RADIATION THERAPY (RADIOTHERAPY (RT))

Table of contents :

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nonionizing radiations (NIR) light amplification by stimulated emission of radiation (LASER) light therapy / phototherapy heliotherapy

ionizing radiations : cancer radiotherapy teletherapy / external beam radiation therapy (EBRT) brachytherapy radiopharmaceutical therapy

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• nonionizing radiations (NIR)
• light amplification by stimulated emission of radiation (LASER)

Relative positions of various types of lasers on the electromagnetic spectrum :

• infrared lasers
• carbon-dioxide (CO₂) laser (l = 10,600 nm; 10-200 W, transmission with articulated arm and mirrors, absorbed by water, low cicatrization, penetration for 0.1 mm, incision and vaporization) : a laser with carbon dioxide gas as the active medium that produces infrared radiation at 10,600 nm; used to excise and incise tissue and to vaporize
• hydrogen fluoride laser (l = 2950 nm)
• Er:YAG (l = 2940 nm)
• holmium:YAG laser : a laser whose active medium is a crystal of yttrium, aluminum, and garnet doped with holmium ions, and whose beam is in the near infrared spectrum at 2100 nm; used for photocoagulation and photoablation.
• neodymium:yttrium-aluminum-garnet (Nd:YAG) laser (l = 1320 nm and 1024 nm; P = 1-150 W, trasmission by optic fibers, absorbed by proteins, high cicatrization, penetration for 2-5 mm, coagulation) : a laser whose active medium is a crystal of yttrium, aluminum, and garnet doped with neodymium ions, and whose beam is in the near infrared spectrum at 1060 nm; used for photocoagulation and photoablation.
• visible lasers :
• gallium arseniure (l = 940 nm)
• rubine (l = 694 nm)
• helium-neon laser  (l = 632-633 nm) : a laser with a mixture of ionized helium and neon gases as the active medium whose beam is in the red visible light spectrum; used as a guiding beam for lasers operating at nonvisible wavelengths.
• gold laser (l = 628 nm)
• copper laser (l = 578 and 511 nm)
• potassium titanyl phosphate (KTP) laser : a laser in which a beam generated from a neodymium:YAG crystal is directed through a potassium titanyl phosphate crystal to produce a beam in the green visible spectrum at 532 nm; its properties are similar to those of the argon laser and it is used for photoablation and photocoagulation.
• argon laser  (l = 488 and 514 nm; P = 1-20 W, transmission by optic fibers, absorbed by hemoglobin and melanin; moderate cicatrization, penetration for 1-1.5 mm, used for coagulation and vaporization) : a laser with ionized argon as the active medium whose beam is in the blue and green visible light spectrum, with two energy peaks; used for photocoagulation.
• dye laser : a laser with organic dye dissolved in a solvent as the active medium whose beam is in the visible light spectrum; used in photodynamic therapy (PDT)
• pulsed dye laser : a dye laser in which excitation of the dye by pulses of intense light from a flashlamp produces a beam in the yellow visible light spectrum with a wavelength of 577 or 585 nm, with alternating on and off phases of a few microseconds each; used to decolorize pigmented lesions.
• UV lasers :
• XeF (l = 351 nm)
• KrF (l = 248 nm)
• ArF  (l = 193 nm)
• tunable dye laser : a dye laser whose active medium can be altered so that the beam has any of several wavelengths.
• ion laser : a laser that uses one of the inert gases (argon, helium, neon, or krypton) as the active medium.
• krypton laser : a laser with krypton ionized by electric current as the active medium whose beam is in the yellow-red visible light spectrum; used for photocoagulation.
• excited dimer (excimer) laser : a laser with rare gas halides as the active medium whose beam is in the ultraviolet spectrum and penetrates tissues only a small distance; the beam breaks chemical bonds instead of generating heat to destroy tissue. Used in ophthalmological procedures and laser angioplasty.
• laser microprobe or microscope : a laser beam utilized to vaporize a minute area of tissue, as in a biopsy specimen, which is then subjected to emission spectrography.
• high energy repetitive CUOS laser system (HERCULES) : applications of ultrashort (30 fs) pulses span virtually all fields of science, but an important practical application for HERCULES is ion therapy used to treat cancer. Ion therapy uses high-intensity particle beams to destroy cancer cells. It's a preferred method of treating cancer because it causes minimal damage to neighboring healthy tissues. Another advantage of ion therapy is that it causes more damage to tumor cells than other kinds of cancer treatments. Ion therapy isn't widely available, however, because the particle accelerators—devices that employ electric fields to propel charged particles—used for the treatment are large and expensive. HERCULES, however, can be used in compact particle accelerators, which would make ion therapy more affordable and accessible. HERCULES could also be used in other areas that require ultrafast lasers, such as ophthalmology, dermatology and neurosurgery.

