauthors = Sharma A, Gaidamakova EK, Grichenko O, Matrosova VY, Hoeke V, Klimenkova P, Conze IH, Volpe RP, Tkavc R, Gostinčar C, Gunde-Cimerman N, DiRuggiero J, Shuryak I, Ozarowski A, Hoffman BM, Daly MJ | display-authors = 6 | title = Across the tree of life, radiation resistance is governed by antioxidant Mn<sup>2+</sup>, gauged by paramagnetic resonance | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 114 | issue = 44 | pages = E9253–E9260 | date = October 2017 | pmid = 29042516 | pmc = 5676931 | doi = 10.1073/pnas.1713608114 | bibcode = 2017PNAS..114E9253S | doi-access = free }}</ref> An association was confirmed between total cellular manganese contents and their variation, and clinically inferred radioresponsiveness in different tumor cells, a finding that may be useful for more precise radiodosages and improved treatment of cancer patients.<ref>{{cite journal | vauthors = Doble PA, Miklos GL | title = Distributions of manganese in diverse human cancers provide insights into tumour radioresistance | journal = Metallomics | volume = 10 | issue = 9 | pages = 1191–1210 | date = September 2018 | pmid = 30027971 | doi = 10.1039/c8mt00110c | doi-access = free | hdl = 10453/128630 | hdl-access = free }}</ref>