Web resources : Center for Ultrafast Optical Science (CUOS) at the University of Michigan in Ann Arbor
Biological effects :
• electromechanical :
• photoablation : volatilization of tissue by ultraviolet rays emitted by a laser
• thermal :
• photochemical : 10-1000 s continuos wave
• photocoagulation : condensation of protein material by the controlled use of an intense beam of light (e.g., xenon arc light or argon laser); used especially in treatment of retinal detachment and destruction of abnormal retinal vessels, or of intraocular tumor masses
Clinical applications :
• dermatology
• ophthalmology
• gastroenterology : esophageal varices, vascular malformations, bening colorectal neoplasms, palliation of malignant stenoses
• bronchopneumology : tracheal and bronchial exophytic neoplasms, relapsing respiratory papillomatoses
• urology : superficial bladder cancer, transitional cell carcinoma, genital neoplasms, urethral stenosis
• gynaecology : external genital neoplasms, uterine cervix cancer, uterine tube diseases, endometriosis
• otorhinolaryngology : cavernous hemangioma, relapsing papillomas, hereditary hemorrhagic teleangiectasis
• neurosurgery : vascular tumors
• radiology : laser-assisted percutaneous translumenal angioplasty
• light therapy / phototherapy
• solar therapy / heliotherapy :  the treatment of disease by exposing the body to the sun's rays; the therapeutic use of the sun bath
• UVA-1 irradiation at low (20 J/cm²), medium (50 J/cm²), or high (130 J/cm²) doses reaches epidermal structures, but also on mid-dermal and deep dermal components, especially blood vessels. It is used for treatment of ACD, mycosis fungoides and Sezary's syndrome, urticaria pigmentosa, and localized scleroderma.UVA-1 phototherapy, in contrast to UV-B therapy, does not activate HIV-1 in human skin.
• broad band UV-B : standard UVB units employ TL-12 type fluorescent tubes, which emit between 280-350 nm, with a narrow peak at 305 nm.
• alone
• with vegetal catram (Goeckerman protocol)
• with anthraline (Ingram protocol)
• photodynamic therapy (PDT)
• ionizing radiations : cancer radiotherapy (99% of all applications). In the USA 41% of all new patients with cancer in 1995 received radiation treatment, with specific rates for some particular sites/conditions being 80% for lung, 70% for breast, 30% for uterine cervix, 75% for uterine body and 1% for leukemia. Corresponding radiotherapy utilization rates for cancer patients in Russia in 1995 were 23% (all cancer patients), 21% (lung cancer), 2% (breast cancers), 68% (uterine cervix), 7% (uterine body), and 3% (leukemia). Overall, only about 50% of those who receive radiotherapy in the hope of a cure are actually cured, partly due to the fact that in the aftermath of radiation treatment, tumour cells produce cytokines that promote the growth of new blood vessels to replace those killed by the radiation treatment. After radiation treatment, the tumours have higher levels of HIF-1 than before^ref.
• gross tumor volume (GTV) : detected on physical examination or imaging studies. In postoperative cases, the GTV is defined as the preoperative GTV
• clinical target volume (CTV) : includes all potential areas at risk for microscopic tumor involvement by either direct extension or nodal spread including a margin for patient motion and setup errors.
• planning target volume (PTV) is generated using a 1 cm margin around the CTV
• isodose curves : diagrams delimiting body areas receiving equal quantities of radiation in radiotherapy
• isoeffect lines : lines on a rectangular graph representing doses of radiation having tumoricidal effects and those having complicating necrotic effects in normal tissues.
Mechanisms of action :
• direct killing of tumour stem cells
• direct killing of endothelial cells in the microvasculature within growing tumours : after irradiation with 10-20 Gy, a marked increase in endothelial cell apoptosis is seen in the first 6 hours. The endothelium synthesizes 20 times more acid sphingomyelinase (ASMase) than any other cell in the body and the sphingomyelin apoptotic pathway is integrally involved in the response of endothelial cells to radiations. Tumor endothelial cells lacking acid sphingomyelinase lack radiation sensitivity.
• radiosurgery : surgery in which tissue destruction is by means of ionizing radiation rather than surgical incision; the radiation may be from an implant or an external source.
Radiosensitivity : malignant tumors differ greatly in radiosensitivity because of innate sensitivity, mitotic activity, hypoxic component, and blood supply
• very sensitive tumours
• Hodgkin's lymphoma (HL)
• non-Hodgkin lymphomas (NHL)
• germinoma
• neuroblastoma
• retinoblastoma
• small cell cancers
• moderately sensitive (most)
• head and neck cancers
• breast adenocarcinoma
• prostate adenocarcinoma
• cervical carcinoma
• endometrial carcinoma
• esophageal cancers
• rectal cancers
• lung carcinoma
• poorly sensitive (treated mainly with surgery)
• melanoma
• spongioblastoma multiforme / glioblastoma multiforme
• renal cell carcinoma (RCC)
• pancreas adenocarcinoma
• sarcomas
Web resources : Apoptosis, Radiosensitivity and the Cell Cycle at OncoLink
Hit or target theory : the theory advanced to explain some biological effects of radiation on the basis of ionization occurring in a very small sensitive region within the cell, which postulates that one or more ionizing events, or “hits,” within the sensitive volume are necessary to bring about the biological end-effect
Radioresistance :
• both normal cells and cancer cells are affected by radiation and are similar in their responses to RT but only cancer cells are believed to undergo reoxygenation. Hypoxic cells are approximately 3 times more radio-resistant than normoxic cells which is thought to result primarily from the ability of oxygen to react with, and chemically modify the initial radiation-induced DNA radicals. Approaches to counteract ... :
• chronic hypoxia
• the central, most hypoxic area of tumor is overdosed (radiotherapeutical burst) by 10-15 Gy
• fractionation : this is the division of a total prescribed dose into smaller doses per exposure or fractions but no decrease in overall treatment span; done to 4 "R"'s :
• sublethal damage repair : the total dose has to be greater as the number of fractions is
• hypoxic cell reoxygenation : in radiobiology, the phenomenon in which surviving hypoxic (and thus radioresistant) tumor cells become more exposed to oxygen (and thus more radiosensitive) by coming into closer proximity to capillaries after death and loss of other tumor cells (decreased competition for O₂ and decompression of small blood vessels) due to previous irradiation
• redistribution of cycling cells : hemisynchronization of surviving tumour cells in the most sensitive stages of cell cycle
• spares normal tissues because of repair of damage between fractions and repopulation of cells if overall time is sufficient
Fractionation decreases late side effects while delivering an equivalent or greater total dose. Daily fractions generally are 180–200 cGy.
• hypofractionated radiotherapy : > 2 Gy per fraction, < 1 fraction per day, < 5 days a week (alternibus diebus; used expecially for palliative radiotherapy), lesser total dose
• melanoma (4 Gy per fraction in 3-4 weeks)
• conventionally fractionated radiotherapy : 2 Gy per fraction, 1 fraction per day, 5 days a week (not in week-ends), for 5-7 weeks
• hyperfractionated radiotherapy / hyperfractionation / hyperfractionated external beam irradiation (HEBI) : < 2 Gy per fraction (1.1-1.2 Gy), 2 fractions per day (the second dose is generally lower and separated by > 6-8 hours to allow for repair of damage to the normal tissues from the first dose before administering the second dose), constant total duration and dose (used expecially for radioresistant tumors)
• accelerated hyperfractionated radiotherapy : < 2 Gy per fraction (usually 1.5-1.6 Gy), 2-3 fractions per day, 5 days a week (used expecially for radioresistant tumors)
• UADTC : 1.5-1.8 Gy per fraction
Ellis' formula : nominal standard dose (NSD) = k = absorbed dose (cGy) / [t^{0.11 .} (number of fraction)^0.24]  [ret (rad equivalent therapy)]
• increased O₂ delivery
• hemoglobin-based oxygen carriers (HBOCs)
• perfluorochemical emulsions (PFCE)
• accelerated radiotherapy with carbogen (breathing 95% O₂ and 5% CO₂) and nicotinamide (ARCON)
• alterated Hgb affinity for O₂
• RSR13 / efaproxiral / 2,4-[[(3,5-dimethylanilino)carbonyl]methyl] phenoxy]-2-methylpropionic acid is an allosteric modifier which noncovalently binds to hemoglobin, reduces oxygen-binding affinity, and increases oxygen unloading to hypoxic tissue
• Hsp90 antagonists prevent elimination of HIF-1a
• mild hyperthermia
• electron-affinic and hypoxic cell sensitizers : thiol modifiers
• gadolinium texaphyrin : biolocalization properties using MRI
• bioreductive prodrugs
• YC-1 has not yet been tested in humans. But an endogenous metabolite of estrogen, 2-methoxyestradiol (2ME2) (Panzem), has been shown to inhibit HIF-1 production in human cancer patients and can also kill cancer cells^{ref1, ref2}
• acute hypoxia
• increased O₂ delivery : likely to have minimal impact
• electron-affinic and hypoxic cell sensitizers : likely to have minimal impact
• bioreductive prodrugs would need rapid action
• hyperthermia (thermoradiotherapy : application of ionizing radiation to an anatomical site whose tissue temperature has been elevated by artificial means on the theory of increasing its radiosensitivity)
• chemotherapy (?)
Source location :
• teletherapy / teleroentgentherapy / transcutaneous or external beam radiotherapy (EBRT) / external radiation therapy (EXRT) : treatment by radiation emitted from a source located at a distance from the body
• grid therapy : through a metal grid having a pattern of small, evenly spaced perforations.
• rotation therapy : circular movement of the patient or of the radiation source and beam around a fixed anatomical axis during a treatment exposure; it may entail complete, partial, or skip-field exposure
• direct field irradiation, opposed field irradiation (2 opposed sources) and box irradiation (4 sources opposed 2 by 2) are used for very deep cancers
• telecurietherapy : treatment with a radioactive source, e.g., radium, located at a distance from the body
Energy :
• high-voltage radiotherapy : > 300 KV
• kilovoltage or orthovoltage radiotherapy : 40- 300 KV; X-rays from conventional X-ray tubes (roentgentherapy)
• Chaoul therapy : short source-to-tissue distance, low-voltage x-ray therapy
• contact radiotherapy (40-50 KV)
• superficial radiotherapy (50-150 KV)
• orthovoltage (deep therapy) radiotherapy (150-400 KV). Optimal focal distance from target is 50 cm.
Larger penumbra and peak absorption on skin (I_{5 cm below skin} = 65% I_skin; I_{10 cm below skin} = 40% I_skin) => used for superficial-seated cancers
• supervoltage radiotherapy : 400-1000 KV
• megavoltage radiotherapy : > 1 MV
• X-rays from electron beams from LINACs or betatron (4-45 MeV) (high-energy radiotherapy)
• g-rays from ⁶⁰Co (telecobaltotherapy) or ¹³⁷Cs (telecesiotherapy) (E = 1.2 MeV; treatment depth is comparable to a 4 MeV x-ray beam (maximum dose at 5 mm depth))
• electron beams (electronotherapy) produced by LINACs or betatrons (6-50 MeV)
• proton beams (protonotherapy) produced by cyclotrons
• neutron beams (neutronotherapy) produced by cyclotron or ²H-³H generator
Smaller penumbra and peak absorption below skin (directly related with voltage : e.g. E = 20 MV => peak 5 cm below skin and I_{10 cm below skin} = 85% I_skin) => used for deep-seated cancers
Irradiation field :
• extended field irradiation or radiotherapy : irradiation of an extended field in the treatment of malignant lymphomas (paraaortic lymph nodes and spleen peduncle in case of previous splenectomy)
• inverted Y field irradiation or radiotherapy : irradiation of an inverted Y field (pelvic b + c lymph nodes) in the treatment of malignant lymphomas
• mantle or Y  field irradiation or radiotherapy : irradiation of a mantle field (supradiaphragmatic lymph nodes) as a treatment for malignant lymphomas
• involved field irradiation or radiotherapy : irradiation of only the involved field in the treatment of malignant lymphomas
• hemibody irradiation or radiotherapy : external beam radiotherapy involving exposure of half the body
• subtotal nodal irradiation (STNI) / subtotal lymphoid irradiation (STLI) : a + b, used in the treatment of stage I and supradiaphragmatic Hodgkin's disease
• total nodal irradiation (TNI) / total lymphoid irradiation (TLI) : irradiation of all the lymph node–bearing areas of the body, including the spleen, the thymus, and Waldeyer's tonsillar ring; used in the treatment of Hodgkin's disease
• thoraco-abdominal radiation (TAI)
• total body irradiation (TBI) / whole-body irradiation or radiotherapy : external beam radiotherapy involving exposure of the entire body
• ex vivo radiotherapy : removing the organ, treating it with ...
• boron neutron capture radiotherapy (difficult to apply in vivo as the neutron beam is easily blocked from reaching the tumour by obstructions such as bones, and because of toxicity to normal tissues)
• ultraviolet blood irradiation (UBI)
... and returning it to the patient.
• brachytherapy (BT) / brachyradiotherapy / curietherapy : the therapeutic use of radionuclides with b or g decay that are sealed within metal containers; radioactive particles and/or rays penetrate the container to treat the disease. Small volumes of normal tissue and cancer can be irradiated to relatively high doses, but the CTV (i.e. regional lymphatic and lymph nodes) are not irradiated in this way, so BT is usually accompanied by EBRT..
• temporary brachytherapy : sealed radioactive source(s) is removed after the prescribed dose is reached in the calculated number of hours.

Sources => dose rating :
• high dose rate (HDR) treatment : ⁶⁰Co or ¹⁹²Ir (wire or pellets) => 2-5 Gy/min. 1 or several doses are administered and separated by at least 6 hours. Each dose is administered over a few minutes. Used in breast cancers
• medium dose rate (MDR)treatment : higher activity ¹³⁷Cs sources => 2-12 Gy/hr
• low dose rate (LDR) treatment : ¹³⁷Cs (needles or pellets) or ²²⁶Ra (no longer used) sources => 0.4-2.0 Gy/hr. Continuous LDR treatment is administered over several days. Used in uterine corpus cancers
• permanent brachytherapy : sealed radioactive source(s) is left permanently in the tissue either as individual grains (seeds) or loaded in sutures

Sources used for permanent placement have relatively short halflives and weak g emissions :
• ⁹⁰Sr (for small-sized tumors)
• ¹⁰³Pd (for medium- and large-sized tumors)
• ¹⁰⁶Ru (for small-sized tumors)
• ¹²⁵I (for medium- and large-sized tumors)
• radiogold (¹⁹⁸Au) seed : a solid piece of radioactive gold wire about 2.5 mm. long and 0.8 mm. thick, which has been used as a permanent interstitial radioactive implant in the treatment of certain types of cancer.
• radon (²²⁶Ra) seed : a small sealed container or tube for carrying radon, made of gold or glass, for insertion into tissues for the treatment of certain malignant diseases; it is visible radiographically.
Indications (often palliative) :
• pancreas cancers
• lung cancers
• central nervous system (CNS) cancers
• pelvic cancers
Manually or remote after-loading to ...
• contact or surface brachytherapy via implantation of holders, applicators, or moulds preloaded with sources

Indications :
• skin cancers
• eye cancers (the form factor of these applicators is a spherically concave silver bowl with an inner radius of curvature between 12 and 14 mm, and a total shell thickness of 1 mm. The radioactive nuclide is deposited in a layer 0.1 mm below the concave surface of the applicator)
• intracavitary brachytherapy : that in which the radioactive element is introduced into a natural body cavity via implantation of holders, applicators, or moulds preloaded with sources

Indications :
• esophageal cancers
• rectal cancers
• bile duct cancers
• trachea
• bronchi
• uterine corpus cancers
• uterine cervix cancers
• vaginal cancers
• interstitial brachytherapy : that administered with the radioactive element contained in devices (e.g., needles or wire) inserted directly into body tissue

Indications :
• easily accessible tissues
• skin cancers
• head and neck
• oral cavity cancers
• tongue cancers
• breast cancers
• prostate cancers (complications : recto-urethral fistula (RUF) or several bladder neck contracture (BNC))
• rectal cancers
• vaginal cancers
• surgically exposed tissues
• biodegradable chips each holding radioactive isotopes that will destroy cells within 8 mm (0.3 inches) injected into tumors are effective in the treatment of liver cancer
Brachytherapy is often used in combination with teletherapy (e.g. in uterine cervix cancers, breast cancers, and tongue cancers)
• radiopharmaceutical therapy : treatment with unsealed radioactive sources that are ingested, injected, or instilled; each radionuclide has characteristics that determine where it can concentrate in the body
• palliative radionuclide therapy of painful bone metastases (RTBM) : i.v. bone-seeking radiopharmaceuticals with enhanced bone uptake and minimized clearance. They end in osteoblastic sites and have effect on peritumoral bone tissue and tumour cells. Treatment may be repeated at approximately 8- to 12-week intervals, depending on the time of return to normal leukocytes and platelet counts. Tumoricidal effects are probably not the sole mechanism of pain relief (no effect on visceral pain !)

	b (MeV)	mm in H2O (average	mm in bone (average /max)	g (keV)	partial response	complete response	palliation begins after ... [weeks]	lasts for ... [weeks]
89SrCl2 (Metastron®)	1.46	6.8	1.5/4.5	---	70-75%	25-30%	2-4	12-24
153Sm(III)- ethylenedi- aminetetramethylene phosphonic acid (EDTMP) (lexidronam) (Quadramet®)	1.07	4.7	0.7/3.2	137	65-75%	25-35%	1-2	8-12
186Re- or 188Re-1,1- hydroxyethylidine diphosphonate (etidronate) (188Re-HEDP) (1.15 GBq (31 mCi) - 4.6 GBq (124 mCi))	0.81	3.3	0.3/2.3	103	65-75%	25-35%	1 week	> 16 weeks
32P
117mSn
188Re-alendronate (ABP)

Indications :
• polystational pain in patient with bone metastases confirmed by bone scintigraphuy
• monostational pain despite bone scintigraphy is positive in more lcations associated with radiotherapy on the primary tumor
• primary prostate or breast cancer (others are not excluded)
• therapy with major analgesics
• adequate hematological status
• preserved renal functionality
Contraindications
• absolute
• pregnancy
• bone metastases that don't captate osteotropic radiopharmaceuticals. Hypersensitivity to components of the radiopharmaceuticals
• imminent risk of pathologic fracture of spinal cord compressoin
• acute or chonic renal failure
• reduced bone marrow reserve or fast worsening of blood (platelet > 60,000/mL, WBCs < 2,500/mL)
• risk of DIC
• life expectancy < 3 months
• relative
• co-existence of parenchymal metastases
• Karnofsky's index < 50
• platelet < 60,000-100,000/mL
Pre-treatment evaluation :
• clinical examination : pain and life quality examination
• whole-body bone scintigraphy and eventual targeted radiological imaging
• blood tests : renal functioanlity, CBC, coagulation tests
• tumor-specific markers
• bone remodeling markers
Administration schedule :
• ambulatory regimen
• fasting not necessary
• catheterization is required for radioprotection in case of incontinence of poor urination control
• suspension of calcium or bisphosphonate therapy (controverse theme)
• hydratation
• slow i.v. infusion
• observation for 1-2 hours
• indications on radioprotection to prevent urine contamination of home within first 48 hours
Post-therapy evaluation :
• scintigraphy after 6-48 hours (with b- and g-emitting radiopharmaceuticals) and after 3-6 hours (bone scintigraphy)
• pain : weekly evaluation of flare effect, requirement for analgesics and life quality
• bone marrow toxicity : CBC every 1-2 weeks for 2-3 months
• renal toxicity : creatininemia since week 2 to month 3
• tumor-specific markers
• bone remodeling markers
Effectiveness of ⁸⁹Sr or ¹⁸⁶Re in prostate carcinoma :
• excellent response : 26.4%
• good response : 33.3%
• mild response : 21.3%
• no response : 19%
Retreatment : time interval varies according to radiopharmaceutical previously used, therapeutic response previously achieved and current clinical conditions. Patients who had no response shouldn't be retreated
• ⁸⁹Sr : 61.5% => retreatment : 49% cure rate
• ¹⁸⁶Re : 49.3% => retreatment : 44% cure rate
Cytotoxic chemotherapy increases OS in patients undergoing radiometabolic therapy
Side effects : mild-to-moderate pancytopenia and an occasional brief flare of pain, and treatment of patients with disseminated intravascular coagulation (DIC) must be avoided because it may predispose the patient to severe thrombocytopenia
• radiometabolic therapy : a biologically effective radioisotope is administered
• p.o. ¹³¹I (Iodotope Therapeutic^®) for NIS-expressing differentiated thyroid carcinomas

Indications : radioablation of thyroid tissue => flogosis
• Graves' disease
• V < 80 mL
• relapse after drug therapy
• intolerance to thyrostatic drugs
• hyperthyroidism in elderlies
• previous thyroidectomy
• contraindications or denial to thyroidectomy
Contraindications (i.e. indications for surgical ablation) :
• age < 18 years
• thyroid carcinoma
• compresive phenomena
• pregnancy
• lactation
• poorly captating mass
Side effects :
• worsening of thyroid-associated ophthalmopathy (15%, expecially if severe, high TRAb, smoker, preexisting ophthalmopathy, high FT₃. It can be prevented with GR agonists
Fibrosis leads to a volume decrease of 30%, and surviving cells don't work.
Preparation :
• suspension of drugs that inhibit captation
• MMI for...
• 3-5 days in Graves' disease
• 21 days in thyroid adenoma and toxic multinodular goitre (TMNG)
• PTU 21 days before
• hypoiodic diet : suspend uptake of
• multivitamins : 7 days before
• amiodarone : 3-6 months before
• contrast agents : 21-28 days before
• creams and toothpastes : 21 days before
• marine algae : 21 days before
• fasting drugs : 21 days before
• iodine tincture : 21 days before
• expectorating/Lugol's soluction/disinfectants : 21 days before
Dose :
• fixed empirical :
• 185 MBq (66.6% cure rate)
• 370 MBq (84.% cure rate)
• calculated :
• 60 Gy (54% cure rate)
• 150 Gy (84% cure rate)
Complications :
• acute :
• nausea and vomiting (prevented with drugs)
• cervicalgia
• acute sialoadenitis
• rarely transient hypoparathyroidism
• parageusia
• chronic
• hyperparathyroidism
• chronic sialoadenitis
• toxic multinodular goitre (TMNG)
• thyroid adenoma
• thyroid carcinoma : adjuvant therapy on 1-2 g of residuating thyroid tissue after thyroidectomy to avoid confusion in detection of eventual metastases at whole-body scintigraphy and in [thyroglobulin]_serum. Doubtful utility in T1 carcinomas. Most have captation reduced to 5% of normal thyroid tissue => higher doses are required and the whole thyroid couldn't be radioablated.

Cumulative relapse rate 35 years after thyroidectomy is reduced by 40% to 10%
Preparation : suspend T4 for 30-40 days and T3 for 15 days or administer i.v. rhuTSH > 25-30 mIU/mL in the previous 2 days
• hypoiodic diet (ioduria < 50 mg/L)
• thyroid uptake < 5% / 24 hours (preferably < 1-2%)
• a diagnostic ¹³¹I-WBS is practiced before treatment to prevent stunning
Dose :
• fixed empiric dose : 1.11 GBq (cure rate = 60-80%) - 3.7 GBq (100 mCi) (cure rate = 80-90%). The maximum tolerated dose (MTD) = 5 GBq.
Even liver is marked in scintigram due to catabolism of radiolabeled thyroid hormones that have been synthetized before cell death.
• metastases : response is more effective in metastases < 1 cm; no cumulative dose limit exists even if risk for iatrogenic cancers increases
• maximal safe dose : whole body dosimetry and on blood samples to calculate the dose that releases at max 2 Gy into the blood, whole-body retention < 120 mCi after 24 hours
• local metastases : 150-200 mCi
• lymph nodes - mediastinum : 100-175 mCi
• increased thyroglobulin with positive WBS : 150 mCi
• lung metastases : 175-200 mCi
• diffuse : cure rate = 83% (side effect : pulmonary fibrosis)
• micronoduar : cure rate = 53%
• macronodular : cure rate = 10%
• bone metastases : 200 mCi (cure rate = 10%)
• ¹³¹I-m-I-benzylguanidine (¹³¹I-MIBG) for neuroendocrine tumors (expecially pheochromocytoma, neuroblastoma, carcinoids, and medullary thyroid carcinoma). Biological heterogeneity, heterogeneity of ¹³¹I captation, possible insorgence of radioresistant clones and other factors let unlikely a therapeutic effect of  when used as a single therapeutical agent^ref. => e.g. in neuroblastoma it is used in consolidation therapy (iinduction with high-dose chemotherapy and surgery) together with high-dose chemotherapy (carboplatin, etoposide and melphalan) and autologous PBSCT/BMT^ref
• ⁹⁰Y-[DTPA⁰]-octreotide
• ⁹⁰Y-1,4,7,10-tetra-azacyclododecan-4,7,10-tricarboxy-methyl-1-yl-acetyl-D-Phe (DOTA)⁰-Tyr³]-octreotide (⁹⁰Y-DOTATOC) : IC₅₀ for ...
• SST₁ > 10,000 nM
• SST₂ = 11 +/- 1.7 nM
• SST₃ = 389 +/- 13 nM
• SST₄ > 10,000 nM
• SST₅ = 114 +/- 29 nM
• pancreatic head carcinoid^{ref1 (> 8 GBq; response duration = 1-61 months (average 20 months)), ref2 (MCA : 1.7-27 GBq), ref3 (MCA 7.4 GBq)} : ; 26% experience objective responses; reasonably safe for kidneys and bone marrow up to 25-27 Gy
• SD = 53-55%
• PD = 18-28%
• PR + CR = 23%
• CR = 4%
• PR = 22%
• receptor radionuclide therapy (RRT)
• radioimmunotherapy (RIT)
• peptide receptor radionuclide therapy (PRRT)
• ⁹⁰Y
• ⁹⁰Y-minigastrin for CCK₂-expressing medullary thyroid carcinoma
• ¹¹¹In-DTPA-octreotide / ¹¹¹In-pentetreotide (OctreoScan^®) is widely used in nuclear oncology for scintigraphy imaging of different SST₂-expressing tumors (e.g. gastroenteropancreatic (GEP) tumors, pituitary tumors, and carcinoids)
• ¹⁷⁷Lu
Preparation : CT scan => contouring => personalized immobilizators and shielding
• 3D conformational radiotherapy (3D-CRT)
• image-guided radiotherapy (IGRT)
• intensity modulated radiation therapy (IMRT) : a form of external beam radiation therapy that uses CT to create a 3-D picture of the target organ and surrounding organs so a high dose of radiation rays can be delivered only to the target gland
• simultaneous integrated boost (SIB)
=> simulation => setting of multileaf collimator
• stereotactic radiotherapy (SRT) (see also stereotactic surgery) is used in the treatment of selected primary tumorsand metastases of encephalus (including pituitary tumors, small benign meningioma and vestibular schwannoma, and nasopharyngeal carcinoma), but also can obliterate 80-90% of small cerebral arteriovenous malformation (AVM). It verifies isocenter accuracy in patient space.
• Clinac^®
• Cyberknife^® is based on a robotic arm-driven linear accelerator that divides the high-dose radiation necessary to ablate the lesion completely into up to 1200 beams. No invasive head frame fixed to the head with pins is necessary unlike other conventional stereotactic radiosurgery instruments
• Gamma Knife^®
• X-knife^® provides a very good choice to those not suitable to receive craniotomy, such as the aged and the weak. Indications :
• all kinds of non-infiltrative benign intracranial tumors : acoustic neuroma (facial paralysis is seldom observed after treatment, and hearing is not affected), meningioma, hypophysoma and parenchymatous pituitary ameloblastoma no larger than 32 mm
• intracranial metastasis tumor
• cerebral arteriovenous malformation (AVM) and other intracranial hemangiomas
• tumor remnants after surgery
• palliative treatment: benign and malignant intracranial tumors that are non-operable and have been previously treated with radiotherapy
• brain stem tumors and deep brain tumors.
• conventional radiosurgery
• brachyradiosurgery
• external radiosurgery
• stereotactic interstitial radiosurgery using the photon radiosurgery system (PRS)
Scheduling :
• stereotactic radiosurgery (SRS) : single dose induces necrosis (not apoptosis as for conventional fractionated radiotherapy)
• fractionated stereotactic radiotherapy (FSR)
• hypofractionated stereotactic radiotherapy (HSRT)
• digitally reconstructed radiographs (DRRs)
Critical factors :
• physiological movements : breathing, heart beating, oesophagogastrointestinal peristalsis
• accuracy of devices
• accuracy of personnel
Goals of cancer radiotherapy :
• curative or radical radiotherapy : when there is a likelihood > 20-30% to eradicate all cancer cells capable of cell division in the primary and regional areas; the patient is expected to have a normal life span.
• neoadjuvant or preoperative radiotherapy : radiotherapy used as neoadjuvant therapy for cancer
• intraoperative radiotherapy (IORT) refers to the delivery of a single high dose of radiation therapy at the time of surgical ablation, when the tumor bed can be precisely defined and adjacent normal tissue maximally protected. It can be effectively delivered using either electrons (intraoperative electron beam radiation therapy (IOERT) / electron intraoperative treatment (ELIOT) ) or photons produced from a high-dose-rate gamma emitting radioisotope (intraoperative high-dose-rate radiotherapy (HDR-IORT / IOHDR)) and has been explored primarily for locally advanced or recurrent tumors at high risk for local failure despite extensive resection and full dose external beam radiation. With coordinated multidisciplinary interaction, IORT can be integrated in a combined-modality setting without undue additional toxicity^ref.  Although several modalities have been discussed, a comprehensive intraoperative program should have IOERT, IOHDR, and perioperative brachytherapy facilities available to treat all sites. Interstitial brachytherapy is preferable for the treatment of gross residual tumor; IORT (IOERT for accessible sites and IOHDR for poorly accessible sites) is added to irradiate intraoperatively the surrounding margins after gross resection; and fractionated EBRT could be used in moderate doses post-operatively to irradiate the entire area of potential microscopic disease. Depending on the volume and location of the tumor, and the available expertise and equipment, IOERT, IOHDR, or perioperative brachytherapy could be used along with EBRT and surgery for the optimal management of malignancies. Finally, the best results of IOHDR are obtained when used as a conformal boost to the tumor bed after resection in conjunction with supplementary EBRT^ref. IORT has been used for many years for treating patients with various locally-advanced malignancies, usually combined with EBRT. Long-term results confirm that IORT improves local control, which is generally associated with increased survival. Recently, IOERT has been used as the sole treatment for patients with earlier-stage cancers, especially for breast tumors, with extremely promising results at the European Institute of Oncology in Milan
• adjuvant or postoperative radiotherapy : to control growth of tumors previously removed with surgery but with high risk of local relapses, including areas of subclinical spreading (e.g. regional lymph nodes)
• prophylactic radiotherapy : to treat asymptomatic sites that are likely to have microscopic disease to prevent growth of the cancer cells
• palliative radiotherapy : for advanced tumors with metastases, elderlies, cachectic patients; it uses low doses (=> no side effects) and less complex techniques to improve quality of life by reducing symptoms related to compression, invasion, obstruction, or mass effect; palliative RT is not expected to extend the life span.
• control radiotherapy : to limit the growth of the cancer and provide the patient with a symptom-free interval
Radiosensitivity, tolerance doses and side effects on various organs
Radiosensitizing agents : PV- 10 (source : Provectus Pharmaceuticals, Inc.) for prostate cancer
Prevention : increasing the tolerance of normal tissues (radioprotectant agents)
Radiotherapy in combination with other therapeutical modalities for cancer : the goal is to improve the therapeutic ratio relative to the use of a single modality of treatment
• radiotherapy + surgery
• preoperatory radiotherapy to reduce volume of large tumors down to ablation-permissive sizes or to allow a less demolitive surgery
• advantages : good oxygenation, evaluation of radiosensitivity, conservative therapy
• disadvantages : large size => poor effect; interference with surgical recovery, surgery delay, decreased accuracy in staging
• intraoperatory radiotherapy after removal of tumor mass
• advantages : immediate therapy, eye-guided individuation of remaining tumor mass, spares organs between skin and remaining tumor
• disadvantages : single dose, increases surgical morbidity, complex logistics
• postoperatory radiotherapy : 1 month after surgery
• disadvantages : poor oxygenation (scars), impossibility to evaluate radiosensitivity, unpracticeable on patients with surgical complications, increased risk of late injuries (e.g. prolapse of intestinal loops after rectum resecation leads to fibrosis and intestinal loops no longer move => increased irradiation of limited areas)
• radiotherapy + chemotherapy
• contemporary : synergic effect on a same target (inhibit repair of sublethal radiation damages)
• sequential (space cooperation) : different targets (radiotherapy on local tumor and chemotherapy on metastases out of irradiation field to prevent geographical missing)
• immune depression by total irradiation
• total lymphoid irradiation (TLI) : used sometimes to induce immunosuppression prior to transplantation
• neck radiotherapy was once used to treat :
• cervical lymphadenitis
• thymomegaly
• relapsing tonsillitis
• facial acne (no longer practiced)
Currently it occurs only in treatment of
• lymphomas
• breast cancers (side irradiation)
It may cause papillary thyroid carcinoma

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